Current & Recent Scholars – Edge for Scholars at Vanderbilt

Current Scholars	Project Abstract
Rogelio (Roy) Coronado, PhD, MPT Assistant Professor Orthopaedics & Rehabilitation Began VFRS in April 2019 Received KL2 in May 2021	Integration of an Internet-based Self-management Program into Physical Therapy for Chronic Spine Pain Dr. Rogelio Coronado is a Research Assistant Professor in the Department of Orthopaedic Surgery and Department of Physical Medicine and Rehabilitation at Vanderbilt University Medical Center. His long-term career goal is to become a recognized leader in musculoskeletal pain rehabilitation, specifically focused on the optimization of behavioral-based physical therapy interventions and implementation of evidence-based strategies and pathways that have high-impact on musculoskeletal pain care. His short-term goal is to gain the necessary skills to become an independently-funded investigator within a research-intensive environment focused on clinically-relevant research. This Faculty Research Scholars proposal will provide support to achieve these goals by 1) strengthening his grantsmanship skills for securing external R-level funding, 2) expanding his expertise in behavioral intervention development and optimization and clinical trial methodology, and 3) broadening his proficiency in implementation and integration methods for evaluating pain management strategies and pathways in clinical practice. Chronic spine pain is a significant global health problem. To address the multidimensional nature of the condition, psychologically-informed physical therapy (PIPT) has been advocated as this involves the incorporation of psychological strategies into routine practice. However, barriers to PIPT include the necessity for advanced clinical training and time for delivery of behavioral interventions. Internet-based self-management (IBSM) programs have been developed for use within the context of clinical care and offer a more scalable and sustainable approach for PIPT. There is a knowledge gap on the integration of this technology within physical therapy. This proposal will determine the feasibility, acceptability, and efficacy of an IBSM program for improving physical health in patients with chronic spine pain. Aim 1 of the project will determine whether integrating a 7-lesson IBSM program within physical therapy can be successfully implemented, result in acceptable patient adherence, and lead to treatment satisfaction. In Aim 2, efficacy of integrated IBSM and physical therapy will be assessed on physical health and important psychological risk factors. Successful completion of these aims will lead to further development and optimization of a PIPT intervention that can be implemented across a variety of health care settings. Dr. Coronado will receive structured mentorship from Dr. Kristin Archer and engage in didactic coursework in grantsmanship, implementation science, and clinical trials. This training experience at Vanderbilt will enable Dr. Coronado to successfully transition to an independent investigator.
Naira Baregamian, MD, MMS, FACS Assistant Professor Surgery Began award in May 2022	Modulatory Role of Glutathione Metabolism in Immunometabolic Reprogramming of Thyroid Cancer Failure of conventional and targeted chemotherapeutic regimes to control advanced metastatic and radioactive iodine (RAI) refractory thyroid cancer (TC) and current lack of clinical trials of drugs targeting cancer immunometabolic reprogramming in TC highlights an urgent need for novel treatment strategies for advanced TC. Glutathione (GSH) redox metabolic reprogramming, immunosuppressive microenvironment, and antitumor immune responses are critical contributors to chemotherapeutic failure and tumor progression and remain understudied in TC. In our recent study of human TC tumors, we observed substantial abundance of Glutathione (GSH, ~14-fold increase) and robust redox metabolic reprogramming in tumor microenvironment (TME) in contrast to normal thyroids with high basal antioxidant capacity. Pharmacologic targeting of cytoprotective axis, GSH/Glutathione Peroxidase 4 enzyme (GPX4), in TC in vitro activated ferroptosis. GSH-rich human TC tumors exhibited enhanced CD4+>CD8+>T regulatory (Treg) tumor infiltrating T lymphocyte (TIL) infiltration marked by crucial spatial alignment of these TILs along the “leading” invasive edge of the tumor into the adjacent normal tissues. Immunohistochemical (IHC) evaluation of TC tissues revealed that CD8+TIL infiltration is often accompanied by impaired CD8+TIL cytolytic activity and may predict relapse in TC. GSH is a notable culprit for chemotherapeutic drug resistance in many cancers, and a known critical immunomodulator of T lymphocytes, however, the role of GSH metabolism in regulating CD8+TIL infiltration, anergy and cytolytic dysfunction in TC TME is currently not well defined. Our preliminary data uncovering robust tumor GSH enrichment, effective ablation of GSH/GPX4 axis in vitro, and intriguing TIL spatial alignment and signature in human TC have further reinforced highly likely chemo- and immune-evasive tumor phenotype that can undermine the efficacy of existing therapies. In our proposal, we seek to define and develop novel immunometabolic approaches focused on targeting GSH-dependent regulation of tumor metabolic and immune responses in TME. Abrogating GSH-driven tumor metabolic and immunosuppressive reprogramming by ablating GSH synthesis in TC TME will be strategic in overcoming therapeutic resistance commonly seen in advanced TC.
Jason Gokey, PhD Assistant Professor Medicine/Allergy, Pulmonary & Critical Care Medicine Began award in May 2022	YAP Regulation of Alveolar Epithelial Progenitor Cells during Normal and Fibrotic Lung Repair In the lung, the alveolar epithelium consists of two cell types, alveolar type 1 cells (AT1s) that line 95% of the alveolar surface area facilitating gas exchange in close proximity to the alveolar capillaries, and alveolar type 2 cells (AT2s) that secrete pulmonary surfactants and lipids to maintain alveolar homeostasis. Maintenance of an intact and functional alveolar epithelium is essential for gas-exchange in the lung. Across the lifespan, the alveolar epithelium is subject to injury from a myriad of insults including respiratory viruses (including SARS-CoV-2, seasonal influenza and others), tobacco smoke, airborne particulates and other toxic chemicals, and failure of normal injury-repair mechanisms in the alveolar epithelium is believed to contribute to the pathogenesis of numerous chronic lung diseases including idiopathic pulmonary fibrosis (IPF). During normal regeneration, alveolar repair is achieved, at least in part, through a subset of AT2 cells termed alveolar epithelial progenitor cells (AEPs) that self-renew and differentiate into AT1 cells. In order to elucidate how abnormal alveolar repair contributes to disease pathogenesis (and potentially be therapeutically targeted), we must first understand the molecular pathways and programs regulating AEP specification and cell fate decisions. Using single-cell RNA-sequencing (scRNA-seq) we and others have demonstrated the presence of abnormally differentiated alveolar epithelial cells in the IPF lung, and our preliminary data implicate YAP signaling as an important regulator of alveolar epithelial differentiation. In order to investigate the role of YAP signaling in alveolar repair, we have generated novel mouse models enabling inducible Yap activation in all AT2 cells or specifically in AEPs. Initial analysis of isolated Yap active AT2 cells indicated increased expression of cell markers associated with both AT1 and airway epithelial cells, suggesting multiple distinct populations of abnormally differentiated AT2 cells. We have generated mice with Yap active specifically in AEPs, and our preliminary data suggest this leads to subsequent loss of AEPs available for regeneration. This leads us to hypothesize that Yap regulates AEP and non-AEP AT2 cell fate decisions and persistent Yap activation leads to a loss of AECs through forcing terminal differentiation of the progenitor cell population resulting in abnormal alveolar repair. We will test this hypothesis through in-vivo lineage tracing and single cell RNA sequencing in a mouse model with inducible Yap activation in both AEP and non-AEP AT2 cells that allows for isolation and analysis of both populations independently during lung injury and repair. We will also utilize ex-vivo alveolar organoids generated with Yap active AECs, AECs isolated from IPF patient lungs, and respective controls to assess the role of YAP signaling in AEC maintenance and differentiation. Together, these studies will provide a paradigm for a novel therapeutic strategy to enhance alveolar repair.
Kimberly Rengel, MD Assistant Professor Anesthesiology Began award in May 2022	Muscle Ultrasound in Critical Illness to Understand Long-Term Impairment and Recovery Each year, millions of patients develop newly acquired functional disability after critical illness. Patients highly value quality of life and the ability to return to pre-illness function, but both are negatively impacted by acquired disability. While awareness and identification of new chronic impairments after critical illness are increasing, understanding of the factors that contribute to disability after major surgery or critical illness is currently limited. Understanding mechanisms and risk factors that contribute to acquired disability is vital to guide future prevention and treatment strategies to ease burden of acquired disability. The Muscle Ultrasound in Critical Illness to Understand Long-Term ImpAirment and Recovery (MUSCULAR) Study will examine the potential role of skeletal muscle health in acquired disability after critical illness. We will use a pragmatic bedside ultrasound examination to quantify muscle mass and quality in patients admitted for critical illness and record changes to muscle health throughout critical illness and into recovery (Aim 1). We will then identify risk factors associated with decline in muscle mass and quality during critical illness (Aim 2) and examine the association between muscle mass, quality, and change in both at distinct timepoints throughout critical illness and recovery with long-term physical function after discharge (Aim 3). We will perform this nested prospective study in two ongoing NIH-supported, prospective patient cohorts that are collecting extensive data on hospital course and performing robust physical outcomes evaluations at 3- and 12-months after discharge. Currently, the relationship between long-term recovery after critical illness and the health of skeletal muscle before, during, and after critical illness remains unclear. The MUSCLAR study addresses this knowledge gap and will help identify targets for prevention and treatment of acquired disability. I am a physician-scientist trained in anesthesiology and critical care medicine and I have assembled a committee of mentors and content experts committed to guiding me in the conduct of high quality research and achieving my long-term career goal to become an independent NIH-funded investigator who studies mechanism of disability and interventions to reduce the burden of acquired disability after acute illness.
McKenzie Roddy, PhD Assistant Professor Medicine/General Internal Medicine & Public Health Began award in July 2022 Received KL2 in July 2023	Developing an Adaptive Self-Care Support Intervention for Adults with Type 2 Diabetes and their Close Interpersonal Relationships Dr. McKenzie Roddy is a Clinical Psychologist and Research Assistant Professor in the Division of General Internal Medicine and Public Health at Vanderbilt University Medical Center. Her long-term career goal is to become a recognized leader in the influence of close interpersonal relationships (CIR) on health, specifically focused on the optimization of behavioral interventions to improve health for patients with chronic conditions within the context of their CIR. Her short-term goal is to gain the necessary skills to become an independently funded investigator within a research-intensive environment focused on clinically relevant research. This Faculty Research Scholars proposal will provide support to achieve these goals by (1) gaining experience using mediation and moderation with health data to understand how and for whom behavioral interventions are most effective (2) developing proficiency in mixed-method evaluations of behavioral interventions (3) gaining experience in developing and running focus groups, (4) gain content knowledge and experience in behavioral diabetes research, (5) strengthening her grantsmanship skills for securing external K- and R-level funding, and (6) developing content knowledge and mentor relationship in adaptive intervention design and analysis. Dr. Roddy will receive structured mentorship from her primary mentor, Dr. Lindsay Mayberry, engage in didactic coursework in mediation analyses, grantsmanship, mixed-methods research, and adaptive designs, and participate in experiences designed to apply learned skills in the context of the mentor’s R01. The FAMS 2.0 intervention (R01DK119282, PI-Mayberry) aims to improve glycemic control and diabetes distress for adults with T2D. This proposal is the first to our knowledge to apply adaptive intervention methodologies to behavioral management of type 2 diabetes (T2D), where the majority of adults are not meeting self-management goals. Self-management of T2D occurs in the home and in the context of patients’ CIR. To optimally manage T2D, activating CIR to increase support and minimize harm is crucial for long-term success. However, the relational contexts of adults with T2D are diverse and complex as is the amount and types of support adults with T2D need or desire. Family self-care support interventions in T2D have inconsistent and mixed results. More work is needed to understand why some individuals benefit from relational-focused interventions while others do not. To inform development of an adaptive intervention, we aim to: (Aim 1) use data currently being collected through the mentor’s R01 to explore mediators and moderators of effects of the FAMS 2.0 intervention to develop hypotheses to be tested in a subsequent adaptive intervention, and (Aim 2) use a mixed-method approach to understand how individual, relational, and clinical factors moderate engagement with FAMS 2.0 and identify alternative intervention components for consideration in the design of the adaptive intervention. Successful completion of these Aims and training plain will provide the necessary preliminary data for the PI to submit an application to design and pilot an adaptive intervention for adults with T2D and their CIR.
Rei Ukita, PhD Assistant Professor Medicine/Cardiovascular Medicine Began award in December 2022	Deciphering the Unique Molecular and Hemodynamic Signatures of Right Ventricular Adaptation, Failure, and Recovery in Large Animal Model The purpose of this proposal is to foster the professional development of the applicant, Rei Ukita PhD, by conducting a cutting-edge investigation on right ventricular failure and recovery in a large animal model of pulmonary hypertension. Pulmonary hypertension (PH) is a family of diseases that elevates blood pressure in the lungs. The right ventricle (RV) initially adapts to the increasing afterload by developing the needed muscles, blood vessels, and the metabolic infrastructure. But as the disease becomes more severe, the RV will ultimately succumb to maladaptive failure. Proper intervention prior to failure is critical but challenging due to its sudden, unpredictable nature, such that a seemingly stable patient can suddenly die from RV failure. Meanwhile, proper surgical intervention that unloads the right heart, such as lung transplantation, can lead to recovery and normalization of right heart function. This is a growing scientific area that warrants more attention since the molecular pathways that underlie both processes of RV failure and recovery may be the ideal targets for deriving novel therapies to prevent and treat the disease. Due to the sudden, unpredictable nature of RV failure in human patients, however, these molecular pathways may be better studied using clinically relevant animal model for PH. This proposal will therefore study both processes of RV failure and recovery in a large animal sheep model of reversible PH. In this model, the sheep’s pulmonary artery is banded using an adjustable vascular occluder. The frequency and the magnitude of occluder inflation can be controlled such that this model can induce both adaptive and maladaptive RV profiles. Moreover, the occluder can also be deflated to unload the RV, which can therefore model RV recovery. During RV loading and unloading, animal subjects will be scrutinized from multiple angles: quantification of RV function, blood sample analyses for metabolic species, and RV biopsies to study changes in gene expression, histologic, and metabolomic profiles. We will piece all of this information together to determine an ideal panel of biomarkers that can discriminate subjects undergoing RV failure, and also identify markers that signify the recovery of RV. To achieve the proposed research, Dr. Ukita will receive mentorship and support from clinical, scientific, and engineering experts in the field of pulmonary hypertension and right ventricular function and failure. Under this plan, Dr. Ukita will complete didactic and practical training in leadership, grantsmanship, and molecular analyses such as transcriptomic analysis. Dr. Ukita will ultimately take the combined experience and training from this proposed work to be competitive for his future independent research proposal, in which he will extend his findings toward future preclinical and clinical investigations on PH, RV failure, and mechanical circulatory support technology.
Ryan Ceddia, PhD Instructor Medicine/Cardiovascular Medicine Began award in March 2023	Natriuretic Peptide and cGMP Signaling in the Adipocyte Thermogenic Program This proposal outlines a VFRS career development plan to aid the continued progression of Dr. Ryan Ceddia into an independent research scientist with expertise in obesity and adipose tissue (AT) under the mentorship of Dr. Sheila Collins. Obesity is a significant risk factor for many diseases including both diabetes and cardiovascular disease. Lifestyle changes such as increased exercise or reduced food consumption have poor adherence while pharmacological approaches aimed at decreasing caloric intake have limited long-term efficacy. An alternative approach is to increase energy expenditure. Energy expenditure in AT is increased in response to cold exposure. Cold induction of the adipocyte thermogenic program is classically mediated through the sympathetic nervous system which signals through the β-adrenergic (βAR)-cAMP-PKA signaling pathway. The Collins’ lab and others have demonstrated that the cardiac natriuretic peptide (NP)-cGMP-PKG signaling pathway also increases adipocyte thermogenic activity. Dr. Ceddia’s recent studies demonstrate that removal of an enzyme which specifically degrades cGMP, phosphodiesterase 9 (PDE9), allows a mild cold challenge to cause a larger than expected induction of the AT thermogenic program. As cold-stimulation of AT thermogenesis is known to occur through cAMP-PKA signaling pathways, this effect of a cGMP-specific PDE suggests that cGMP-PKG signaling constitutes a previously underappreciated component of this process. In Aim 1, Dr. Ceddia will investigate his hypothesis that PDE9 regulated cGMP is a significant component of the cold-induced adipocyte thermogenic program. The goal of Aim 1 is to determine how cGMP serves as a critical regulator of cold-induced AT thermogenesis. Pharmacological and genetic tools will be used to manipulate PDE9 and the receptor for the cardiac NPs, NPRA, to probe the role of this pool of PDE9 regulated cGMP in cold-induced AT thermogenesis. The NPs are also regulated by a protease called neprilysin that degrades NPs and other vasoactive peptides. Neprilysin is highly expressed in adipocytes, but its role in AT thermogenesis is not well understood. Neprilysin is the target of a class of heart failure medication called Angiotensin Receptor-Neprilysin inhibitor (ARNi). ARNi has been shown to improve glycemic control in mice and humans, but the mechanism for this improvement in glucose homeostasis is not fully understood. Increased glycemic control, insulin sensitivity, and thermogenic energy expenditure can all be mediated by the actions of NPs in AT. Because of this, in Aim 2 Dr. Ceddia will test his hypothesis that inhibition of neprilysin improves insulin action and enhances the adipocyte thermogenic program through the actions of cardiac natriuretic peptides on adipose tissue. He will compare the effects of ARNi in mice which have or lack NPRA specifically in their AT to determine if ARNi affects insulin action and thermogenesis in AT through NP signaling. The proposed training will build upon Dr. Ceddia’s prior work in adipose tissue biology and receptor signaling being instrumental in his transition into an independent principal investigator with a lab investigating signaling mechanisms that regulate AT thermogenesis.
Heather Ward, MD Assistant Professor Psychiatry Began KL2 in April 2023	Network-Targeted Neuromodulation for Nicotine Dependence in Schizophrenia Tobacco use is the top preventable cause of early mortality in schizophrenia, leading to a 20-year decreased life expectancy compared to the general population. Current smoking cessation treatments are derived from people without psychosis and are significantly less effective for people with schizophrenia. We used a data-driven, agnostic approach to identify a schizophrenia-specific circuit of nicotine dependence (the Default Mode Network, DMN) then tested pharmacologic and neuromodulation interventions on this circuit. We observed craving was bidirectionally mediated by DMN connectivity: 1) nicotine administration (which reduces craving) decreased DMN connectivity in schizophrenia, while 2) a single session of intermittent theta burst stimulation (iTBS), which increases connectivity, applied to a DMN node acutely increased craving in schizophrenia. This provides evidence that 1) nicotine craving is mediated by this network and 2) this target can be engaged bidirectionally via multiple interventions. This K23 mentored patient-oriented career development award proposes to test if multiple repetitive transcranial magnetic stimulation (rTMS) sessions lead to enduring circuit change and reduce nicotine craving. Our central hypothesis is that the brain circuit most effective to reduce nicotine craving in schizophrenia is distinct from the pathway identified in a non-schizophrenia population. To test this hypothesis, we will compare 1) DMN-targeted continuous theta burst stimulation (cTBS) to 2) iTBS targeted to the left dorsolateral prefrontal cortex (L DLPFC), which reduces cigarette consumption and craving in smokers without psychosis. cTBS has been shown to decrease network connectivity. By applying cTBS to the DMN, we aim to decrease connectivity, thereby decreasing craving. We will determine if rTMS manipulates functional connectivity and craving and if craving change correlates with connectivity change for each rTMS target. To optimize rTMS response, we will also test if variability in rTMS response is explained by individual differences in network controllability. The applicant is a psychiatrist with fellowship-level training in neuroimaging and rTMS for substance use disorders in schizophrenia. Her long-term career goal is to build an independent research program using neuroimaging to identify brain networks linked to substance use in psychotic disorders then test neuroscience-based, network-targeted rTMS interventions in clinical trials for co-occurring substance use disorders in schizophrenia. To accomplish these goals, the applicant requires additional training in: 1) design and conduct of personalized network-targeted rTMS interventions, 2) individualized neuroimaging to optimize rTMS response, and 3) clinical trials and biostatistics. Training will include formal coursework, didactics, and on-site trainings, guided under a mentorship team of experts in network-targeted rTMS interventions in psychotic disorders, computational analysis of networks in psychotic disorders, and clinical trials design for rTMS and smoking cessation. Mentored training and completion of the proposed project will provide the applicant the skills and experience necessary to launch a successful independent research career.
Jeffrey Freiberg, MD, PhD Instructor Medicine/Infectious Diseases Began award in July 2023	*Understanding the Role of Arginine Metabolism in Antibiotic Treatment Failure during Staphylococcus aureus* Infections** Staphylococcus aureus is a leading cause of a wide range of bacterial infections globally and is associated with significant morbidity and mortality. These poor outcomes are driven by the high rates of antibiotic treatment failure seen with many types of S. aureus infections. Antibiotic tolerance, which is defined as the ability of bacteria to survive in the face of antibiotics through phenotypic changes without the acquisition of antibiotic resistance, is the major driver of antibiotic treatment failure in S. aureus infections. Despite the clinical significance of antibiotic tolerance, the mechanisms by which it occurs is poorly understood. However, there has been a growing appreciation for the potential role of metabolism in antibiotic tolerance among bacteria. My preliminary experiments have identified an increase in antibiotic tolerance in mature S. aureus communities when arginine is depleted. I also discovered increases in the abundance of proteins involved in arginine degradation and corresponding decreases in the abundance of proteins involved in arginine synthesis in S. aureus in response to treatment with multiple antibiotics. In addition to being an essential amino acid for S. aureus growth, arginine is also required for the production of nitric oxide by host immune cells such as neutrophils and macrophages. The importance of nitric oxide production to the host response to S. aureus infections, establishes arginine as an important contributor to the ability of the immune system to combat S. aureus. Collectively, these results support the hypothesis that S. aureus influences arginine levels during infection by carefully regulating arginine metabolism as a means to survive both in the face of antibiotics and the innate immune response. Through this proposal, I plan to test this hypothesis by (1) elucidating the mechanism(s) by which arginine metabolism influences antibiotic tolerance in S. aureus, (2) determining the role of S. aureus arginine metabolism in persistence in the presence of innate immune effector cells, and (3) identifying the contribution of S. aureus arginine metabolism to persistence and antibiotic treatment failure during infection. Together, these experiments will better define the role of an essential amino acid at the host-pathogen interface. Furthermore, this work has the potential to uncover new targets for therapeutics to address the issue of treating recalcitrant infections that fail conventional therapies.
Matthew Mart, MD, MSCI Instructor Medicine/Allergy, Pulmonary & Critical Care Medicine Began KL2 in July 2023	The Role of Mitochondrial Dysfunction in Physical Recovery after Acute Respiratory Failure Each year, millions of adults survive a critical care hospitalization for acute respiratory failure, yet half or more will go on to develop devastating and persistent impairments in physical function such as exercise intolerance and reduced walking distance. Rehabilitation studies have demonstrated limited efficacy to date, and little is known about the mechanistic underpinnings that link acute respiratory failure and reduced physical function. Improved understanding of underlying mechanisms is urgently needed to improve long-term outcomes and develop effective interventions. During critical illness due to acute respiratory failure, patients suffer from profound alterations in energy generation in skeletal muscle due to disruptions in oxidative phosphorylation and reduced mitochondrial oxidative capacity. Whether mitochondrial oxidative capacity normalizes in survivors of acute respiratory failure, however, is unknown. Our preliminary data indicates that survivors of acute respiratory failure may experience reduced mitochondrial oxidative capacity that limits physical recovery months after critical care hospitalization. The central hypothesis for this proposal is that reduced mitochondrial oxidative capacity in survivors is associated with worse physical function. To test this hypothesis, this proposal will measure mitochondrial oxidative capacity in skeletal muscle using 31P-magnetic resonance spectroscopy (31P-MRS), systemic oxidative capacity in peripheral blood mononuclear cells, and post-hospital physical activity in survivors of acute respiratory failure at 3 months post-discharge and determine their association with physical function at 12 months after hospitalization. Aim 1 will test the hypothesis that reduced muscle-specific mitochondrial oxidative capacity, measured using 31P-MRS, at 3 months post discharge is associated with worse physical function at 12-month follow-up. Aim 2 will test the hypothesis that reduced systemic mitochondrial oxidative capacity measured in peripheral blood mononuclear cells at 3 months post-discharge is associated with reduced physical function at 12-month follow-up. Aim 3 will test the hypothesis that reduced post-hospital physical activity, measured using accelerometry, is associated with reduced physical function at 12-month follow-up, and in exploratory analyses, whether it is also associated with mitochondrial function at 3 months. These studies will define the role of mitochondrial capacity and physical activity on long-term physical function after acute respiratory failure. This work will advance the field by utilizing novel research approaches to characterize understudied mechanisms of physical recovery and provide a foundation for physiologically targeted interventions. This proposal will also foster the candidate’s development into a national leader on physical recovery after acute respiratory failure, merging the insights of applied physiology with critical care outcomes to improve the lives of survivors.
Alison Carroll, MD, MPH Assistant Professor Pediatrics/General Pediatrics Began KL2 in September 2023	Integration of Social Determinants of Health in a Prediction Model for Pediatric Healthcare Reutilization Emergency department revisits and hospital readmissions (i.e., reutilization) in children following hospital discharge, is a marker of suboptimal health, is burdensome for caregivers, and is costly to the healthcare system. While illness severity and medical complexity explain some of the variation in pediatric reutilization, important preventable disparities are evident with higher reutilization among children with public or no insurance, low socioeconomic status, and children exposed to racial or ethnic bias. We posit that an incomplete understanding of reutilization risk, including failure to address important social determinants of health (SDOH), are critical drivers of these disparities. An objective measure of reutilization risk that incorporates both social and clinical risk factors within the electronic health record could improve care delivery and reduce disparities by targeting patient-level interventions to where they are most needed. The central hypothesis of this proposal is that integrating SDOH with key clinical factors will more accurately identify risk for post-discharge reutilization. Dr. Carroll will test this hypothesis through the following specific aims: 1) Update and validate a suite of existing prognostic models for all-cause 30-day hospital readmissions using an administrative database of 49 US children’s hospitals; 2) Define critical barriers and facilitators to the implementation of a pediatric reutilization risk stratification tool into hospital-based care; 3) Integrate and evaluate the best performing prognostic models within the electronic health record at Vanderbilt University Medical Center, evaluating prospective prediction performance and testing for potential unintended disparities.
Kelly Watson PhD Assistant Professor Neurology Began KL2 in September 2023	Social Isolation and Social Cognition in Adolescents with Tourette Syndrome Candidate: Kelly Watson, PhD is Assistant Professor in the Department of Neurology and a clinical psychologist who provides a specialized, evidence-based behavioral therapy to adolescents with Tourette syndrome (TS). Dr. Watson strives to establish an independent program of patient-oriented research, with an emphasis in social and cognitive processes in TS. She earned her PhD in clinical psychological science from Vanderbilt University (2016) where she then completed her research-focused fellowship on a NIMH T32 training grant. In her early career, Dr. Watson has served as a co-I on two extramural grants and co-authored numerous scientific publications. Her background demonstrates strong potential for a productive long-term research career translating key findings into the development, evaluation, and dissemination of psychosocial interventions in TS. Research Project: TS is a neurodevelopmental disorder characterized by motor and vocal tics with a prevalence of 1% in adolescence. While current treatments focus on tic reduction, patients commonly report clinically distressing social problems. Yet, limited research in adolescence has focused on risk factors that contribute to social problems or examined the impact of these problems on social isolation. The aims of the proposed study are to: (1) quantify the prevalence of social isolation in TS adolescents; (2) assess explicit social cognition in TS adolescents; and (3) apply aye-tracking techniques to assess implicit social cognition in TS adolescents. An exploratory aim will be to determine the contributions of social cognition to social problems in TS adolescents. Fifty adolescents with TS and 50 matched controls will be recruited, along with their parents, to complete a multi-method assessment battery. Results have the potential to inform clinical interventions to improve quality of life. Career Development: The training associated with this career development award will support Dr. Watson to achieve her goal of becoming an independently funded clinician scientist in TS. To achieve this goal, she has developed a focused career development plan that includes formal coursework, workshops, webinars, conferences, and individualized training from a strong interdisciplinary mentorship team. Dr. Watson’s specific training goals include advanced training in: 1) TS, 2) social cognitive assessment, 3) eye-tracking methods, and 4) professional development. The Vanderbilt Faculty Research Scholars Award will provide the comprehensive mentorship support, resources, and protected time needed to obtain independent NIH grant funding in TS. Environment: VUMC is an optimal academic environment for cultivating Dr. Watson’s development into an independently funded clinical investigator specializing in patient-centered research in TS. The institution has an exceptional track record for fostering productive and independently funded clinician-scientists. VUMC offers a wealth of resources to support this work, including a specialty clinic with a large population of adolescents with TS; VUMC is one of only 21 Tourette Association of America Centers of Excellence in the country.
Antentor Hinton, Jr., PhD Assistant Professor Molecular Physiology & Biophysics Began award in October 2023	Estrogen Regulation of Stress-Induced Hypertension in the Medial Amygdala During Pregnancy Hypertensive disorders affect up to 10% of pregnancies in the United States. Hypertension (HTN) in pregnancy is associated with a higher risk for complications in both the fetus and mother, including intrauterine growth restriction and maternal mortality, respectively. We hypothesize that estrogen receptor-α (ERα)-initiated signaling pathways in medial amygdala (MeA) neurons prevent stress-induced HTN during pregnancy. In humans, psychological stress contributes to the development of HTN, which is partly mediated by amygdalar neurons. In humans and rodents, MeA neuronal signaling is positively associated with changes in blood pressure (BP) during stress. Additionally, estrogen attenuates stress-induced c-fos expression in the MeA via ERα, yet the mechanisms for stress-induced HTN during pregnancy remain unknown. Although estrogen replacement therapy (ERT) lowers BP in postmenopausal women, its off-target effects can increase the risk of stroke and thromboembolism. During pregnancy, steroids (e.g., 17β estradiol) are synthesized in large amounts by the placenta, while MeA neurons have a high expression of ERα. We have shown that 17β-estradiol replacement reduces BP in ovariectomized female mice via ERα. Understanding the specific pathways underlying the anti-hypertensive effects of estrogens may lead to novel and safer therapies for HTN during pregnancy. In Aim 1, we hypothesize that MeA neurons mediate stress-induced HTN during pregnancy. We generated Sim1-Cre mice that were subjected to pregnancy and injected with inhibitory and activating DREADD virus. Although SIM-1 MeA neurons are involved in stress-induced HTN, we are not aware of their role during pregnancy. We will stereotaxically inject DREADD in MeA of pregnant female mice and determine its effect on BP and stress-induced HTN in mothers and offsprings, as well as the structure and dynamics of mitochondria in reproductive tissues. In Aim 2, we hypothesize that ERα or Erβ in the MeA mediates estrogenic effects to prevent stress-induced HTN during pregnancy. We will generate ERα or Erβ knockout mice and evaluate whether ERα or ERβ in the MeA alone is sufficient to rescue the anti-hypertensive effects of estrogens during psychologic stress during pregnancy and also determine how stress impacts SIM1-MeA neuronal signaling. By integrating the results of these independent aims we will significantly advance our knowledge of the role of estrogen signaling in the MeA on the regulation of stress-induced HTN during pregnancy. Our studies will demonstrate that selective activation of MeA ERα or MeA Erβ, can decrease BP during stress-induced pregnancy. Our ultimate goal is to develop novel therapeutic targets for patients with stress-induced HTN during pregnancy.
Lauren Klein, MD Instructor Pediatrics/Gastroenterology Began award in October 2023	A Randomized Controlled Feasibility Trial to Treat Underweight Children 5 Years and Older with Sickle Cell Disease in Nigeria This proposal aims to provide a mentored experience for an early physician-scientist to determine the feasibility of treating underweight children with sickle cell disease (SCD) aged 5 years and older. Underweight is a term to describe children with low weight relative to their age (weight-for-age) from acute, chronic, or both acute and chronic malnutrition. There are no evidence-based strategies to treat malnutrition in children with SCD at any age. In preparation for this proposal, the applicant completed the following: (1) demonstrated the high prevalence of underweight (weight-for-age z-score <-2) in older children with SCD living in Nigeria, 57.8% (manuscript under review); (2) identified the novel association of lower weight-for-age z-score with mortality in older children with SCD (Blood Advances 2022); (3) co-led an NIH-sponsored trial for severe acute malnutrition in 110 children with SCD in Nigeria (manuscript in preparation); the primary outcome (feasibility) was met, with recruitment, retention, and adherence rates all >94% for the 12-week trial with supplemental ready-to-use therapeutic food (RUTF; 500-1,000 daily calories). Previously associated with mortality in adults with SCD, arginine deficiency may be a potentially modifiable risk factor for death in underweight children with SCD. Chronic hemolysis in SCD increases intravascular arginase activity, depleting arginine, the sole nitrogen substrate for nitric oxide production. The therapeutic dosage of RUTF for nutritional recovery in older children with SCD is unknown and therefore requires adaptation from the (1) World Health Organization guidelines for children under 5 years old (~200 kcal/kg/day) and (2) nutrition practice recommendations for children with HIV over 5 years old (~75 kcal/kg/day). The applicant will obtain the prerequisite data to eventually test the global hypothesis that in underweight older children with SCD, treatment with ~200 kcal/kg/day (maximum 2,500 daily calories) of RUTF improves weight-for-age z-score greater than treatment with ~75 kcal/kg/day of RUTF. The applicant will also determine whether RUTF will improve arginine levels or if additional arginine supplementation is required. The proposed feasibility trial will randomly allocate 50 underweight (weight-for-age z-score <-2) children aged 5.00-10.99 with SCD. The first aim is to determine the feasibility (recruitment, retention, and adherence rates) of a randomized controlled trial (RCT) with RUTF at ~75 kcal/kg/day versus ~200 kcal/kg/day to treat underweight children with SCD over a 20-week intervention. All participants will receive moderate-dose hydroxyurea (fixed-dose 20 mg/kg/day), a previously demonstrated safe and now standard care therapy to prevent SCD-related morbidities in Nigeria. Mothers of participants will receive education on preparing locally available nutrient-dense food to increase sustainability in a setting with common food sharing. The second aim is to assess arginine bioavailability in underweight children with SCD before and after treatment in both arms. Based on this proposal, the applicant will submit a K23 application for a two-site feasibility RCT, potentially with additional arginine supplementation.
Jamie Robinson, MD, PhD Assistant Professor Pediatric Surgery Began award in October 2023	Improving Risk-stratification for Venous Thromboembolism Using Genomics” Venous thromboembolism (VTE), which encompasses both deep venous thrombosis (DVT) and pulmonary embolism (PE), is the leading cause of preventable in-hospital death. Surgical procedures, acute medical problems, and trauma are known risk factors for VTE in adults and children; however, VTE prophylaxis protocols based on type of procedure or patient presentation do not fully account for the variable propensity to develop VTE. Even with improved adherence to current VTE prophylaxis protocols, neither the incidence of VTE nor mortality among VTE patients with PE has declined in the most recent decade. While data demonstrate that genomics can strongly predict VTE, a barrier to VTE prevention is the lack of risk-stratification models incorporating clinical and genomic factors to identify high-risk adults or children who would benefit from VTE pharmacologic prophylaxis. A tailored, personalized-medicine approach to pharmacologic prophylaxis regimens based on genomic and clinical risk factors could have a major impact on the incidence of VTE and its subsequent morbidity. This proposal describes my career development plan and a research program of “Improving Risk-stratification for Venous Thromboembolism Using Genomics”, motivated by my direct clinical experience caring for patients with VTE during my adult and pediatric surgical training. Many patients I treat have increased risk for VTE, yet guidance on prophylaxis is limited and does not incorporate known genomic predictors. This research and career development plan will provide protected effort and resources to develop expertise in advanced phenotyping methods, statistical modeling for genomic data, and assessment of risk-stratification techniques. We are using clinical and genomic data generated and available at Vanderbilt University Medical Center (VUMC) through the Synthetic Derivative and BioVU. The first Aim is to develop with high fidelity a phenotype for VTE that is reproducible in adult and pediatric patients. Next, I will develop a polygenic risk score (PRS) including over 1 million SNPs for VTE using known large-scale genome-wide association analyses (Aim 2). Lastly, I will compare risk-stratification for VTE using the PRS to clinical predictors alone or the polygenic and clinical risk factors in combination while additionally assessing for prophylaxis-associated bleeding complications in each model (Aim 3). The career development plan integrates coursework and individualized mentor-directed instruction in computational phenotyping, statistical and population genetics, grant preparation, and scientific communication and leadership. I will participate in local and national seminars and conferences to advance my expertise. I have designed a multidisciplinary mentored research experience that builds on relationships I have made during my surgical and informatics training at VUMC and the highly supportive research environment of the Biomedical Informatics, Pediatrics, and Pediatric Surgery departments.

