Vanderbilt University Medical Center

NIH Research Projects · FY 2025 · 2024-03

Rhythm and timing are critical to successful social interactions as rhythm sensitivity enables us to form predictions and adapt and coordinate our behavior with each other. This is particularly evident during spoken communication such as through the occurrence of conversational entrainment (or convergence), in which interlocutors temporally adapt their speech patterns to those of their partner. We recently demonstrated links between rhythm and speech entrainment by adapting a novel and automated beat-tracking algorithm, originally designed for use with musical rhythms, to speech in order to reveal the underlying metrical timing of spoken utterances. We observed that typically developing adults converge their speech rhythms during spontaneous conversation, suggesting an underlying rhythm mechanism that is present in spoken communication. This conversational entrainment process occurs automatically but is also moderated by social factors: Greater conversational entrainment occurs between dyads with higher versus lower social agreement throughout the interaction. These results, which suggest that both underlying rhythm processing and situational social factors contribute to interpersonal communication, inform mechanisms of social communication in typical development, as well as disruptions in social communication in autism (ASD). A common and lifelong disorder, individuals on the autism spectrum exhibit challenges in rhythm and timing of social communication and interaction including reduced interpersonal coordination. Individuals on the autism spectrum also exhibit impairments in non-social rhythm skills, with particular difficulties perceiving and synchronizing motor movements to a regular auditory beat. Building on our prior work, the current project proposes that impairments in flexibly tracking and updating rhythmic behavior underlies challenges across sensorimotor and social communication domains in autism. This R21 study investigates underlying processes and outcomes of conversational entrainment in adults with and without autism including the relationship between sensorimotor synchronization and conversational entrainment (Aim 1), adaptation to dynamic social factors as a moderator of conversational entrainment (Aim 2), and conversational entrainment as a predictor of social affiliation (Aim 3). In accordance with PA-21-200, this project advances research into the role of sensory, motor, and social factors in social interactions and communication in autism. Results will inform theories of communication impairment focused on specific rhythmic processes as an underlying mechanism disrupted in autism and demonstrate how individual and dyadic attributes contribute to social communication success.

NIH Research Projects · FY 2026 · 2024-03

Project Summary We propose to develop and optimize Susceptibility Weighted MRI (SWI) for the human SC in vivo at 7T and 3T and apply/evaluate/validate in patients with MS to identify abnormal venous hallmarks of MS pathology. We observed abnormally large anterior/posterior spinal veins, central vein sign (CVS), paramagnetic rims around lesions and increased contrast from the venous plexus surrounding the SC are all present in the MS SC compared to healthy volunteers. Yet, SC SWI has not been adequately optimized and validated at any field strength. We address the knowledge gap of understudied SC SWI, and evaluating and validating in MS, opening the door for application to pathologies that have previously been studied in the brain such as traumatic injury, microbleeds, SC compression, and other vascular abnormalities. Our goal is to develop, optimize, and apply/evaluate/validate SC SWI using both clinical (3T) and research (7T) field strengths in healthy controls relapsing-remitting MS patients. SWI has implemented clinically in the brain for years. Recent work show that 7T and 3T SWI is useful for improving diagnostic specificity in MS, providing evidence for expanding/evolving lesions, and insight into the biogenesis and evolution of the disease. While the same literature points to the need to evaluate the SC with SWI, and post-mortem indicates similar pathological hallmarks in the SC in MS, to date, exceedingly few studies have attempted SC SWI. And in those, brain-optimized SWI were moved into the SC. There are no SC targeted developmental SWI studies and no studies at 7T. Of course, application of developed techniques is critical to the validation process. One of the radiological “wins” for MS has been identifying hallmark central vein sign (CVS) and/or paramagnetic rims indicating lesion evolution which has led to controversial discussions about improved diagnostic specificity. Recently a consensus prepared by the North American Imaging in MS consortium (NAIMS), of which the PI is a contributor, describes expectations for brain SWI and argues for SC SWI to solidify SWI as improving diagnostic specificity. Yet there are no studies providing this evidence. Operating under the premise that brain SWI has provided rich information about diseases such as MS, TBI, etc, has improved our understanding of MS and MS lesion evolution, and armed with our preliminary data at 7T that demonstrates MS patients have 1) abnormally large anterior spinal veins, 2) some lesions have apparent CVW and paramagnetic rim, and 3) abnormally apparent venous plexus surrounding the SC, we propose that developing and optimizing a SC-specific SWI acquisition and post- processing toolbox would offer unique ability to assess the venous structures of the SC and lead to further opportunities in other diseases. 7T is considered the gold standard for SWI in MS in the brain, and we will explore that, but recognize that 3T is more clinically relevant. Thus we will optimize across both 3T and 7T using vendor stock sequences and advanced, sequences. The former to provide consideration for multi- vendor, multi-site studies, and the latter, to vet and validate SWI as a biomarker for SC vascular abnormalities.

NIH Research Projects · FY 2026 · 2024-02

PROJECT SUMMARY/ABSTRACT One in 10 pregnant women in the United States smokes at the beginning of pregnancy, increasing the risk of miscarriage, preterm birth, low birth weight, and neonatal death. Among these women who smoke, virtually all report a desire to quit, yet only 25% abstain throughout pregnancy. A known behavioral economic mechanism behind this “intention-action gap” is delay discounting (DD), the tendency to discount delayed outcomes when choosing present actions. Because the negative consequences of smoking are delayed, whereas its benefits are immediate, DD reinforces tobacco use even when one desires abstinence. In pregnancy, existing smoking cessation pharmacotherapies are generally considered unsafe and/or ineffective, and thus DD may provide a novel therapeutic target for smoking cessation treatment. However, three critical knowledge gaps currently limit this possibility: (1) the optimal approach to measuring DD in the context of addiction is unclear, (2) the longitudinal relationship between DD and smoking in pregnancy is poorly characterized, and (3) no pharmacologic agent for reducing DD that is safe in pregnancy is known. To address these gaps, I will pursue a set of training and research activities centered around “Measuring and Modifying Delay Discounting as a Mechanism of Smoking in Pregnancy (The MM-DD Study)”. Leveraging (1) the Effort Delay Discounting Task (EDDT), a novel mobile phone-based instrument that I have developed for measuring DD based on willingness to exert cognitive and physical effort, (2) a mentorship committee with expertise in nicotine dependence, behavioral economics, neuroscience, and structural equation modeling, and (3) an ongoing NIH-sponsored RCT of high-dose omega-3 polyunsaturated fatty acid supplementation for pregnant smokers, my SPECIFIC AIMS are to: (1) jointly measure and test the factor structure of cognitive effort DD, physical effort DD, and monetary DD, (2) characterize the longitudinal relationship between DD and smoking in pregnancy, and (3) safely test the modifiability of DD in pregnancy through a clinical trial. In parallel with these Aims, building on previous training in behavioral economics, I will pursue four integrated training objectives, in which I will gain: (1) advanced expertise in DD research, (2) foundational knowledge of the neurobiology of addiction, (3) competence in structural equation modeling, and (4) skills to build scholarly productivity in biomedical research. IMPACT: This career development award will (1) advance addiction science by systematically measuring and attempting to modify DD as a novel therapeutic target for smoking cessation in pregnancy and (2) advance my career by enabling me to secure R01 funding to further investigate novel approaches to measuring and modifying DD across addiction contexts. In so doing, this award will position me to become an independent investigator of interventions that prevent and treat addiction by targeting its behavioral economic mechanisms, including DD.

