Vanderbilt University Medical Center

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY Substance use and associated HIV, hepatitis C (HCV), and mental health comorbidities continue to drive morbidity and mortality. Interdisciplinary, interinstitutional collaborations can challenge paradigms to achieve advances in substance use treatment that limit the spread of HIV/HCV and decrease morbidity and death. Vanderbilt University Medical Center (VUMC) and Oregon Health and Science University (OHSU) are national leaders in substance use research and are located in states with high rates of substance use and new HIV infections. For these reasons, this application seeks to establish the Vanderbilt Oregon COllaborative Scholar Training in Addiction Research (COSTAR) K12 program to train and mentor the next generation of substance use researchers. We propose to support a minimum of three faculty Scholars who have completed an MD or PhD in the health sciences at a level of 75% effort for up to five years. VUMC and OHSU have a rich research environment and highly successful history of developing the careers of research scientists . Additional strengths of VUMC/OHSU include four addiction fellowship programs, the Tennessee Center for AIDS Research, the Vanderbilt Center for Tobacco Addiction and Lifestyle at VUMC and the Western States Node of the National Drug Abuse Treatment Clinical Trials Network, the Portland Alcohol Research Center, and the Rural Opioids Initiative at OHSU. In this application, Drs. Tindle (nicotine dependence), Freiberg (unhealthy alcohol use), and Korthuis (drug use) will partner with interdisciplinary faculty mentors from both VUMC and OHSU to develop and implement COSTAR. The COSTAR training curriculum includes (1) mentored research projects, (2) didactic education, (3) completion of a structured institutional career development program, and (4) optional multisite research training. COSTAR objectives and Specific Aims: 1. To create a sustainable K12 program that fosters interdisciplinary, intensive mentored research training and career development for early career MD, PhD, MD/PhD investigators that focuses on substance use/disorders with an emphasis on vulnerable populations (e.g., people with HIV); 2. To produce a diverse group of well-trained Scholars with the expertise to study: the risk factors for, and mechanisms underlying, substance use/disorders, and the behavioral and health disparity aspects of substance use/disorders and its associated morbidity; 3. To provide Scholars with a research environment that offers mentors and topic experts with expertise in key research domains and protected time to innovate and build an individualized research program; 4. To leverage VUMC and OHSU existing infrastructure and location to provide Scholars with hands-on instruction in a mentor’s laboratory, didactic education, access to existing cohort/trial data and statistical support and facilitate participation in a mentored research project that leads to an R01 or external career development award submission; and 5. To build the administrative structure that creates program cohesion, guides selection of mentors, oversees steady progress in career development, and continuously improves program components.

NIH Research Projects · FY 2025 · 2024-08

Project Summary With age, dividing cells acquire DNA mutations. A small number of these somatic mutations confer a selective advantage leading to clonal outgrowth. In blood, this process is termed ‘clonal hematopoiesis’ (CH) which includes both point mutations in cancer driver genes (eg. clonal hematopoiesis of indeterminate potential ‘CHIP’) and megabase-scale deletions, duplications and copy-neutral loss-of-heterozygosity (eg, mosaic chromosomal alterations, ‘mCAs’). CH is associated with mortality, infection, cardiovascular disease, cancer and other aging diseases with differential mutations conferring different risk. CH is commonly found in extremely aged individuals implying that a set of individuals have resiliency to CH. Here we seek to identify Clonal Hematopoiesis Aging Resilience Mechanisms (CHARMs). CH clones that expand to make up a larger proportion of the blood confer worse health outcomes. However, we do not know what factors predict the rate of clonal expansion, how rate expansion associates with disease outcomes and whether CH confers differential disease risk across the lifespan. Overall, we hypothesize that CH with higher rates of clonal expansion confer a greater impact on health and that the propensity to expand has genetic and environmental underpinnings. A barrier to addressing this gap is a paucity of large-scale collections of longitudinally-sampled blood. Our team has two recent accomplishments that enable us to address this gap: 1) a survey of CH in >800,000 genomes and 2) development of a novel computational method to estimate the rate of CH expansion from a single timepoint rather than requiring serial samples. The project comprises three key aims: In Aim 1, we will apply a computational method called PACER, which estimates CH expansion rates from a single genome sequenced blood sample to >1.6 Million individuals. This approach allows for the identification of inherited genetic factors that confer resilience to CH expansion. In Aim 2, we will focus on the role of circulating proteins, metabolites, and medications in modulating CH expansion. In vitro and in vivo models will be used to elucidate the mechanisms underlying these CHARMs. In Aim 3, we seek to comprehensively assess the impact of CH on health and disease across the entire human lifespan. By studying two large and diverse cohorts, NIH All of Us (N~750,000) and Vanderbilt BioVU (N~250,000), encompassing individuals that span the entire lifespan from birth to centenarians, the project will analyze the relationship between CH and aging diseases. Our multidisciplinary team with deep expertise in CH, human genomics, experimental hematology, and genetic epidemiology is uniquely poised to accomplish this scientific program. Successful execution of these aims has the potential to improve risk models to stratify individuals with CH for personalized prevention interventions. Additionally, each CHARM we identify would be a potential target for therapeutic development.