Current Scholars

Project Abstract

Rogelio (Roy) Coronado, PhD, MPT
Assistant Professor
Orthopaedics & Rehabilitation
Began VFRS in April 2019
Received KL2 in May 2021

Integration of an Internet-based Self-management Program into Physical Therapy for Chronic Spine Pain

Dr. Rogelio Coronado is a Research Assistant Professor in the Department of Orthopaedic Surgery and Department of Physical Medicine and Rehabilitation at Vanderbilt University Medical Center. His long-term career goal is to become a recognized leader in musculoskeletal pain rehabilitation, specifically focused on the optimization of behavioral-based physical therapy interventions and implementation of evidence-based strategies and pathways that have high-impact on musculoskeletal pain care. His short-term goal is to gain the necessary skills to become an independently-funded investigator within a research-intensive environment focused on clinically-relevant research. This Faculty Research Scholars proposal will provide support to achieve these goals by 1) strengthening his grantsmanship skills for securing external R-level funding, 2) expanding his expertise in behavioral intervention development and optimization and clinical trial methodology, and 3) broadening his proficiency in implementation and integration methods for evaluating pain management strategies and pathways in clinical practice. Chronic spine pain is a significant global health problem. To address the multidimensional nature of the condition, psychologically-informed physical therapy (PIPT) has been advocated as this involves the incorporation of psychological strategies into routine practice. However, barriers to PIPT include the necessity for advanced clinical training and time for delivery of behavioral interventions. Internet-based self-management (IBSM) programs have been developed for use within the context of clinical care and offer a more scalable and sustainable approach for PIPT. There is a knowledge gap on the integration of this technology within physical therapy. This proposal will determine the feasibility, acceptability, and efficacy of an IBSM program for improving physical health in patients with chronic spine pain. Aim 1 of the project will determine whether integrating a 7-lesson IBSM program within physical therapy can be successfully implemented, result in acceptable patient adherence, and lead to treatment satisfaction. In Aim 2, efficacy of integrated IBSM and physical therapy will be assessed on physical health and important psychological risk factors. Successful completion of these aims will lead to further development and optimization of a PIPT intervention that can be implemented across a variety of health care settings. Dr. Coronado will receive structured mentorship from Dr. Kristin Archer and engage in didactic coursework in grantsmanship, implementation science, and clinical trials. This training experience at Vanderbilt will enable Dr. Coronado to successfully transition to an independent investigator.

Naira Baregamian, MD, MMS, FACS
Assistant Professor
Surgery
Began award in May 2022

Modulatory Role of Glutathione Metabolism in Immunometabolic Reprogramming of Thyroid Cancer

Failure of conventional and targeted chemotherapeutic regimes to control advanced metastatic and radioactive iodine (RAI) refractory thyroid cancer (TC) and current lack of clinical trials of drugs targeting cancer immunometabolic reprogramming in TC highlights an urgent need for novel treatment strategies for advanced TC. Glutathione (GSH) redox metabolic reprogramming, immunosuppressive microenvironment, and antitumor immune responses are critical contributors to chemotherapeutic failure and tumor progression and remain understudied in TC.
In our recent study of human TC tumors, we observed substantial abundance of Glutathione (GSH, ~14-fold increase) and robust redox metabolic reprogramming in tumor microenvironment (TME) in contrast to normal thyroids with high basal antioxidant capacity. Pharmacologic targeting of cytoprotective axis, GSH/Glutathione Peroxidase 4 enzyme (GPX4), in TC in vitro activated ferroptosis. GSH-rich human TC tumors exhibited enhanced CD4+>CD8+>T regulatory (Treg) tumor infiltrating T lymphocyte (TIL) infiltration marked by crucial spatial alignment of these TILs along the “leading” invasive edge of the tumor into the adjacent normal tissues. Immunohistochemical (IHC) evaluation of TC tissues revealed that CD8+TIL infiltration is often accompanied by impaired CD8+TIL cytolytic activity and may predict relapse in TC.
GSH is a notable culprit for chemotherapeutic drug resistance in many cancers, and a known critical immunomodulator of T lymphocytes, however, the role of GSH metabolism in regulating CD8+TIL infiltration, anergy and cytolytic dysfunction in TC TME is currently not well defined. Our preliminary data uncovering robust tumor GSH enrichment, effective ablation of GSH/GPX4 axis in vitro, and intriguing TIL spatial alignment and signature in human TC have further reinforced highly likely chemo- and immune-evasive tumor phenotype that can undermine the efficacy of existing therapies. In our proposal, we seek to define and develop novel immunometabolic approaches focused on targeting GSH-dependent regulation of tumor metabolic and immune responses in TME. Abrogating GSH-driven tumor metabolic and immunosuppressive reprogramming by ablating GSH synthesis in TC TME will be strategic in overcoming therapeutic resistance commonly seen in advanced TC.

Jason Gokey, PhD
Assistant Professor
Medicine/Allergy, Pulmonary & Critical Care Medicine
Began award in May 2022

YAP Regulation of Alveolar Epithelial Progenitor Cells during Normal and Fibrotic Lung Repair

In the lung, the alveolar epithelium consists of two cell types, alveolar type 1 cells (AT1s) that line 95% of the alveolar surface area facilitating gas exchange in close proximity to the alveolar capillaries, and alveolar type 2 cells (AT2s) that secrete pulmonary surfactants and lipids to maintain alveolar homeostasis. Maintenance of an intact and functional alveolar epithelium is essential for gas-exchange in the lung. Across the lifespan, the alveolar epithelium is subject to injury from a myriad of insults including respiratory viruses (including SARS-CoV-2, seasonal influenza and others), tobacco smoke, airborne particulates and other toxic chemicals, and failure of normal injury-repair mechanisms in the alveolar epithelium is believed to contribute to the pathogenesis of numerous chronic lung diseases including idiopathic pulmonary fibrosis (IPF). During normal regeneration, alveolar repair is achieved, at least in part, through a subset of AT2 cells termed alveolar epithelial progenitor cells (AEPs) that self-renew and differentiate into AT1 cells. In order to elucidate how abnormal alveolar repair contributes to disease pathogenesis (and potentially be therapeutically targeted), we must first understand the molecular pathways and programs regulating AEP specification and cell fate decisions. Using single-cell RNA-sequencing (scRNA-seq) we and others have demonstrated the presence of abnormally differentiated alveolar epithelial cells in the IPF lung, and our preliminary data implicate YAP signaling as an important regulator of alveolar epithelial differentiation. In order to investigate the role of YAP signaling in alveolar repair, we have generated novel mouse models enabling inducible Yap activation in all AT2 cells or specifically in AEPs. Initial analysis of isolated Yap active AT2 cells indicated increased expression of cell markers associated with both AT1 and airway epithelial cells, suggesting multiple distinct populations of abnormally differentiated AT2 cells. We have generated mice with Yap active specifically in AEPs, and our preliminary data suggest this leads to subsequent loss of AEPs available for regeneration. This leads us to hypothesize that Yap regulates AEP and non-AEP AT2 cell fate decisions and persistent Yap activation leads to a loss of AECs through forcing terminal differentiation of the progenitor cell population resulting in abnormal alveolar repair. We will test this hypothesis through in-vivo lineage tracing and single cell RNA sequencing in a mouse model with inducible Yap activation in both AEP and non-AEP AT2 cells that allows for isolation and analysis of both populations independently during lung injury and repair. We will also utilize ex-vivo alveolar organoids generated with Yap active AECs, AECs isolated from IPF patient lungs, and respective controls to assess the role of YAP signaling in AEC maintenance and differentiation. Together, these studies will provide a paradigm for a novel therapeutic strategy to enhance alveolar repair.

Kimberly Rengel, MD
Assistant Professor
Anesthesiology
Began award in May 2022

Muscle Ultrasound in Critical Illness to Understand Long-Term Impairment and Recovery

Each year, millions of patients develop newly acquired functional disability after critical illness. Patients highly value quality of life and the ability to return to pre-illness function, but both are negatively impacted by acquired disability. While awareness and identification of new chronic impairments after critical illness are increasing, understanding of the factors that contribute to disability after major surgery or critical illness is currently limited. Understanding mechanisms and risk factors that contribute to acquired disability is vital to guide future prevention and treatment strategies to ease burden of acquired disability.

The Muscle Ultrasound in Critical Illness to Understand Long-Term ImpAirment and Recovery (MUSCULAR) Study will examine the potential role of skeletal muscle health in acquired disability after critical illness. We will use a pragmatic bedside ultrasound examination to quantify muscle mass and quality in patients admitted for critical illness and record changes to muscle health throughout critical illness and into recovery (Aim 1). We will then identify risk factors associated with decline in muscle mass and quality during critical illness (Aim 2) and examine the association between muscle mass, quality, and change in both at distinct timepoints throughout critical illness and recovery with long-term physical function after discharge (Aim 3). We will perform this nested prospective study in two ongoing NIH-supported, prospective patient cohorts that are collecting extensive data on hospital course and performing robust physical outcomes evaluations at 3- and 12-months after discharge.

Currently, the relationship between long-term recovery after critical illness and the health of skeletal muscle before, during, and after critical illness remains unclear. The MUSCLAR study addresses this knowledge gap and will help identify targets for prevention and treatment of acquired disability. I am a physician-scientist trained in anesthesiology and critical care medicine and I have assembled a committee of mentors and content experts committed to guiding me in the conduct of high quality research and achieving my long-term career goal to become an independent NIH-funded investigator who studies mechanism of disability and interventions to reduce the burden of acquired disability after acute illness.

McKenzie Roddy, PhD
Assistant Professor
Medicine/General Internal Medicine & Public Health
Began award in July 2022
Received KL2 in July 2023

Developing an Adaptive Self-Care Support Intervention for Adults with Type 2 Diabetes and their Close Interpersonal Relationships

Dr. McKenzie Roddy is a Clinical Psychologist and Research Assistant Professor in the Division of General Internal Medicine and Public Health at Vanderbilt University Medical Center. Her long-term career goal is to become a recognized leader in the influence of close interpersonal relationships (CIR) on health, specifically focused on the optimization of behavioral interventions to improve health for patients with chronic conditions within the context of their CIR. Her short-term goal is to gain the necessary skills to become an independently funded investigator within a research-intensive environment focused on clinically relevant research. This Faculty Research Scholars proposal will provide support to achieve these goals by (1) gaining experience using mediation and moderation with health data to understand how and for whom behavioral interventions are most effective (2) developing proficiency in mixed-method evaluations of behavioral interventions (3) gaining experience in developing and running focus groups, (4) gain content knowledge and experience in behavioral diabetes research, (5) strengthening her grantsmanship skills for securing external K- and R-level funding, and (6) developing content knowledge and mentor relationship in adaptive intervention design and analysis. Dr. Roddy will receive structured mentorship from her primary mentor, Dr. Lindsay Mayberry, engage in didactic coursework in mediation analyses, grantsmanship, mixed-methods research, and adaptive designs, and participate in experiences designed to apply learned skills in the context of the mentor’s R01. The FAMS 2.0 intervention (R01DK119282, PI-Mayberry) aims to improve glycemic control and diabetes distress for adults with T2D. This proposal is the first to our knowledge to apply adaptive intervention methodologies to behavioral management of type 2 diabetes (T2D), where the majority of adults are not meeting self-management goals. Self-management of T2D occurs in the home and in the context of patients’ CIR. To optimally manage T2D, activating CIR to increase support and minimize harm is crucial for long-term success. However, the relational contexts of adults with T2D are diverse and complex as is the amount and types of support adults with T2D need or desire. Family self-care support interventions in T2D have inconsistent and mixed results. More work is needed to understand why some individuals benefit from relational-focused interventions while others do not. To inform development of an adaptive intervention, we aim to: (Aim 1) use data currently being collected through the mentor’s R01 to explore mediators and moderators of effects of the FAMS 2.0 intervention to develop hypotheses to be tested in a subsequent adaptive intervention, and (Aim 2) use a mixed-method approach to understand how individual, relational, and clinical factors moderate engagement with FAMS 2.0 and identify alternative intervention components for consideration in the design of the adaptive intervention. Successful completion of these Aims and training plain will provide the necessary preliminary data for the PI to submit an application to design and pilot an adaptive intervention for adults with T2D and their CIR.

Rei Ukita, PhD
Assistant Professor
Medicine/Cardiovascular Medicine
Began award in December 2022

Deciphering the Unique Molecular and Hemodynamic Signatures of Right Ventricular Adaptation, Failure, and Recovery in Large Animal Model

The purpose of this proposal is to foster the professional development of the applicant, Rei Ukita PhD, by conducting a cutting-edge investigation on right ventricular failure and recovery in a large animal model of pulmonary hypertension. Pulmonary hypertension (PH) is a family of diseases that elevates blood pressure in the lungs. The right ventricle (RV) initially adapts to the increasing afterload by developing the needed muscles, blood vessels, and the metabolic infrastructure. But as the disease becomes more severe, the RV will ultimately succumb to maladaptive failure. Proper intervention prior to failure is critical but challenging due to its sudden, unpredictable nature, such that a seemingly stable patient can suddenly die from RV failure. Meanwhile, proper surgical intervention that unloads the right heart, such as lung transplantation, can lead to recovery and normalization of right heart function. This is a growing scientific area that warrants more attention since the molecular pathways that underlie both processes of RV failure and recovery may be the ideal targets for deriving novel therapies to prevent and treat the disease. Due to the sudden, unpredictable nature of RV failure in human patients, however, these molecular pathways may be better studied using clinically relevant animal model for PH.

This proposal will therefore study both processes of RV failure and recovery in a large animal sheep model of reversible PH. In this model, the sheep’s pulmonary artery is banded using an adjustable vascular occluder. The frequency and the magnitude of occluder inflation can be controlled such that this model can induce both adaptive and maladaptive RV profiles. Moreover, the occluder can also be deflated to unload the RV, which can therefore model RV recovery. During RV loading and unloading, animal subjects will be scrutinized from multiple angles: quantification of RV function, blood sample analyses for metabolic species, and RV biopsies to study changes in gene expression, histologic, and metabolomic profiles. We will piece all of this information together to determine an ideal panel of biomarkers that can discriminate subjects undergoing RV failure, and also identify markers that signify the recovery of RV. To achieve the proposed research, Dr. Ukita will receive mentorship and support from clinical, scientific, and engineering experts in the field of pulmonary hypertension and right ventricular function and failure. Under this plan, Dr. Ukita will complete didactic and practical training in leadership, grantsmanship, and molecular analyses such as transcriptomic analysis. Dr. Ukita will ultimately take the combined experience and training from this proposed work to be competitive for his future independent research proposal, in which he will extend his findings toward future preclinical and clinical investigations on PH, RV failure, and mechanical circulatory support technology.