NIH Research Projects · FY 2026 · 2024-02

Project Abstract Pulmonary hypertension (PH), which causes right ventricular failure (RVF), is a life-threatening disease with limited long-term treatment options and a 5-year survival rate of only 50% despite advances in medical therapy, which temporarily ameliorate it. Lung transplant is the only definitive treatment; however, PH patients can acutely deteriorate and become ineligible for transplant. It is difficult to predict and intervene prior to RVF due to the limited physiologic understanding about end-stage PH and also because patients with severe PH do not tolerate exercise testing that would otherwise better predict their prognosis. Mechanical cardiopulmonary support (MCS) technology, notably extracorporeal membrane oxygenation (ECMO), is used sometimes to rescue patients with PH-RVF and has occasionally served as a bridge to lung transplant. However, it is a limited intervention because of its many technological shortcomings: its complexity of operation, poor durability and biocompatibility, and bulky size that limits patient mobility and ambulatory use. Moreover, ECMO does not address the specific physiologic and metabolic deficits incurred by end-stage PH patients, which change drastically between rest and exercise states and remain poorly characterized. Due to the ethical challenges and barriers of studying severe PH in clinical subjects, our team proposes to use a large animal model to address this challenging disease. We will use our group’s high-fidelity large animal model of PH-RVF that utilizes progressive pulmonary artery banding approach in sheep subjects. Our prior work with this animal model has demonstrated that the sheep subjects accurately recapitulate the clinical pathophysiology of PH that spans across multiple organ systems. Using our established expertise with this animal model, we will first reveal the exercise limitations associated with this severe disease, and use this physiologic understanding to develop a more durable, wearable MCS that can support patients with end-stage PH-RVF. Under Aim 1, the PH-RVF sheep subjects will undergo treadmill exercise testing to characterize the longitudinal changes in cardiopulmonary reserve, metabolism, and exercise tolerance during disease progression. Under Aim 2, the PH-RVF sheep will receive 14 days of MCS to address the specific physiologic and metabolic deficits that were characterized under Aim 1. The novel portable MCS system consists of low-resistance, low-profile, highly biocompatible gas exchangers coupled with a ventricular assist device pump. The mode of attachment will be varied between two optimized configurations (right atrium- left atrium, RA-LA, and right atrium-aorta, RA-Ao) that were narrowed down in our team’s previous investigation, R01HL140231. During 14 days of wearable device support, RV and device function will be studied under conditions of dynamic exercise induced stress using multi-scale analysis to assess the impact on RV recovery and end-organ function. We hypothesize that RA-LA will better provide physiologic restoration of blood flow, RV function, and exercise tolerance compared to RA-Ao.

NIH Research Projects · FY 2026 · 2024-02

Project Summary The current standard of care for evaluation and surveillance of regional and metastatic disease in advanced stage head and neck squamous cell carcinoma (HNSCC) is 18F-FDG-PET/CT scan, which is highly sensitive but not specific and as a result identifies a significant number of indeterminate lesions. Interrogation of these lesions leads to unnecessary procedures, overdiagnosis/upstaging, patient anxiety, increased cost, and possible treatment delays due to the need for repeat imaging. To address this, we will investigate whether PET imaging using a radiolabeled anti-EGFR antibody (89Zr-panitumumab) can be used to detect cancer with high specificity. We will use 89Zr-panitumumab PET/CT to assess HNSCC patients with indeterminate findings on 18F-FDG PET/CT and determine the positive predictive value of 89Zr- pan PET/CT for detection of metastatic disease. The nonspecific nature of 18F-FDG-PET/CT also limits its usefulness in detecting small primary tumors in patients with oropharyngeal cancer. This study will assess the effectiveness of 89Zr-pan PET/CT imaging for detecting unknown primary tumors in patients presenting with an enlarged neck node without identification of the primary tumor on exam or conventional imaging. Successful detection of the primary tumor using 89Zr-pan PET/CT would avoid the invasive biopsies typically required to locate the primary tumor in these patients. The novel imaging modality developed in this study could overcome the limitations of metabolic 18F-FDG PET/CT imaging, thereby reducing the number of invasive procedures and avoiding delays in treatment due to indeterminate findings.

NIH Research Projects · FY 2026 · 2024-02

in vivo MR characterization of pathological changes in liver microstructures Summary Liver biopsy is currently the gold standard for diagnosing and evaluating the extent of most liver diseases, but it is an invasive procedure that carries risks such as sampling errors, rare complications, intra/inter-observer variability, and significant patient anxiety. Noninvasive tests and imaging techniques for the diagnosis and management of liver diseases have gained significant interest due to the limitations of liver biopsy, particularly for identifying nonalcoholic steatohepatitis (NASH), the most severe form of Nonalcoholic fatty liver disease (NAFLD). Due to the obesity pandemic and type 2 diabetes, an increased number of NASH patients (~ 27 million NASH patients by 2030 in the US alone) is expected in the near future. The ability to differentiate NASH from simple steatosis is critically important for the clinical management of NAFLD patients. Currently, NASH is exclusively diagnosed invasively through liver biopsy to assess steatosis, inflammation, ballooning and fibrosis. While MRI-based PDFF and elastography have been shown to reliably quantify steatosis and fibrosis, respectively, the lack of a non-invasive tool to assess inflammation in NASH remains a significant gap in the daily clinical care of this common disease. Our lab has developed a novel concept that cell size and cell density could serve as indicators of hepatic inflammation and has developed a multi-compartment diffusion MRI-based method called in vivo quantitative Temporal Diffusion Spectroscopy (qTDS), which quantifies cell size and cell density by fitting multi-b value- multi-diffusion time fat-suppressed diffusion-weighted MRI signals to a three-compartment (blood, intra and extracellular water) signal model. Recently, qTDS has shown promising results in in vivo NASH patients and ex vivo human liver specimens with different pathologies, including normal liver tissues, cirrhosis, steatosis, and cirrhotic regenerative nodules (CRN). This grant proposal aims to establish the relationship between qTDS-derived parameters and histology values in a mouse model of NASH, optimize a clinical qTDS protocol for reliable in vivo quantification of cell size and cell density in human livers within a short period (less than 12 minutes), and demonstrate the efficacy of qTDS in characterizing hepatic inflammation, a key diagnostic component for differentiating NASH from simple steatosis. Successful completion of these aims will provide a solid foundation for a large-scale clinical trial to develop a noninvasive diagnostic metric for NASH, offer a standard qTDS imaging protocol that can be implemented on clinical 3T MR scanners, and provide a qTDS data processing toolbox that can be downloaded online. These outcomes will advance the use of noninvasive microstructure imaging in the diagnosis and management of liver diseases.

NIH Research Projects · FY 2026 · 2024-02

PROJECT SUMMARY 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.