NIH Research Projects · FY 2026 · 2024-08

Abnormal valve development contributes to many common congenital heart malformations. Developmental signaling events that regulate early valve formation have been studied extensively, however, the mechanisms that underlie latter stages of remodeling to mature valves remain poorly understood. We have recently identified a critical time point at the early stage of semilunar valve remodeling that is fundamental for normal aortic valve formation and have also identified a unique endocardial signaling axis, TIE2-PI3K/AKT- FOXO1, that plays a pivotal role in orchestrating this early remodeling process. Therefore, we propose to 1) Delineate the unique roles of TIE2 signaling in heart valve remodeling in vivo. We will utilize our newly developed inducible endocardial Cell (EC) specific Nfatc1CreERT2 line, pan-endocardial (Nfatc1Cre) line, and valvular endocardial specific (Nfatc1enCre) line, to generate valvular EC-specific Tie2 conditional knockout (ko) models. PostnMCM will likewise be used to generate valvular mesenchymal cell ko mutants. We will thoroughly examine the cardiac phenotypes of these conditional mutant mice and determine the direct effectors of endocardial TIE2 signaling in heart valve remodeling. 2) Define the role of the TIE2-PI3K/AKT-FOXO1 signaling during semilunar valve remodeling in vivo. We will generate an EC overexpression of a gain-of- function FOXO1 mouse line (FOXO1CA). We will also generate Tie2 and FoxO1 double knock out mutants via utilization of Nfatc1CreERT2 and Tie2 and FoxO1 floxed alleles and EC overexpression of a gain-of-function PI3K mouse line (PIK3CAH1047R) via Nfatc1Cre and Nfatc1enCre, respectively. The resultant mutant mice will be thoroughly analyzed to determine which components of the cardiac valve defects seen in Tie2-icko and Nfatc1enCre;PIK3CAH1047R mutant mice are phenocopied or rescued, thus defining the specific roles of TIE2- PI3K/AKT-FOXO1 signaling in valve formation. 3) Identify additional down-stream targets of TIE2 activation that regulate heart valve remodeling. To validate and reinforce the TIE2-FOXO1 linear pathway proposed based on in vivo studies, we will analyze candidate gene/protein expression of cultured endothelial cells exposed to CAng1, a potent Angpt1 variant agonist, and PI3K inhibitor (LY294002) in the presence or absence of Tie2. In addition, we will use bulk RNAseq of cultured cells and scRNAseq of outflow tracts harvested from control and inducible endocardial Tie2 ko embryos to identify and characterize additional TIE2- dependent signaling pathways required for semilunar valve development. These studies will provide the first characterization of the critical period of aortic valve remodeling immediately following EMT. This work will also elucidate a uniqe endocardial signaling mechanism (namely, the TIE2-FOXO1 axis) that modulates remodeling in cardiac valve formation. These studies are essential to advance our understanding of normal cardiac valve ontogeny and will be foundational for deciphering the mechanisms of disease pathology related to valve formation and function.

NIH Research Projects · FY 2026 · 2024-08

ABSTRACT. Alzheimer’s disease (AD) is a public health crisis that disproportionately affects individuals in the Black community. With recent advances in treatment, the need for early identification of AD pathology has never been greater. Early detection allows for early intervention which may be essential to slowing or stopping the progression of AD prior to widespread, irreversible neuronal loss. Further, early disclosure of increased risk for AD has been shown to motivate positive health behaviors and planning for long-term care. Blood-based biomarkers have been developed to provide a first line screening for the presence of AD pathology. These biomarkers, such as plasma levels of tau phosphorylated at threonine 217 (p-tau217), have shown great promise as accessible and accurate early indicators of AD pathology, yet these biomarkers have been developed in predominantly White cohorts. Plasma biomarkers are affected by systemic health conditions such as obesity and chronic kidney disease. These medical conditions disproportionately affect Black adults and may affect the performance of blood-based biomarkers in the Black community. However, the effect of these factors has not yet been quantified in cohorts that are representative of the population and no potential means of ameliorating any racial differences in plasma p-tau217 performance has yet been investigated. We propose to study the effect of the various sociodemographic and medical factors that disproportionately affect Black adults on plasma p-tau217 levels in local, unique, diverse, and deeply phenotyped cohorts. We will first quantify the impact of various sociodemographic and medical factors on plasma p-tau217 levels in 3500 individuals (2/3 Black) from the Southern Community Cohort Study. Next, the sociodemographic/medical factors which significantly affected p-tau217 levels will be evaluated as mediators of the association between p-tau217 and incident dementia to determine if these factors affect the predictive accuracy of this biomarker. Finally, the effect of race on the association between p-tau217 and incident dementia will be investigated in the Vanderbilt Memory and Aging Project and Tennessee Alzheimer’s Project cohorts (estimated n=1300, 325 Black). Should racial differences exist, analyses will be repeated using the plasma p-tau217/amyloid-b42 ratio as predictor to determine if using a ratio increases the predictive accuracy of p-tau217. This proposal will provide excellent training opportunities in the epidemiology of AD, increase my understanding of the causes and consequences of racial disparities in AD, expand my knowledge and technical expertise for utilizing plasma biomarkers in AD, and provide the essential professional and leadership skills necessary to advance my career as a productive clinician-scientist. These training goals will be accomplished with the aid of an expert interdisciplinary mentorship team to ensure my success. The skills in AD epidemiology, biostatistics, Medicare claims data analysis, and plasma biomarker analysis gained through this training plan will fuel my future successful independent research program and establish me as a leader in the field of community-based screening for AD and related dementias.

NIH Research Projects · FY 2025 · 2024-08

Tuberculosis (TB) is the leading cause of death among people with HIV (PWHIV), and the risk of morbidity and mortality is also high among young children and pregnant women. TB preventive therapy (TPT) to treat TB infection (TBI) is especially important in these priority populations, but it must be safe and well-tolerated given that TPT is largely provided to asymptomatic, healthy individuals. The Tuberculosis Trials Consortium (TBTC) of the Centers for Disease Control and Prevention (CDC) is conducting ASTERoiD, a Phase 3 trial of rifamycin- based TPT comparing six weeks of daily rifapentine (6wP) with local rifamycin-based standard of care (once- weekly isoniazid and rifapentine for twelve weeks, 3HP; four months of daily rifampin (4R), or 3 months of daily isoniazid and rifampin (3HR)). There are currently no pharmacokinetic (PK) assessments in ASTERoiD, and optimal dosing of dolutegravir in PWHIV and rifapentine in priority populations in the context of 6wP has not been firmly established. For this reason, PWHIV taking dolutegravir, children < 12 years, and pregnant women are currently excluded from ASTERoiD We propose to enroll PWHIV taking DTG, children, and pregnant women into a 6wP semi-intensive PK sub-cohort to confirm that model-informed doses of TB and HIV drugs achieve target exposures in these participants (Aim 1). We will employ sparse PK sampling and use population PK modeling to characterize exposure to rifapentine, explore sources of PK variability, and confirm that translational modeling-informed dosing achieves clinical exposure targets in the majority of participants taking 6wP for TPT (Aim 2). We will evaluate TB drug exposures and pharmacogenetics as explanatory factors for drug discontinuation due to adverse drug reactions, as well as other safety and tolerability outcomes, in both the experimental and control arms in ASTERoiD (Aim 3). Finally, nesting clinical pharmacology into ASTERoiD will provide us with the opportunity to understand whether or not key outcomes are related to drug exposures and, importantly, will allow us to include key populations with the highest risk of TB disease and TB-related morbidity and mortality into this Phase 3 trial of 6wP, an ultra-short, single-agent TPT that, if successful, could transform TB prevention.