Ryan Ceddia, PhD
Instructor
Medicine/Cardiovascular Medicine
Began award in March 2023

Natriuretic Peptide and cGMP Signaling in the Adipocyte Thermogenic Program

This proposal outlines a VFRS career development plan to aid the continued progression of Dr. Ryan Ceddia into an independent research scientist with expertise in obesity and adipose tissue (AT) under the mentorship of Dr. Sheila Collins. Obesity is a significant risk factor for many diseases including both diabetes and cardiovascular disease. Lifestyle changes such as increased exercise or reduced food consumption have poor adherence while pharmacological approaches aimed at decreasing caloric intake have limited long-term efficacy. An alternative approach is to increase energy expenditure. Energy expenditure in AT is increased in response to cold exposure. Cold induction of the adipocyte thermogenic program is classically mediated through the sympathetic nervous system which signals through the β-adrenergic (βAR)-cAMP-PKA signaling pathway. The Collins’ lab and others have demonstrated that the cardiac natriuretic peptide (NP)-cGMP-PKG signaling pathway also increases adipocyte thermogenic activity. Dr. Ceddia’s recent studies demonstrate that removal of an enzyme which specifically degrades cGMP, phosphodiesterase 9 (PDE9), allows a mild cold challenge to cause a larger than expected induction of the AT thermogenic program. As cold-stimulation of AT thermogenesis is known to occur through cAMP-PKA signaling pathways, this effect of a cGMP-specific PDE suggests that cGMP-PKG signaling constitutes a previously underappreciated component of this process. In Aim 1, Dr. Ceddia will investigate his hypothesis that PDE9 regulated cGMP is a significant component of the cold-induced adipocyte thermogenic program. The goal of Aim 1 is to determine how cGMP serves as a critical regulator of cold-induced AT thermogenesis. Pharmacological and genetic tools will be used to manipulate PDE9 and the receptor for the cardiac NPs, NPRA, to probe the role of this pool of PDE9 regulated cGMP in cold-induced AT thermogenesis. The NPs are also regulated by a protease called neprilysin that degrades NPs and other vasoactive peptides. Neprilysin is highly expressed in adipocytes, but its role in AT thermogenesis is not well understood. Neprilysin is the target of a class of heart failure medication called Angiotensin Receptor-Neprilysin inhibitor (ARNi). ARNi has been shown to improve glycemic control in mice and humans, but the mechanism for this improvement in glucose homeostasis is not fully understood. Increased glycemic control, insulin sensitivity, and thermogenic energy expenditure can all be mediated by the actions of NPs in AT. Because of this, in Aim 2 Dr. Ceddia will test his hypothesis that inhibition of neprilysin improves insulin action and enhances the adipocyte thermogenic program through the actions of cardiac natriuretic peptides on adipose tissue. He will compare the effects of ARNi in mice which have or lack NPRA specifically in their AT to determine if ARNi affects insulin action and thermogenesis in AT through NP signaling. The proposed training will build upon Dr. Ceddia’s prior work in adipose tissue biology and receptor signaling being instrumental in his transition into an independent principal investigator with a lab investigating signaling mechanisms that regulate AT thermogenesis.

Heather Ward, MD
Assistant Professor Psychiatry
Began KL2 in April 2023

Network-Targeted Neuromodulation for Nicotine Dependence in
Schizophrenia

Tobacco use is the top preventable cause of early mortality in schizophrenia, leading to a 20-year decreased life expectancy compared to the general population. Current smoking cessation treatments are derived from people without psychosis and are significantly less effective for people with schizophrenia. We used a data-driven, agnostic approach to identify a schizophrenia-specific circuit of nicotine dependence (the Default Mode Network, DMN) then tested pharmacologic and neuromodulation interventions on this circuit. We observed craving was bidirectionally mediated by DMN connectivity: 1) nicotine administration (which reduces craving) decreased DMN connectivity in schizophrenia, while 2) a single session of intermittent theta burst stimulation (iTBS), which increases connectivity, applied to a DMN node acutely increased craving in schizophrenia. This provides evidence that 1) nicotine craving is mediated by this network and 2) this target can be engaged bidirectionally via multiple interventions. This K23 mentored patient-oriented career development award proposes to test if multiple repetitive transcranial magnetic stimulation (rTMS) sessions lead to enduring circuit change and reduce nicotine craving. Our central hypothesis is that the brain circuit most effective to reduce nicotine craving in schizophrenia is distinct from the pathway identified in a non-schizophrenia population. To test this hypothesis, we will compare 1) DMN-targeted continuous theta burst stimulation (cTBS) to 2) iTBS targeted to the left dorsolateral prefrontal cortex (L DLPFC), which reduces cigarette consumption and craving in smokers without psychosis. cTBS has been shown to decrease network connectivity. By applying cTBS to the DMN, we aim to decrease connectivity, thereby decreasing craving. We will determine if rTMS manipulates functional connectivity and craving and if craving change correlates with connectivity change for each rTMS target. To optimize rTMS response, we will also test if variability in rTMS response is explained by individual differences in network controllability. The applicant is a psychiatrist with fellowship-level training in neuroimaging and rTMS for substance use disorders in schizophrenia. Her long-term career goal is to build an independent research program using neuroimaging to identify brain networks linked to substance use in psychotic disorders then test neuroscience-based, network-targeted rTMS interventions in clinical trials for co-occurring substance use disorders in schizophrenia. To accomplish these goals, the applicant requires additional training in: 1) design and conduct of personalized network-targeted rTMS interventions, 2) individualized neuroimaging to optimize rTMS response, and 3) clinical trials and biostatistics. Training will include formal coursework, didactics, and on-site trainings, guided under a mentorship team of experts in network-targeted rTMS interventions in psychotic disorders, computational analysis of networks in psychotic disorders, and clinical trials design for rTMS and smoking cessation. Mentored training and completion of the proposed project will provide the applicant the skills and experience necessary to launch a successful independent research career.

Jeffrey Freiberg, MD, PhD
Instructor
Medicine/Infectious Diseases
Began award in July 2023

Understanding the Role of Arginine Metabolism in Antibiotic Treatment Failure during Staphylococcus aureus Infections

Staphylococcus aureus is a leading cause of a wide range of bacterial infections globally and is associated with significant morbidity and mortality. These poor outcomes are driven by the high rates of antibiotic treatment failure seen with many types of S. aureus infections. Antibiotic tolerance, which is defined as the ability of bacteria to survive in the face of antibiotics through phenotypic changes without the acquisition of antibiotic resistance, is the major driver of antibiotic treatment failure in S. aureus infections. Despite the clinical significance of antibiotic tolerance, the mechanisms by which it occurs is poorly understood. However, there has been a growing appreciation for the potential role of metabolism in antibiotic tolerance among bacteria. My preliminary experiments have identified an increase in antibiotic tolerance in mature S. aureus communities when arginine is depleted. I also discovered increases in the abundance of proteins involved in arginine degradation and corresponding decreases in the abundance of proteins involved in arginine synthesis in S. aureus in response to treatment with multiple antibiotics. In addition to being an essential amino acid for S. aureus growth, arginine is also required for the production of nitric oxide by host immune cells such as neutrophils and macrophages. The importance of nitric oxide production to the host response to S. aureus infections, establishes arginine as an important contributor to the ability of the immune system to combat S. aureus. Collectively, these results support the hypothesis that S. aureus influences arginine levels during infection by carefully regulating arginine metabolism as a means to survive both in the face of antibiotics and the innate immune response. Through this proposal, I plan to test this hypothesis by (1) elucidating the mechanism(s) by which arginine metabolism influences antibiotic tolerance in S. aureus, (2) determining the role of S. aureus arginine metabolism in persistence in the presence of innate immune effector cells, and (3) identifying the contribution of S. aureus arginine metabolism to persistence and antibiotic treatment failure during infection. Together, these experiments will better define the role of an essential amino acid at the host-pathogen interface. Furthermore, this work has the potential to uncover new targets for therapeutics to address the issue of treating recalcitrant infections that fail conventional therapies.

Matthew Mart, MD, MSCI
Instructor
Medicine/Allergy, Pulmonary & Critical Care Medicine
Began KL2 in July 2023

The Role of Mitochondrial Dysfunction in Physical Recovery after Acute Respiratory Failure

Each year, millions of adults survive a critical care hospitalization for acute respiratory failure, yet half or more will go on to develop devastating and persistent impairments in physical function such as exercise intolerance and reduced walking distance. Rehabilitation studies have demonstrated limited efficacy to date, and little is known about the mechanistic underpinnings that link acute respiratory failure and reduced physical function. Improved understanding of underlying mechanisms is urgently needed to improve long-term outcomes and develop effective interventions. During critical illness due to acute respiratory failure, patients suffer from profound alterations in energy generation in skeletal muscle due to disruptions in oxidative phosphorylation and reduced mitochondrial oxidative capacity. Whether mitochondrial oxidative capacity normalizes in survivors of acute respiratory failure, however, is unknown. Our preliminary data indicates that survivors of acute respiratory failure may experience reduced mitochondrial oxidative capacity that limits physical recovery months after critical care hospitalization. The central hypothesis for this proposal is that reduced mitochondrial oxidative capacity in survivors is associated with worse physical function. To test this hypothesis, this proposal will measure mitochondrial oxidative capacity in skeletal muscle using 31P-magnetic resonance spectroscopy (31P-MRS), systemic oxidative capacity in peripheral blood mononuclear cells, and post-hospital physical activity in survivors of acute respiratory failure at 3 months post-discharge and determine their association with physical function at 12 months after hospitalization. Aim 1 will test the hypothesis that reduced muscle-specific mitochondrial oxidative capacity, measured using 31P-MRS, at 3 months post discharge is associated with worse physical function at 12-month follow-up. Aim 2 will test the hypothesis that reduced systemic mitochondrial oxidative capacity measured in peripheral blood mononuclear cells at 3 months post-discharge is associated with reduced physical function at 12-month follow-up. Aim 3 will test the hypothesis that reduced post-hospital physical activity, measured using accelerometry, is associated with reduced physical function at 12-month follow-up, and in exploratory analyses, whether it is also associated with mitochondrial function at 3 months. These studies will define the role of mitochondrial capacity and physical activity on long-term physical function after acute respiratory failure. This work will advance the field by utilizing novel research approaches to characterize understudied mechanisms of physical recovery and provide a foundation for physiologically targeted interventions. This proposal will also foster the candidate’s development into a national leader on physical recovery after acute respiratory failure, merging the insights of applied physiology with critical care outcomes to improve the lives of survivors.

Alison Carroll, MD, MPH
Assistant Professor
Pediatrics/General Pediatrics
Began KL2 in September 2023

Integration of Social Determinants of Health in a Prediction Model for Pediatric Healthcare Reutilization

Emergency department revisits and hospital readmissions (i.e., reutilization) in children following hospital discharge, is a marker of suboptimal health, is burdensome for caregivers, and is costly to the healthcare system. While illness severity and medical complexity explain some of the variation in pediatric reutilization, important preventable disparities are evident with higher reutilization among children with public or no insurance, low socioeconomic status, and children exposed to racial or ethnic bias. We posit that an incomplete understanding of reutilization risk, including failure to address important social determinants of health (SDOH), are critical drivers of these disparities. An objective measure of reutilization risk that incorporates both social and clinical risk factors within the electronic health record could improve care delivery and reduce disparities by targeting patient-level interventions to where they are most needed. The central hypothesis of this proposal is that integrating SDOH with key clinical factors will more accurately identify risk for post-discharge reutilization. Dr. Carroll will test this hypothesis through the following specific aims: 1) Update and validate a suite of existing prognostic models for all-cause 30-day hospital readmissions using an administrative database of 49 US children’s hospitals; 2) Define critical barriers and facilitators to the implementation of a pediatric reutilization risk stratification tool into hospital-based care; 3) Integrate and evaluate the best performing prognostic models within the electronic health record at Vanderbilt University Medical Center, evaluating prospective prediction performance and testing for potential unintended disparities.

Kelly Watson PhD
Assistant Professor
Neurology
Began KL2 in September 2023

Social Isolation and Social Cognition in Adolescents with Tourette Syndrome

Candidate: Kelly Watson, PhD is Assistant Professor in the Department of Neurology and a clinical psychologist who provides a specialized, evidence-based behavioral therapy to adolescents with Tourette syndrome (TS). Dr. Watson strives to establish an independent program of patient-oriented research, with an emphasis in social and cognitive processes in TS. She earned her PhD in clinical psychological science from Vanderbilt University (2016) where she then completed her research-focused fellowship on a NIMH T32 training grant. In her early career, Dr. Watson has served as a co-I on two extramural grants and co-authored numerous scientific publications. Her background demonstrates strong potential for a productive long-term research career translating key findings into the development, evaluation, and dissemination of psychosocial interventions in TS.
Research Project: TS is a neurodevelopmental disorder characterized by motor and vocal tics with a prevalence of 1% in adolescence. While current treatments focus on tic reduction, patients commonly report clinically distressing social problems. Yet, limited research in adolescence has focused on risk factors that contribute to social problems or examined the impact of these problems on social isolation. The aims of the proposed study are to: (1) quantify the prevalence of social isolation in TS adolescents; (2) assess explicit social cognition in TS adolescents; and (3) apply aye-tracking techniques to assess implicit social cognition in TS adolescents. An exploratory aim will be to determine the contributions of social cognition to social problems in TS adolescents. Fifty adolescents with TS and 50 matched controls will be recruited, along with their parents, to complete a multi-method assessment battery. Results have the potential to inform clinical interventions to improve quality of life.
Career Development: The training associated with this career development award will support Dr. Watson to achieve her goal of becoming an independently funded clinician scientist in TS. To achieve this goal, she has developed a focused career development plan that includes formal coursework, workshops, webinars, conferences, and individualized training from a strong interdisciplinary mentorship team. Dr. Watson’s specific training goals include advanced training in: 1) TS, 2) social cognitive assessment, 3) eye-tracking methods, and 4) professional development. The Vanderbilt Faculty Research Scholars Award will provide the comprehensive mentorship support, resources, and protected time needed to obtain independent NIH grant funding in TS.
Environment: VUMC is an optimal academic environment for cultivating Dr. Watson’s development into an independently funded clinical investigator specializing in patient-centered research in TS. The institution has an exceptional track record for fostering productive and independently funded clinician-scientists. VUMC offers a wealth of resources to support this work, including a specialty clinic with a large population of adolescents with TS; VUMC is one of only 21 Tourette Association of America Centers of Excellence in the country.

Antentor Hinton, Jr., PhD
Assistant Professor
Molecular Physiology & Biophysics
Began award in October 2023

Estrogen Regulation of Stress-Induced Hypertension in the Medial
Amygdala During Pregnancy

Hypertensive disorders affect up to 10% of pregnancies in the United States. Hypertension (HTN) in pregnancy is associated with a higher risk for complications in both the fetus and mother, including intrauterine growth restriction and maternal mortality, respectively. We hypothesize that estrogen receptor-α (ERα)-initiated signaling pathways in medial amygdala (MeA) neurons prevent stress-induced HTN during pregnancy. In humans, psychological stress contributes to the development of HTN, which is partly mediated by amygdalar neurons. In humans and rodents, MeA neuronal signaling is positively associated with changes in blood pressure (BP) during stress. Additionally, estrogen attenuates stress-induced c-fos expression in the MeA via ERα, yet the mechanisms for stress-induced HTN during pregnancy remain unknown. Although estrogen replacement therapy (ERT) lowers BP in postmenopausal women, its off-target effects can increase the risk of stroke and thromboembolism. During pregnancy, steroids (e.g., 17β estradiol) are synthesized in large amounts by the placenta, while MeA neurons have a high expression of ERα. We have shown that 17β-estradiol replacement reduces BP in ovariectomized female mice via ERα. Understanding the specific pathways underlying the anti-hypertensive effects of estrogens may lead to novel and safer therapies for HTN during pregnancy.

In Aim 1, we hypothesize that MeA neurons mediate stress-induced HTN during pregnancy. We generated Sim1-Cre mice that were subjected to pregnancy and injected with inhibitory and activating DREADD virus. Although SIM-1 MeA neurons are involved in stress-induced HTN, we are not aware of their role during pregnancy. We will stereotaxically inject DREADD in MeA of pregnant female mice and determine its effect on BP and stress-induced HTN in mothers and offsprings, as well as the structure and dynamics of mitochondria in reproductive tissues. In Aim 2, we hypothesize that ERα or Erβ in the MeA mediates estrogenic effects to prevent stress-induced HTN during pregnancy. We will generate ERα or Erβ knockout mice and evaluate whether ERα or ERβ in the MeA alone is sufficient to rescue the anti-hypertensive effects of estrogens during psychologic stress during pregnancy and also determine how stress impacts SIM1-MeA neuronal signaling.

By integrating the results of these independent aims we will significantly advance our knowledge of the role of estrogen signaling in the MeA on the regulation of stress-induced HTN during pregnancy. Our studies will demonstrate that selective activation of MeA ERα or MeA Erβ, can decrease BP during stress-induced pregnancy. Our ultimate goal is to develop novel therapeutic targets for patients with stress-induced HTN during pregnancy.

Lauren Klein, MD
Instructor
Pediatrics/Gastroenterology
Began award in October 2023

A Randomized Controlled Feasibility Trial to Treat Underweight Children 5 Years and Older with Sickle Cell Disease in Nigeria

This proposal aims to provide a mentored experience for an early physician-scientist to determine the feasibility of treating underweight children with sickle cell disease (SCD) aged 5 years and older. Underweight is a term to describe children with low weight relative to their age (weight-for-age) from acute, chronic, or both acute and chronic malnutrition. There are no evidence-based strategies to treat malnutrition in children with SCD at any age. In preparation for this proposal, the applicant completed the following: (1) demonstrated the high prevalence of underweight (weight-for-age z-score <-2) in older children with SCD living in Nigeria, 57.8% (manuscript under review); (2) identified the novel association of lower weight-for-age z-score with mortality in older children with SCD (Blood Advances 2022); (3) co-led an NIH-sponsored trial for severe acute malnutrition in 110 children with SCD in Nigeria (manuscript in preparation); the primary outcome (feasibility) was met, with recruitment, retention, and adherence rates all >94% for the 12-week trial with supplemental ready-to-use therapeutic food (RUTF; 500-1,000 daily calories). Previously associated with mortality in adults with SCD, arginine deficiency may be a potentially modifiable risk factor for death in underweight children with SCD. Chronic hemolysis in SCD increases intravascular arginase activity, depleting arginine, the sole nitrogen substrate for nitric oxide production. The therapeutic dosage of RUTF for nutritional recovery in older children with SCD is unknown and therefore requires adaptation from the (1) World Health Organization guidelines for children under 5 years old (~200 kcal/kg/day) and (2) nutrition practice recommendations for children with HIV over 5 years old (~75 kcal/kg/day). The applicant will obtain the prerequisite data to eventually test the global hypothesis that in underweight older children with SCD, treatment with ~200 kcal/kg/day (maximum 2,500 daily calories) of RUTF improves weight-for-age z-score greater than treatment with ~75 kcal/kg/day of RUTF. The applicant will also determine whether RUTF will improve arginine levels or if additional arginine supplementation is required. The proposed feasibility trial will randomly allocate 50 underweight (weight-for-age z-score <-2) children aged 5.00-10.99 with SCD. The first aim is to determine the feasibility (recruitment, retention, and adherence rates) of a randomized controlled trial (RCT) with RUTF at ~75 kcal/kg/day versus ~200 kcal/kg/day to treat underweight children with SCD over a 20-week intervention. All participants will receive moderate-dose hydroxyurea (fixed-dose 20 mg/kg/day), a previously demonstrated safe and now standard care therapy to prevent SCD-related morbidities in Nigeria. Mothers of participants will receive education on preparing locally available nutrient-dense food to increase sustainability in a setting with common food sharing. The second aim is to assess arginine bioavailability in underweight children with SCD before and after treatment in both arms. Based on this proposal, the applicant will submit a K23 application for a two-site feasibility RCT, potentially with additional arginine supplementation.

Jamie Robinson, MD, PhD
Assistant Professor
Pediatric Surgery
Began award in October 2023

Improving Risk-stratification for Venous Thromboembolism Using Genomics”

Venous thromboembolism (VTE), which encompasses both deep venous thrombosis (DVT) and pulmonary embolism (PE), is the leading cause of preventable in-hospital death. Surgical procedures, acute medical problems, and trauma are known risk factors for VTE in adults and children; however, VTE prophylaxis protocols based on type of procedure or patient presentation do not fully account for the variable propensity to develop VTE. Even with improved adherence to current VTE prophylaxis protocols, neither the incidence of VTE nor mortality among VTE patients with PE has declined in the most recent decade. While data demonstrate that genomics can strongly predict VTE, a barrier to VTE prevention is the lack of risk-stratification models incorporating clinical and genomic factors to identify high-risk adults or children who would benefit from VTE pharmacologic prophylaxis. A tailored, personalized-medicine approach to pharmacologic prophylaxis regimens based on genomic and clinical risk factors could have a major impact on the incidence of VTE and its subsequent morbidity.

This proposal describes my career development plan and a research program of “Improving Risk-stratification for Venous Thromboembolism Using Genomics”, motivated by my direct clinical experience caring for patients with VTE during my adult and pediatric surgical training. Many patients I treat have increased risk for VTE, yet guidance on prophylaxis is limited and does not incorporate known genomic predictors. This research and career development plan will provide protected effort and resources to develop expertise in advanced phenotyping methods, statistical modeling for genomic data, and assessment of risk-stratification techniques. We are using clinical and genomic data generated and available at Vanderbilt University Medical Center (VUMC) through the Synthetic Derivative and BioVU. The first Aim is to develop with high fidelity a phenotype for VTE that is reproducible in adult and pediatric patients. Next, I will develop a polygenic risk score (PRS) including over 1 million SNPs for VTE using known large-scale genome-wide association analyses (Aim 2). Lastly, I will compare risk-stratification for VTE using the PRS to clinical predictors alone or the polygenic and clinical risk factors in combination while additionally assessing for prophylaxis-associated bleeding complications in each model (Aim 3). The career development plan integrates coursework and individualized mentor-directed instruction in computational phenotyping, statistical and population genetics, grant preparation, and scientific communication and leadership. I will participate in local and national seminars and conferences to advance my expertise. I have designed a multidisciplinary mentored research experience that builds on relationships I have made during my surgical and informatics training at VUMC and the highly supportive research environment of the Biomedical Informatics, Pediatrics, and Pediatric Surgery departments.