NIH Research Projects · FY 2026 · 2024-01

PROJECT SUMMARY/ABSTRACT Duchenne and Becker muscular dystrophy (DMD/BMD) are devastating diseases with no cure resulting in loss of ambulation, respiratory failure, cardiomyopathy, and premature death. Dystrophin associated cardiomyopathy (defined here as CM) is the leading cause of death in DMD/BMD, and an under-studied concern in DMD and BMD mutation carriers (MDC). CM progression is variable and poorly described in the current era. There are no blood or imaging biomarkers that can predict the pace of progression or the risk of early mortality. More importantly, there are no established cardiac outcome measures. Novel, targeted therapeutics are necessary to treat CM, but these significant knowledge gaps make clinical trials challenging. A better understanding of DMD/BMD/MDC cardiovascular disease progression and the identification of surrogate outcome measures are critical for the field to advance. To address these obstacles, we propose to leverage the Duchenne muscular dystrophy cardiac care consortium (DMDCCC). Created with grants from the NHLBI and the FDA, this consortium consists of eight high-volume sites with similar DMD/BMD/MDC cardiovascular treatment and diagnostic protocols, including surveillance CMR imaging every 1-2 years. This proposal will create a comprehensive prospective registry of DMD/BMD/MDC patients with meticulously collected clinical data and cardiac magnetic resonance (CMR) images; we anticipate enrollment of 950 patients with over 4000 CMR studies. This cohort will be used to better define the progression of CM and to determine associations with mortality. The central hypothesis of our proposal is that integrated statistical modeling based on advanced imaging can improve prediction of CM progression and mortality. Aim 1 will create a comprehensive cohort of DMD/BMD/MDC patients and model the progression of CM. Aim 2 will determine cardiovascular measures that are associated with CM mortality or rapid progression using novel, data-driven, personalized machine learning models. Aim 3 will create a portal for DMD/BMD/MDC centers to determine patient risk. This multi-PI proposal leverages expertise in clinical care, cardiac imaging, biomedical engineering, complex image analysis, and neural networks. To our knowledge, this study will create the largest cohort of DMD/BMD/MDC patients with CMR images, allowing for a better understanding of CM progression and identifying biomarkers that associate with poor outcomes. The resulting risk portal will provide clinicians all over the world with a method to assess their patient’s risk in real time, allowing intensification of therapy for those deemed high risk. By building on prior productive collaborations, particularly that of the DMDCCC, this proposal will expand our understanding of CM, improving clinical care and future cardiac-specific therapeutic trials.

NIH Research Projects · FY 2025 · 2024-01

PROJECT SUMMARY/ABSTRACT Language outcomes are highly heterogenous in autism and can impact long-term psychosocial, educational, and vocational outcomes for children on the autism spectrum. Thus, there is a pressing need to identify novel approaches to language intervention, ideally those that can be implemented in early stages of development, when brain and behavior are most plastic. Many have begun to consider “pre-emptive” interventions for infants with autistic older siblings (Baby Sibs), who are highly likely be diagnosed with autism or developmental language disorder themselves. The Looking and Language Project (LoLa) seeks to (a) validate a theoretical model of language development in Baby Sibs, whereby looking to the mouth of a speaker increases later language skill via caregiver-child engagement and prelinguistic vocal complexity and to (b) systematically test the effects of a novel intervention that encourages looking to audiovisual speech by moving the referent of interventionist talk near the mouth (Milieu Teaching-AV). I will utilize the K99 portion to conduct a longitudinal correlational study with 52 Baby Sibs and follow them from 6 months to 15 months. I will additionally use this period to evaluate the feasibility of Milieu Teaching-AV with this population and assess parent attitudes towards and perceived barriers of “pre-emptive” interventions for Baby Sibs. The training portion of the K99 will focus on (a) mastering strategies necessary to train coaches to fidelity on intervention procedures, (b) developing expertise in implementation science methods, and (c) mastering advanced methodological and statistical approaches to randomized controlled trials (RCTs). During the R00 phase, I will evaluate the effects of Milieu Teaching-AV compared to a business as usual control in 60 Baby Sibs within the context of an RCT. This RCT will examine direct effects on (a) looking to the mouth of a speaker, (b) caregiver-child engagement, (c) prelinguistic vocal complexity, and (d) expressive and receptive language. The RCT will also allow for an exploratory look at moderated effects (i.e., determining for whom the intervention yields optimal outcomes) of the intervention on the basis of (a) language ability and (b) caregiver-child engagement at study entry and (c) preliminary autism diagnosis at 15 months. Additionally, I will evaluate the acceptability of the intervention and outcome measures for key interested parties, including adolescent and adult siblings of autistic individuals (i.e., grown-up Baby Sibs), autistic-self advocates, caregivers of autistic children, and community early intervention providers. NOVELTY AND IMPACT: If my hypotheses are born out, the proposed project will provide empirical support for a novel approach to preemptive intervention that is acceptable to key interested parties and motivated by theory and a large extant literature involving autistic children. The results of the RCT will provide the groundwork for my first R01 submission to further evaluate and establish the efficacy of this approach.

NIH Research Projects · FY 2025 · 2024-01

Patients with rare diseases (RDs) face tremendous physical, psychosocial, and economic suffering in their protracted journeys toward diagnosis and therapy. These journeys, known as diagnostic and therapeutic odysseys, are riddled with diagnostic delays and difficulties finding effective treatment strategies. Undiagnosed Diseases Network (UDN) at the NIH was established to diagnose individuals who a The re living with the often dire consequences of an RD. Despite the UDN’s comprehensive diagnostic approach, 70% of patients remain undiagnosed, highlighting the need for novel diagnostic strategies. The diagnostic approach at the UDN currently relies on manual extraction of RD phenotypes from clinical notes in electronic health records (EHR), which is laborious and time-consuming. A promising alternative is to leverage natural language processing (NLP) models, which can automatically extract fine-grained RD phenotypes from clinical notes, to support timely diagnosis at the UDN. Existing general NLP models, however, are not suitable for supporting diagnosis at the UDN. Furthermore, NLP models have limited impact on diagnosis due to scarce infrastructure for delivering them to the clinic, highlighting the need to bridge the implementation gap between NLP and practice. Even after diagnosis, patients often undergo therapeutic odysseys. Despite advancements in gene therapy, evidence shows that genetics alone do not account for the wide diversity in RD phenotypes. Exposures also play a critical role, but less is known about how their causal effects vary across individuals. This knowledge gap underscores the need to elucidate the complex phenome-genome-exposome interplay on an individual-level basis, which is crucial in informing personalized disease management strategies. The overall objective of this proposal is to develop and implement advanced statistical machine learning (ML) methods aimed at shortening RD odysseys. During the K99 phase, I will develop a novel NLP system to extract RD phenotypes from clinical notes (Aim 1) and implement it using REDCap at the Vanderbilt UDN (Aim 2). During the R00 phase, I will leverage phenomic, genomic, and exposomic data from All of Us and build a causal inference framework that uses modern statistical ML techniques to estimate personalized causal effects of exposures on RD phenotypes (Aim 3). The expected outcomes are a novel, open-source NLP system for RDs, an implementation framework using REDCap to support timely diagnosis at the Vanderbilt UDN, and an advanced, reproducible causal inference framework to elucidate the complex phenome-genome- exposome interplay underlying RDs on an individual-level basis. During the K99 phase, the PI will be mentored by experts in NLP, REDCap, EHR phenotyping, and RDs at Vanderbilt, and develop competencies in those areas. This proposal will yield results for subsequent studies on data-driven approaches aimed at shortening RD odysseys. This award will provide the necessary training to supplement the PI’s expertise in statistical ML and causal inference and help her transition into an independent career in biomedical data science.