NIH Research Projects · FY 2024 · 2024-08

PROJECT SUMMARY/ABSTRACT: OVERALL Using the well-established framework of a very active and strong multidisciplinary Vanderbilt-Ingram Cancer Center (VICC) Breast Cancer Program that is robustly supported by the SPORE mechanism, we have made significant progress in our current project period. With supplemental funding, our overall goal remains the same: To conduct collaborative, multidisciplinary and mechanism-based translational research that will have the highest possible impact on women and men with or at risk for breast cancer. After planning and internal and external advisory board evaluation, we propose to continue our research on three translational projects, primarily targeting triple-negative breast cancer, with integrated guidance from patient advocates, to ensure that we are inclusive of the patient perspective in meeting our goals. The projects are as follows: Project 2 - Strategies to Improve Outcomes for TNBC Patients Integrating Subtype-specific Genomic and Immune-based Discoveries; Project 4 - Targeting Antigen Presentation to Improve Immunotherapy Responses in Breast Cancer; and Project 5 – Liquid Biopsies to Guide Therapies in Triple-Negative Breast Cancers. The projects require three highly integrated shared core resources: Administration and Engagement, Biostatistics and Bioinformatics, and Pathology and Tissue Informatics. The cores bring innovative technology, resources, and personnel with project-specific expertise to the overall VICC Breast SPORE Program and do not duplicate pre- existing shared resources available at VICC or Vanderbilt University Medical Center (VUMC). We have an expert multidisciplinary team that will accomplish the proposed aims and continue to have productive translational collaborations with other Breast Cancer Programs, SPOREs, and national and international groups.

NIH Research Projects · FY 2025 · 2024-08

Project Summary Autism is a pervasive developmental disorder that is characterized by impaired social cognition. Social cognition depends critically on basic perceptual processes, such as the visual perception of faces, mediated by the fusiform face area (FFA). In prior work, we have developed the ability to measure the structure of this region with unprecedented resolution, allowing us to partially elucidate the laminar structure of FFA. Our approach is focused on brain structure rather than function, which avoids potential confounds related to ability, attention, or motivation. We also focus on a small region, functionally defined in individual brains and retained in native space, which affords improved power to conduct hypothesis-driven research relative to methods that rely on atlas-based regions and group averaging. Our prior research suggests an inverse relation between FFA cortical thickness (CT) and perceptual performance, which is specific to face stimuli and does not extend to objects. When probed with ultra high-resolution (UHR) imaging, this effect is most consistent in the deepest layers of the FFA. Our preliminary data in autism guides the following hypotheses: 1) relative to adults without autism, autistic adults will show a higher FFA CT and a more generalized relation between FFA CT and performance of both faces and objects, and 2) the effect will be more distributed along the radial depth of the cortex than in non-autistic adults, reflecting different neuroplastic mechanisms. We will explore the implications of these differences beyond the visual system by measuring functionally-defined white matter passing through the FFA to the anterior temporal lobe. For this we will use a novel diffusion-weighted imaging pipeline that captures both microstructural and macrostructural features of fiber bundles to increase sensitivity to developmental and clinical changes. This project combines state-of-the-art imaging that affords ultra-high- resolution quantification of cortical gray and white matter structure with a comprehensive battery of perceptual tasks assessing face and object perception and memory. The outcome of this study will improve precision in measuring anomalous development of the FFA in autism, enabling localization to distinct cortical laminae and thus providing insight into the developmental timeline and neural mechanisms of altered experience-based perceptual learning of faces in autism.

NIH Research Projects · FY 2026 · 2024-08

Project Summary/Abstract Successful management of type 2 diabetes (T2D) requires daily self-care behaviors which largely occur within the context of patients’ social relationships. Chronic diseases, like T2D, have high levels of heterogeneity in response to self-care support interventions, suggesting a sequential, individualized approach may maximize benefits for the largest proportion of patients. Adaptive interventions mirror clinical care by applying a series of “if-then” decision rules that dictate which intervention components are delivered over time, according to how individuals respond. They are especially well suited to the management of chronic conditions. To date, all adaptive interventions for chronic disease management are delivered individually; none have involved social support. Adaptive interventions leveraging social relationships could reduce heterogeneity in response to self- care support interventions and better meet the needs of adults with T2D. During this K23 award, the principal investigator (PI) will address these gaps in the extant literature while participating in a mentored training experience that will prepare her for success as an independent investigator who develops and tests adaptive interventions to improve the health and well-being of adults with T2D by leveraging the power of social support. Specific training goals include: (1) deepen knowledge in behavioral diabetes research, (2) develop skills in qualitative and mixed methods, (3) apply Multiphase Optimization Strategy (MOST) framework to develop and optimize adaptive interventions, and (4) lead a clinical trial and strengthen responsible conduct of research skills. The proposed research includes two specific aims. Aim 1: The PI will adapt components of an evidence- based family-focused self-care support intervention to target peer-support rather than family-support. Adults with T2D (n=30) will be recruited to participate in focus groups and iterative rounds of testing to refine the peer- support components prior to evaluation. A community engagement studio will advise protocols and recruitment. Aim 2: The PI will recruit and randomize 60 adults with T2D to a pilot sequential multiple assignment randomized trial (SMART) to test the acceptability and feasibility of random assignment to multiple social- support focused interventions. The PI will report on the feasibility and acceptability of this innovative approach to adaptive interventions as well as conduct interviews with participants to further improve the interventions through a robust mixed-methods evaluation. Improvements, if needed, will be made prior to proposing a fully powered SMART to optimize the adaptive interventions. At the conclusion of this work, the PI will have robust preliminary data on the feasibility and acceptability of optimization methodology in adults with T2D, namely multiple randomizations to social support-focused interventions, to inform a R01-funded SMART. This unique expertise will accelerate the PI’s independent research career as an expert in adaptive interventions for adults with T2D. Moreover, it will help the PI reach her ultimate goal of developing and testing adaptive interventions to improve health and well-being of adults with T2D leveraging their social relationships.