Recent Scholars	Project Abstract
Ryan Darby, MD Assistant Professor Neurology Began VFRS in June 2018 Received K23 in June 2021	Social Engagement and Language Development in Autism Spectrum Disorders The proposed project examines visual and vocal entrainment and language development in infants/toddlers with typical development and autism spectrum disorder (ASD). ASD is a common and lifelong disorder that is characterized by impairments in social communication and repetitive behaviors. Yet, there is striking heterogeneity in language development in children with ASD and language delays in ASD are often a first concern for parents that their child is not developing as expected. In typically developing infants, rhythm plays a crucial role in social communication and language development. Caregivers use highly rhythmic, multimodal speech and singing to attract and maintain infants’ attention. Infants and caregivers coordinate their interactions through rhythmic vocalizations, facial expressions, and movements. Individual differences in social rhythm coordination may reflect individual differences in social attunement and predict children’s language development. This project extends my prior work demonstrating rhythmically entrained eye gaze in typical infants and toddlers to infants/toddlers with ASD (Aim 1), and also uses a novel measure of speech rhythm to assess social vocal entrainment in parent-child dyads (Aim 2). Additionally, I will examine how these metrics related to children’s language development (Aim 3). These findings will provide preliminary data to guide future longitudinal investigations of social rhythmic entrainment and language development in children at risk for developing ASD. This research may lead to the development of biomarkers of social entrainment that may inform early ASD assessment and diagnosis, as well as intervention strategies that, if warranted, include rhythm and timing of social interactions as one aspect of comprehensive language intervention for these children.
Miriam Lense, PhD Assistant Professor Otolaryngology Began VFRS in January 2018 Received R61 in September 2019	Social Engagement and Language Development in Autism Spectrum Disorders The proposed project examines visual and vocal entrainment and language development in infants/toddlers with typical development and autism spectrum disorder (ASD). ASD is a common and lifelong disorder that is characterized by impairments in social communication and repetitive behaviors. Yet, there is striking heterogeneity in language development in children with ASD and language delays in ASD are often a first concern for parents that their child is not developing as expected. In typically developing infants, rhythm plays a crucial role in social communication and language development. Caregivers use highly rhythmic, multimodal speech and singing to attract and maintain infants’ attention. Infants and caregivers coordinate their interactions through rhythmic vocalizations, facial expressions, and movements. Individual differences in social rhythm coordination may reflect individual differences in social attunement and predict children’s language development. This project extends my prior work demonstrating rhythmically entrained eye gaze in typical infants and toddlers to infants/toddlers with ASD (Aim 1), and also uses a novel measure of speech rhythm to assess social vocal entrainment in parent-child dyads (Aim 2). Additionally, I will examine how these metrics related to children’s language development (Aim 3). These findings will provide preliminary data to guide future longitudinal investigations of social rhythmic entrainment and language development in children at risk for developing ASD. This research may lead to the development of biomarkers of social entrainment that may inform early ASD assessment and diagnosis, as well as intervention strategies that, if warranted, include rhythm and timing of social interactions as one aspect of comprehensive language intervention for these children.
Daniel Foster, PhD Assistant Professor Pharmacology Began award in July 2018 Received R01 in January 2021	Modulation of Striatal Biology and Repetitive Behaviors by M4 PAMs Repetitive behaviors are commonly observed in disorders such as Obsessive Compulsive Disorder (OCD), Tourette’s Syndrome (TS), and Autism Spectrum Disorders (ASDs).These behaviors can have profound negative effects on patients’ lives and can impair their ability to learn, carry out social interactions, and adapt to changing environments. While selective serotonin reuptake inhibitors, antipsychotics, and behavioral therapy are moderately effective in treating these symptoms, most patients are refractory to these therapies and there is a critical need to identify better treatment strategies to help patients with these disabling symptoms. The striatum is a brain region that plays a key role in integrating information from numerous brain structures and is essential to modulating habitual and goal-directed behaviors. Converging clinical and preclinical data suggest that hyperactive dopaminergic and glutamatergic neurotransmission through specific circuits in the striatum may represent common mechanistic underpinnings of abnormal repetitive behaviors. Interestingly, extensive studies from our lab and others have found that the M4 subtype of muscarinic acetylcholine receptor can exert powerful modulatory control over striatal dopaminergic and glutamatergic transmission, raising the possibility that selective activators of M4 could reverse pathological changes that may give rise to repetitive behaviors. Here we provide preliminary data demonstrating that M4 PAMs reduce excessive grooming in SAPAP3 KO mice (a genetic mouse model that displays a repetitive over-grooming phenotype). This could provide a breakthrough in identifying a novel approach for treatment of disabling symptoms that are resistant to available therapies. We hypothesize that repetitive behaviors are associated with hyperactive glutamate and dopamine release in the striatum, and that M4 PAM treatment can reduce repetitive behaviors by normalizing these forms of neurotransmission. We will test this hypothesis through a series of electrophysiological and behavioral studies using a combination of genetically modified mice, optogenetic approaches, and novel pharmacological tools. These studies will provide important information regarding the physiological role of M4 receptors in regulating basal ganglia function and will elucidate the therapeutic potential of M4 PAMs in providing relief from repetitive behaviors.
Matthew Schrag, MD, PhD Assistant Professor Neurology Began VFRS in April 2017 Received K76 in August 2019 Received R03 in September 2019	Dystrophic Neurites and Lysosome Dysfunction in Alzheimer’s Disease: The Contribution of PLD3 An effective treatment for Alzheimer’s disease (AD) is urgently needed to stem the tide of the ongoing and growing epidemic of dementia. An abnormal protein called β-amyloid is thought to be a major driver of memory loss in AD and many recent clinical trials have attempted to reduce the level of this protein in the brain, either by activating the immune system to clear it or inactivating enzymes that produce it. None of these trials has been successful yet. In this application we propose to explore this problem in a different way. We have discovered that neuronal axons around deposits of β-amyloid are swollen and filled with lysosomes, but these lysosomes are deficient in protein-degrading enzymes. Because lysosomes are so important to protein homeostasis and this pathology is so dramatic, we hypothesize that these abnormal lysosomes contribute to the formation of β-amyloid plaques and if their function could be rescued they may be able to break down these plaques and improve brain function without immune activation or inactivating important enzymes. We will study this by focusing on a novel gene, PLD3, which was identified as contributing to AD risk. We discovered that PLD3 is robustly enriched on these abnormal lysosomes and may suppress the function of protein degrading enzymes. We will silence this gene in a mouse model of AD with an antisense oligonucleotide to learn how it affects cognition, lysosome function and β-amyloid plaques. We will use phospholipase enzymology techniques to evaluate whether PLD3 has phospholipase activity and we will study human brain, blood and cerebrospinal fluid from patients with Alzheimer’s disease to understand how this protein is associated with other AD pathologies. These studies will help us to understand not just how this protein functions in the setting of AD, but also what molecular processes are occurring on these abnormal lysosomes. Understanding the neurobiology of axonal lysosome accumulations will likely lead to new treatment targets for AD. Additionally, these studies will provide an outstanding training mechanism to enable me to work with a phenomenal group of mentors and acquire the necessary expertise to effectively run an independent research program.
Danxia Yu, PhD Assistant Professor Medicine/Epidemiology Began VFRS in April 2017 Received R21 August 2018 Received R01 in July 2020	Linking Long-term Diet, Gut Microbiome, and Their Interactions with Human Metabolism and Diabetes Risk The purpose of this application is to support Dr. Danxia Yu to build an independent research career in nutritional and molecular epidemiology, with a focus on investigation of the diet-gut microbiota interactions as modifiable risk factors for cardiometabolic diseases via integrating ‘multi-omics’ into epidemiologic research. The mentorship, training activities, and research plan are designed to achieve Dr. Yu’s career goals by expanding expertise in nutritional and molecular epidemiology, developing new expertise in metagenomics and metabolomics, and leveraging the outstanding resources, environment, and support from VUMC and her mentoring team. The proposed research plan will serve as a training platform and generate pilot data for developing an R01-level proposal to investigate the role of diet-gut microbiota-host interactions in cardiometabolic disease risk among multi-ethnic populations. The research plan has three aims. Aim 1 is to evaluate long-term dietary pattern and its changes over time in association with risks of type 2 diabetes and cardiovascular disease in two prospective cohort studies of ~135,000 Chinese adults. Repeated dietary survey data will be used to assess long-term diet. Aim 2 is to investigate how long-term diet influences gut microbiota, measured by metagenome shotgun sequencing using newly established resources from these two cohort studies. Two groups of participants with the most and least healthy long-term diet will be selected for this study (based on results from Aim 1). Gut microbial composition and functional potential will be compared between these two groups. Aim 3 is to examine associations of circulating microbial metabolites with risk of type 2 diabetes and to explore potential mediation effects and interactions between diet and microbial metabolites in relation to diabetes risk. The proposed research, to be conducted in large, longitudinal studies of populations undergoing nutrition transitions, applying both metagenomics and metabolomics, is expected to provide novel evidence on the interplays between diet, gut microbiota, metabolites, and host metabolic health, knowledge essential for finding new tools to fight the epidemic of cardiometabolic diseases in both developed and developing countries. An excellent mentoring team was formed to assist Dr. Yu’s career development. It includes leading experts in the fields of chronic disease epidemiology, cardiometabolic disease, gut microbiome, metagenomics, metabolomics, biostatistics, bioinformatics, and multi-omics data analysis. New knowledge and skills will be obtained via focused, hands-on training, including seminars, conferences, workshops, research, publication, and grant application. Through these activities, Dr. Yu will develop new research capabilities, build a collaboration network, and transition into an independent investigator.
Jo Ellen Wilson, MD, MPH Assistant Professor Psychiatry Began VFRS in August 2017 Received KL2 in August 2017	The DeCat (Delirium and Catatonia in Critical Illness) Cohort Study Research Project: To continue her ongoing DeCat (Delirium and Catatonia in Critical Illness) Cohort study, a prospective observational cohort study, which is nested within NIH funded large scale studies in the Critical Illness, Brain Dysfunction and Survivorship (CIBS) Center at Vanderbilt University Medical Center. Aims of the Proposed Research: 1) To describe the predictive risk factors (including biological, e.g., genetic) for catatonia in a critical illness. 2) To determine the interaction of catatonia and delirium on cognitive and psychological sequelae of critical illness, and 3) To identify if catatonia is an independent risk factor for mortality in critically ill patients. Career Development: 1) Formal academic coursework (focused in the early years of the award) to supplement anticipated gaps in knowledge and to focus on advanced methods and measurements intended to support current and future research projects, 2) Writing up our findings and grant writing, 3) Attendance and participation at periodic institutional research seminars and conferences including responsible conduct of research (RCR training), 4) Formal mentorship and development activities with primary mentor, co-mentors and advisors, 5) Attendance and participation at national meetings with the intent to network with leaders in the field and present our work, and 6) Completion of proposed mentored research projects. Environment: VUMC is the ideal setting to allow Dr. Wilson to pursue this line of inquiry and truly become a nationally recognized leader on the topic of catatonia and delirium in critical illness. Using data she proposes to obtain in this study, Dr. Wilson will aim to submit a R01 clinical treatment trial of co-morbid delirium and catatonia in critical illness.
Maribeth Nicholson, MD, MPH Assistant Professor Pediatrics/Gastroenterology Began VFRS in July 2017 Received KL2 in August 2017 Received K23 in December 2020	Clostridium difficile Colonization, Disease, and Recurrence in the Pediatric Host Clostridium difficile (C. difficile) infection is the leading cause of antibiotic-associated diarrhea in the United States. A 2015 Centers for Disease Control and Prevention (CDC) study found that C. difficile caused almost half a million infections and 15,000 deaths among adult and pediatric patients in the United States in a single year. In addition, a national database of hospitalized children reported a doubling of the incidence of C. difficile infections (CDI) from 2003 to 2012. CDI can be associated with significant complications including the development of toxic megacolon, gastrointestinal perforation, sepsis, and death. Recurrence of CDI is common, with an estimated 20-30% of pediatric patients experiencing this complication. Alternatively, C. difficile can also exist as an asymptomatic colonize in the pediatric host, which occurs more frequently in patients with additional comorbidities. These patients also have exposures that result in non-C. difficile associated diarrhea. In this setting, a positive C. difficile test may be unrelated to the etiology of the diarrheal symptoms which often confounds appropriate diagnosis and therapy. To date, there are no reliable markers to distinguish those pediatric patients who are colonized or those who are at highest risk of complications and disease recurrence at the time of initial infection. The research detailed in this proposal responds directly to the need to identify markers of colonization, severity, and recurrence, and includes the following specific aims: 1) To determine the prevalence and characteristics of C. difficile colonization using molecular-based testing in pediatric patients with comorbidities (specifically cancer, cystic fibrosis, and inflammatory bowel disease) and evaluate associated risk factors and outcome; 2) To compare C. difficile toxin abundance and cytotoxicity in stool of colonized versus symptomatic patients as well as compare toxin abundance and cytotoxicity as it relates to the severity of C. difficile symptoms; 3) To determine the differences in the intestinal microbiome in children with C. difficile colonization, disease, and recurrence. For the past 4 years the candidate has worked closely with her mentor, Dr. Kathryn Edwards on a variety of CDI related projects which have included the prospective enrollment of pediatric patients with CDI. She has also collaborated with her co-mentor, Dr. Eric Skaar, for the last 6 months during which time they have used stool specimens to identify markers of severity in pediatric patients. This work resulted in a co-author paper in Nature Medicine. The overarching objective of this mentored career development experience is for the candidate to emerge as an independent clinical investigator of C. difficile in children and become established in toxin determination and microbiome analysis. Throughout the award period, the candidate will work closely with a multidisciplinary team of mentors including experts in infectious diseases, gastroenterology, biostatistics, microbiome analysis, and molecular techniques to carry out her stated aims and career goals.
Mekeila Cook, PhD Assistant Professor Public Health Practice, Meharry Medical College Received KL2 in January 2018	Barriers and Facilitators of Service Utilization among Justice-Involved Girls Vulnerable to Sex Trafficking: A Mixed-Methods Study The purpose of my study is to understand healthcare and service utilization among justice-involved adolescent girls at risk for sex trafficking. Phase I analyzes previously collected data among participants in a court diversion program for sex trafficking survivors. The specific aims are to: 1) identify whether age at entry into court predicts reduction in risk profile (e.g., AWOL, bench warrants, and re-arrests); 2) evaluate whether caregiver abuse and housing instability predict length of time commercially sexually exploited youths engage in a specialty court; and 3) examine whether length of time utilizing treatment (e.g., court appearances, participation in mental health services and substance use treatment) predicts graduation from the program. In Phase II, I will conduct focus groups with non-incarcerated, justice-involved girls regarding their experiences accessing health and social services, barriers and facilitators for accessing services and youth’s definition of resiliency. The specific aims are to: 1) characterize the needs of minority justice-involved girls and identify vulnerable behaviors that may lead to unsafe decisions; 2) modify the “Identity” educational prevention program to address adolescents’ barriers to engagement in services, and 3) test the effectiveness of the updated educational prevention program.
Ryan Doster, MD Assistant Professor Medicine/Infectious Diseases Began VFRS in February 2018 Received K08 in March 2020	Defining the Role of Streptococcus agalactiae Biofilm at the Host-pathogen Interface during Chorioamnionitis Streptococcus agalactiae, also known as Group B Streptococcus (GBS), colonizes up to 50% of pregnant women, and this colonization increases risk for stillbirth, preterm birth, and invasive neonatal disease. The long-term goal of this project is to reduce the burden of infection-related adverse pregnancy outcomes through defining root mechanisms of disease pathogenesis. This proposal tests the hypothesis that GBS biofilm production is important for bacterial colonization, persistence and host immune modulation, culminating in ascending infection of the gravid uterus. Here we define the role of biofilm during GBS colonization and chorioamnionitis (infection of fetal membranes). Aim 1 will use transposon mutagenesis and transcriptomic approaches to identify important pathways for GBS biofilm formation and then verify biofilm candidate genes by constructing and evaluating isogenic mutants. Aim 2 will define the impact of biofilm at the host-microbial interface by evaluating interactions of GBS biofilm mutants with human vaginal epithelial cells, cervical epithelial cells, and fetal membranes. Aim 3 will probe in vivo mouse models of vaginal colonization and chorioamnionitis to examine how biofilm alters GBS pathogenesis and immune activation during infection. Completion of these Aims will shed new light on the role of biofilm during GBS pathogenesis and might reveal preventive and therapeutic targets for reducing the burden of GBS disease during pregnancy. Dr. Ryan Doster is an Instructor in the Division of Infectious Diseases at Vanderbilt University Medical Center. He is also completing a Ph.D. through the Physician Scientist Doctoral Program, a new collaboration between the Vanderbilt Department of Medicine and the Interdisciplinary Graduate Program. This project expands on Dr. Doster’s current dissertation research investigating innate immune responses during pregnancy infections and past research in host microbial interactions at epithelial surfaces to investigate mechanisms of GBS pathogenesis during pregnancy. Furthermore, this project complements Dr. Doster’s clinical training in pediatrics and adult infectious diseases. In this proposal Dr. Doster will master techniques of bacterial mutagenesis strategies, animal models of infection, and working with human cells and tissues. He will also learn new skills utilizing advanced genetic techniques including transcriptomics. Vanderbilt offers cutting-edge technology and expertise in these areas through Vanderbilt Technologies for Advanced Genomics and other shared research core facilities. An interdisciplinary team including Dr. David Aronoff and Dr. Jennifer Gaddy will mentor Dr. Doster in career development and skill acquisition that will prepare him to become an independent researcher investigating the pathogenesis of bacterial infections during pregnancy.
Marcos Lopez, MD, MS Assistant Professor Anesthesiology Began VFRS in July 2018 Received K23 in September 2018	Perioperative Oxygenation, Endothelial Dysfunction, and Organ Injury in Cardiac Surgery This career development award will provide training to Marcos Lopez, MD, MS and help him advance towards his long-term goal of becoming an independent physician-scientist testing hypotheses to reduce organ injury in surgical patients. Dr. Lopez is an anesthesiologist and intensivist at Vanderbilt University Medical Center (VUMC). He is establishing a research niche characterizing the contribution of endothelial dysfunction to perioperative brain and kidney injury. Dr. Lopez assembled a multidisciplinary mentorship committee to facilitate achievement of his goals. Primary mentor Frederic T. Billings IV MD, MSCI is an anesthesiologist and intensivist who conducts clinical trials to reduce kidney injury after cardiac surgery. Co-mentor David Harrison, MD, is a cardiologist and leader in the study of the endothelium. Co-mentor Pratik Pandharipande MD, MSCI, is an anesthesiologist, intensivist, and leader in the study of ICU delirium. Dr. Lopez will combine vascular biology training in the Harrison lab with perioperative clinical trial design and outcome assessments training from Drs. Billings and Pandharipande to achieve independence. Dr. Lopez’s research will assess endothelium-mediated vascular reactivity prior to and following cardiac surgery in patients enrolled in an RCT of intraoperative oxygen treatment (R01GM112871; PI: Billings) to test the hypotheses that normoxia during cardiac surgery improves vascular reactivity compared to hyperoxia and that impaired vascular reactivity correlates with intraoperative oxidative stress (Aim 1), that vascular reactivity in arterioles dissected from mediastinal fat of normoxia-treated patients will be increased compared to hyperoxia-treated patients (Aim 2), and that endothelial dysfunction is associated with increased brain and kidney injury (Aim 3). The study benefits from the subject recruitment, randomization, sampling, and outcomes assessment of the parent trial but tests its own independent hypotheses, providing a route to scientific independence. Dr. Lopez will measure brachial artery flow-mediated dilation, peripheral artery tonometry, and plasma concentrations of plasminogen activator inhibitor-1 and E-selectin pre- and postoperatively. He will measure vascular reactivity in mediastinal fat arterioles at the end of surgery using wire myography. He will compare these data with oxygenation groups, markers of oxidative stress, and with measured brain and kidney injury to test his hypotheses. Dr. Lopez will gain experience recruiting patients into a clinical trial, prospectively collecting data, and managing a clinical research team. Dr. Lopez will progress to independence by completing career development training and this study. He will initiate a research program to reduce perioperative organ injury by targeting endothelial dysfunction.
M. Gunes Kutlu, PhD Instructor Pharmacology Began VFRS in July 2019 Received KL2 in October 2020	The Role of Mesocortical Pathway in Negative Reinforcement Learning Anxiety disorders such as panic disorders, generalized anxiety disorder, and post-traumatic stress disorder (PTSD) affect approximately 18% of the American population with a health care cost of more than $42 billion a year, a significant burden to the US economy. Development and maintenance of anxiety disorders have been attributed to persistent fear memories and inadequate fear extinction. Thus, it is imperative to understand the neural mechanisms underlying encoding, consolidation, and retrieval of fear memories in order to be able to develop efficacious treatments for these disorders. Midbrain dopaminergic projections to limbic and cortical brain regions are essential for detecting and encoding significant and related events in various memory domains (e.g., reward learning, fear learning). The goal of this proposal is to translationally determine how cortical dopamine input guides learning about cues and aversive stimuli and dissociate the role of the VTA→mPFC pathway in discrete aspects of behavior associated with aversive stimuli in mice and humans. I have developed a novel behavioral task in predictive cues are associated with the onset of avoidable aversive stimuli, which can be utilized with both rodent and human subjects. In this task, subjects learn to execute a behavioral response during the cue period to avoid aversive outcomes (footshock for mice and white noise for humans) allowing us to separate the dopaminergic VTA→ mPFC signals that encode cue information, action initiation, successful avoidance, and motivation associated with aversive learning. By combining this task with in vivo imaging tools, I will measure the VTA dopaminergic input into the mPFC in mice as well as VTA-mPFC connectivity in humans (Aim1) and optogenetically manipulate the dopaminergic VTA→mPFC pathway in mice (Aim2) during discrete aspects of negative reinforcement. Finally, I will test the involvement of the VTA→mPFC pathway in aversive information processing in a clinical population with anxiety and stress disorders (Aim3). I hypothesize that the VTA→mPFC dopamine signal drives avoidance of aversive outcomes in both mice and humans and this process is disrupted in patients with anxiety and stress disorders. Overall, the results of these studies will give us a critical translational insight into the anxiety and stress disorders where aversive learning is exaggerated. The VUMC Faculty Research Scholars Award will provide the opportunity to build on my expertise in behavioral and pharmacological aspects of learning and memory while simultaneously developing my training and expertise in cutting-edge research techniques such as in vivo fiber photometry and optogenetics.
Eva Mistry, MD, MBBS Assistant Professor Neurology Began VFRS in July 2019 Received K23 in September 2019	Blood Pressure after Endovascular Stroke Therapy-II: A Randomized Trial Research Project: Blood pressure (BP) management after endovascular mechanical thrombectomy (EVT) for large vessel acute ischemic stroke (AIS) can critically influence brain reperfusion, and thereby patient outcomes. Current guidelines recommend allowing higher than normal BP in the 24 hrs after an EVT without strong evidence. Our preliminary results demonstrate that lower post-EVT systolic BP (SBP) associate with better outcomes. Although low SBP targets are assumed to compromise brain perfusion, no data exist to definitely demonstrate any relationship of harm with post-EVT SBP targets. Such safety assessment of lower SBP targets is a critical prerequisite to conduct larger studies to evaluate their efficacy in improving outcomes of EVT-treated patients. We will conduct the Blood Pressure after Endovascular Stroke Therapy-II (BEST-II) trial, where 120 AIS patients successfully treated with an EVT will be randomized to three SBP targets (<180, <160, and <140 mmHg) to 1) assess the harm of lower SBP targets and 2) determine the probability (hypothesized to be ³25%) of a positive phase III efficacy trial of lower SBP targets to improve patient outcomes. To assess the harm, we will test the null hypotheses that lower SBP targets do not worsen brain ischemia or 90-day functional outcome in patients beyond a level considered safe. This proposal will generate high quality data for the planning of a large, multicenter efficacy trial. Collectively, this set of trials will lead to evidence-based guideline generation for the optimal post-EVT BP management in AIS patients. Candidate: Working closely with her mentors over the past two years, Dr. Eva Mistry designed, led, and successfully completed a large, prospective, multi-institutional study (BEST-I) to demonstrate the association of improved outcomes with lower SBP in EVT-treated AIS patients. This proposal is the direct result of this preliminary work. In addition to seeing her proposal to completion, her short-term goal is to acquire external career development award. She has submitted her NIH/NINDS K23 Career Development Award application in Feb 2019 (pending review) and plans to apply for the American Academy of Neurology and American Heart Association Career Development Awards in October 2019. Her long-term goal is to become a leader in novel designs and electronic facilitation of acute stroke trials to ensure efficient testing of new stroke treatments and improve patient outcomes. Career Development: To achieve her long-term goal, Dr. Mistry will follow an integrated career development plan. Her rigorous training will include coursework, personalized mentoring from mentors and advisors, and experiential training to achieve mastery in 1) trial implementation in acute and critical care settings, 2) adaptive and platform trial designs, 3) electronic facilitation of clinical trials, and 4) leadership skills.
Andrew Wiese, PhD, MPH Assistant Professor Health Policy Began VFRS in July 2019 Received BIRCWH K12 in March 2020	Benzodiazepine Restrictions and the Prevention of Adverse Outcomes The use of benzodiazepines, one of the most commonly prescribed medications in the US, is linked to serious health outcomes, including falls, fractures, motor vehicle crashes, and opioid-related overdoses. Although benzodiazepine coverage restrictions and state-specific regulatory actions have been implemented in the past, it remains unclear whether those policies led to the intended reduction in adverse outcomes or led to other unintended consequences. One such restriction involved the lack of coverage for benzodiazepines among Medicare enrollees with the implementation of Medicare Part D in 2006. Although Medicare enrollees could not access benzodiazepines through this new pharmacy program, most State Medicaid programs continued their coverage of benzodiazepines and offered a source of medications for dual-eligibles enrolled in Medicare and Medicaid. The Tennessee Medicaid (TennCare) program was the only Medicaid program in the US that simultaneously restricted benzodiazepine coverage to their enrollees. Thus, patients enrolled in TennCare (including dual-eligibles) lacked coverage of benzodiazepines from 2006 through 2013. With the implementation of the Affordable Care Act, benzodiazepine coverage was reinstated in Medicare and Medicaid in 2014. This intermittent coverage of benzodiazepines in Tennessee represents a unique natural experiment to evaluate the impact of restrictions on both intended and unintended health outcomes. I will evaluate this critical research priority by addressing two specific aims: Aim 1: Determine the impact of benzodiazepine restriction policies on the incidence of falls, fractures, motor vehicle crashes and opioid-related overdoses in the TennCare population; Aim 2: Determine whether benzodiazepine restriction policies led to an increase in the use of other psychotropic medications. The goal of this investigation is to carefully evaluate the impact of benzodiazepine restriction policies, including their intended and unintended effects. Findings from this study will inform strategies to reduce drug adverse outcomes, including drug overdoses.
Kristin O'Grady, PhD Assistant Professor Radiology & Radiological Sciences Began VFRS in October 2019 Received KL2 in May 2020 Received K01 in July 2020	Examining the Role of Biological Sex in Imaging Biomarkers of Multiple Sclerosis Multiple sclerosis (MS) is a chronic, immune-mediated disease of the central nervous system that results in demyelination and neurodegeneration. Relapsing-remitting MS (RRMS), the most common form of MS, predominantly affects women at a female to male ratio of approximately 3:1, and female patients experience an earlier disease onset and more frequent relapses. In contrast, male sex is a predictor of more severe disease phenotype and rapid physical and cognitive progression. These profound sex differences in disease incidence and progression, along with sex hormone-linked protective factors such as pregnancy, highlight the importance of studying the influence of biological sex in all aspects of MS research, including neuroimaging. Basic science studies and clinical trials have shed light on the involvement of sex hormones in MS; however, magnetic resonance imaging (MRI) outcomes for studying sex differences in MS remain inconsistent. The majority of MRI studies investigating sex differences have used diagnostic T1-and T2-weighted structural MRI to evaluate brain lesions and atrophy, but these methods are non-specific for pathology underlying the radiological appearance of the tissue. There is also a significant knowledge gap with respect to sex differences in spinal cord involvement in MS, despite the known, major impact of spinal cord disease on neurological disability. MS is a complex and heterogeneous disease, so it is challenging to monitor disease progression and treatment response when conventional MRI provides limited correlation with clinical symptoms. MRI biomarkers that are more sensitive and specific to brain and spinal cord pathology as well as sex differences in MS may further the ability of clinicians to employ a more individualized approach to treatment. Consequently, my work is focused on integrating sex/gender biology into MRI studies that deploy quantitative MRI methods sensitive to specific disease processes in the brain and spinal cord in MS patients. Completion of the aims in this proposal will yield new knowledge regarding sex differences in the radiological manifestation of MS through application of advanced microstructural (axonal), macrostructural (myelin), and molecular (protein) MRI in the brain and spinal cord. To achieve my research goals, I will leverage my prior work developing ultrahigh field molecular MRI methods for the brain (chemical exchange saturation transfer, CEST) and spinal cord methodologies optimized for the cervical spinal cord by the Smith lab (magnetization transfer, high resolution anatomical imaging, diffusion tensor imaging, and CEST) to examine sex differences in patients with RRMS. These methods will be extended to the lumbar spinal cord to initiate new research on the pathological substrate of neurogenic bladder in MS patients. Overall, these studies are anticipated to result in sex-specific MRI biomarkers of MS pathology, which will further the possibility of a personalized medicine approach to treatment for MS patients and provide new tools for evaluating novel, neuroprotective therapies.
Bhuminder Singh, PhD Assistant Professor Medicine/Gastroenterology Began VFRS in November 2019 Received KL2 in July 2020 Received R01 in May 2021	Overcoming a New Mode of Cetuximab Resistance in Colorectal Cancer Background: EGF receptor (EGFR) is a receptor tyrosine kinase (RTK) that is overexpressed in over 50% of colorectal cancer (CRC) where it is linked to metastasis and poor prognosis. Cetuximab, an EGFR-targeting monoclonal antibody is approved by US-FDA to treat advanced wild-type KRASCRC. However, cetuximab, as monotherapy, is effective in only about 10% of CRCs and resistance frequently emerges. Thus, there is a pressing need 1) to identify those patients most likely to respond (or not respond) to cetuximab and 2) to devise treatment strategies that would enhance cetuximab response. We propose to address these needs by aggressively pursuing our observations that enhanced activity of the RTKs, MET and RON, confers cetuximab resistance. We made these discoveries using a three-dimensional (3D) type I collagen-based culture system for CRC. Here, we isolated two subpopulations of a CRC line, HCA-7. The two HCA-7 derivatives were termed CC and SC, for their respective cystic and spiky morphology in 3D. SC cells were cetuximab-resistant and showed high MET/RON tyrosine phosphorylation, compared to cetuximab-sensitive CC. Moreover, addition of the dual MET/RON tyrosine kinase inhibitor, crizotinib, restored cetuximab sensitivity in SC. Interestingly, derivatives of CC cells selected to grow in the presence of cetuximab also showed higher MET/RON tyrosine phosphorylation, and could be inhibited by cetuximab/crizotinib combination. Hypothesis: Upregulation of RTK activity (e.g. MET/RON) conferscetuximab resistance in CRC and that it isa viable therapeutic target. Specific Aims: (1) Elucidate the role of RTKs in transformation and conferring cetuximab resistance in CRC. (2) Establish the effectiveness of multi-RTK inhibition in enhancing cetuximab therapy in CRC. Study design: We will exploit our 3D culture system and CRC patient-derived tumor organoids (PDOs) for most subaims of the grant. We will also employ complementary approaches (Transwell cultures, nude mice xenografts, tumor tissue microarrays, phospho-RTK arrays, multiplex immunofluorescence, single-cell RNA-seq and human CRC samples) in relevant sections. Key proteins (MET, RON, ligands, and other positive and negative regulators) will be manipulated (overexpression, CRISPR-mediated knockout, ligand stimulation, and chemical inhibition) to characterize individual contribution. These experiments will be recorded at subcellular localization, morphological, and phenotypic levels to tease out key differences. Cancer relevance: These studies will characterize the new mode of cetuximab resistance, its prevalence in CRC, and optimize treatment to overcome cetuximab resistance for advanced CRC. Moreover, the lessons learned may be applicable to other epithelial cancers where cetuximab is an approved therapeutic.