NIH Research Projects · FY 2026 · 2024-01

Smooth muscle cells (SMCs) play major roles in atherosclerosis, a leading cause of cardiovascular disease (CVD). SMCs can be beneficial or detrimental in atherosclerosis, depending on their transdifferentiation trajectories into atheroprotective (e.g., fibroblast-like cell) or atherogenic (e.g., macrophage) cell types. My recent work, combining an SMC-lineage tracing murine model and single-cell RNA sequencing (scRNA-seq), revealed a novel SMC-derived cell type, “SEM” cell (termed because of co-expression of stem cell, endothelial cell, and monocyte markers). SMC-derived SEM-like cells have also been identified by other groups. SEM cells highly express genes related to proatherogenic functions (e.g., inflammation) and may be the precursors for other SMC- derived cell types (e.g., fibrochondrocyte, macrophage), through which SEM cells may modulate vulnerability and stability of atherosclerotic lesions. My proof of principle studies in mouse models showed that activation of retinoic acid (RA) signaling inhibited SMC to SEM cell transition, reduced atherosclerotic burden, and promoted fibrous cap stability in atherosclerosis. These findings suggest the following central hypotheses: 1) activation of RA signaling attenuates SMC to SEM cell transition by directly suppressing expression of key SEM cell marker genes; 2) activation of RA signaling represses proatherogenic functions (e.g., inflammation) of SEM cells during disease progression; 3) activation of RA signaling is beneficial in established atherosclerosis and accelerates disease regression by promoting SEM cell atheroprotective functions and differentiation trajectories while suppressing atheroprone features of SEM cells. These hypotheses will be addressed through the following aims: Aim 1 (K99 phase) will determine if RA signaling inhibits the SMC to SEM cell transition via RAR/RXR/EZH2- mediated repression of SEM cell marker genes; Aim 2 (K99 phase) will determine if RA signaling attenuates SEM cell inflammation during atherosclerosis progression through LXR-mediated repression of inflammatory genes; Aim 3 (R00 phase) will apply SMC-lineage tracing and atherosclerosis regression mouse models to determine if RA signaling drives differentiation trajectories of SEM cells towards atheroprotective rather than atherogenic cell types in advanced atherosclerosis (Aim 3A) and promotes SEM cell apoptosis and subsequent resorption via macrophage efferocytosis during disease regression (Aim 3B). The proposed studies will be accomplished in the setting of a comprehensive career development program designed to provide the candidate with scientific and leadership skills that facilitate the successful transition to an independent investigator in the field of atherosclerotic CVD. At the K99 phase, the candidate will continue to obtain expertise in molecular, cellular, and biochemical techniques as well as SMC-lineage tracing and mechanistic and functional investigation of RA signaling and SEM cells in atherosclerosis mouse models for progressing, advanced, and regressing lesions. The expert advisory team will guide the candidate in research training, manuscript and grant proposal preparation, and ultimately in the transition to an independence career over the course of the award period.

NIH Research Projects · FY 2026 · 2024-01

Project Summary/Abstract Michael Combs, MD, MS is a Pulmonary and Critical Care physician at the University of Michigan. This K23 proposal outlines the mentored research and training required for Dr. Combs to achieve his long-term goal of becoming an independent physician-scientist and a leader in understanding the factors which cause and perpetuate chronic rejection after lung transplantation. The leading cause of long-term morbidity and mortality after lung transplant is chronic rejection, also called chronic lung allograft dysfunction (CLAD). Currently, no effective prediction models exist either for 1) the development of CLAD among healthy lung transplant recipients and 2) survival after CLAD development. This key research gap limits both clinicians’ ability to personalize care and researchers’ ability to design, power, and stratify clinical trials. CLAD develops and evolves within a complex interplay of 1) altered lung microbiota, 2) recipient-derived immune responses, and 3) fibrotic remodeling orchestrated by activated allograft-derived mesenchymal cells. In previously published studies, Dr. Combs has demonstrated that signals in bronchoalveolar lavage (BAL) fluid from across these biological domains represent novel risk factors for CLAD with plausible roles in disease pathogenesis. In this proposal, Dr. Combs will develop clinical risk prediction models for CLAD development and post-CLAD survival which integrate patient-specific clinical data and the biological signals in BAL fluid. By completing these Aims, Dr. Combs will develop new experience and expertise in patient-oriented clinical research, microbiome-focused computational biology, advanced statistical analysis (including machine learning approaches), and transplant-focused lung immunology. His training will be supervised by his co-mentors, Robert Dickson, MD, and Vibha Lama, MD, MS, who have decades of experience and expertise in clinical research, mentorship of aspiring physician-scientists, and the translational study of lung transplantation, the lung microbiome (Dr. Dickson), and mesenchymal cell biology (Dr. Lama). His training will further be supported by an advisory committee with expertise in advanced computational biology and statistical modeling/machine learning approaches (Susan Murray, ScD) and pulmonary immunology (Bethany Moore, PhD). Completion of this progressively independent research project will lead to subsequent R03 and R01 applications validating these prediction models of CLAD development and post-CLAD survival in prospective, multi-center cohorts.

NIH Research Projects · FY 2026 · 2024-01

PROJECT SUMMARY/ABSTRACT Cognitive impairment, including Alzheimer’s Disease and Related Dementias (ADRD), and cardiopulmonary dysfunction following COVID-19, are components of the chronic syndrome known as Long COVID (LC). LC is an unprecedented public health crisis leading to cognitive, mental health, and functional disabilities for millions of people living in the United States and around the world. Large epidemiologic studies have demonstrated that the risk of ADRD increases multifold in many old and young patients following even mild SARS-CoV-2 infection. Patients with LC also frequently experience profound limitations in physical function and exercise intolerance that, when paired with ADRD, are life altering and result in inability to work and lead a family. Rapidly growing evidence links the clinical manifestations of LC to pathophysiologic mechanisms of abnormal inflammation and immune dysregulation. There is a driving, unmet need for robust clinical trials directly targeting immune dysregulation to reduce ADRD and cardiopulmonary injury related to LC. Our central hypothesis is that immunomodulators may be the most effective treatment for these sequelae of LC. Baricitinib is an immunomodulator (JAK1/2 inhibitor) that is FDA-approved to treat acute COVID-19 infection as well as certain autoimmune chronic diseases like rheumatoid arthritis. JAK1/2 signaling is a cardinal driver of both systemic and neuroinflammation. Our study, the Randomized trial EValuating Baricitinib on pERSistent nEurologic and Cardiopulmonary Symptoms of Long COVID (REVERSE-LC), will enroll 500 patients with LC and cognitive impairment at high risk for long-term ADRD across 4 sites to test the hypothesis that 6 months of baricitinib versus matched placebo will improve neurocognitive and physical function in LC. Aim 1 will measure the trajectory of neurocognitive function at enrollment, 6- and 12-months in baricitinib versus placebo patients using an objective neuropsychological battery as well as patient-reported cognitive function. Aim 2 will measure physical function using cardiopulmonary exercise testing and other functional measures in addition to patient-reported physical symptoms in patients treated with baricitinib versus placebo. Aim 3 will evaluate the effect of baricitinib versus placebo on plasma, cerebrospinal fluid, and neuroimaging inflammatory markers at enrollment, as well as 6- and 12-month follow-up study visits in patients with LC to identify inflammatory mediators of neuropsychological (ADRD) outcomes. The REVERSE-LC trial is novel in targeting immune dysregulation and inflammation for patients with LC and is based on our growing understanding of the mechanism of this emerging, post-infectious cause of rapidly-acquired ADRD risk. Regardless of the outcome of REVERSE-LC, this study will provide crucial insights into treatment of ADRD, sequelae of COVID, and disease pathogenesis. This investigation will also establish an innovative trial platform by which to test future interventions for rapidly-acquired neurocognitive dysfunction, cardiopulmonary disease, LC, and other age- related comorbidities leading to ADRD. It will advance the science of aging brain disease and disability.