NIH Research Projects · FY 2024 · 2024-08

PROJECT SUMMARY While breast cancer prognosis has substantially improved over the last three decades, recurrence remains a significant risk, particularly for African American patients and patients from low- and middle-income countries (LMIC). Novel interventions are needed to prevent cancer recurrence and reduce mortality. Increasing evidence suggests that the gut microbiota may influence the efficacy of cancer therapy, thus impacting cancer prognosis. On the other hand, cancer treatment, particularly chemotherapy, may lead to dysbiosis of the gut microbiota and changes in bacterial metabolic activities. These alterations might persist beyond the time of treatment, resulting in a reduction in beneficial bacteria, thereby influencing long-term breast cancer outcomes. Thus, gut microbiota is a potential target to improve the efficacy of cancer treatment and long-term health outcomes in breast cancer patients. However, the impact of cancer therapy, particularly chemotherapy, on gut microbiota after the completion of therapy, as well as the influence of gut microbiota on long-term breast cancer survival, is largely unknown. To address these knowledge gaps, we propose conducting a pilot study to evaluate the associations of pre- and post-chemotherapy and -radiotherapy gut microbiome profiles with breast cancer recurrence and mortality (Aim 1). We will use the existing pre-systematic treatment gut microbiome data from 364 cases and perform shotgun metagenome sequencing on 110 post-chemotherapy or/and - radiotherapy stool samples in the Vietnam Breast Cancer Study (VBCS). We will also investigate the impact of chemotherapy on the gut microbiome profile (Aim 2). We will examine changes in gut microbial diversity, taxa abundance, microbial metabolic pathways, and microbiome dysbiosis indexes among 110 breast cancer patients with paired pre- and post-chemotherapy stool samples. This proposed study will be the first to evaluate the associations of pre- and post-systemic treatment gut microbiome profiles, as well as their gut microbiome dysbiosis indexes, with the risk of breast cancer recurrence and mortality at 5 years post- diagnosis. Findings from this proposed study will support the launch of a full-scale study to fully understand the role of gut microbiota in breast cancer outcomes, eventually leading to the development of a microbial-based intervention to improve long-term cancer outcomes and quality of life for survivors.

NIH Research Projects · FY 2025 · 2024-08

SUMMARY Hypertrophic cardiomyopathy (HCM) affects up to 1:200 individuals and is a common cause of sudden cardiac death. Guidelines recommend genetic testing in HCM probands to help establish diagnosis, inform risk stratification, and identify at-risk relatives. However, causal variants are identified in fewer than half of patients, many tests return variants of uncertain significance (VUS), and genotype-phenotype associations of known genes are insufficiently characterized to inform medical management. In this proposal we address 4 gaps in HCM research: 1) Most data are from individuals of European ancestry referred for genetic testing, creating bias in estimates of the contribution, penetrance, and phenotype in the broader clinical and community population. 2) Established HCM genes have insufficient genotype-phenotype data to inform gene-specific clinical management. 3) The evidence for most candidate genes is equivocal due to lack of study in cohorts sufficiently large to evaluate pathogenicity. 4) Some disease loci likely remain undiscovered because GWAS and linkage approaches used in prior studies are not well-powered for diseases, such as HCM, with variable age of onset, both high genetic and allelic heterogeneity, and incomplete penetrance. We will address these fundamental knowledge gaps using innovative genetic methods and a novel, large-scale HCM research platform that includes harmonized phenotypic, genotyping, sequencing, and identity-by-descent (IBD) data from six large biobanks comprising ~1.5M participants and >5,000 HCM cases. Specifically, we propose to use rare variant and IBD-based methods to: Aim 1) Define the contribution and phenotypic manifestations of established disease genes in multiple diverse, non-referral HCM populations; Aim 2) Assess the pathogenicity of candidate HCM genes with equivocal evidence and establish a novel platform to evaluate VUS in established genes; and Aim 3) Discover novel HCM loci via IBD mapping and rare variant association within and across biobanks at scale. To balance the innovation of these aims, we present compelling preliminary data demonstrating the feasibility of our approaches which identified a cluster of distantly related individuals harboring a common pathogenic variant in a Mendelian cardiomyopathy gene. We anticipate these analyses will substantially expand our understanding of the genetic factors underlying HCM risk and their clinical manifestations. Once established, our platform will support future clinical and genetic research and advance the long-term goal of implementing targeted interventions at the clinic and population level to reduce the burden of HCM for all patients.

NIH Research Projects · FY 2025 · 2024-08

Sensorineural hearing loss and vestibular dysfunction are common sensory disorders affecting millions of individuals worldwide¹,². The primary cause of both hearing loss and peripheral vestibular disorders in humans is dysfunction of the inner ear, which can occur as a result of noise exposure, aging, genetic defects, environmental exposure to pathogens, and as a side effect of ototoxic medications. There are limited therapies for sensorineural hearing loss and vestibular dysfunction, mainly due to the lack of understanding of some of the molecular mechanisms that govern the hearing and balance organs. There remain key unanswered questions about the genetic architecture and molecular mechanisms of transcriptional control used during mammalian development and within the adult inner ear. Recently, single cell RNA sequencing technology has shown the remarkable transcriptional heterogeneity of cell types and developmental dynamics of the mouse inner ear³??. However, transcriptional diversity and control is only one level of genetic regulation. One of the key underlying mechanisms of transcriptomic and protein diversity is through alternative splicing. Cells use alternative splicing to diversify their number of proteins, change translation efficiency, control transcript localization, and make non-coding RNAs?,?. Only a limited number of genes that undergo alternative splicing have been identified in the inner ear at cell type resolution?. Understanding alternative splicing of genes at the single cell level is critically important as any future therapies targeting a specific gene may have on/off target effects in different subsets of cells. We hypothesize that there is cell type-specific diversity of alternatively spliced mRNA within the mammalian inner ear. Moreover, regulation of alternative splicing events occurs through specific RNA binding proteins (RBPs). We will test this hypothesis through two aims: Aim 1 is to characterize the transcriptome-wide alternative splicing landscape of the mouse inner ear at single cell resolution. Using newly developed computational tools, we will identify alternatively spliced genes within both the developing and adult mouse inner ear for the entire transcriptome. Aim 2 will determine the role of RNA binding proteins in regulating alternative splicing programs in the inner ear at single cell resolution. Regulation of alternative splicing events is a key post-transcriptional mechanism that cells use to determine what splicing program mRNA goes through as carried out by RNA binding proteins. We will characterize the expression of RBPs within the developing mouse inner ear and link this to alternative splicing through computational and validation techniques to develop a spatial and temporal map of alternative splicing programs. In sum, we will define the heterogeneity of cell types based on single cell isoform-level data during development and in the adult mammalian inner ear, and we will identify the key players in regulating alternative splicing. This work will d alternative splicing regulation during development and in the adult inner ear that will be necessary for future development of targeted inner ear therapies.