Matthew Alexander, MD, PhD Assistant Professor Medicine/Clinical Pharmacology Began VFRS in July 2020 Received K08 in July 2020	Role of CCR10+ Regulatory T Cells in Hypertension Hypertension is the leading cause of death and disability-adjusted life years worldwide. Despite current therapies blood pressure remains uncontrolled in approximately 50% of individuals with hypertension, and even with adequate control of BP an elevated risk of cardiovascular events remains. Hence, there is a major unmet need for new therapeutic options for hypertension. Emerging evidence suggests an important role for the immune system in the pathogenesis of hypertension. An immune cell subset termed regulatory T cells (Tregs) is an attractive therapeutic target as it plays a suppressive role to limit inflammation. However, recent evidence suggests that some Tregs can play pathogenic roles in heart failure and lung fibrosis through inhibiting angiogenesis and promoting fibrosis, respectively. Novel evidence provided with this application suggests that a subpopulation of Tregs expressing C-C motif chemokine receptor 10 (CCR10) is selectively decreased in the circulation of hypertensive humans and mice and is increased in the skin of mice with hypertension. Given recent evidence for an important role for skin microvascular rarefaction (defined as loss of microvessels) in hypertension, these results suggest a novel link between CCR10+Tregs, skin microvessels, and hypertension development. In addition, we have evidence that increased endothelial cell stretch, as occurs with elevated blood pressure, selectively increases CCR10+Tregs in vitro. Thus, studies in this application will test the hypothesis that increased endothelial cell stretch augments CCR10 expression in Tregs and promotes CCR10+ Treg recruitment to the skin to enhance microvascular rarefaction and hypertension development. This overall hypothesis will be tested with the following specific aims: 1) test the hypothesis that increased EC stretch enhances CCR10 expression in Tregs via TNFα and that resultant CCR10+Tregs transmigrate and inhibit angiogenesis in response to CCR10 agonism by the skin-specific chemokine CCL27 in vitro, 2) test the hypothesis that CCR10+Tregs promote skin microvascular rarefaction leading to elevated BP in salt and angiotensin II-induced hypertensive mouse models in vivo, and 3) test the hypothesis that CCR10and its skin-specific ligand CCL27 promote hypertension in humans using a genetic approach of Mendelian randomization. Execution of the outlined studies will provide a platform for me to gain further understanding and technical skills related to the study of regulatory T cells and skin microvasculature as well as human genetic approaches such as Mendelian randomization. The outstanding resources and mentorship integrated into this proposal will enable successful attainment of my career goals. These goals include becoming an independent physician scientist integrating the care of patients with hypertension with investigation of the role of regulatory T cells in hypertension development, with the ultimate goal of enabling the development of new immunotherapy-based treatments for this condition.
Mona Mashayekhi, MD, PhD Instructor Medicine/Diabetes, Endocrinology & Metabolism Began VFRS in July 2020 Received KL2 in December 2020	The Contribution of Arachidonic Acid Metabolites EETs to Inflammation in Obesity The prevalence of obesity is increasing worldwide, and many of the cardiometabolic diseases associated with obesity, including type 2 diabetes and hyperlipidemia, can be linked to changes in adipose tissue function. Obesity disrupts the immune environment within adipose tissue to create a pro-inflammatory milieu, which interrupts its normal energy storage and metabolic regulatory functions. Therapies that effectively reduce obesity-related chronic inflammation may improve adverse cardio-metabolic outcomes and are urgently needed. We propose to investigate if genetic polymorphisms or pharmacologic agents that increase the arachidonic acid epoxide metabolites epoxyeicosatrienoic acids (EETs) in humans are associated with lower adipose tissue inflammation in obese individuals. EETs are lipid signaling molecules that have beneficial metabolic and hemodynamic effects by promoting vasodilation and sodium excretion and protecting against endothelial cell dysfunction. In humans, circulating EET levels correlate with insulin sensitivity, and may confer cardio-protective benefits based on studies of genetic variants in the EET pathway that are associated with cardiovascular disease. In addition, EETs have an anti-inflammatory role in rodent models of obesity, but it is unknown if they have anti-inflammatory effects in humans. We hypothesize that EETs act as anti-inflammatory agents in humans and are a novel target for treatment of chronic inflammation in obesity. We will test this hypothesis by performing unbiased transcriptome analysis and T cell subset profiling to characterize the inflammatory milieu in adipose tissue and blood from obese individuals with genetic polymorphisms (Aim 1) or pharmacologic treatments (Aim 2) that increase EETs. We will also correlate these findings with measures of insulin sensitivity and endothelial function using hyperinsulinemic-euglycemic clamps and forearm blood flow measurements, respectively. In preliminary studies we have shown that pharmacologic inhibition of the enzyme that hydrolyzes EETs, soluble epoxide hydrolase (sEH), decreases circulating levels of F2-isoprostanes, which are markers of oxidative damage and inflammation. Understanding the contribution of EETs to immune modulation could lead to new strategies to decrease obesity-associated inflammation and reduce the risk of metabolic and cardiovascular diseases.
Erin Wilfong, MD, PhD Instructor Medicine/Rheumatology Began VFRS in July 2020 Received KL2 in February 2021	Pathological Role of B Cells in Idiopathic Inflammatory Myopathies (IIM) The idiopathic inflammatory myopathies (IIM) are a family of rare systemic rheumatologic diseases commonly affecting the skin, muscles, and lung. Despite the morbidity and mortality of IIM, there are currently no FDA approved therapies for these conditions. One limitation in developing targeted therapeutics for IIM is the limited understanding of the dysregulated immune mechanisms driving the underlying disease process. There is increasing evidence that B cells are important in the development of IIM. Various autoantibodies are associated with specific disease phenotypes; treatment with anti-CD20 antibodies (rituximab) leads to clinical improvement for many patients. My preliminary work investigating IIM immunophenotypes using mass cytometry by time of flight (CyTOF) discovered three autoimmune prone B cell populations increased in subsets of patients with IIM. All three of these populations had decreased surface expression of CD180, which can activate B cells after ligand binding and internalization. Additional studies demonstrated that B cells recognizing the Jo-1 autoantigen have decreased surface CD180 compared to B cells that fail to recognize Jo-1. In chronic lymphocytic leukemia, cells are surface CD180lo but have high intracellular CD180 and are highly activated. TLR9 also works synergistically with CD180 to cause B cell activation, and TLR9 has a well-established role in autoimmunity. Based on these preliminary findings, we hypothesize that CD180 is an active signaling pathway in IIM that augments signaling from the BCR and TLR9 to contribute to IIM disease pathogenesis. This proposal seeks to leverage these preliminary findings and perform mechanistic studies to understand how CD180 signaling leads to B cell dysregulation in IIM and identify additional dysregulated pathways amenable to future targeted therapeutics. To achieve this goal, I will investigate how B cell receptor (BCR) signaling differs in CD180lo compared to CD180+ B cells in IIM patients. I will probe how the CD180, BCR, and TLR9 signaling pathways interact with one another using healthy B cells. Finally, I will use single cell transcriptomics profiles to both look for additional abnormal signaling cascades and investigate clonality of the three myositis specific populations identified in our preliminary immunophenotyping. By defining how B cells in IIM behave differently compared to healthy B cells, we will identify potential therapeutic targets to improve outcomes in patients suffering from IIM.
Mallory Hacker, PhD Assistant Professor Neurology Began VFRS in July 2019	One million Americans live with Parkinson’s disease (PD), a progressive neurodegenerative disease characterized by cardinal motor features that include tremor, bradykinesia, rigidity, and postural instability. Symptoms are treated with dopaminergic medications (early-stage) and deep brain stimulation (DBS, mid-to advanced-stage), but all current therapies are only symptomatic – there is no intervention that slows, stops, or reverses the progression of any feature of the disease. Although reserved for later PD stages, DBS has strong evidence that it protects against nigral neuron death when applied animal models of early-stage PD. The consistent findings from preclinical studies motivated the first prospective, randomized, pilot clinical trial evaluating DBS in early-stage PD, led by Vanderbilt investigators (IDEG050016, IRB040797). Recent findings from that trial provided class II evidence that early DBS slows the progression of rest tremor, a common and often distressing symptom for early-stage patients. This landmark finding must now be tested, and a prospective, multicenter, randomized, safety and efficacy trial is approved by the FDA. That phase 3 trial will implement the same method to evaluate underlying motor symptom progression by using week-long therapeutic washouts. The pilot’s washout design facilitated a rigorous method of evaluating patients in an untreated state, but ultimately the study, like all clinical trials for PD, had to rely on subjective clinical ratings. In the years since the pilot trial began, new objective methods to evaluate PD have emerged, including metabolic networks identified from F-fluorodeoxyglucose (FDG) positron electron tomography (PET) scans and wearable biosensors. Including these unbiased measures alongside standard clinical assessments after a week-long therapeutic washout offers the opportunity to objectively determine if early DBS slows PD progression. These measures were not available when the original trial began, and this study seeks to quickly resolve uncertainties regarding incorporating new objective assessments into the phase 3 protocol. Aim 1 will determine the feasibility of including off therapy FDG-PET scans to facilitate analysis of three PD-related metabolic networks associated with bradykinesia& rigidity, tremor, and cognitive dysfunction. Aim 2 will pilot two types of wearable biosensors to objectively measure symptoms in early-stage PD patients in both the treated state and following one-week off of medications. This study will fill critical knowledge gaps concerning utilization of new objective measures during a washout in very early-stage PD. This new information will be used to finalize the protocol of a phase 3 trial to determine if early DBS slows Parkinson’s disease progression.
William Nobis, MD, PhD Assistant Professor Neurology Began VFRS in July 2019 Received KL2 in March 2022	The Role of the Extended Amygdala in Respiratory Control and Sudden Unexpected Death in Epilepsy The Neurology Department has an unwavering commitment to the career development of Dr. Nobis and, towards that goal, he was recruited from Northwestern following his clinical epilepsy fellowship as a clinical instructor with plans for quick transition to a tenure-track position. The candidate was given a generous startup package and institutional support including clearly delineated protected research time of at least 75%. The candidate will have a graded mentored experience such that during the latter years of the award he will be in a position to apply for independent R01 funding. A career development committee will guide this transition and provide scientific pre-review of future grant proposals. Dr. Dane Chetkovich, Chairman of the Neurology Department will serve as primary scientific mentor with secondary mentors consisting of Dr. Sachin Patel in the Psychiatry Department and outside mentorship by Dr. Jennifer Kearney in the Department of Pharmacology at Northwestern University. The candidate plans to obtain further training in electrophysiology, epilepsy models, in vivo optogenetics, analysis of respiratory function in mice, and in vivo neuromodulation with optogenetics and chemogenetics by taking advantage of a host of internal collaborators at VUMC. Vanderbilt University is an exceptional institution for this depth of translational multidisciplinary training and the development of young physician-scientists with a highly collaborative environment. Additionally, the candidate has put together a group of internal and external consultants to offer expert training and guidance for the proposed project, which is entitled “The role of the extended amygdala in respiratory control and sudden unexplained death in epilepsy”. Sudden unexplained death in epilepsy (SUDEP) is the most frequent cause of death in epilepsy patients. The candidate’s recent data in human epilepsy patients shows that both seizures and stimulation of a portion of the amygdala produces apnea. This finding suggests that the amygdala has mechanistic implications for respiratory function and in particular seizure induced apneas, however, the precise pathways by which apnea is mediated are unknown. Aim 1 will evaluate whether an amygdalar region, the bed nucleus of the striaterminalis (BNST), has projections to the parabrachial nucleus (PBN) that are influential in respiratory function. In Aim 2 he will use mouse models of SUDEP, the Dravet Syndrome mice and the DBA/2 audiogenic seizure mice to determine whether there are functional neuronal alterations in BNST neurons in these models. Finally, Aim 3 provides clinical relevance by examining effects of modulation of this circuit on seizure induced apneas and survival in the DS model. Overall, completion of this project will provide a clearer understanding of the BNST’s role in respiratory control, describe alterations in the BNST in epilepsy models, and establish this pathway as a target for SUDEP prevention. Receiving a VFRS will allow the applicant the protected time for research and provide the best chance of launching a successful career as an independent physician-scientist.
Naeem Patil, MD, PhD, MBBS Assistant Professor Anesthesiology Began VFRS in July 2020	Targeting Mitochondrial Quality Control to Improve Host Immunity during Sepsis Sepsis is a leading cause of death in the United States with a healthcare burden of ~ $14 billion. Sepsis survivors suffer increased mortality as compared to the general population (~15% death rate in the first year after hospital discharge). No definitive therapy currently exists to treat sepsis and there is a critical need to identify novel biological targets and therapeutics. Sepsis causes immune cell dysfunction, which weakens patients’ abilities to fight existing infections and predisposes them to secondary hospital acquired infections. Studies indicate an association between impaired organ and leukocyte mitochondrial function with sepsis outcomes. Our preliminary results show that therapeutic strategies causing sustained augmentation of macrophage mitochondrial function significantly protect against sepsis caused by common nosocomial pathogens such as Pseudomonas aeruginosa and Staphylococcus aureus. We found that TLR4 agonist, monophosphoryl lipid A, promotes macrophage mitochondrial biogenesis via increased PGC-1α and Nrf2 targeted gene expression, along with 400 fold induction of mitochondrial immunoresponsive gene 1 and its product itaconate, which is a potent antimicrobial agent. MPLA treatment more than doubles the expression of mitochondrial fission protein, Drp1and inhibition of Drp1 attenuates MPLA induced augmentation of macrophage mitochondrial function. We hypothesize that TLR4 agonist induced early induction of mitochondrial quality control pathways including biogenesis and fission in conjunction with itaconate generation significantly enhance host innate immunity leading to protection against sepsis. The overall theme of this application is to study how sepsis affects leukocyte mitochondrial quality control pathways (biogenesis, fission, mitophagy and fusion) and is mitochondrial function a druggable target to develop prophylactic therapies for at risk individuals and for treatment after sepsis diagnosis. Aim 1: Determine the molecular mechanisms by which mitochondrial metabolic reprogramming drugs such as MPLA augment host innate immunity. Aim 1 will focus on understanding the role of PGC-1α, Irg1, itaconate and Nrf2 in regulation of macrophage mitochondrial dynamics. Aim 2: Evaluate the therapeutic benefit of augmenting mitochondrial biogenesis and function as a novel strategy to treat sepsis. Aim 2 will focus on performing pre-clinical evaluation of itaconate and MPLA alone or in combination to protect against sepsis. Aim 3: Define the status of mitochondrial quality control pathways in leukocytes isolated from septic patients. Studies in aim 3 will perform a detailed characterization of mitochondrial quality control pathway markers in peripheral blood mononuclear cells from septic patients and measure plasma mitochondrial metabolites to correlate them with patient outcomes. Augmenting leukocyte mitochondrial function represents an entirely novel approach to protect against sepsis. Understanding the status of mitochondrial quality control pathways in leukocytes from septic patients will help drive the field of sepsis management into new and underexplored area of leukocyte mitochondrial metabolic reprogramming.
Brittney Snyder, PhD Instructor Medicine/Allergy, Pulmonary & Critical Care Medicine Began VFRS in July 2021 Received K01 in July 2022	Identifying Molecular Pathways in Childhood Asthma Pathogenesis by Integrating Newborn Metabolic Profiles and GWAS Data Childhood asthma is a common, burdensome disease for which there are currently no effective prevention strategies. This is due in part to our limited understanding of the molecular determinants of asthma pathogenesis. As the development of asthma is highly influenced by genetic and environmental factors, assessment of both genetic and metabolomic profiles can improve our understanding of disease pathogenesis and identify potential targets for treatment and prevention. The overall research objective of this proposal is to elucidate metabolic and upstream genetic pathways underlying childhood asthma pathogenesis. Our central hypotheses are that metabolic profiles at birth are associated with subsequent development of childhood asthma and that this association is due in part to the effect of genetic variants on intermediate metabolic profiles and childhood asthma. To test these central hypotheses, we will pursue the following specific aims: 1) identify metabolic profiles at birth associated with the development of childhood asthma, and 2) determine the genetic contribution to variation in metabolite concentrations at birth and identify genetic pathways linking metabolic profiles at birth with childhood asthma. To achieve Aim 1, we will capitalize upon a unique resource of longitudinal birth cohorts with newborn metabolic data and rich phenotypic data (n=6209 children). To achieve Aim 2, we will utilize genotypes for children within the largest of these cohorts to perform a metabolite genome-wide association study. We will then leverage these findings, along with summary statistics from the largest GWAS of childhood asthma performed to date, to perform a genetic co-localization analysis. The purpose of this VFRS proposal is for Dr. Snyder to build on her prior training in maternal-child health epidemiology and experience with utilizing metabolomics data in large epidemiologic studies by taking on leadership roles in the conduct of epidemiologic studies, applying modern statistical methods for high-dimensional data, and receiving advanced training in genetic epidemiology so that she can more effectively address fundamental questions about upstream pathways of disease development. Through the comprehensive career development plan applied directly to the research, the complementary expertise of the mentorship team, and an outstanding institutional environment, Dr. Snyder will acquire the knowledge, skills, and resources necessary to advance her toward her long-term career goal of becoming a recognized leader in maternal-child health epidemiology, with a focus on integrating genetics and metabolomics in large epidemiologic studies to understand and prevent childhood respiratory diseases. The experience, training, and findings generated through this proposal will result in Dr. Snyder developing critical research skills to move toward independence and the submission of a highly competitive R01 application.
Katherine McDonell, MD, MSCI Assistant Professor Neurology Began VFRS in April 2019 Received K23 in August 2022	Risky Behavior in Huntington Disease Risky behaviors are common in Huntington disease (HD) and can be extremely detrimental to both patients and caregivers. Engagement in high-risk, high-reward activities such as pathological gambling, substance abuse, hypersexuality, and reckless driving are frequently observed in the HD population and can lead to serious social and legal consequences. These behaviors often emerge early in the disease course, prior to the onset of motor symptoms and frequently before patients and family members are aware that they might be affected. Identifying and screening for these behaviors can therefore prove challenging. The currently available behavioral screening tools used in HD do not address risky decision making or impulsivity, and patients who engage in these behaviors are frequently missed. The frequency and scope of these symptoms in the HD population has also not been well-studied, and our understanding of the underlying neurobiological mechanisms that drive these behaviors is quite limited. The aims of the proposed study are: (1) To define the breadth and clinical impact of risky behaviors in HD; (2) To develop and validate a novel clinical measure to assess risky behaviors in the HD population; and (3) To conduct exploratory analyses examining correlations with clinical variables and measures of reward responsivity. This proposal is supported by a multidisciplinary team of mentors with expertise in clinical scale development, risk and reward processing, behavioral psychology, and advanced statistical analysis. The candidate’s institution offers a wealth of resources to support this work, including a Level 1 Center of Excellence with a large and diverse population of HD patients and extensive clinical research experience in HD. This proposal will also serve as a robust training platform, with a comprehensive career development plan including expert mentorship and coursework in clinical scale development, advanced biostatistics. The impact of this study will be to greatly broaden our understanding of the burden and clinical significance of risky behavior in HD and to generate a novel clinical scale that can be incorporated into future observational and therapeutic trials. The proposed aims will also provide critical preliminary data to support future studies with the goal of identifying patients at risk for these symptoms during the premanifest stages of their disease, characterizing underlying neural network changes, and testing interventions to prevent the development of dangerous behaviors. The educational impact of this proposal will be to provide the candidate with advanced training in clinical scale development and statistical methods to develop the necessary skills to transition into an independent investigator studying behavioral dysregulation in neurodegenerative disorders.
David Isaacs, MD, MPH Assistant Professor Neurology Began VFRS in July 2021 Received KL2 in August 2022	Neural Correlates of Sensory Phenomena in Tourette Syndrome Candidate: David Isaacs, MD, MPH, is Assistant Professor in the Department of Neurology. He demonstrates marked enthusiasm and aptitude for patient-centered research, with emphasis on non-motor aspects of movement disorders and clinical trials. He graduated from Vanderbilt’s MPH program in 2019. Early career highlights include extramural grant funding for assessment of neuropsychiatric symptoms in Huntington’s disease; conceptualization and implementation of longitudinal outcomes study in a cohort with Parkinson’s disease following deep brain stimulation; and foundation of Vanderbilt’s Adult Tourette Syndrome (TS) Clinic. Candidate has served as site PI for several industry-sponsored clinical trials and is 2019-2021 fellow for the NeuroNEXT Clinical Research Training Program. Dr. Isaacs aspires to become a leading investigator in neurophysiologic biomarkers of movement disorders. Research Project: TS is a neurodevelopmental disorder affecting 1% of school-aged children, one-third of whom suffer bothersome tics into adulthood. Tics are the defining characteristic in TS, but sensory symptoms, in the form of premonitory urges and sensory hypersensitivity, afflict 90% and 80% of patients respectively, and impair quality of life. Despite this, sensory symptoms are poorly understood, both clinically and pathophysiologically. EEG is an ideal tool for identifying neurophysiologic markers of TS sensory symptoms because of its capacity to capture millisecond-level neural dynamics at a global and regional scale. We hypothesize that gamma frequency (>30 Hz) network oscillation dysfunction, measurable with surface EEG, underlies TS sensory symptoms. We seek to determine the longitudinal predictive value of patient-reported hypersensitivity and urges in TS adults (Aim 1) and to identify EEG signatures of these phenomena (Aims 2 and 3). Career Development: Dr. Isaacs has carefully crafted a curriculum incorporating formal coursework, workshops, conferences, and individualized training with mentors and collaborators in order to adequately prepare himself for independent research in neurophysiologic biomarkers of movement disorders. His short- term career goals are to become: 1) expert in clinical characterization of sensory and neuropsychiatric symptoms (Aim 1); 2) proficient in event-related potentials and quantitative EEG (Aims 2 and 3); and 3) competent in neurophysiologic biomarker development (Aims 2 and 3). Environment: VUMC is an optimal academic environment for nurturing Dr. Isaacs’ maturation into a fully- fledged independent researcher specializing in neurophysiologic biomarkers of movement disorders. The institution has an exceptional track record for fostering productive, independently funded, and internationally renowned clinician-scientists. The primary mission of Vanderbilt’s CTSA is provision of infrastructure for clinical research excellence, with an entire arm devoted to training and career development.
Jessica Schwartzman, PhD Assistant Professor Psychiatry Began VFRS in May 2022 Received KL2 in October 2022	A Multimethod, Longitudinal Approach to Reward Responsivity and Depression in Youth with Autism Adolescents with Autism Spectrum Disorder experience depression at rates nearly twice that of their neurotypical peers (20% vs. 11%). Untreated depression is associated with adverse short (e.g., school refusal) and long-term outcomes (e.g., poor physical health, lower employment) that impair quality of life. Adolescents with autism also face a 7x increase in the risk for premature death by suicide than their neurotypical peers. Risk factors to depression in autism are not well understood and measurement efforts may be complicated by social communication difficulties (i.e., autism symptomatology) that interfere with adolescents’ efforts to identify and explain emotional experiences to providers and family members. Therefore, more objective measures (e.g., electroencephalogram [EEG], specifically event-related potentials [ERPs]) may provide a better understanding of risk factors to depression in adolescents with autism. Altered reward responsivity (Research Domain Criteria [RDoC] Positive Valence) and disrupted social processes (RDoC Affiliation and Attachment) are key risk factors to depression for neurotypical adolescents, but have not been investigated in autism. Clinical and neural measures of social and nonsocial reward responsivity and associations with depression symptoms have not been examined in autism, which may provide meaningful information about developmental trajectories. Consistent with the NIMH Strategic Plan, Strategic Goal 2, “to identify and understand risk factors, biomarkers and behavioral indicators of mental illness,” this application aims to examine clinical and neural markers of social and nonsocial reward responsivity and associations with depression symptoms in adolescents with autism, including longitudinal investigations. Under the mentorship of a diverse team of experts in autism, depression, reward responsivity, psychophysiological methods, and longitudinal and statistical methodologies, this proposal will examine the predictive influences of these RDoC constructs to depression in adolescents 14-17 years old with autism. Adolescence is a key developmental period for early detection and intervention as it is characterized by spikes in depression prevalence and an increasing importance of peer relationships. Specifically, this proposal will use EEG/ERP techniques and clinician-rated interviews to measure social and nonsocial reward responsivity in adolescents with autism and test relationships with depression symptoms. Adolescents will be assessed one year later to investigate how clinical and neural measures predict depression symptoms over time, which will inform the developmental course of these RDoC constructs in this vulnerable population. The applicant’s long- term goal is to understand the neurobiological and behavioral development of reward responsivity in autism and associations with depression from adolescence to adulthood so as to inform screening methods and intervention development. Mentored training will allow the applicant to gain expertise in multimethod measures (e.g., ERP methodologies, clinician-rated interviews) and longitudinal design and analysis, with an emphasis on assessing mechanisms associated with the onset, maintenance, and treatment of depression in autism.
Anandharajan Rathinasabapathy, PhD Instructor Medicine/Allergy, Pulmonary & Critical Care Medicine Began VFRS in February 2019	Targeting Metabolism to Rescue Vascular Function in PAH Dr. Rathinasabapathy is a Research Instructor in the Division of Allergy, Pulmonary and Critical Care Medicine at Vanderbilt University Medical Center. He obtained his PhD in 2015 from the University of Florida, where he investigated the application of stem cells, small molecules and biological proteins in the animal models of lung and heart diseases. Prior to this, he has worked in the pharmaceutical industry, specializing his skills in the metabolic disorder. In 2016, he joined the laboratory of Dr. West as a Post-Doctoral Fellow to investigate the molecular etiology and pharmacological intervention of idiopathic and heritable pulmonary arterial hypertension (PAH). After the award of VUMC Faculty Research Scholars Grant, he will continue his research in Dr. West’s lab. Dr. West is an internationally renowned researcher in the field of PAH. Dr. West has rich experience in applying the basic, clinical and genomic tools towards investigation of cellular, molecular and metabolic etiology PAH. Since joining his lab, Dr. Rathinasabapathy has accomplished various projects including KCNK3, Cav1, ACE2and Sirt3. PAH group in Vanderbilt is bestowed with world class, well-funded principal investigators, touted to be one of the best in the nation. Laboratory of Dr. West and Vanderbilt PAH community provides Dr. Rathinasabapathy, a scintillating and persuasive environment to accelerate his career into the line of independence. In addition, the Vanderbilt ambience also provides him unlimited career growth opportunities. Apart from this VFRS grant, Dr. Rathinasabapathy is planning on submitting grant application for a K award in the summer and AHA’s CDG award in the fall. Pulmonary Arterial Hypertension is a debilitating, complex, rare lung disorder, often triggered due to endothelial dysfunction causing extensive lung tissue and right heart remodeling, eventually resulting in death, if left untreated. In this grant, Dr. Rathinasabapathy has devised novel strategy to decipher the nuances of metabolism, which drives the etiology of PAH. He would be using a host of in vitro and in vivo lines along with a variety of molecular tools to disseminate the original hypothesis that Metabolic defects associated with SOD2 and Sirt3 signals dysregulate the lipid pathways and their pharmacological intervention would improve the vascular function in PAH. In detail, he will investigate the role of acetylation of SOD2 and LCAD in Sirt3-defect mediated PAH and the impact of loss of Sirt3 in endothelial dysfunction driven by loss of fatty acid oxidation and eventually, the pharmacological intervention to rescue the defects associated with SOD2 andSirt3 signals in PAH.
Kimberly Albert, PhD Instructor Psychiatry Began VFRS in July 2021 Received K01 in September 2023	The Role of Attention Network Dysfunction and AD Pathology in Subjective Cognitive Decline Candidate: Dr. Kimberly Albert, PhD is a research instructor in the Department of Psychiatry and Behavioral Sciences at the Vanderbilt University Medical Center with a strong background in cognitive and systems neuroscience. Her long-term career goals include gaining the necessary training to become an independent investigator with research focused on disruptions in brain network function and attentional processes in pathological aging that will inform early detection of Alzheimer’s disease (AD) and help develop intermediate cognitive and neuroimaging markers for intervention trials. Career Development: To achieve this career goal, Dr. Albert requires advanced training in 1) using EEG to examine event-related potential measures of cognitive network function; 2) network-based approaches for neuroimaging analysis; 3) The application of neuroimaging and experimental probes to clinical studies. Her training strategy includes one-on-one mentoring, focused academic coursework including clinical trial design and statistics, and practical experience focused on data analysis and communication. This training will build on Dr. Albert’s prior experience in human cognitive neuroscience using functional neuroimaging and support her transition to independence. Research Project: These career goals will be facilitated through a research study focused on brain attention network changes in subjective cognitive decline and cognitive complaints in aging. The early pattern of β-amyloid accumulation in frontal and parietal brain regions may have specific impact on attention networks, thus contributing to cognitive complaints in aging that reflect early AD pathology. The proposed study will focus on attention deficits as an early marker of AD risk and examine the relationships between AD-related pathology and cholinergic neurotransmitter mechanisms that may underlie the contribution of attention deficits to subjective cognitive complaints in aging. The ultimate aim of the study is to identify the role of attention network changes in subjective cognitive decline and whether attentional changes inform early detection of pathological cognitive aging, using EEG and fMRI as complimentary neuroimaging approaches. Anticholinergic challenge will be employed to model AD progression and examine the relationships between cognitive complaints, attention, and AD pathology. The results of this study will improve our understanding of attention network changes in a population at increased risk for AD and help support future work developing markers of AD risk. Environment: Mentoring, collaborations, and resources available through the Department of Psychiatry and Behavioral Sciences, the Center for Cognitive Medicine, and the Vanderbilt Alzheimer’s Disease Research Center provide an ideal environment to support Dr. Albert’s transition to independent funding in the near future and leadership in the field of attentional changes in cognitive aging.
Lauren Wareham, PhD Assistant Professor Ophthalmology Began VFRS in July 2022 Appointed to K12 in July 2023	Neuronal-Glial-Vascular Interactions in Age-related Degenerations Neurons are metabolically demanding, relying on synchrony with the blood supply to exchange energy substrates and waste products in a phenomenon known as “neurovascular coupling”. Neurovascular interactions are important in optic neuropathies, in which the retinal ganglion cell (RGC) projection to the brain degenerates and causes blindness. Of these, glaucoma is the most burdensome, afflicting more than 120 million people worldwide, representing the leading cause of irreversible blindness. Glaucoma progresses with age through sensitivity to intraocular pressure (IOP) conveyed as stress to the unmyelinated axon segment as it leaves the retina through the optic nerve head. Treatment in the clinic serves only to delay progression, with many patients still experiencing vision loss. The scientific objective of this career development proposal is to test how failure of neurovascular coupling influences RGC axon survival in glaucoma. The long-term goal is to understand the role of neurovascular dysfunction in glaucoma and other optic neuropathies for the purpose of identifying novel therapeutic targets to slow or prevent vision loss. In this proposal Dr. Wareham will use an innovative imaging modality, developed through her collaboration with co- mentor Dr. Kenny Tao, Ph.D., that enables longitudinal in vivo retinal and optic nerve vasculature imaging in mice. Aims 1 and 2 will use this imaging modality to investigate how cGMP signaling and two primary risk factors in glaucoma (age and IOP) affect neurovascular coupling in the retina, impacting RGC axon survival. In Aim 3, harnessing tissues from Aims 1 and 2, she will investigate how cGMP signaling, age, and IOP alter astrocytic networks in the retina, impacting RGC vulnerability in glaucoma. The work described in this proposal aims to identify key neurovascular mechanisms in glaucoma pathophysiology. With a strong background in laboratory research, a solid mentorship plan that includes experts in her research field, and significant progress already underway in these experiments, Dr. Wareham is excited to use the additional protected research time and funds from the Vanderbilt Faculty Research Scholars Program to transition to independence and acquire extramural research funding.
Fabien Bock, MD, PhD Instructor Nephrology Began VFRS in October 2022 Received K08 in July 2023	Neuronal-Glial-Vascular Interactions in Age-related Degenerations Polarized epithelial tubes are critical for an intact kidney. They control water, electrolyte, and nutrient homeostasis, all of which are deranged in chronic kidney disease. These specialized epithelia require a highly organized actin cytoskeleton that determines cellular shape and function. During renal epithelial repair, the actin cytoskeleton of proliferating cells is rapidly re-organized to form the complex polarized architecture of an epithelial tube. The small Rho GTPase Rac1 is a multifunctional molecular switch and a master regulator of the actin cytoskeleton. We recently demonstrated that Rac1 is required to maintain actin cytoskeletal integrity, epithelial polarity, and cell shape of the mature collecting duct (CD) epithelium. It is still unknown how the actin cytoskeleton is regulated in epithelial cell repair and what role Rac1 plays in this process. For coordinated epithelial tube regeneration, epithelial cells need to rapidly progress through the cell cycle and divide in the correct direction along the tissue plane by undergoing oriented mitosis. A critical step in renal epithelial repair is the activation of the master mitotic kinase cyclin B–CDK1 complex which drives the G2/M transition and prepares the actin cytoskeleton for oriented mitosis. Correctly orienting the mitotic spindle in a confined tight epithelial space is a challenging process, which requires the cells to round up against the pressure of their neighboring epithelial cells. This so-called mitotic rounding depends on the actin cytoskeleton forming a dense contractile actomyosin cortex, which is tethered to the cell membrane by ERM Proteins (Ezrin), a known target of Rac1 and its main effector p21-activated kinase (Pak1). Defects in mitotic morphology lead to spindle misorientation, which cause cell cycle delays, cell death and abnormal repair. How actin cytoskeletal dynamics are molecularly coordinated and how the cell shape is connected to cell cycle control during these critical biological processes in kidney repair is not known. After we identified a role of Rac1 in CD homeostasis we hypothesized that it also plays a role in repair. We therefore deleted Rac1 in the collecting duct after development was complete and performed reversible unilateral ureteric obstruction (R-UUO). The mutant epithelium was unable to restore normal collecting duct morphology and persistent injury led to excessive tubule dilation. The repairing Rac1 mutants in vivo showed defects in the actin cytoskeleton during mitotic rounding, misoriented cell division, they were unable to proliferate and demonstrated lower total and nuclear levels of the mitotic cyclin B1. Consistent with these data, we found defective mitosis of wounded Rac1-deficient epithelial cells in vitro suggesting that Rac1 is required to normally progress through mitosis in repair. This forms the basis for our hypothesis that Rac1 controlled actin-dependent mitotic morphology mediated via its effector Pak1 and the linker protein Ezrin is required for oriented cell division to promote tissue repair, which will be tested in the following aims. Aim 1: Define the role of Rac1 in renal epithelial repair. Aim 2: Define the mechanism whereby Rac1 controls renal epithelial proliferation in repair.