NIH Research Projects · FY 2025 · 2024-01

Realizing Accelerated Progress, Investigation, Implementation, and Dissemination in Learning Health Systems (RAPID-LHS) Major gaps exist between the generation of clinical evidence, widespread implementation of proven interventions, and formulation of informed policy. The learning health system (LHS) aims “to generate and apply the best evidence for the collaborative healthcare choices of each patient and provider; to drive the process of discovery as a natural outgrowth of patient care; and to ensure innovation, quality, safety, and value in healthcare.” Vanderbilt will formally train a cadre of RAPID-LHS scientists well versed in the best methods for integrating patient-centered outcomes, evidence implementation, and evaluation of health policies within the LHS. We propose to establish the Realizing Accelerated Progress, Investigation, Implementation, and Dissemination in Learning Health Systems (RAPID-LHS) Center to train faculty to conduct high-impact research that is embedded in the LHS. In cross-training scientists and embedding them in the health system, we will draw together scientists and mentors across disciplines and model the team science integral to LHS. We will provide forums that demonstrate the intellectual productivity and practical benefits of interdisciplinary research in advancing human health. We endorse team approaches to filling gaps in knowledge and translating knowledge into application. A diverse pool of scientists from internal (Vanderbilt University Medical Center) and partner health systems (Meharry Medical College, the VA Quality Scholars Program, Vanderbilt University, Vanderbilt Health Affiliated Network, Safety Net Clinics, and the STAR Clinical Research network) is available. Career milestones for scientists will include impact on health equity, population health and patient health, publications and grants. LHS lessons learned during project development will advance LHS science. All RAPID-LHS scientists will conduct embedded projects in conjunction with Research and Data Analysis Core (RDAC), focusing on 1) patient-centered outcomes research, 2) dissemination and implementation science, 3) health policy/public health, 4) stakeholder engagement and health equity, and 5) methods advancement. Each embedded project will begin with in-depth feedback from a Community Engagement Studio and LHS Platform Studio, which will follow a structured process to ensure that the clinical question is important and that the research is needed. All scientists will then meet with RDAC mentors to determine their needs and prepare a structured workplan. The research will use a health equity lens to prevent unintended consequences of interventions in the health system. Each scientist will engage in integrated didactic and experiential training through the Research Education Core. The RAPID-LHS scientists’ progress will be facilitated by VUMC’s rich environment for training in LHS and supporting projects with real-world impact.

NIH Research Projects · FY 2026 · 2024-01

PROJECT SUMMARY/ABSTRACT Rates of emergency department (ED) visits for psychiatric emergencies in adolescents have increased substantially in the past decade, including for suicidality, self-harm, and aggression. A substantial number of these adolescents will be discharged home from the ED with referrals to outpatient mental health treatment. Yet, engagement in outpatient mental health treatment among adolescents is low, and rates of repeated emergency services utilization are high, highlighting the need for better supports for these youth and families. While effective, brief interventions have been developed to directly support adolescents at the time of their ED visit, no evidence-based interventions have been developed to support parents of these youth. Further, the period following an emergency visit is known to be high risk, yet no existing services support parents during the transition home, while waiting for connection to outpatient services. In this intervention development study, we seek to iteratively develop, refine, and test an automated, text-messaging intervention for parents of youth discharged from the ED after a psychiatric emergency. The 8-week intervention (iPEACE; intervention for parent education after care in the ED) will directly target (1) parent mental health literacy and (2) parent self- efficacy, with the goal of reducing ED utilization and enhancing outpatient mental health service use and engagement. In the first phase of the study, we aim to develop and refine the intervention with stakeholder feedback. Parents (N=15) will receive the 8-week iPEACE starting immediately following ED discharge. Parents will provide both in-the-moment feedback via text-message surveys and in-depth feedback at the end of the 8-week period via semi-structured qualitative interviews and self-report measures. We will also conduct qualitative interviews with enrolled parents’ children and key ED stakeholders. We will use this feedback to refine the intervention materials. In the second phase of the study, we will conduct a pilot randomized controlled trial (N=90), with n=30 parents randomized to enhanced usual care, n=30 randomized to enhanced usual care with text-message reminders, and n=30 randomized to receive iPEACE. Parents will complete follow-up assessments at 4-, 8- and 12-weeks to assess key intervention targets (self-efficacy and mental health literacy) and outcomes (outpatient mental health service utilization and ED utilization). The goals for the proposed project include: (1) developing and refining the iPEACE text-messaging intervention; and (2) piloting the iPEACE intervention compared to enhanced usual care only and enhanced usual care with text-message reminders to assess key study outcomes and mechanisms to inform a fully-power randomized trial. This R34 has important clinical implications, as findings from this study may support the testing and implementation of a digital health intervention to improve outcomes for high-risk youth and families. The proposed study has the potential to inform the provision of clinical services to support families during high-risk clinical transitions.

NIH Research Projects · FY 2026 · 2023-12

The long-term goal of our research is to identify pro-regenerative to improve liver regeneration. The only curative therapy for end-stage liver disease is liver transplantation as no regenerative therapies exist. Liver transplantation is limited by donor graft supply. Living donor transplantation or split liver transplantation, in which one organ is split among two patients, rely on the regenerative capacity of the liver to restore its mass. The number of these interventions has increased to gap the bridge between demand and supply but post- hepatectomy or ‘small-for-size’ syndrome, which reflect a regenerative failure, present severe complications for which only supportive but no regenerative therapies exist. We have identified a novel hepatic growth factor, neurotrophin-3 (NTF3), that induces hepatocyte proliferation in culture and increases liver mass after administration to rodents. NTF3 is a member of the nerve growth factor family, that is secreted by hepatic stellate cells (HSC) and signals through tropomyosin kinase receptors (TRKs). While HSCs contribute to liver fibrogenesis during injury, HSCs are known to release growth factors which may be critical during liver regeneration. Using a novel HSC-depletion mouse model that used genetically engineered T cells to deplete HSCs after adoptive transfer, we discovered that HSCs maintain liver zonation, hepatocyte proliferation and liver mass. As liver regeneration occurs staggered in a zonal fashion to ensure functioning hepatocytes at any time during the process, liver zonation is critically important for liver regeneration. Our preliminary data indicate that HSCs and NTF3 promote liver regeneration and that NTF3-TRK signaling is relevant to humans as well. As there are known TRK-agonists and FDA-approved TRK-antagonists, our central hypothesis is that HSCs and HSC- derived NTF3 promote liver regeneration and that TRK-agonists improve liver regeneration. We will test our hypothesis in three specific aims: 1. To determine if NTF3 and TRK signaling maintain liver zonation and promote liver regeneration in rodent models of liver regeneration; 2. To establish NTF3 and TRK signaling in human liver, primary hepatocytes and hepatic organoids; 3. To clarify NTF3-TRK downstream signaling pathways in cultured liver cells. Our proposed studies will provide important insights into a novel hepatocyte growth signaling pathway and generate preclinical data to assess TRK-agonists for potential regenerative therapies.