NIH Research Projects · FY 2025 · 2024-08

Due to the broad etiological heterogeneity of autistic phenotypes, unitary theories of autism often fall short of describing the entirety, or even the majority, of the autism spectrum. Recent predictive coding hypotheses avoid this core issue by arguing autism is caused by altered parameters for updating mental models of the world, while leaving the details of those changes open. Attempts at building falsifiable predictive coding theories by specifying these details, such as the slow-updating and high-precision hypotheses of predictive coding in autism, have led to conflicting empirical results, implying they encounter the same dilemma as other unitary theories. Different prediction strategies may appear in different subsets of the heterogenous autistic population or be more relevant in specific tasks or contexts. In addition, there may be dissociations between prediction strategies and behavior in autism that lead to behavioral differences between autism and typical development without an altered underlying predictive mechanism. This project aims to assess multiple theories of predictive coding in a task-driven, non-social context and a task-free, social context. We use multiple measurement paradigms, including phenotypic characterization, eye-tracking, and functional neuroimaging, to obtain as complete a picture as possible of the entire cognitive mechanism, spanning multiple constructs across several domains of human functioning. This evidence will allow us to disentangle both individual-level heterogeneity in coding impairments from task- or context-level heterogeneity and dissociation between behavioral outcomes and neural correlates of predictive coding. Our work will contribute to our understanding of both the "how" and the "why" of temporal prediction by measuring how typical and atypical temporal prediction are encoded in the brain and variation in the links between temporal prediction and social behaviors across social behavioral phenotypes. Focusing on autism, which is typified by impairments in social function, allows us to determine how much temporal prediction is a direct factor in the ease with which individuals attain their desired social connectedness, or whether it is largely mediated through other cognitive constraints. More generally, this project will provide insight on what temporal prediction is for. In clinical knowledge and practice, this research will lead to improvements in our ability to precisely target interventions, particularly those involving structured sensory experiences, to specific patients by building on existing predictive coding capabilities to scaffold the development of social behaviors. It will also lead to assessments of these interventions' effects on cognitive mechanisms, rather than relying purely on behavioral or phenotypic outcomes. This will allow clinicians to more effectively capitalize on autistic individuals' existing skills to achieve their own social and relational goals. Such work is crucial now given rising incidence and diagnosis rates of autism and related neurodevelopmental disorders, an increasingly chaotic sensory environment, and the ongoing search for more effective and efficient interventions and assessments for autism.

NIH Research Projects · FY 2025 · 2024-07

Patients regularly have myocardial infarctions or strokes, despite being on treatment to lower low-density lipoprotein cholesterol (LDL-C) and blood pressure (BP). This residual risk of atherosclerotic cardiovascular disease (ASCVD) remains a substantial medical burden globally. To understand and control residual ASCVD risk, we need to answer three questions: (1) what are the underlying mechanisms? (2) who is at higher risk? (3) are there new treatment options? Building on our experience, we propose to fill these knowledge gaps: (1) The genetics of residual ASCVD risk remain largely unexplored. Existing genetic studies focus primarily on baseline risk (e.g., risk of CHD) or response to CHD-relevant drugs (e.g., LDL-C change on statins), not the residual ASCVD risk. Our group has previously identified and replicated LPA variants associated with residual CHD events in patients on statin treatment independent of LDL-C change. In Aim 1, we will identify new users of drugs to lower LDL-C or BP in the biobank at Vanderbilt (BioVU) and conduct a GWAS comparing those who have an ASCVD event while on treatment to those without an event. We will conduct replication in eMERGE and All of US (AoU) and construct polygenic risk scores. (2) There is a dearth of generalizable and accurate models to predict residual ASCVD risk. Electronic health records (EHRs) contain granular, longitudinal, real-world data that are inherently medically relevant. Additionally, large programs, such as AoU, collect information on lifestyle (e.g., smoking) and social determinants of health (e.g., insurance and employment status). Recently, we applied machine learning (ML) algorithms for CHD risk prediction on longitudinal EHR data and found that ML outperformed the ACC/AHA risk equation for prediction of ASCVD. The performance was further improved by including additional factors. In Aim 2, we will leverage longitudinal EHRs at Vanderbilt and apply advanced ML method to construct prediction models for residual ASCVD risk. We will then validate the model in AoU and eMERGE, and improve the performance by including genetic, environmental, and social information. (3) There are few drug therapies to reduce ASCVD risk other than ones to lower LDL-C and BP. Recent advances in genetics, informatics, and large real-world clinical datasets provide opportunities for systematic drug repurposing. Our group recently pioneered a new drug-repurposing approach. We first leveraged existing GWAS to impute genetically determined transcriptome signatures (the virtual transcriptome) associated with elevated LDL-C or raised BP. We then screened the transcriptome signature in a drug perturbation database to identify candidate drugs, followed by validating them in real-world clinical data. In Aim 3, we will conduct drug repurposing for residual ASCVD risk. We will use two approaches: (a) impute the genetically determined transcriptome and (b) large-scale Mendelian randomization. We will validate the identified candidate drugs in Medicare and AoU. These studies will have potential high impact for residual ASCVD risk by identifying: (1) underlying mechanisms; (2) patients at higher risk; and (3) novel drugs to reduce residual risk.

NIH Research Projects · FY 2025 · 2024-07

PROJECT SUMMARY Among adults with type 2 diabetes (T2D), daily diabetes self-management occurs in social contexts with close family and friends (herein, “family”). We recently developed, replicated, and longitudinally validated a typology of diabetes-specific family functioning. We identified four conceptually distinct profiles ("types") which were independently associated with diabetes self-management and psychological well-being, cross-sectionally and over time. The typology is applicable across diverse family structures, replicated in racially diverse samples, can be assessed through a survey tool, and has the potential to lead to breakthroughs in interventions for adults with diabetes. Therefore, within our recently completed randomized controlled trial (RCT) evaluating a family- focused mobile phone-delivered intervention we applied the typology post-hoc to explore intervention engagement and effects by family functioning type. From these analyses, we know which types did and did not benefit from the family-focused intervention and have developed hypotheses informed by mixed-methods preliminary data about how to tailor the existing intervention to benefit other types. Therefore, we propose to apply the family functioning typology proactively to inform an innovative, adaptive intervention to meet participants' evolving needs. The proposed type-informed adaptive intervention leverages our existing infrastructure to provide mobile phone-delivered intervention components, including: goal setting and monitoring (via phone coaching and text message support), skill building (via phone coaching), and the option to invite a friend or family member to participate in the intervention as a support person. These components will be turned on/off or adapted per most recent type assessment, tailoring both intervention form (individual vs. family) and content focus (disease vs. personal skills). We will enroll N=405 adults with T2D receiving primary care in the mid-South in a RCT lasting 16 months, including a 12-month intervention period, with assessments every 4 months. We aim to (1) evaluate the innovative type-informed adaptive mobile phone- delivered intervention relative to enhanced treatment as usual on hemoglobin A1c, diabetes distress, global well-being, diabetes self-efficacy and self-care behaviors, and (2) evaluate intervention effects for each type to discern which types experienced clinical benefit and inform which types need different intervention components. We will evaluate effects during the intervention, post-intervention, and sustained 4 months after the intervention ends. This project aligns with the NIH-wide strategic plan 2021-2025 to advance research on “giving the right treatment to the right patient at the right time” (p.12) and advances this plan through its novel focus on (a) a behavioral intervention and (b) family context as a key tailoring variable. Moreover, the proposed intervention is consistent with the American Diabetes Association's Standards of Care 2023 recommendation for systems that combine automated technology and coaching to support adults with diabetes.