Recent Scholars

Project Abstract

Ryan Darby, MD
Assistant Professor
Neurology
Began VFRS in June 2018
Received K23 in June 2021

Social Engagement and Language Development in Autism Spectrum Disorders

The proposed project examines visual and vocal entrainment and language development in infants/toddlers with typical development and autism spectrum disorder (ASD). ASD is a common and lifelong disorder that is characterized by impairments in social communication and repetitive behaviors. Yet, there is striking heterogeneity in language development in children with ASD and language delays in ASD are often a first concern for parents that their child is not developing as expected. In typically developing infants, rhythm plays a crucial role in social communication and language development. Caregivers use highly rhythmic, multimodal speech and singing to attract and maintain infants’ attention. Infants and caregivers coordinate their interactions through rhythmic vocalizations, facial expressions, and movements. Individual differences in social rhythm coordination may reflect individual differences in social attunement and predict children’s language development. This project extends my prior work demonstrating rhythmically entrained eye gaze in typical infants and toddlers to infants/toddlers with ASD (Aim 1), and also uses a novel measure of speech rhythm to assess social vocal entrainment in parent-child dyads (Aim 2). Additionally, I will examine how these metrics related to children’s language development (Aim 3). These findings will provide preliminary data to guide future longitudinal investigations of social rhythmic entrainment and language development in children at risk for developing ASD. This research may lead to the development of biomarkers of social entrainment that may inform early ASD assessment and diagnosis, as well as intervention strategies that, if warranted, include rhythm and timing of social interactions as one aspect of comprehensive language intervention for these children.

Miriam Lense, PhD
Assistant Professor
Otolaryngology
Began VFRS in January 2018
Received R61 in September 2019

Daniel Foster, PhD
Assistant Professor
Pharmacology
Began award in July 2018
Received R01 in January 2021

Modulation of Striatal Biology and Repetitive Behaviors by M4 PAMs

Repetitive behaviors are commonly observed in disorders such as Obsessive Compulsive Disorder (OCD), Tourette’s Syndrome (TS), and Autism Spectrum Disorders (ASDs).These behaviors can have profound negative effects on patients’ lives and can impair their ability to learn, carry out social interactions, and adapt to changing environments. While selective serotonin reuptake inhibitors, antipsychotics, and behavioral therapy are moderately effective in treating these symptoms, most patients are refractory to these therapies and there is a critical need to identify better treatment strategies to help patients with these disabling symptoms. The striatum is a brain region that plays a key role in integrating information from numerous brain structures and is essential to modulating habitual and goal-directed behaviors. Converging clinical and preclinical data suggest that hyperactive dopaminergic and glutamatergic neurotransmission through specific circuits in the striatum may represent common mechanistic underpinnings of abnormal repetitive behaviors. Interestingly, extensive studies from our lab and others have found that the M4 subtype of muscarinic acetylcholine receptor can exert powerful modulatory control over striatal dopaminergic and glutamatergic transmission, raising the possibility that selective activators of M4 could reverse pathological changes that may give rise to repetitive behaviors. Here we provide preliminary data demonstrating that M4 PAMs reduce excessive grooming in SAPAP3 KO mice (a genetic mouse model that displays a repetitive over-grooming phenotype). This could provide a breakthrough in identifying a novel approach for treatment of disabling symptoms that are resistant to available therapies. We hypothesize that repetitive behaviors are associated with hyperactive glutamate and dopamine release in the striatum, and that M4 PAM treatment can reduce repetitive behaviors by normalizing these forms of neurotransmission. We will test this hypothesis through a series of electrophysiological and behavioral studies using a combination of genetically modified mice, optogenetic approaches, and novel pharmacological tools. These studies will provide important information regarding the physiological role of M4 receptors in regulating basal ganglia function and will elucidate the therapeutic potential of M4 PAMs in providing relief from repetitive behaviors.

Matthew Schrag, MD, PhD
Assistant Professor
Neurology
Began VFRS in April 2017
Received K76 in August 2019
Received R03 in September 2019

Dystrophic Neurites and Lysosome Dysfunction in Alzheimer’s Disease: The Contribution of PLD3

An effective treatment for Alzheimer’s disease (AD) is urgently needed to stem the tide of the ongoing and growing epidemic of dementia. An abnormal protein called β-amyloid is thought to be a major driver of memory loss in AD and many recent clinical trials have attempted to reduce the level of this protein in the brain, either by activating the immune system to clear it or inactivating enzymes that produce it. None of these trials has been successful yet. In this application we propose to explore this problem in a different way. We have discovered that neuronal axons around deposits of β-amyloid are swollen and filled with lysosomes, but these lysosomes are deficient in protein-degrading enzymes. Because lysosomes are so important to protein homeostasis and this pathology is so dramatic, we hypothesize that these abnormal lysosomes contribute to the formation of β-amyloid plaques and if their function could be rescued they may be able to break down these plaques and improve brain function without immune activation or inactivating important enzymes. We will study this by focusing on a novel gene, PLD3, which was identified as contributing to AD risk. We discovered that PLD3 is robustly enriched on these abnormal lysosomes and may suppress the function of protein degrading enzymes. We will silence this gene in a mouse model of AD with an antisense oligonucleotide to learn how it affects cognition, lysosome function and β-amyloid plaques. We will use phospholipase enzymology techniques to evaluate whether PLD3 has phospholipase activity and we will study human brain, blood and cerebrospinal fluid from patients with Alzheimer’s disease to understand how this protein is associated with other AD pathologies. These studies will help us to understand not just how this protein functions in the setting of AD, but also what molecular processes are occurring on these abnormal lysosomes. Understanding the neurobiology of axonal lysosome accumulations will likely lead to new treatment targets for AD. Additionally, these studies will provide an outstanding training mechanism to enable me to work with a phenomenal group of mentors and acquire the necessary expertise to effectively run an independent research program.

Danxia Yu, PhD
Assistant Professor
Medicine/Epidemiology
Began VFRS in April 2017
Received R21 August 2018
Received R01 in July 2020

Linking Long-term Diet, Gut Microbiome, and Their Interactions with Human Metabolism and Diabetes Risk

The purpose of this application is to support Dr. Danxia Yu to build an independent research career in nutritional and molecular epidemiology, with a focus on investigation of the diet-gut microbiota interactions as modifiable risk factors for cardiometabolic diseases via integrating ‘multi-omics’ into epidemiologic research.

The mentorship, training activities, and research plan are designed to achieve Dr. Yu’s career goals by expanding expertise in nutritional and molecular epidemiology, developing new expertise in metagenomics and metabolomics, and leveraging the outstanding resources, environment, and support from VUMC and her mentoring team. The proposed research plan will serve as a training platform and generate pilot data for developing an R01-level proposal to investigate the role of diet-gut microbiota-host interactions in cardiometabolic disease risk among multi-ethnic populations.

The research plan has three aims. Aim 1 is to evaluate long-term dietary pattern and its changes over time in association with risks of type 2 diabetes and cardiovascular disease in two prospective cohort studies of ~135,000 Chinese adults. Repeated dietary survey data will be used to assess long-term diet. Aim 2 is to investigate how long-term diet influences gut microbiota, measured by metagenome shotgun sequencing using newly established resources from these two cohort studies. Two groups of participants with the most and least healthy long-term diet will be selected for this study (based on results from Aim 1). Gut microbial composition and functional potential will be compared between these two groups. Aim 3 is to examine associations of circulating microbial metabolites with risk of type 2 diabetes and to explore potential mediation effects and interactions between diet and microbial metabolites in relation to diabetes risk.

The proposed research, to be conducted in large, longitudinal studies of populations undergoing nutrition transitions, applying both metagenomics and metabolomics, is expected to provide novel evidence on the interplays between diet, gut microbiota, metabolites, and host metabolic health, knowledge essential for finding new tools to fight the epidemic of cardiometabolic diseases in both developed and developing countries.

An excellent mentoring team was formed to assist Dr. Yu’s career development. It includes leading experts in the fields of chronic disease epidemiology, cardiometabolic disease, gut microbiome, metagenomics, metabolomics, biostatistics, bioinformatics, and multi-omics data analysis. New knowledge and skills will be obtained via focused, hands-on training, including seminars, conferences, workshops, research, publication, and grant application. Through these activities, Dr. Yu will develop new research capabilities, build a collaboration network, and transition into an independent investigator.

Jo Ellen Wilson, MD, MPH
Assistant Professor
Psychiatry
Began VFRS in August 2017
Received KL2 in August 2017

The DeCat (Delirium and Catatonia in Critical Illness) Cohort Study

Research Project: To continue her ongoing DeCat (Delirium and Catatonia in Critical Illness) Cohort study, a prospective observational cohort study, which is nested within NIH funded large scale studies in the Critical Illness, Brain Dysfunction and Survivorship (CIBS) Center at Vanderbilt University Medical Center.
Aims of the Proposed Research: 1) To describe the predictive risk factors (including biological, e.g., genetic) for catatonia in a critical illness. 2) To determine the interaction of catatonia and delirium on cognitive and psychological sequelae of critical illness, and 3) To identify if catatonia is an independent risk factor for mortality in critically ill patients.
Career Development: 1) Formal academic coursework (focused in the early years of the award) to supplement anticipated gaps in knowledge and to focus on advanced methods and measurements intended to support current and future research projects, 2) Writing up our findings and grant writing, 3) Attendance and participation at periodic institutional research seminars and conferences including responsible conduct of research (RCR training), 4) Formal mentorship and development activities with primary mentor, co-mentors and advisors, 5) Attendance and participation at national meetings with the intent to network with leaders in the field and present our work, and 6) Completion of proposed mentored research projects.
Environment: VUMC is the ideal setting to allow Dr. Wilson to pursue this line of inquiry and truly become a nationally recognized leader on the topic of catatonia and delirium in critical illness. Using data she proposes to obtain in this study, Dr. Wilson will aim to submit a R01 clinical treatment trial of co-morbid delirium and catatonia in critical illness.

Maribeth Nicholson, MD, MPH
Assistant Professor
Pediatrics/Gastroenterology
Began VFRS in July 2017
Received KL2 in August 2017
Received K23 in December 2020

Clostridium difficile Colonization, Disease, and Recurrence in the Pediatric Host

Clostridium difficile (C. difficile) infection is the leading cause of antibiotic-associated diarrhea in the United States. A 2015 Centers for Disease Control and Prevention (CDC) study found that C. difficile caused almost half a million infections and 15,000 deaths among adult and pediatric patients in the United States in a single year. In addition, a national database of hospitalized children reported a doubling of the incidence of C. difficile infections (CDI) from 2003 to 2012. CDI can be associated with significant complications including the development of toxic megacolon, gastrointestinal perforation, sepsis, and death. Recurrence of CDI is common, with an estimated 20-30% of pediatric patients experiencing this complication. Alternatively, C. difficile can also exist as an asymptomatic colonize in the pediatric host, which occurs more frequently in patients with additional comorbidities. These patients also have exposures that result in non-C. difficile associated diarrhea. In this setting, a positive C. difficile test may be unrelated to the etiology of the diarrheal symptoms which often confounds appropriate diagnosis and therapy. To date, there are no reliable markers to distinguish those pediatric patients who are colonized or those who are at highest risk of complications and disease recurrence at the time of initial infection. The research detailed in this proposal responds directly to the need to identify markers of colonization, severity, and recurrence, and includes the following specific aims: 1) To determine the prevalence and characteristics of C. difficile colonization using molecular-based testing in pediatric patients with comorbidities (specifically cancer, cystic fibrosis, and inflammatory bowel disease) and evaluate associated risk factors and outcome; 2) To compare C. difficile toxin abundance and cytotoxicity in stool of colonized versus symptomatic patients as well as compare toxin abundance and cytotoxicity as it relates to the severity of C. difficile symptoms; 3) To determine the differences in the intestinal microbiome in children with C. difficile colonization, disease, and recurrence. For the past 4 years the candidate has worked closely with her mentor, Dr. Kathryn Edwards on a variety of CDI related projects which have included the prospective enrollment of pediatric patients with CDI. She has also collaborated with her co-mentor, Dr. Eric Skaar, for the last 6 months during which time they have used stool specimens to identify markers of severity in pediatric patients. This work resulted in a co-author paper in Nature Medicine. The overarching objective of this mentored career development experience is for the candidate to emerge as an independent clinical investigator of C. difficile in children and become established in toxin determination and microbiome analysis. Throughout the award period, the candidate will work closely with a multidisciplinary team of mentors including experts in infectious diseases, gastroenterology, biostatistics, microbiome analysis, and molecular techniques to carry out her stated aims and career goals.

Mekeila Cook, PhD
Assistant Professor
Public Health Practice, Meharry Medical College
Received KL2 in January 2018

Barriers and Facilitators of Service Utilization among Justice-Involved Girls Vulnerable to Sex Trafficking: A Mixed-Methods Study

The purpose of my study is to understand healthcare and service utilization among justice-involved adolescent girls at risk for sex trafficking. Phase I analyzes previously collected data among participants in a court diversion program for sex trafficking survivors. The specific aims are to: 1) identify whether age at entry into court predicts reduction in risk profile (e.g., AWOL, bench warrants, and re-arrests); 2) evaluate whether caregiver abuse and housing instability predict length of time commercially sexually exploited youths engage in a specialty court; and 3) examine whether length of time utilizing treatment (e.g., court appearances, participation in mental health services and substance use treatment) predicts graduation from the program. In Phase II, I will conduct focus groups with non-incarcerated, justice-involved girls regarding their experiences accessing health and social services, barriers and facilitators for accessing services and youth’s definition of resiliency. The specific aims are to: 1) characterize the needs of minority justice-involved girls and identify vulnerable behaviors that may lead to unsafe decisions; 2) modify the “Identity” educational prevention program to address adolescents’ barriers to engagement in services, and 3) test the effectiveness of the updated educational prevention program.