NIH Research Projects · FY 2025 · 2023-12

PROJECT SUMMARY/ABSTRACT The overall objective of this proposal is to further our understanding of the biology and therapeutic potential of C-type natriuretic peptide in hypertrophic cardiomyopathy (HCM). Cardiac fibrosis a key risk factor for the development adverse outcomes in HCM, however, there is no proven medical therapy for HCM that modifies fibrosis in humans, which represents a critical unmet need. The natriuretic peptides ANP and BNP are increased in HCM. However, there is also a third natriuretic peptide, CNP, and we show that HCM is a state of CNP deficiency. CNP is the most potent anti-fibrotic natriuretic peptide, and augmenting CNP is a novel approach to target fibrosis in HCM. However, systemic delivery of CNP requires innovative approaches to minimize CNP degradation. C53 is a potent CNP analog with resistance to degradation. Our preliminary data demonstrate that administration of C53 attenuates the emergence of fibrosis in the 403/+ mouse model of HCM. The objective of this proposal is to validate the anti-fibrotic mechanism of C53 in HCM, and determine if C53 can attenuate or reverse fibrosis in established HCM. To further define the antifibrotic effects of C53 in HCM, the following Specific Aims will be addressed. 1) Define the mechanism by which C53 modifies fibrosis (K99 phase). With tailored training, the candidate will learn and perform established functional in vitro assays using pharmacologic modulators to define the mechanism by which C53 modifies fibrosis. 2) Develop expertise in small animal cardiac MRI to evaluate myocardial fibrosis in vivo (K99 phase). 3) Test the hypothesis C53 can attenuate or reverse established HCM, and validate the molecular and cellular mechanism of C53 in vivo (R00 phase). The candidate’s career goals are to become an independent physician-scientist focusing on innovative approaches to target fibrosis in HCM. The career development plan focuses on learning new skills for in vitro quantification of fibroblast activity, learning advanced histologic quantification of fibrosis, and learning small animal cardiac MRI for evaluation of cardiac fibrosis in vivo. The Merryman lab at Vanderbilt is an ideal environment to acquire such training as Dr. Merryman is an expert in cardiopulmonary mechanobiology and fibrosis. The training received throughout this award will enable the PI to secure an independent research position and lead a multi-faceted, R01-funded research laboratory focusing on fibrosis in HCM. In summary, the PI will utilize this K99/R00 award to establish a program aimed at uncovering new mechanisms of fibrosis in HCM, and evaluate new therapeutic targets. This project will lay the groundwork to further our understanding of the biology and therapeutic potential of natriuretic peptides as antifibrotic agents in HCM, and define the course of the PI’s goal of becoming an independent physician-scientist.

NIH Research Projects · FY 2026 · 2023-12

PROJECT SUMMARY/ABSTRACT In individuals with drug-resistant focal epilepsy, epilepsy surgery can often reduce or eliminate seizures by resection or ablation of regions responsible for seizure generation, or epileptogenic zones (EZs). Successful epilepsy surgery depends critically on accurate and complete localization of these EZs. Current clinical strategies for EZ localization include noninvasive presurgical evaluation, plus invasive intracranial monitoring with stereo- SEEG (SEEG) in over 50% of cases. However, 33-50% of patients continue to suffer from disabling seizures after surgery, as traditional presurgical testing does not consider the connectivity of presumed EZs to other brain regions. We hypothesize that true EZs are network nodes with abnormal and identifiable connectivity patterns, and brain network connectivity measurements may supplement standard clinical testing to guide EZ localization. Here we propose innovative, multimodal studies incorporating structural and functional MRI connectivity measures, resting-state and seizure (ictal) SEEG recordings, and electrically-stimulated cortico-cortical evoked potentials (CCEPs) to help guide surgical decisions and localize “true” EZs using network connectivity. In Aim 1, we will develop a novel supervised machine-learning approach using whole-brain MRI structural connectivity to identify epilepsy subtypes and predict surgical outcomes. These measures may guide initial surgical decisions, and help patients avoid intracranial monitoring when it is not necessary. In Aim 2, we will use a combination of resting-state and ictal SEEG as well as CCEPs to define connectivity fingerprints of true EZs, which we hypothesize will demonstrate increased inward (inhibitory) connectivity at rest but increased outward (excitatory) connectivity at seizure onset (the Interictal Suppression Hypothesis). Using these measures, we will create a combined SEEG connectivity model to supplement traditional ictal interpretation and improve EZ localization. In Aim 3, we will relate SEEG and functional MRI connectivity measures to each other using penalized regression, aligning brain states during both modalities using simultaneous scalp EEG. This will allow us to identify noninvasive functional MRI network measures for EZ localization that are validated by SEEG in the same patients. Our multimodal network approaches will use both electrophysiology and neuroimaging connectivity measures, combining invasive and noninvasive techniques, to ultimately aid accurate EZ localization and guide surgical decisions. Overall, our goal is to develop novel and innovative network measures that can be applied broadly using existing hardware at surgical centers to improve patient care in drug-resistant focal epilepsy.

NIH Research Projects · FY 2026 · 2023-11

Project Summary/Abstract The regulation of luminal surveillance and antigen sampling across mucosal surfaces remains an important and fundamental area of investigation. This is particularly true for the intestinal epithelium, which is constantly challenged to maintain homoeostasis with the complex microbiome while protecting the mucosa from pathogenic organisms. Microfold (M) cells of the Peyer’s patch (PP) play a crucial role in immune surveillance of the gut environment by transporting luminal antigens to underlying immune cells. Through their ability to move cargo across the epithelium, M cells can (1) benefit the host by translocating luminal contents (e.g. dietary antigens, microbes, vaccines) to induce appropriate innate and adaptive immune responses or (2) harm the host upon infection by invasive pathogens. However, the mechanisms responsible for antigen uptake by M cells and delivery to immune cells are not completely understood in humans. The significance of our proposed research is that we will define the basic mechanism responsible for the major function (i.e. transcytosis) of human M cells. Revealing what controls transcytosis in human M cells has the potential to improve our understanding of how luminal gut contents are delivered to immune cells under normal conditions or during enteric infections. Our recent discoveries using human enteroids enriched in M cells as a relevant ex vivo model of the human PP epithelium demonstrate that (1) coronin 1a is required for uptake and transcytosis of luminal cargo across human M cells, (2) update and transcytosis of gut antigens occurs by a apical-dependent bulk endocytosis process that involves coronin 1a-mediated signaling, and (3) PP macrophages synergize with M cell-expressing human enteroids to increase M cell-dependent uptake and transcytosis of luminal gut. SPECIFIC AIMS: We propose to test the hypotheses that human M cell expressing enteroids respond to luminal microbial and serosal immune signals to induce uptake and transcytosis of gut cargo by a unique coronin 1a dependent mechanism. Our central hypotheses are that coronin 1a expression in human M cells is necessary for: (i) terminal differentiation of FAE progenitor cells to become functionally mature M cells, (ii) synergism between PP macrophages and the human FAE to enhance luminal sampling of gut antigens, and (iii) mediating luminal- and serosal-derived signals that stimulate entry and transcytosis of luminal gut cargo to underlying immune cells. The studies will improve our understanding of how human M cells function and may lead to development of novel therapeutic strategies to treat GI disorders, such as Crohn’s disease, or even possibly development of new strategies to enhance oral vaccine delivery.