NIH Research Projects · FY 2026 · 2024-07

Project Summary: Antisocial behaviors like lying, stealing, reactive aggression, and sexually inappropriate behaviors are common in behavioral variant frontotemporal dementia (bvFTD), and can be severe, leading some patients to be charged with crimes, lose substantial amounts of money, or irrevocably damage social relationships. Despite how problematic these symptoms are, the behavioral phenotype for antisocial behaviors in bvFTD has yet to be clearly defined and the underlying mechanisms remain poorly understood. Work in non- diseased and psychiatric populations suggests that antisocial behaviors might be differentiated into factors for aggressive vs. rule-breaking behaviors with different underlying mechanisms. In preliminary data, we developed a novel informant-based questionnaire called the social behavior questionnaire (SBQ) to measure antisocial behavior in bvFTD and also found distinct factors for aggressive vs. rule breaking behaviors. In Aim 1 we will provide further evidence to support distinct antisocial behavioral phenotypes for aggressive vs. rule- breaking behaviors in bvFTD by administering an established measure of aggression and rule-breaking validated in non-patient populations and showing convergent validity between this established measure and our novel, bvFTD-specific measure. In Aim 2 we will investigate the neural correlates for aggression and rule- breaking in bvFTD. Patterns of brain atrophy in bvFTD are heterogeneous between patients but preferentially affect two intrinsic functional connectivity networks within the brain: the salience network (SN) and the semantic appraisal network (SAN). We have developed a novel method called atrophy network mapping to localize neurological symptoms to a brain network rather than to a specific brain region. In preliminary data using atrophy network mapping we found that aggressive behaviors in bvFTD localized to the SAN and rule- breaking behaviors localized to the SN, hypotheses we will test in Aim 2. bvFTD is characterized by early and prominent changes to socioemotional processes, a neuropsychological pattern of impairment that is also seen in other patients with antisocial behavior even without executive dysfunction. Our preliminary data suggests that different socioemotional impairments relate to different types of antisocial behaviors in bvFTD, with aggressive behaviors relating to impaired empathic concern and rule-breaking behaviors relating to impaired perspective taking, hypotheses we will test in aim 3. Determining whether aggressive and nonaggressive behaviors are dissociable at the behavioral, neural, or decision-making levels would have a potential impact on clinical care, helping in early diagnosis, prognosis, and counseling. Study results would also have an impact on guiding future research efforts to prevent or treat antisocial behaviors in bvFTD.

NIH Research Projects · FY 2026 · 2024-07

Persecutory delusions, or the strongly held belief that others intend me harm, are distressing and disabling transdiagnostic symptoms. They are the most common manifestation of delusions in psychotic disorders, present in over 70% of cases, and exist at the extreme end of the paranoia spectrum. Persecutory delusions are a leading cause of suicidal ideation and hospitalization amongst individuals with schizophrenia, yet effective, sustainable treatments remain limited. One potential route towards developing new treatments is identification of cognitive processes that directly contribute their maintenance. Predictive coding is a prominent mechanistic account of delusions based in the process of belief updating, which describes how we learn about the world and develop new beliefs. Development of adaptive, rational beliefs depends on an accurate understanding of the volatility of the environment, or how frequently the probabilities underlying the environment change. Over-estimation of volatility (i.e. inferring that the environment has changed when it has not) drives the formation of new beliefs that are based on faulty inference. There is growing support that aspects of volatility-related belief updating contribute to paranoia and persecutory delusions specifically. Longitudinal data from the PI’s K23 newly demonstrate that volatility-related belief updating is abnormal in delusional patients with schizophrenia, normalizes with symptom improvement, and is associated with activation in specific brain regions. Yet, these data remain limited by their correlational nature. Randomized controlled trials are the gold standard of causal inference testing, drawing more definitive conclusions about mechanism. Therefore, to push this research forward and directly test the belief updating model of delusions, we will recruit 120 individuals with a schizophrenia-spectrum disorder endorsing a persistent persecutory delusion and randomize them to receive either formulation-driven cognitive-behavioral therapy for persecutory delusions (CBTp), which has been previously shown to reduce delusion severity, or an active control therapy (befriending). We will then test whether modification of persecutory delusion severity using psychotherapy impacts belief updating at the level of behavior (Aim 1) and neurobiology (Aim 2), investigating specific brain circuits underlying distinct volatility parameters. Our ultimate goal is to leverage the insights gained into new, mechanistically informed treatments for persecutory delusions and paranoia, translating computational neuroscience to clinical applications.

NIH Research Projects · FY 2026 · 2024-07

PROJECT SUMMARY Lower respiratory tract infections are the leading cause of mortality for children under 5 years old1,2. Although exposure to respiratory pathogens is common, very few children have severe or life-threatening disease3. A better understanding of this inter-individual variability may allow us to more effectively prevent or treat serious infections in those most at-risk. Inborn errors of immunity (IEI) are rare monogenic diseases that serve as ‘experiments of nature’ to pinpoint genes and immune pathways critical to defense against specific pathogens. However, despite the clear value that IEI research offers, IEI are vastly underdiagnosed. We investigated a consanguineous family with two children affected by severe and recurrent bacterial respiratory infections including Streptococcus pneumoniae. By whole exome sequencing we discovered these patients were homozygous for the novel mutation N10Kfs*17 in TANK. We showed that this mutation leads to a complete loss of TANK protein expression, indicating that we identified the first ever reported cases of TANK deficiency. TANK is an adaptor protein assumed to participate in signaling pathways downstream of several immune receptors4,5. However, its function in the human immune system remains largely unknown. To tackle this knowledge gap, we performed in depth immunophenotyping of these patients’ samples. We found that TANK is critical for B cell activation and differentiation, and production of immunoglobulins. Thus, we hypothesize that TANK is critical for B cell activation and that genetic variants altering its pathway cause human diseases. Capitalizing on the unique scientific opportunity that these patients offer we will characterize in depth the immunological consequences of TANK deficiency (Aim 1). TANK has been implicated in the non-canonical NF-κB pathway and mutations that cause similar clinical and immunological consequences affect this pathway6–8. Hence, Aim 2 will focus on deciphering the role of TANK in non-canonical NF-κB pathway signaling4,5. We have shown that we can leverage knowledge from rare and high-impact genetic variants that cause IEI to understand how more frequent genetic variants contribute to common immunological and infectious diseases9,10. Therefore, in Aim 3 we will take advantage of our access to several large biorepositories of genetic data linked to de-identified electronic health records to ascertain the impact of genetic variants in the TANK pathway on human disease phenotypes. The work proposed in this application has far reaching clinical and immunological implications. We will characterize the function of TANK in the human immune system, particularly its role in B cell activation and differentiation. Our findings will showcase a novel mechanism of non-canonical NF-κB activation mediated by TANK. Finally, we will unravel the consequences of genetic variants in TANK and its pathway in human diseases. In summary, by studying a rare genetic disease we have recently identified, we will gain unique insights into the basic mechanisms of human immunity and their relevance to human health.