Ryan Doster, MD
Assistant Professor
Medicine/Infectious Diseases
Began VFRS in February 2018
Received K08 in March 2020

Defining the Role of Streptococcus agalactiae Biofilm at the Host-pathogen Interface during Chorioamnionitis

Streptococcus agalactiae, also known as Group B Streptococcus (GBS), colonizes up to 50% of pregnant women, and this colonization increases risk for stillbirth, preterm birth, and invasive neonatal disease. The long-term goal of this project is to reduce the burden of infection-related adverse pregnancy outcomes through defining root mechanisms of disease pathogenesis. This proposal tests the hypothesis that GBS biofilm production is important for bacterial colonization, persistence and host immune modulation, culminating in ascending infection of the gravid uterus. Here we define the role of biofilm during GBS colonization and chorioamnionitis (infection of fetal membranes). Aim 1 will use transposon mutagenesis and transcriptomic approaches to identify important pathways for GBS biofilm formation and then verify biofilm candidate genes by constructing and evaluating isogenic mutants. Aim 2 will define the impact of biofilm at the host-microbial interface by evaluating interactions of GBS biofilm mutants with human vaginal epithelial cells, cervical epithelial cells, and fetal membranes. Aim 3 will probe in vivo mouse models of vaginal colonization and chorioamnionitis to examine how biofilm alters GBS pathogenesis and immune activation during infection. Completion of these Aims will shed new light on the role of biofilm during GBS pathogenesis and might reveal preventive and therapeutic targets for reducing the burden of GBS disease during pregnancy.

Dr. Ryan Doster is an Instructor in the Division of Infectious Diseases at Vanderbilt University Medical Center. He is also completing a Ph.D. through the Physician Scientist Doctoral Program, a new collaboration between the Vanderbilt Department of Medicine and the Interdisciplinary Graduate Program. This project expands on Dr. Doster’s current dissertation research investigating innate immune responses during pregnancy infections and past research in host microbial interactions at epithelial surfaces to investigate mechanisms of GBS pathogenesis during pregnancy. Furthermore, this project complements Dr. Doster’s clinical training in pediatrics and adult infectious diseases. In this proposal Dr. Doster will master techniques of bacterial mutagenesis strategies, animal models of infection, and working with human cells and tissues. He will also learn new skills utilizing advanced genetic techniques including transcriptomics. Vanderbilt offers cutting-edge technology and expertise in these areas through Vanderbilt Technologies for Advanced Genomics and other shared research core facilities. An interdisciplinary team including Dr. David Aronoff and Dr. Jennifer Gaddy will mentor Dr. Doster in career development and skill acquisition that will prepare him to become an independent researcher investigating the pathogenesis of bacterial infections during pregnancy.

Marcos Lopez, MD, MS
Assistant Professor
Anesthesiology
Began VFRS in July 2018
Received K23 in September 2018

Perioperative Oxygenation, Endothelial Dysfunction, and Organ Injury in Cardiac Surgery

This career development award will provide training to Marcos Lopez, MD, MS and help him advance towards his long-term goal of becoming an independent physician-scientist testing hypotheses to reduce organ injury in surgical patients. Dr. Lopez is an anesthesiologist and intensivist at Vanderbilt University Medical Center (VUMC). He is establishing a research niche characterizing the contribution of endothelial dysfunction to perioperative brain and kidney injury. Dr. Lopez assembled a multidisciplinary mentorship committee to facilitate achievement of his goals. Primary mentor Frederic T. Billings IV MD, MSCI is an anesthesiologist and intensivist who conducts clinical trials to reduce kidney injury after cardiac surgery. Co-mentor David Harrison, MD, is a cardiologist and leader in the study of the endothelium. Co-mentor Pratik Pandharipande MD, MSCI, is an anesthesiologist, intensivist, and leader in the study of ICU delirium. Dr. Lopez will combine vascular biology training in the Harrison lab with perioperative clinical trial design and outcome assessments training from Drs. Billings and Pandharipande to achieve independence.

Dr. Lopez’s research will assess endothelium-mediated vascular reactivity prior to and following cardiac surgery in patients enrolled in an RCT of intraoperative oxygen treatment (R01GM112871; PI: Billings) to test the hypotheses that normoxia during cardiac surgery improves vascular reactivity compared to hyperoxia and that impaired vascular reactivity correlates with intraoperative oxidative stress (Aim 1), that vascular reactivity in arterioles dissected from mediastinal fat of normoxia-treated patients will be increased compared to hyperoxia-treated patients (Aim 2), and that endothelial dysfunction is associated with increased brain and kidney injury (Aim 3). The study benefits from the subject recruitment, randomization, sampling, and outcomes assessment of the parent trial but tests its own independent hypotheses, providing a route to scientific independence. Dr. Lopez will measure brachial artery flow-mediated dilation, peripheral artery tonometry, and plasma concentrations of plasminogen activator inhibitor-1 and E-selectin pre- and postoperatively. He will measure vascular reactivity in mediastinal fat arterioles at the end of surgery using wire myography. He will compare these data with oxygenation groups, markers of oxidative stress, and with measured brain and kidney injury to test his hypotheses. Dr. Lopez will gain experience recruiting patients into a clinical trial, prospectively collecting data, and managing a clinical research team.

Dr. Lopez will progress to independence by completing career development training and this study. He will initiate a research program to reduce perioperative organ injury by targeting endothelial dysfunction.

M. Gunes Kutlu, PhD
Instructor
Pharmacology
Began VFRS in July 2019
Received KL2 in October 2020

The Role of Mesocortical Pathway in Negative Reinforcement Learning

Anxiety disorders such as panic disorders, generalized anxiety disorder, and post-traumatic stress disorder (PTSD) affect approximately 18% of the American population with a health care cost of more than $42 billion a year, a significant burden to the US economy. Development and maintenance of anxiety disorders have been attributed to persistent fear memories and inadequate fear extinction. Thus, it is imperative to understand the neural mechanisms underlying encoding, consolidation, and retrieval of fear memories in order to be able to develop efficacious treatments for these disorders. Midbrain dopaminergic projections to limbic and cortical brain regions are essential for detecting and encoding significant and related events in various memory domains (e.g., reward learning, fear learning).

The goal of this proposal is to translationally determine how cortical dopamine input guides learning about cues and aversive stimuli and dissociate the role of the VTA→mPFC pathway in discrete aspects of behavior associated with aversive stimuli in mice and humans. I have developed a novel behavioral task in predictive cues are associated with the onset of avoidable aversive stimuli, which can be utilized with both rodent and human subjects. In this task, subjects learn to execute a behavioral response during the cue period to avoid aversive outcomes (footshock for mice and white noise for humans) allowing us to separate the dopaminergic VTA→ mPFC signals that encode cue information, action initiation, successful avoidance, and motivation associated with aversive learning. By combining this task with in vivo imaging tools, I will measure the VTA dopaminergic input into the mPFC in mice as well as VTA-mPFC connectivity in humans (Aim1) and optogenetically manipulate the dopaminergic VTA→mPFC pathway in mice (Aim2) during discrete aspects of negative reinforcement. Finally, I will test the involvement of the VTA→mPFC pathway in aversive information processing in a clinical population with anxiety and stress disorders (Aim3). I hypothesize that the VTA→mPFC dopamine signal drives avoidance of aversive outcomes in both mice and humans and this process is disrupted in patients with anxiety and stress disorders. Overall, the results of these studies will give us a critical translational insight into the anxiety and stress disorders where aversive learning is exaggerated.

The VUMC Faculty Research Scholars Award will provide the opportunity to build on my expertise in behavioral and pharmacological aspects of learning and memory while simultaneously developing my training and expertise in cutting-edge research techniques such as in vivo fiber photometry and optogenetics.

Eva Mistry, MD, MBBS
Assistant Professor
Neurology
Began VFRS in July 2019
Received K23 in September 2019

Blood Pressure after Endovascular Stroke Therapy-II: A Randomized Trial

Research Project: Blood pressure (BP) management after endovascular mechanical thrombectomy (EVT) for large vessel acute ischemic stroke (AIS) can critically influence brain reperfusion, and thereby patient outcomes. Current guidelines recommend allowing higher than normal BP in the 24 hrs after an EVT without strong evidence. Our preliminary results demonstrate that lower post-EVT systolic BP (SBP) associate with better outcomes. Although low SBP targets are assumed to compromise brain perfusion, no data exist to definitely demonstrate any relationship of harm with post-EVT SBP targets. Such safety assessment of lower SBP targets is a critical prerequisite to conduct larger studies to evaluate their efficacy in improving outcomes of EVT-treated patients. We will conduct the Blood Pressure after Endovascular Stroke Therapy-II (BEST-II) trial, where 120 AIS patients successfully treated with an EVT will be randomized to three SBP targets (<180, <160, and <140 mmHg) to 1) assess the harm of lower SBP targets and 2) determine the probability (hypothesized to be ³25%) of a positive phase III efficacy trial of lower SBP targets to improve patient outcomes. To assess the harm, we will test the null hypotheses that lower SBP targets do not worsen brain ischemia or 90-day functional outcome in patients beyond a level considered safe. This proposal will generate high quality data for the planning of a large, multicenter efficacy trial. Collectively, this set of trials will lead to evidence-based guideline generation for the optimal post-EVT BP management in AIS patients.

Candidate: Working closely with her mentors over the past two years, Dr. Eva Mistry designed, led, and successfully completed a large, prospective, multi-institutional study (BEST-I) to demonstrate the association of improved outcomes with lower SBP in EVT-treated AIS patients. This proposal is the direct result of this preliminary work. In addition to seeing her proposal to completion, her short-term goal is to acquire external career development award. She has submitted her NIH/NINDS K23 Career Development Award application in Feb 2019 (pending review) and plans to apply for the American Academy of Neurology and American Heart Association Career Development Awards in October 2019. Her long-term goal is to become a leader in novel designs and electronic facilitation of acute stroke trials to ensure efficient testing of new stroke treatments and improve patient outcomes.

Career Development: To achieve her long-term goal, Dr. Mistry will follow an integrated career development plan. Her rigorous training will include coursework, personalized mentoring from mentors and advisors, and experiential training to achieve mastery in 1) trial implementation in acute and critical care settings, 2) adaptive and platform trial designs, 3) electronic facilitation of clinical trials, and 4) leadership skills.

Andrew Wiese, PhD, MPH
Assistant Professor
Health Policy
Began VFRS in July 2019
Received BIRCWH K12 in March 2020

Benzodiazepine Restrictions and the Prevention of Adverse Outcomes

The use of benzodiazepines, one of the most commonly prescribed medications in the US, is linked to serious health outcomes, including falls, fractures, motor vehicle crashes, and opioid-related overdoses. Although benzodiazepine coverage restrictions and state-specific regulatory actions have been implemented in the past, it remains unclear whether those policies led to the intended reduction in adverse outcomes or led to other unintended consequences. One such restriction involved the lack of coverage for benzodiazepines among Medicare enrollees with the implementation of Medicare Part D in 2006. Although Medicare enrollees could not access benzodiazepines through this new pharmacy program, most State Medicaid programs continued their coverage of benzodiazepines and offered a source of medications for dual-eligibles enrolled in Medicare and Medicaid. The Tennessee Medicaid (TennCare) program was the only Medicaid program in the US that simultaneously restricted benzodiazepine coverage to their enrollees. Thus, patients enrolled in TennCare (including dual-eligibles) lacked coverage of benzodiazepines from 2006 through 2013. With the implementation of the Affordable Care Act, benzodiazepine coverage was reinstated in Medicare and Medicaid in 2014. This intermittent coverage of benzodiazepines in Tennessee represents a unique natural experiment to evaluate the impact of restrictions on both intended and unintended health outcomes. I will evaluate this critical research priority by addressing two specific aims: Aim 1: Determine the impact of benzodiazepine restriction policies on the incidence of falls, fractures, motor vehicle crashes and opioid-related overdoses in the TennCare population; Aim 2: Determine whether benzodiazepine restriction policies led to an increase in the use of other psychotropic medications. The goal of this investigation is to carefully evaluate the impact of benzodiazepine restriction policies, including their intended and unintended effects. Findings from this study will inform strategies to reduce drug adverse outcomes, including drug overdoses.

Kristin O'Grady, PhD
Assistant Professor
Radiology & Radiological Sciences
Began VFRS in October 2019
Received KL2 in May 2020
Received K01 in July 2020

Examining the Role of Biological Sex in Imaging Biomarkers of Multiple Sclerosis

Multiple sclerosis (MS) is a chronic, immune-mediated disease of the central nervous system that results in demyelination and neurodegeneration. Relapsing-remitting MS (RRMS), the most common form of MS, predominantly affects women at a female to male ratio of approximately 3:1, and female patients experience an earlier disease onset and more frequent relapses. In contrast, male sex is a predictor of more severe disease phenotype and rapid physical and cognitive progression. These profound sex differences in disease incidence and progression, along with sex hormone-linked protective factors such as pregnancy, highlight the importance of studying the influence of biological sex in all aspects of MS research, including neuroimaging. Basic science studies and clinical trials have shed light on the involvement of sex hormones in MS; however, magnetic resonance imaging (MRI) outcomes for studying sex differences in MS remain inconsistent. The majority of MRI studies investigating sex differences have used diagnostic T1-and T2-weighted structural MRI to evaluate brain lesions and atrophy, but these methods are non-specific for pathology underlying the radiological appearance of the tissue. There is also a significant knowledge gap with respect to sex differences in spinal cord involvement in MS, despite the known, major impact of spinal cord disease on neurological disability. MS is a complex and heterogeneous disease, so it is challenging to monitor disease progression and treatment response when conventional MRI provides limited correlation with clinical symptoms. MRI biomarkers that are more sensitive and specific to brain and spinal cord pathology as well as sex differences in MS may further the ability of clinicians to employ a more individualized approach to treatment. Consequently, my work is focused on integrating sex/gender biology into MRI studies that deploy quantitative MRI methods sensitive to specific disease processes in the brain and spinal cord in MS patients. Completion of the aims in this proposal will yield new knowledge regarding sex differences in the radiological manifestation of MS through application of advanced microstructural (axonal), macrostructural (myelin), and molecular (protein) MRI in the brain and spinal cord. To achieve my research goals, I will leverage my prior work developing ultrahigh field molecular MRI methods for the brain (chemical exchange saturation transfer, CEST) and spinal cord methodologies optimized for the cervical spinal cord by the Smith lab (magnetization transfer, high resolution anatomical imaging, diffusion tensor imaging, and CEST) to examine sex differences in patients with RRMS. These methods will be extended to the lumbar spinal cord to initiate new research on the pathological substrate of neurogenic bladder in MS patients. Overall, these studies are anticipated to result in sex-specific MRI biomarkers of MS pathology, which will further the possibility of a personalized medicine approach to treatment for MS patients and provide new tools for evaluating novel, neuroprotective therapies.

Bhuminder Singh, PhD
Assistant Professor
Medicine/Gastroenterology
Began VFRS in November 2019
Received KL2 in July 2020
Received R01 in May 2021

Overcoming a New Mode of Cetuximab Resistance in Colorectal Cancer

Background: EGF receptor (EGFR) is a receptor tyrosine kinase (RTK) that is overexpressed in over 50% of colorectal cancer (CRC) where it is linked to metastasis and poor prognosis. Cetuximab, an EGFR-targeting monoclonal antibody is approved by US-FDA to treat advanced wild-type KRASCRC. However, cetuximab, as monotherapy, is effective in only about 10% of CRCs and resistance frequently emerges. Thus, there is a pressing need 1) to identify those patients most likely to respond (or not respond) to cetuximab and 2) to devise treatment strategies that would enhance cetuximab response. We propose to address these needs by aggressively pursuing our observations that enhanced activity of the RTKs, MET and RON, confers cetuximab resistance. We made these discoveries using a three-dimensional (3D) type I collagen-based culture system for CRC. Here, we isolated two subpopulations of a CRC line, HCA-7. The two HCA-7 derivatives were termed CC and SC, for their respective cystic and spiky morphology in 3D. SC cells were cetuximab-resistant and showed high MET/RON tyrosine phosphorylation, compared to cetuximab-sensitive CC. Moreover, addition of the dual MET/RON tyrosine kinase inhibitor, crizotinib, restored cetuximab sensitivity in SC. Interestingly, derivatives of CC cells selected to grow in the presence of cetuximab also showed higher MET/RON tyrosine phosphorylation, and could be inhibited by cetuximab/crizotinib combination.

Hypothesis: Upregulation of RTK activity (e.g. MET/RON) conferscetuximab resistance in CRC and that it isa viable therapeutic target.

Specific Aims: (1) Elucidate the role of RTKs in transformation and conferring cetuximab resistance in CRC. (2) Establish the effectiveness of multi-RTK inhibition in enhancing cetuximab therapy in CRC.

Study design: We will exploit our 3D culture system and CRC patient-derived tumor organoids (PDOs) for most subaims of the grant. We will also employ complementary approaches (Transwell cultures, nude mice xenografts, tumor tissue microarrays, phospho-RTK arrays, multiplex immunofluorescence, single-cell RNA-seq and human CRC samples) in relevant sections. Key proteins (MET, RON, ligands, and other positive and negative regulators) will be manipulated (overexpression, CRISPR-mediated knockout, ligand stimulation, and chemical inhibition) to characterize individual contribution. These experiments will be recorded at subcellular localization, morphological, and phenotypic levels to tease out key differences.

Cancer relevance: These studies will characterize the new mode of cetuximab resistance, its prevalence in CRC, and optimize treatment to overcome cetuximab resistance for advanced CRC. Moreover, the lessons learned may be applicable to other epithelial cancers where cetuximab is an approved therapeutic.

Matthew Alexander, MD, PhD
Assistant Professor
Medicine/Clinical Pharmacology
Began VFRS in July 2020
Received K08 in July 2020

Role of CCR10+ Regulatory T Cells in Hypertension

Hypertension is the leading cause of death and disability-adjusted life years worldwide. Despite current therapies blood pressure remains uncontrolled in approximately 50% of individuals with hypertension, and even with adequate control of BP an elevated risk of cardiovascular events remains. Hence, there is a major unmet need for new therapeutic options for hypertension. Emerging evidence suggests an important role for the immune system in the pathogenesis of hypertension. An immune cell subset termed regulatory T cells (Tregs) is an attractive therapeutic target as it plays a suppressive role to limit inflammation. However, recent evidence suggests that some Tregs can play pathogenic roles in heart failure and lung fibrosis through inhibiting angiogenesis and promoting fibrosis, respectively. Novel evidence provided with this application suggests that a subpopulation of Tregs expressing C-C motif chemokine receptor 10 (CCR10) is selectively decreased in the circulation of hypertensive humans and mice and is increased in the skin of mice with hypertension. Given recent evidence for an important role for skin microvascular rarefaction (defined as loss of microvessels) in hypertension, these results suggest a novel link between CCR10+Tregs, skin microvessels, and hypertension development. In addition, we have evidence that increased endothelial cell stretch, as occurs with elevated blood pressure, selectively increases CCR10+Tregs in vitro. Thus, studies in this application will test the hypothesis that increased endothelial cell stretch augments CCR10 expression in Tregs and promotes CCR10+ Treg recruitment to the skin to enhance microvascular rarefaction and hypertension development. This overall hypothesis will be tested with the following specific aims: 1) test the hypothesis that increased EC stretch enhances CCR10 expression in Tregs via TNFα and that resultant CCR10+Tregs transmigrate and inhibit angiogenesis in response to CCR10 agonism by the skin-specific chemokine CCL27 in vitro, 2) test the hypothesis that CCR10+Tregs promote skin microvascular rarefaction leading to elevated BP in salt and angiotensin II-induced hypertensive mouse models in vivo, and 3) test the hypothesis that CCR10and its skin-specific ligand CCL27 promote hypertension in humans using a genetic approach of Mendelian randomization. Execution of the outlined studies will provide a platform for me to gain further understanding and technical skills related to the study of regulatory T cells and skin microvasculature as well as human genetic approaches such as Mendelian randomization. The outstanding resources and mentorship integrated into this proposal will enable successful attainment of my career goals. These goals include becoming an independent physician scientist integrating the care of patients with hypertension with investigation of the role of regulatory T cells in hypertension development, with the ultimate goal of enabling the development of new immunotherapy-based treatments for this condition.

Mona Mashayekhi, MD, PhD
Instructor
Medicine/Diabetes, Endocrinology & Metabolism
Began VFRS in July 2020
Received KL2 in December 2020

The Contribution of Arachidonic Acid Metabolites EETs to Inflammation in Obesity

The prevalence of obesity is increasing worldwide, and many of the cardiometabolic diseases associated with obesity, including type 2 diabetes and hyperlipidemia, can be linked to changes in adipose tissue function. Obesity disrupts the immune environment within adipose tissue to create a pro-inflammatory milieu, which interrupts its normal energy storage and metabolic regulatory functions. Therapies that effectively reduce obesity-related chronic inflammation may improve adverse cardio-metabolic outcomes and are urgently needed.

We propose to investigate if genetic polymorphisms or pharmacologic agents that increase the arachidonic acid epoxide metabolites epoxyeicosatrienoic acids (EETs) in humans are associated with lower adipose tissue inflammation in obese individuals. EETs are lipid signaling molecules that have beneficial metabolic and hemodynamic effects by promoting vasodilation and sodium excretion and protecting against endothelial cell dysfunction. In humans, circulating EET levels correlate with insulin sensitivity, and may confer cardio-protective benefits based on studies of genetic variants in the EET pathway that are associated with cardiovascular disease. In addition, EETs have an anti-inflammatory role in rodent models of obesity, but it is unknown if they have anti-inflammatory effects in humans.

We hypothesize that EETs act as anti-inflammatory agents in humans and are a novel target for treatment of chronic inflammation in obesity. We will test this hypothesis by performing unbiased transcriptome analysis and T cell subset profiling to characterize the inflammatory milieu in adipose tissue and blood from obese individuals with genetic polymorphisms (Aim 1) or pharmacologic treatments (Aim 2) that increase EETs. We will also correlate these findings with measures of insulin sensitivity and endothelial function using hyperinsulinemic-euglycemic clamps and forearm blood flow measurements, respectively. In preliminary studies we have shown that pharmacologic inhibition of the enzyme that hydrolyzes EETs, soluble epoxide hydrolase (sEH), decreases circulating levels of F2-isoprostanes, which are markers of oxidative damage and inflammation. Understanding the contribution of EETs to immune modulation could lead to new strategies to decrease obesity-associated inflammation and reduce the risk of metabolic and cardiovascular diseases.

Erin Wilfong, MD, PhD
Instructor
Medicine/Rheumatology
Began VFRS in July 2020
Received KL2 in February 2021

Pathological Role of B Cells in Idiopathic Inflammatory Myopathies (IIM)

The idiopathic inflammatory myopathies (IIM) are a family of rare systemic rheumatologic diseases commonly affecting the skin, muscles, and lung. Despite the morbidity and mortality of IIM, there are currently no FDA approved therapies for these conditions. One limitation in developing targeted therapeutics for IIM is the limited understanding of the dysregulated immune mechanisms driving the underlying disease process. There is increasing evidence that B cells are important in the development of IIM. Various autoantibodies are associated with specific disease phenotypes; treatment with anti-CD20 antibodies (rituximab) leads to clinical improvement for many patients. My preliminary work investigating IIM immunophenotypes using mass cytometry by time of flight (CyTOF) discovered three autoimmune prone B cell populations increased in subsets of patients with IIM. All three of these populations had decreased surface expression of CD180, which can activate B cells after ligand binding and internalization. Additional studies demonstrated that B cells recognizing the Jo-1 autoantigen have decreased surface CD180 compared to B cells that fail to recognize Jo-1. In chronic lymphocytic leukemia, cells are surface CD180lo but have high intracellular CD180 and are highly activated. TLR9 also works synergistically with CD180 to cause B cell activation, and TLR9 has a well-established role in autoimmunity. Based on these preliminary findings, we hypothesize that CD180 is an active signaling pathway in IIM that augments signaling from the BCR and TLR9 to contribute to IIM disease pathogenesis.

This proposal seeks to leverage these preliminary findings and perform mechanistic studies to understand how CD180 signaling leads to B cell dysregulation in IIM and identify additional dysregulated pathways amenable to future targeted therapeutics. To achieve this goal, I will investigate how B cell receptor (BCR) signaling differs in CD180lo compared to CD180+ B cells in IIM patients. I will probe how the CD180, BCR, and TLR9 signaling pathways interact with one another using healthy B cells. Finally, I will use single cell transcriptomics profiles to both look for additional abnormal signaling cascades and investigate clonality of the three myositis specific populations identified in our preliminary immunophenotyping. By defining how B cells in IIM behave differently compared to healthy B cells, we will identify potential therapeutic targets to improve outcomes in patients suffering from IIM.

Mallory Hacker, PhD
Assistant Professor
Neurology
Began VFRS in July 2019

One million Americans live with Parkinson’s disease (PD), a progressive neurodegenerative disease characterized by cardinal motor features that include tremor, bradykinesia, rigidity, and postural instability. Symptoms are treated with dopaminergic medications (early-stage) and deep brain stimulation (DBS, mid-to advanced-stage), but all current therapies are only symptomatic – there is no intervention that slows, stops, or reverses the progression of any feature of the disease. Although reserved for later PD stages, DBS has strong evidence that it protects against nigral neuron death when applied animal models of early-stage PD. The consistent findings from preclinical studies motivated the first prospective, randomized, pilot clinical trial evaluating DBS in early-stage PD, led by Vanderbilt investigators (IDEG050016, IRB040797). Recent findings from that trial provided class II evidence that early DBS slows the progression of rest tremor, a common and often distressing symptom for early-stage patients. This landmark finding must now be tested, and a prospective, multicenter, randomized, safety and efficacy trial is approved by the FDA. That phase 3 trial will implement the same method to evaluate underlying motor symptom progression by using week-long therapeutic washouts. The pilot’s washout design facilitated a rigorous method of evaluating patients in an untreated state, but ultimately the study, like all clinical trials for PD, had to rely on subjective clinical ratings. In the years since the pilot trial began, new objective methods to evaluate PD have emerged, including metabolic networks identified from F-fluorodeoxyglucose (FDG) positron electron tomography (PET) scans and wearable biosensors. Including these unbiased measures alongside standard clinical assessments after a week-long therapeutic washout offers the opportunity to objectively determine if early DBS slows PD progression. These measures were not available when the original trial began, and this study seeks to quickly resolve uncertainties regarding incorporating new objective assessments into the phase 3 protocol. Aim 1 will determine the feasibility of including off therapy FDG-PET scans to facilitate analysis of three PD-related metabolic networks associated with bradykinesia& rigidity, tremor, and cognitive dysfunction. Aim 2 will pilot two types of wearable biosensors to objectively measure symptoms in early-stage PD patients in both the treated state and following one-week off of medications. This study will fill critical knowledge gaps concerning utilization of new objective measures during a washout in very early-stage PD. This new information will be used to finalize the protocol of a phase 3 trial to determine if early DBS slows Parkinson’s disease progression.