NIH Research Projects · FY 2025 · 2023-09

Abstract Approximately 1 million total knee arthroplasty (TKA) procedures are carried out in the U.S. annually to address pathology underlying knee joint pain and functional limitations resulting from osteoarthritis. TKAs are conducted primarily in older adults, and while effective for pain reduction in many, 15% or more of TKA patients report unsatisfactory long-term pain outcomes despite a technically successful surgery. Post-TKA pain at up to 4-year follow-up has been reported to be worse than the preoperative pain in 7% of TKA patients. While mechanisms contributing to long-term pain post-TKA are not well-understood, our prior longitudinal project (R01AG048915) found evidence that oxidative stress (OS) may be one contributor to post-TKA chronic pain. Elevated intraoperative pre-incision levels of F2-isoprostanes and isofurans (the most sensitive in vivo OS biomarkers) and increased expression of these biomarkers during tourniquet application in standard TKA procedures predicted greater post-TKA pain intensity (past 24 hour and past week) at 6-months post-TKA. The proposed project builds on this prior work and will answer a critical clinical question: does reducing OS in the preoperative and perioperative period improve long-term post-TKA pain outcomes? We propose a prospective randomized placebo-controlled trial that will examine preoperative, perioperative, and long-term OS; pain; and functional outcomes and test for the first time the hypothesis that a potent antioxidant intervention (Glycine plus N-acetylcysteine [GlyNAC]) reduces OS and chronic postsurgical pain in patients undergoing TKA. GlyNAC has been shown to dramatically decrease F2-isoprostanes in initial trials, supporting its potential utility as an antioxidant intervention for improving post-TKA pain outcomes. Given the large number of older adults experiencing adverse post-TKA chronic pain outcomes each year (≈150,000 annually), the proposed project could potentially have practice-changing clinical implications. We will enroll older adult osteoarthritis patients undergoing primary unilateral TKA and randomize them to receive GlyNAC (n=74) or placebo (alanine; n = 74) beginning 4 weeks prior to TKA with continuation until 6 weeks post-TKA. Baseline pain and psychosocial phenotyping will be carried out and OS will be assessed in the patient’s home at 4 weeks pre-TKA (T0) and again after 4 weeks of the intervention [3 days prior to TKA] (T1); perioperatively at pre-incision [T2], 45 minutes after tourniquet application [T3], and 15 minutes post-tourniquet removal [T4]; and at post-TKA follow- ups. Pain, function, and opioid use outcomes will be assessed at 6-week, 6-month, and 12-month follow-up. We will test the hypothesis that GlyNAC reduces OS and pain intensity, improves function, and reduces opioid analgesic use at 6-week and 6-month (primary) follow-up compared to placebo. We will also test whether GlyNAC-related reductions in pain intensity at 6-month follow-up are maintained at 12-month follow-up, and whether pre-GlyNAC baseline OS levels moderate efficacy of GlyNAC for improving long-term pain outcomes.

NIH Research Projects · FY 2024 · 2023-09

Abstract Approximately 1 million total knee arthroplasty (TKA) procedures are carried out in the U.S. annually to address pathology underlying knee joint pain and functional limitations resulting from osteoarthritis. TKAs are conducted primarily in older adults, and while effective for pain reduction in many, 15% or more of TKA patients report unsatisfactory long-term pain outcomes despite a technically successful surgery. Post-TKA pain at up to 4-year follow-up has been reported to be worse than the preoperative pain in 7% of TKA patients. While mechanisms contributing to long-term pain post-TKA are not well-understood, our prior longitudinal project (R01AG048915) found evidence that oxidative stress (OS) may be one contributor to post-TKA chronic pain. Elevated intraoperative pre-incision levels of F2-isoprostanes and isofurans (the most sensitive in vivo OS biomarkers) and increased expression of these biomarkers during tourniquet application in standard TKA procedures predicted greater post-TKA pain intensity (past 24 hour and past week) at 6-months post-TKA. The proposed project builds on this prior work and will answer a critical clinical question: does reducing OS in the preoperative and perioperative period improve long-term post-TKA pain outcomes? We propose a prospective randomized placebo-controlled trial that will examine preoperative, perioperative, and long-term OS; pain; and functional outcomes and test for the first time the hypothesis that a potent antioxidant intervention (Glycine plus N-acetylcysteine [GlyNAC]) reduces OS and chronic postsurgical pain in patients undergoing TKA. GlyNAC has been shown to dramatically decrease F2-isoprostanes in initial trials, supporting its potential utility as an antioxidant intervention for improving post-TKA pain outcomes. Given the large number of older adults experiencing adverse post-TKA chronic pain outcomes each year (≈150,000 annually), the proposed project could potentially have practice-changing clinical implications. We will enroll older adult osteoarthritis patients undergoing primary unilateral TKA and randomize them to receive GlyNAC (n=74) or placebo (alanine; n = 74) beginning 4 weeks prior to TKA with continuation until 6 weeks post-TKA. Baseline pain and psychosocial phenotyping will be carried out and OS will be assessed in the patient’s home at 4 weeks pre-TKA (T0) and again after 4 weeks of the intervention [3 days prior to TKA] (T1); perioperatively at pre-incision [T2], 45 minutes after tourniquet application [T3], and 15 minutes post-tourniquet removal [T4]; and at post-TKA follow- ups. Pain, function, and opioid use outcomes will be assessed at 6-week, 6-month, and 12-month follow-up. We will test the hypothesis that GlyNAC reduces OS and pain intensity, improves function, and reduces opioid analgesic use at 6-week and 6-month (primary) follow-up compared to placebo. We will also test whether GlyNAC-related reductions in pain intensity at 6-month follow-up are maintained at 12-month follow-up, and whether pre-GlyNAC baseline OS levels moderate efficacy of GlyNAC for improving long-term pain outcomes.