NIH Research Projects · FY 2025 · 2024-07

The Cardiology Division at Vanderbilt has a long and outstanding track record of training cardiovascular scientists across a broad array of disciplines in cardiology. Over the last 5 years, the Division has experienced (1) major growth in research funding, with >$20 million NIH funding last year ($1.4 million increase over previous year) and over $28 million in total funding last year (26% increase); (2) success of our investigative faculty through transdisciplinary collaboration; and (3) increase in trainees applying for/attaining K-series (or similar) funding. We propose to continue this trend under a transdisciplinary Vanderbilt University Cardiovascular Medicine T32 (VUCM-T32) NRSA training grant consisting of 4 post-doctoral trainees annually (2-3 year appointment). We aim to foster career development of cardiovascular investigators by training of individuals by an accomplished, committed faculty. Vanderbilt houses unique resources central to the success of our trainees and mentors, including (1) intense institutional commitment via divisional financial support and an NIH CTSA (Vanderbilt Institute for Clinical/Translational Research [VICTR]) that centralizes mentor/trainee education and wellness and guidance and support during K/R-series application (among many other services); (2) integrated electronic health record/OMICS platform (“BioVU”, “Synthetic Derivative”) successfully used by our trainees in research; (3) broad faculty interests across multiple areas of cardiovascular research, basic and clinical; (4) training in leadership and integrity, including responsible conduct of research, with an emphasis on methodologic rigor and reproducibility; among others. Our recruitment programs focus on our clinical fellowship (with a “short-track” Harrison Society program for those dedicated to careers as physician-scientists) as well as internal and external recruitment efforts. We have demonstrated success in recruitment/retention and attainment of career development funding to date. Training is mentor-supervised research (>85%), supplemented by core didactics, conference series, and opportunities to develop leadership, communication, and scientific training (including funding for formal Master’s training). Mentors are selected by trainees prior to matriculation, with training (including a “mentor-in-training” program) to ensure mentor development. A consistently updated Individualized Development Plan (IDP) and meetings with an Individualized Primary Mentoring Committee and PD/PIs will help guide trainees to success and serve as quantitative metrics to measure T32 effectiveness. Administration is led by 2 PD/PIs (Freedman; Shah), supported by an (1) External Advisory Board and (2) Internal Executive and Steering Committees to guide trainee selection and provide oversight. VUCM-T32 success is ensured by significant institutional support by Vanderbilt, via VICTR, Office of Biomedical Research and Training, and Department of Medicine. We envision VUCM-T32 will provide trainees expertise to sustain life-long investigation, starting with attainment of research-focused positions and funding.

NIH Research Projects · FY 2026 · 2024-07

PROJECT SUMMARY Chronic hyperglycemia has been linked to systemic inflammation, which may underlie several comorbidities, and infection is a significant concern for persons with diabetes. Based on our published and preliminary data, the scientific premise of this proposal is rooted in the finding that hyperglycemia-enhanced low-grade inflammation prompts phagocytes to hyper-respond to pathogens, amplifying the severity of unchecked inflammatory responses, the risk of multiple organ dysfunction syndrome (MODS) and mortality from sepsis in persons with diabetes. Also, the lack of understanding of the pathogenesis of systemic infection during diabetes poses a major barrier to developing effective treatments. We and others have shown that the lipid mediator leukotriene B4 (LTB4) is a critical component of the inflammatory response. However, we have also shown that excessive amounts of this bioactive lipid enhance systemic inflammation and promote susceptibility to infection in diabetic animals. However, 1) we did not determine the mechanisms involved in aberrant LTB4 receptor 1 (BLT1; the high-affinity receptor for LTB4) activation in diabetic animals; 2) we did not assess whether preventing BLT1 actions after sepsis had protective effects during sepsis and diabetes. Here, we aim to determine how epigenetic alterations caused by high glucose exposure accelerate the transcription of genes involved in LTB4/BLT1 actions that render diabetic mice more vulnerable to systemic infections. This proposal is based on the surprising preliminary data showing that peritoneal macrophages from diabetic mice exhibit high basal histone acetyltransferase (HAT) activity and increased acetylation of H3 histone, favoring gene transcription. HAT inhibition decreases exaggerated Ltb4r1 mRNA expression in diabetic animals. We also discovered that treating diabetic mice with a BLT1 antagonist 6 h after i.v. infection increased survival and decreased bacterial load in diabetic mice. Notably, the relevance of our findings is underscored by our preliminary observation that LTB4 levels and BLT1 expression are higher in people with diabetes and sepsis than in individuals with sepsis and nondiabetes. These data led to our hypothesis that hyperglycemia primes HAT activation to promote sustained and amplified BLT1 activation, leading to an intense but ineffectual inflammatory response to systemic infection, resulting in severe MODS and enhanced death rates. We propose two Specific Aims, which will use innovative approaches to test our hypothesis, including cutting-edge murine systems, testing newly generated concepts (metabolic memory) in the pathogenesis of sepsis, and new potential treatment protocols that might help translate our findings to the bedside. Aim 1 will determine whether hyperglycemia promotes metabolic memory to sustain aberrant BLT1 activation. Aim 2 will test the hypothesis that the threshold of BLT1 activation dictates the severity of the infection and MODS in humans and mice with diabetes. Understanding how altered metabolism intersects with epigenetic modifications in inflammation and sepsis could lead to the development of therapeutics to reduce chronic low- grade inflammation in diabetes that will improve the outcome of systemic infections associated with this disease.