William Nobis, MD, PhD
Assistant Professor
Neurology
Began VFRS in July 2019
Received KL2 in March 2022

The Role of the Extended Amygdala in Respiratory Control and Sudden Unexpected Death in Epilepsy

The Neurology Department has an unwavering commitment to the career development of Dr. Nobis and, towards that goal, he was recruited from Northwestern following his clinical epilepsy fellowship as a clinical instructor with plans for quick transition to a tenure-track position. The candidate was given a generous startup package and institutional support including clearly delineated protected research time of at least 75%. The candidate will have a graded mentored experience such that during the latter years of the award he will be in a position to apply for independent R01 funding. A career development committee will guide this transition and provide scientific pre-review of future grant proposals. Dr. Dane Chetkovich, Chairman of the Neurology Department will serve as primary scientific mentor with secondary mentors consisting of Dr. Sachin Patel in the Psychiatry Department and outside mentorship by Dr. Jennifer Kearney in the Department of Pharmacology at Northwestern University. The candidate plans to obtain further training in electrophysiology, epilepsy models, in vivo optogenetics, analysis of respiratory function in mice, and in vivo neuromodulation with optogenetics and chemogenetics by taking advantage of a host of internal collaborators at VUMC. Vanderbilt University is an exceptional institution for this depth of translational multidisciplinary training and the development of young physician-scientists with a highly collaborative environment.

Additionally, the candidate has put together a group of internal and external consultants to offer expert training and guidance for the proposed project, which
is entitled “The role of the extended amygdala in respiratory control and sudden unexplained death in epilepsy”. Sudden unexplained death in epilepsy (SUDEP) is the most frequent cause of death in epilepsy patients. The candidate’s recent data in human epilepsy patients shows that both seizures and stimulation of a portion of the amygdala produces apnea. This finding suggests that the amygdala has mechanistic implications for respiratory function and in particular seizure induced apneas, however, the precise pathways by which apnea is mediated are unknown. Aim 1 will evaluate whether an amygdalar region, the bed nucleus of the striaterminalis (BNST), has projections to the parabrachial nucleus (PBN) that are influential in respiratory function. In Aim 2 he will use mouse models of SUDEP, the Dravet Syndrome mice and the DBA/2 audiogenic seizure mice to determine whether there are functional neuronal alterations in BNST neurons in these models. Finally, Aim 3 provides clinical relevance by examining effects of modulation of this circuit on seizure induced apneas and survival in the DS model. Overall, completion of this project will provide a clearer understanding of the BNST’s role in respiratory control, describe alterations in the BNST in epilepsy models, and establish this pathway as a target for SUDEP prevention. Receiving a VFRS will allow the applicant the protected time for research and provide the best chance of launching a successful career as an independent physician-scientist.

Naeem Patil, MD, PhD, MBBS
Assistant Professor
Anesthesiology
Began VFRS in July 2020

Targeting Mitochondrial Quality Control to Improve Host Immunity during Sepsis

Sepsis is a leading cause of death in the United States with a healthcare burden of ~ $14 billion. Sepsis survivors suffer increased mortality as compared to the general population (~15% death rate in the first year after hospital discharge). No definitive therapy currently exists to treat sepsis and there is a critical need to identify novel biological targets and therapeutics. Sepsis causes immune cell dysfunction, which weakens patients’ abilities to fight existing infections and predisposes them to secondary hospital acquired infections. Studies indicate an association between impaired organ and leukocyte mitochondrial function with sepsis outcomes. Our preliminary results show that therapeutic strategies causing sustained augmentation of macrophage mitochondrial function significantly protect against sepsis caused by common nosocomial pathogens such as Pseudomonas aeruginosa and Staphylococcus aureus. We found that TLR4 agonist, monophosphoryl lipid A, promotes macrophage mitochondrial biogenesis via increased PGC-1α and Nrf2 targeted gene expression, along with 400 fold induction of mitochondrial immunoresponsive gene 1 and its product itaconate, which is a potent antimicrobial agent. MPLA treatment more than doubles the expression of mitochondrial fission protein, Drp1and inhibition of Drp1 attenuates MPLA induced augmentation of macrophage mitochondrial function. We hypothesize that TLR4 agonist induced early induction of mitochondrial quality control pathways including biogenesis and fission in conjunction with itaconate generation significantly enhance host innate immunity leading to protection against sepsis.

The overall theme of this application is to study how sepsis affects leukocyte mitochondrial quality control pathways (biogenesis, fission, mitophagy and fusion) and is mitochondrial function a druggable target to develop prophylactic therapies for at risk individuals and for treatment after sepsis diagnosis. Aim 1: Determine the molecular mechanisms by which mitochondrial metabolic reprogramming drugs such as MPLA augment host innate immunity. Aim 1 will focus on understanding the role of PGC-1α, Irg1, itaconate and Nrf2 in regulation of macrophage mitochondrial dynamics. Aim 2: Evaluate the therapeutic benefit of augmenting mitochondrial biogenesis and function as a novel strategy to treat sepsis. Aim 2 will focus on performing pre-clinical evaluation of itaconate and MPLA alone or in combination to protect against sepsis. Aim 3: Define the status of mitochondrial quality control pathways in leukocytes isolated from septic patients. Studies in aim 3 will perform a detailed characterization of mitochondrial quality control pathway markers in peripheral blood mononuclear cells from septic patients and measure plasma mitochondrial metabolites to correlate them with patient outcomes. Augmenting leukocyte mitochondrial function represents an entirely novel approach to protect against sepsis. Understanding the status of mitochondrial quality control pathways in leukocytes from septic patients will help drive the field of sepsis management into new and underexplored area of leukocyte mitochondrial metabolic reprogramming.

Brittney Snyder, PhD
Instructor
Medicine/Allergy, Pulmonary & Critical Care Medicine
Began VFRS in July 2021
Received K01 in July 2022

Identifying Molecular Pathways in Childhood Asthma Pathogenesis by Integrating Newborn Metabolic Profiles and GWAS Data

Childhood asthma is a common, burdensome disease for which there are currently no effective prevention strategies. This is due in part to our limited understanding of the molecular determinants of asthma pathogenesis. As the development of asthma is highly influenced by genetic and environmental factors, assessment of both genetic and metabolomic profiles can improve our understanding of disease pathogenesis and identify potential targets for treatment and prevention. The overall research objective of this proposal is to elucidate metabolic and upstream genetic pathways underlying childhood asthma pathogenesis. Our central hypotheses are that metabolic profiles at birth are associated with subsequent development of childhood asthma and that this association is due in part to the effect of genetic variants on intermediate metabolic profiles and childhood asthma. To test these central hypotheses, we will pursue the following specific aims: 1) identify metabolic profiles at birth associated with the development of childhood asthma, and 2) determine the genetic contribution to variation in metabolite concentrations at birth and identify genetic pathways linking metabolic profiles at birth with childhood asthma. To achieve Aim 1, we will capitalize upon a unique resource of longitudinal birth cohorts with newborn metabolic data and rich phenotypic data (n=6209 children). To achieve Aim 2, we will utilize genotypes for children within the largest of these cohorts to perform a metabolite genome-wide association study. We will then leverage these findings, along with summary statistics from the largest GWAS of childhood asthma performed to date, to perform a genetic co-localization analysis.

The purpose of this VFRS proposal is for Dr. Snyder to build on her prior training in maternal-child health epidemiology and experience with utilizing metabolomics data in large epidemiologic studies by taking on leadership roles in the conduct of epidemiologic studies, applying modern statistical methods for high-dimensional data, and receiving advanced training in genetic epidemiology so that she can more effectively address fundamental questions about upstream pathways of disease development. Through the comprehensive career development plan applied directly to the research, the complementary expertise of the mentorship team, and an outstanding institutional environment, Dr. Snyder will acquire the knowledge, skills, and resources necessary to advance her toward her long-term career goal of becoming a recognized leader in maternal-child health epidemiology, with a focus on integrating genetics and metabolomics in large epidemiologic studies to understand and prevent childhood respiratory diseases. The experience, training, and findings generated through this proposal will result in Dr. Snyder developing critical research skills to move toward independence and the submission of a highly competitive R01 application.

Katherine McDonell, MD, MSCI
Assistant Professor
Neurology
Began VFRS in April 2019
Received K23 in August 2022

Risky Behavior in Huntington Disease

Risky behaviors are common in Huntington disease (HD) and can be extremely detrimental to both patients and caregivers. Engagement in high-risk, high-reward activities such as pathological gambling, substance abuse, hypersexuality, and reckless driving are frequently observed in the HD population and can lead to serious social and legal consequences. These behaviors often emerge early in the disease course, prior to the onset of motor symptoms and frequently before patients and family members are aware that they might be affected. Identifying and screening for these behaviors can therefore prove challenging.
The currently available behavioral screening tools used in HD do not address risky decision making or impulsivity, and patients who engage in these behaviors are frequently missed. The frequency and scope of these symptoms in the HD population has also not been well-studied, and our understanding of the underlying neurobiological mechanisms that drive these behaviors is quite limited.

The aims of the proposed study are: (1) To define the breadth and clinical impact of risky behaviors in HD; (2) To develop and validate a novel clinical measure to assess risky behaviors in the HD population; and (3) To conduct exploratory analyses examining correlations with clinical variables and measures of reward responsivity.

This proposal is supported by a multidisciplinary team of mentors with expertise in clinical scale development, risk and reward processing, behavioral psychology, and advanced statistical analysis. The candidate’s institution offers a wealth of resources to support this work, including a Level 1 Center of Excellence with a large and diverse population of HD patients and extensive clinical research experience in HD. This proposal will also serve as a robust training platform, with a comprehensive career development plan including expert mentorship and coursework in clinical scale development, advanced biostatistics.
The impact of this study will be to greatly broaden our understanding of the burden and clinical significance of risky behavior in HD and to generate a novel clinical scale that can be incorporated into future observational and therapeutic trials. The proposed aims will also provide critical preliminary data to support future studies with the goal of identifying patients at risk for these symptoms during the premanifest stages of their disease, characterizing underlying neural network changes, and testing interventions to prevent the development of dangerous behaviors. The educational impact of this proposal will be to provide the candidate with advanced training in clinical scale development and statistical methods to develop the necessary skills to transition into an independent investigator studying behavioral dysregulation in neurodegenerative disorders.

David Isaacs, MD, MPH
Assistant Professor
Neurology
Began VFRS in July 2021
Received KL2 in August 2022

Neural Correlates of Sensory Phenomena in Tourette Syndrome

Candidate: David Isaacs, MD, MPH, is Assistant Professor in the Department of Neurology. He demonstrates marked enthusiasm and aptitude for patient-centered research, with emphasis on non-motor aspects of movement disorders and clinical trials. He graduated from Vanderbilt’s MPH program in 2019. Early career highlights include extramural grant funding for assessment of neuropsychiatric symptoms in Huntington’s disease; conceptualization and implementation of longitudinal outcomes study in a cohort with Parkinson’s disease following deep brain stimulation; and foundation of Vanderbilt’s Adult Tourette Syndrome (TS) Clinic. Candidate has served as site PI for several industry-sponsored clinical trials and is 2019-2021 fellow for the NeuroNEXT Clinical Research Training Program. Dr. Isaacs aspires to become a leading investigator in neurophysiologic biomarkers of movement disorders.

Research Project: TS is a neurodevelopmental disorder affecting 1% of school-aged children, one-third of whom suffer bothersome tics into adulthood. Tics are the defining characteristic in TS, but sensory symptoms, in the form of premonitory urges and sensory hypersensitivity, afflict 90% and 80% of patients respectively, and impair quality of life. Despite this, sensory symptoms are poorly understood, both clinically and pathophysiologically. EEG is an ideal tool for identifying neurophysiologic markers of TS sensory symptoms because of its capacity to capture millisecond-level neural dynamics at a global and regional scale. We hypothesize that gamma frequency (>30 Hz) network oscillation dysfunction, measurable with surface EEG, underlies TS sensory symptoms. We seek to determine the longitudinal predictive value of patient-reported hypersensitivity and urges in TS adults (Aim 1) and to identify EEG signatures of these phenomena (Aims 2 and 3).

Career Development: Dr. Isaacs has carefully crafted a curriculum incorporating formal coursework, workshops, conferences, and individualized training with mentors and collaborators in order to adequately prepare himself for independent research in neurophysiologic biomarkers of movement disorders. His short- term career goals are to become: 1) expert in clinical characterization of sensory and neuropsychiatric symptoms (Aim 1); 2) proficient in event-related potentials and quantitative EEG (Aims 2 and 3); and 3) competent in neurophysiologic biomarker development (Aims 2 and 3).

Environment: VUMC is an optimal academic environment for nurturing Dr. Isaacs’ maturation into a fully- fledged independent researcher specializing in neurophysiologic biomarkers of movement disorders. The institution has an exceptional track record for fostering productive, independently funded, and internationally renowned clinician-scientists. The primary mission of Vanderbilt’s CTSA is provision of infrastructure for clinical research excellence, with an entire arm devoted to training and career development.

Jessica Schwartzman, PhD
Assistant Professor
Psychiatry
Began VFRS in May 2022
Received KL2 in October 2022

A Multimethod, Longitudinal Approach to Reward Responsivity and Depression in Youth with Autism

Adolescents with Autism Spectrum Disorder experience depression at rates nearly twice that of their neurotypical peers (20% vs. 11%). Untreated depression is associated with adverse short (e.g., school refusal) and long-term outcomes (e.g., poor physical health, lower employment) that impair quality of life. Adolescents with autism also face a 7x increase in the risk for premature death by suicide than their neurotypical peers. Risk factors to depression in autism are not well understood and measurement efforts may be complicated by social communication difficulties (i.e., autism symptomatology) that interfere with adolescents’ efforts to identify and explain emotional experiences to providers and family members. Therefore, more objective measures (e.g., electroencephalogram [EEG], specifically event-related potentials [ERPs]) may provide a better understanding of risk factors to depression in adolescents with autism. Altered reward responsivity (Research Domain Criteria [RDoC] Positive Valence) and disrupted social processes (RDoC Affiliation and Attachment) are key risk factors to depression for neurotypical adolescents, but have not been investigated in autism. Clinical and neural measures of social and nonsocial reward responsivity and associations with depression symptoms have not been examined in autism, which may provide meaningful information about developmental trajectories. Consistent with the NIMH Strategic Plan, Strategic Goal 2, “to identify and understand risk factors, biomarkers and behavioral indicators of mental illness,” this application aims to examine clinical and neural markers of social and nonsocial reward responsivity and associations with depression symptoms in adolescents with autism, including longitudinal investigations. Under the mentorship of a diverse team of experts in autism, depression, reward responsivity, psychophysiological methods, and longitudinal and statistical methodologies, this proposal will examine the predictive influences of these RDoC constructs to depression in adolescents 14-17 years old with autism. Adolescence is a key developmental period for early detection and intervention as it is characterized by spikes in depression prevalence and an increasing importance of peer relationships. Specifically, this proposal will use EEG/ERP techniques and clinician-rated interviews to measure social and nonsocial reward responsivity in adolescents with autism and test relationships with depression symptoms. Adolescents will be assessed one year later to investigate how clinical and neural measures predict depression symptoms over time, which will inform the developmental course of these RDoC constructs in this vulnerable population. The applicant’s long- term goal is to understand the neurobiological and behavioral development of reward responsivity in autism and associations with depression from adolescence to adulthood so as to inform screening methods and intervention development. Mentored training will allow the applicant to gain expertise in multimethod measures (e.g., ERP methodologies, clinician-rated interviews) and longitudinal design and analysis, with an emphasis on assessing mechanisms associated with the onset, maintenance, and treatment of depression in autism.

Anandharajan Rathinasabapathy, PhD
Instructor
Medicine/Allergy, Pulmonary & Critical Care Medicine
Began VFRS in February 2019

Targeting Metabolism to Rescue Vascular Function in PAH

Dr. Rathinasabapathy is a Research Instructor in the Division of Allergy, Pulmonary and Critical Care Medicine at Vanderbilt University Medical Center. He obtained his PhD in 2015 from the University of Florida, where he investigated the application of stem cells, small molecules and biological proteins in the animal models of lung and heart diseases. Prior to this, he has worked in the pharmaceutical industry, specializing his skills in the metabolic disorder. In 2016, he joined the laboratory of Dr. West as a Post-Doctoral Fellow to investigate the molecular etiology and pharmacological intervention of idiopathic and heritable pulmonary arterial hypertension (PAH). After the award of VUMC Faculty Research Scholars Grant, he will continue his research in Dr. West’s lab.

Dr. West is an internationally renowned researcher in the field of PAH. Dr. West has rich experience in applying the basic, clinical and genomic tools towards investigation of cellular, molecular and metabolic etiology PAH. Since joining his lab, Dr. Rathinasabapathy has accomplished various projects including KCNK3, Cav1, ACE2and Sirt3. PAH group in Vanderbilt is bestowed with world class, well-funded principal investigators, touted to be one of the best in the nation. Laboratory of Dr. West and Vanderbilt PAH community provides Dr. Rathinasabapathy, a scintillating and persuasive environment to accelerate his career into the line of independence. In addition, the Vanderbilt ambience also provides him unlimited career growth opportunities. Apart from this VFRS grant, Dr. Rathinasabapathy is planning on submitting grant application for a K award in the summer and AHA’s CDG award in the fall.

Pulmonary Arterial Hypertension is a debilitating, complex, rare lung disorder, often triggered due to endothelial dysfunction causing extensive lung tissue and right heart remodeling, eventually resulting in death, if left untreated. In this grant, Dr. Rathinasabapathy has devised novel strategy to decipher the nuances of metabolism, which drives the etiology of PAH. He would be using a host of in vitro and in vivo lines along with a variety of molecular tools to disseminate the original hypothesis that Metabolic defects associated with SOD2 and Sirt3 signals dysregulate the lipid pathways and their pharmacological intervention would improve the vascular function in PAH. In detail, he will investigate the role of acetylation of SOD2 and LCAD in Sirt3-defect mediated PAH and the impact of loss of Sirt3 in endothelial dysfunction driven by loss of fatty acid oxidation and eventually, the pharmacological intervention to rescue the defects associated with SOD2 andSirt3 signals in PAH.

Kimberly Albert, PhD
Instructor
Psychiatry
Began VFRS in July 2021
Received K01 in September 2023

The Role of Attention Network Dysfunction and AD Pathology in Subjective Cognitive Decline

Candidate: Dr. Kimberly Albert, PhD is a research instructor in the Department of Psychiatry and Behavioral Sciences at the Vanderbilt University Medical Center with a strong background in cognitive and systems neuroscience. Her long-term career goals include gaining the necessary training to become an independent investigator with research focused on disruptions in brain network function and attentional processes in pathological aging that will inform early detection of Alzheimer’s disease (AD) and help develop intermediate cognitive and neuroimaging markers for intervention trials.

Career Development: To achieve this career goal, Dr. Albert requires advanced training in 1) using EEG to examine event-related potential measures of cognitive network function; 2) network-based approaches for neuroimaging analysis; 3) The application of neuroimaging and experimental probes to clinical studies. Her training strategy includes one-on-one mentoring, focused academic coursework including clinical trial design and statistics, and practical experience focused on data analysis and communication. This training will build on Dr. Albert’s prior experience in human cognitive neuroscience using functional neuroimaging and support her transition to independence.

Research Project: These career goals will be facilitated through a research study focused on brain attention network changes in subjective cognitive decline and cognitive complaints in aging. The early pattern of β-amyloid accumulation in frontal and parietal brain regions may have specific impact on attention networks, thus contributing to cognitive complaints in aging that reflect early AD pathology. The proposed study will focus on attention deficits as an early marker of AD risk and examine the relationships between AD-related pathology and cholinergic neurotransmitter mechanisms that may underlie the contribution of attention deficits to subjective cognitive complaints in aging. The ultimate aim of the study is to identify the role of attention network changes in subjective cognitive decline and whether attentional changes inform early detection of pathological cognitive aging, using EEG and fMRI as complimentary neuroimaging approaches. Anticholinergic challenge will be employed to model AD progression and examine the relationships between cognitive complaints, attention, and AD pathology. The results of this study will improve our understanding of attention network changes in a population at increased risk for AD and help support future work developing markers of AD risk.

Environment: Mentoring, collaborations, and resources available through the Department of Psychiatry and Behavioral Sciences, the Center for Cognitive Medicine, and the Vanderbilt Alzheimer’s Disease Research Center provide an ideal environment to support Dr. Albert’s transition to independent funding in the near future and leadership in the field of attentional changes in cognitive aging.

Lauren Wareham, PhD
Assistant Professor
Ophthalmology
Began VFRS in July 2022
Appointed to K12 in July 2023

Neuronal-Glial-Vascular Interactions in Age-related Degenerations

Neurons are metabolically demanding, relying on synchrony with the blood supply to exchange energy substrates and waste products in a phenomenon known as “neurovascular coupling”. Neurovascular interactions are important in optic neuropathies, in which the retinal ganglion cell (RGC) projection to the brain degenerates and causes blindness. Of these, glaucoma is the most burdensome, afflicting more than 120 million people worldwide, representing the leading cause of irreversible blindness. Glaucoma progresses with age through sensitivity to intraocular pressure (IOP) conveyed as stress to the unmyelinated axon segment as it leaves the retina through the optic nerve head. Treatment in the clinic serves only to delay progression, with many patients still experiencing vision loss. The scientific objective of this career development proposal is to test how failure of neurovascular coupling influences RGC axon survival in glaucoma. The long-term goal is to understand the role of neurovascular dysfunction in glaucoma and other optic neuropathies for the purpose of identifying novel therapeutic targets to slow or prevent vision loss.
In this proposal Dr. Wareham will use an innovative imaging modality, developed through her collaboration with co- mentor Dr. Kenny Tao, Ph.D., that enables longitudinal in vivo retinal and optic nerve vasculature imaging in mice. Aims 1 and 2 will use this imaging modality to investigate how cGMP signaling and two primary risk factors in glaucoma (age and IOP) affect neurovascular coupling in the retina, impacting RGC axon survival. In Aim 3, harnessing tissues from Aims 1 and 2, she will investigate how cGMP signaling, age, and IOP alter astrocytic networks in the retina, impacting RGC vulnerability in glaucoma.
The work described in this proposal aims to identify key neurovascular mechanisms in glaucoma pathophysiology. With a strong background in laboratory research, a solid mentorship plan that includes experts in her research field, and significant progress already underway in these experiments, Dr. Wareham is excited to use the additional protected research time and funds from the Vanderbilt Faculty Research Scholars Program to transition to independence and acquire extramural research funding.

Fabien Bock, MD, PhD
Instructor
Nephrology
Began VFRS in October 2022
Received K08 in July 2023

Neuronal-Glial-Vascular Interactions in Age-related Degenerations

Polarized epithelial tubes are critical for an intact kidney. They control water, electrolyte, and nutrient homeostasis, all of which are deranged in chronic kidney disease. These specialized epithelia require a highly organized actin cytoskeleton that determines cellular shape and function. During renal epithelial repair, the actin cytoskeleton of proliferating cells is rapidly re-organized to form the complex polarized architecture of an epithelial tube. The small Rho GTPase Rac1 is a multifunctional molecular switch and a master regulator of the actin cytoskeleton. We recently demonstrated that Rac1 is required to maintain actin cytoskeletal integrity, epithelial polarity, and cell shape of the mature collecting duct (CD) epithelium. It is still unknown how the actin cytoskeleton is regulated in epithelial cell repair and what role Rac1 plays in this process. For coordinated epithelial tube regeneration, epithelial cells need to rapidly progress through the cell cycle and divide in the correct direction along the tissue plane by undergoing oriented mitosis. A critical step in renal epithelial repair is the activation of the master mitotic kinase cyclin B–CDK1 complex which drives the G2/M transition and prepares the actin cytoskeleton for oriented mitosis. Correctly orienting the mitotic spindle in a confined tight epithelial space is a challenging process, which requires the cells to round up against the pressure of their neighboring epithelial cells. This so-called mitotic rounding depends on the actin cytoskeleton forming a dense contractile actomyosin cortex, which is tethered to the cell membrane by ERM Proteins (Ezrin), a known target of Rac1 and its main effector p21-activated kinase (Pak1). Defects in mitotic morphology lead to spindle misorientation, which cause cell cycle delays, cell death and abnormal repair. How actin cytoskeletal dynamics are molecularly coordinated and how the cell shape is connected to cell cycle control during these critical biological processes in kidney repair is not known. After we identified a role of Rac1 in CD homeostasis we hypothesized that it also plays a role in repair. We therefore deleted Rac1 in the collecting duct after development was complete and performed reversible unilateral ureteric obstruction (R-UUO). The mutant epithelium was unable to restore normal collecting duct morphology and persistent injury led to excessive tubule dilation. The repairing Rac1 mutants in vivo showed defects in the actin cytoskeleton during mitotic rounding, misoriented cell division, they were unable to proliferate and demonstrated lower total and nuclear levels of the mitotic cyclin B1. Consistent with these data, we found defective mitosis of wounded Rac1-deficient epithelial cells in vitro suggesting that Rac1 is required to normally progress through mitosis in repair. This forms the basis for our hypothesis that Rac1 controlled actin-dependent mitotic morphology mediated via its effector Pak1 and the linker protein Ezrin is required for oriented cell division to promote tissue repair, which will be tested in the following aims. Aim 1: Define the role of Rac1 in renal epithelial repair. Aim 2: Define the mechanism whereby Rac1 controls renal epithelial proliferation in repair.

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