NIH Research Projects · FY 2024 · 2023-09

Opioid use disorder (OUD), a physical and psychological reliance on opioids, kills more than 60,000 Americans each year and has cost the United States healthcare system more than $30 billion. Continuous treatment with pharmacotherapy (e.g., buprenorphine) for the duration of physical and psychological reliance is crucial to optimal outcomes. Many patients with OUD now struggle with stimulant use disorder (StimUD), which significantly increases the risk of relapse and overdose by complicating OUD treatment. While the best approach to preventing relapse and overdose is by using long-term monitoring and individualized treatment, there is limited guidance for treating comorbid disorders and monitoring treatment effectiveness for tailored therapy. Given the barriers to accomplishing continuous pharmacotherapy, interventions are urgently needed that routinely incorporate patient-reported outcome measures (PROMs) and patient preferences in monitoring and clinical decision making. The research planned for this K08 award aims to (1) create a PROM-based intervention that supports patient-centered care during treatment of OUD and StimUD, (2) test the hypothesis that compared to routine care, patient-provider dyads will perceive enhanced decision-making using the PROM-based intervention in a simulated setting, and (3) test the hypothesis that compared to standard care, the PROM-based intervention will increase adherence to buprenorphine in a pilot clinical trial. Importantly, this project will increase our understanding of treating comorbid substance use disorders and develop methods of using PROMs, patient preferences, and clinical decision support that can be used for other chronic conditions. Findings from this research will provide preliminary data for an R-level award to evaluate the PROM-based intervention in a multicenter randomized trial. Support from this Mentored Career Development Award will enable Thomas J Reese, PharmD, PhD to acquire additional skills he needs to position himself as a proficient learning health system researcher. Dr. Reese is board-certified pharmacist and clinical informatician at Vanderbilt University Medical Center. He has a track record of productive collaborations and patient-oriented research. This project expedites Dr. Reese’s path to research independence in the health system innovation pipeline by combining his prior training and experience with an excellent research environment. His training domains include (1) advanced research methods; (2) health equity and patient-centered care; (3) improvement and implementation science; and (4) engagement, leadership, and research management. Dr. Reese will acquire skills in each of these domains through a purposeful mentorship program, as well as didactic and experiential training that will advance his knowledge about OUD and StimUD and enable him to apply a patient-centered approach to treatment decision making. Dr. Reese’s path to research independence will be guided by a multidisciplinary mentorship team with expertise in each training domain.

NIH Research Projects · FY 2025 · 2023-09

Kidney disease affects nearly one in three adults worldwide and is associated with significant morbidity and mortality. Throughout the last three decades there has been tremendous progress in understanding kidney disease mechanisms that have led recently to new therapies including healthcare delivery strategies to enhance delivery of health information and promote successful self-care, however quality of life as well as survival remains poor especially for those living with advanced kidney disease including kidney failure. Importantly the NIH/NIDDK has invested in ensuring that patient partners are integral to the process of prioritizing as well as carrying out research. Similarly, NIH/NIDDK is further investing in the academic research workforce. This is a critical objective across the spectrum of kidney disease research including basic science, clinical and translational, and policy research. Dr. Cavanaugh is a well-recognized expert in kidney disease clinical trials, health literacy and its implications, formative research to elucidate and integrate stakeholder perspectives into research and community engagement. Her objective is to use the support of the K26 NIDDK Investigator Award to Support Mentoring of Early Career Researchers to focus on training the next generation of scientists to bring transformative advancements in kidney disease research. The candidate’s immediate and long-term career objectives to be a leader in research faculty development are directly in line with the goals of the NIH K26 award, to provide support for protected time for awardees to devote to mentoring training and active mentoring for post-doctoral students and junior faculty. Specifically, this award will allow her to focus on the development of a multi-level mentoring program to facilitate the career development of emerging early investigators. This award will provide protected time for the candidate to devote specifically to executing rigorous research, serving as a primary, collaborative, advocacy and network mentor, and to developing mentoring skills in research. Her objective is to recruit and mentor post-doctoral fellows and junior faculty for successful clinical research careers in kidney disease and to support the career advancement of her current trainees. She will accomplish this objective by leveraging her research program resources as well as robust institutional, regional and national resources. The aims include (a) continued impactful research to expand opportunities for mentees; (b) development and deployment of a novel psychological and instrumental advocacy kidney disease research mentor program; (c) acquisition of mentoring skills training informed by an expert advisory committee; and (d) execution of recruitment programs to identify and engage promising mentees. Completion of these aims will enhance the career advancement of kidney disease scientists to grow the future workforce of faculty dedicated to understanding and eliminating kidney disease.

NIH Research Projects · FY 2026 · 2023-09

HIV remains a major public health concern in the United States (US) with a disproportionate burden of disease in the US South, including Tennessee. The proportion of people with HIV (PWH) in Tennessee in 2019 who knew their HIV status (85%), were linked to care (61%), were retained in clinical care (59%), and had suppressed viral loads (65%), were well below US Ending the HIV epidemic goals (90%). The burden of HIV infection is uneven, but poor HIV continuum of care outcomes can be found throughout the state of Tennessee. Some of the poorest outcomes can be found in Memphis/Shelby County, a Phase 1 EHE Priority Jurisdiction and a Metropolitan Statistical Area (MSA) that ranks 3rd in the US for HIV incidence. In this public health context, new strategies are being employed to target, disseminate, and implement HIV testing and prevention to improve the health and well-being of those at risk of HIV acquisition and those living with HIV. Implementation of new strategies including changes to community-based outreach, target data-driven interventions, and the re-organization of integrated HIV services to deliver evidence-based delivery of HIV testing, treatment, and prevention services represents an urgent quasi-experimental event that requires evaluation. Thus, our overarching goal is to provide a near-real-time assessment of whether and how new strategies to deliver evidence-based care will impact HIV outcomes, particularly among populations highly susceptible to HIV. We are uniquely positioned to perform the work in this proposal as our study team has complementary expertise in Tennessee clinical HIV testing and prevention, HIV modeling, and qualitative research to ensure the timely initiation of the project with minimum delay. Our findings will provide clear, rigorous evidence in a near-real-time assessment of whether and how changes to implementation of HIV prevention and care in Tennessee affect HIV outcomes. Although focused on Tennessee, results are relevant to broader discussions around the direction of evidence-based strategies to improve community-based organizational capacity for public health programs already emerging across the US South. Importantly, our work will support Tennessee communities in reaching their Ending the HIV Epidemic (EHE) goals through the leveraging of our unique academic and community-based partnerships.

NIH Research Projects · FY 2025 · 2023-09

There is growing recognition that area-level biological and physical exposures associated with residential location across the life-course must be considered for more precise cancer risk and outcomes. Yet many cohort studies lack comprehensive residential history information or limit analyses to the residence at enrollment or cancer diagnosis, a critical limitation in assessment of exposure causation potentially leading to misclassification or biased associations. Residential histories derived from commercial vendors offer an exciting opportunity to integrate the neighborhood environment into cancer research. Little research has been conducted incorporating life-course residential history information into cohort studies, particularly in poverty regions such as in the Southeast. Populations living in the Southeast have the highest cancer risk and some of the poorest health outcomes among all U.S. populations. To address gaps in knowledge of how best to integrate geospatial data via life-course residential histories into cancer research cohort studies, we propose to evaluate residential histories in a well-resourced and large-scale observational prospective cohort of adults, with the following specific aims: 1) collect and describe self-reported adult life-course residential histories, 2) develop algorithms to reconstruct temporal residential histories, and 3) evaluate residential mobility and spatiotemporal changes in area-level life-course exposures and cancer risk. We hypothesize concordance of residential history between vendor and self-report varies by population group and incorporating residential mobility improves exposure assessment and reduces bias in cancer research. We propose to construct residential histories, link residential histories to geospatial exposures, and test associations between geospatial exposures across the life-course and cancer risk. We will focus on the four most common cancers (breast, lung, colorectal, prostate) in over 84,000 participants recruited across 12 Southern states. Our design focuses on robust methods to identify factors predictive of residential history patterns, including those living in poverty regions, and novel translation of residential history information into an interpretable context. Our project then examines neighborhoods which can influence cancer risk over space and time. Our project fosters innovative collaborations among a multidisciplinary team with scientific expertise in cancer epidemiology, survey design, geospatial analyses, small area estimation, and biostatistics. Findings from our multidisciplinary approach will have sustained impact since it will reveal pathways for improved precision to incorporate area-level exposures across the life-course.