NIH Research Projects · FY 2025 · 2024-07

Project Summary One of the most highly debated questions for caregivers of deaf and hard of hearing (DHH) children and the professionals who serve them is that of which “communication mode” to use. Will the child have higher language skills if they are taught American Sign Language (ASL) or spoken English or both? Caregivers face this decision when their child is diagnosed, their hearing status changes, and they show language difficulties. Professional guidance is hampered by contradictory perspectives and limited evidence on how communication mode affects long-term outcomes. Limited data for language growth expectations make it unclear whether a DHH child is making sufficient progress to achieve age expectations. The relevant data are spotty, especially for ASL, and often restricted to a subpopulation, single measure, and/or short time span. As a result, DHH children are at risk for receiving ineffective intervention. To provide vital empirical guidance on the impact of exposure to ASL and/or English and whether children are making expected progress, we first need to characterize the language development of DHH children who vary in their access to signed versus spoken languages and developmental histories. Currently, no such natural history data exists, which is a major roadblock. Our team will collaborate with the Kansas Language Assessment Program – DHH to analyze data from one of the largest sources of ASL and English development data currently available. We create growth curves of expressive ASL and English skills of 250 DHH children (0–8 years old) from this population-based sample. These models will provide novel information regarding the natural history of language development in DHH children, which is critical for making intervention decisions and improving language outcomes (Aim 1). Without knowledge of expected developmental trajectories and which lead to age-expected language skills, professionals currently risk providing suboptimal or even detrimental amounts or types of intervention. We also initiate a programmatic line of research to identify sources of variation in language outcomes across DHH children and then address malleable factors to improve outcomes. In this proposed project, we focus on elucidating the effects of language access on language growth because our sample is uniquely positioned to address this far-reaching and longstanding question (Aims 2 and 3). Importantly, the participants are exposed to varying amounts of ASL and English and such data are collected systematically. We not only evaluate the influence of language access on ASL and English growth, but also its predictive value when traditional communication mode (i.e., "sign" versus "oral”) is already accounted for (Aim 3). This study provides a robust foundation for analyzing an enduring population-based sample with enormous potential. Future studies will take advantage of the growing sample to predict longer-term outcomes and intervene on malleable factors to improve outcomes. Improving outcomes is critical because of the persistent language deficits for DHH individuals and long-term negative academic, vocational, and social implications.

NIH Research Projects · FY 2025 · 2024-07

Each year approximately 3 million United States citizens incur traumatic brain injury (TBI). An additional 50,000 United States citizens derive permanent vision loss from direct ocular trauma. Both brain and ocular trauma can involve the optic nerve causing traumatic optic neuropathy (TON) even in the absence of physical damage, i.e. indirect (ITON). ITON occurs in 2-5% of TBI civilian patients. Currently there are no effective treatments available for ITON. Secondary axon degeneration and resulting vision loss occurs 3-6 weeks post-injury in ITON patients. Similarly, in our mouse model of ITON, there is immediate loss of axons followed by a second wave of axon degeneration at 14 days post-injury. This gap between initial insult and secondary degeneration represents a window of therapeutic opportunity. In our model, initiation of secondary degeneration coincides with an increase in the mitochondrial oxygen free radical, superoxide and a decrease in the scavenger, superoxide dismutase 2 (SOD2). Further, treatment with vitamin E prevents these changes and promotes RGC axon survival and preservation of vision. These data support a role for dysfunctional mitochondria in secondary axon degeneration. In other optic neuropathy models, astrocytes promote RGC axon function through transfer of healthy mitochondria, while delivery of metabolic resources prolongs axon survival. Based on these results, we propose that the timing of secondary axon degeneration after ITON is controlled by astrocyte support of the ratio of normal to dysfunctional mitochondria in surviving axons. As a corollary to this hypothesis, we also propose that exogenous mitochondrial transplantation will delay onset of secondary degeneration. We will test this through the following Specific Aims: 1) Quantify mitochondria dysfunction following ITON; 2) Quantify resource sharing from astrocytes to surviving RGC axons prior to onset of secondary neurodegeneration after ITON; 3) Quantify mitochondrial dysfunction immediately prior to and during ITON-induced secondary neurodegeneration. Upon successful completion of these studies we will know how mitochondria and mitochondrial quality control processes determine the timing of onset of secondary neurodegeneration after ITON. This insight will allow us, in future studies, to test novel therapies that could further slow, prevent, or decrease secondary neurodegeneration after ITON.

NIH Research Projects · FY 2025 · 2024-07

Metastatic prostate cancer remains incurable and inevitably progresses to lethal disease despite expanding treatment options. Standard of care includes therapies targeting the androgen receptor (AR) pathway, a key regulator of prostate lineage and survival. Despite a decade of approvals of more potent AR Signaling Inhibitors (ARSI), nearly all patients with metastatic prostate cancer develop recurrence due to the emergence of castration-resistant prostate cancer (mCRPC). Even with recent advances, the mechanisms driving metastatic progression and the diverse molecular underpinnings of ARSI resistance remain to be fully elucidated, thereby complicating the development of therapies to overcome resistance. Within the tumor microenvironment (TME), cancer associated fibroblasts (CAF) are phenotypically and functionally heterogenous and have varying roles in tumor progression and therapeutic resistance, however, many of these mechanisms remain elusive. We and others have revealed that Asporin (ASPN)+ CAF are associated with worse oncological outcomes including metastasis, and we have further demonstrated that they are enriched in therapy resistant metastases. As a secreted protein, ASPN has been shown to communicate throughout the TME to orchestrate cancer cell migration and metastatic development. Our new data indicate that ASPN also protects prostate cancer cells from enzalutamide, a second-generation ARSI. Preliminary data support that ASPN in the TME regulates metastasis and therapy resistance through the activation of HER2/3, a targetable pathway with reported involvement in migration, metastasis, and ARSI resistance. Consistent with this, preliminary analyses show that ASPN+ CAF co-localize with HER2 and HER3 expression in mCRPC. Preliminary mechanistic data indicate that ASPN binds to HER3 and induces the activation of HER2/3 and downstream pathways including MAPK, PI3K, and calcium signaling. Our preliminary findings highlight the importance of ASPN-HER2/3 mediated release of intracellular calcium stores in both HER2/3 signal amplification and calcium microdomain oscillations which are critical for migration. Collectively, our data strongly support our central hypothesis that ASPN+ CAF potentiate prostate cancer migration, metastasis, and ARSI resistance by activating HER2/3 signaling in adjacent prostate cancer cells. Our goals are to 1) Define the molecular mechanisms of ASPN-induced HER2/3 activation, 2) Determine mechanisms of ASPN-HER2/3 regulated calcium oscillations in cellular migration, and 3) Elucidate the functional role of ASPN-HER2/3 in prostate cancer metastasis and therapy resistance. We expect that the outcomes from the proposed studies will provide 1) critical information on a novel mechanism of HER2/3 activation by ASPN in the TME and 2) opportunities for repurposing HER2/3 directed therapies for innovative therapeutic approaches in prostate cancer. By using cutting edge technologies, we will expand current paradigms pertaining to the role of CAF in cancer metastasis and therapy resistance. Ultimately, these studies have potential to impact cancer therapeutics and patient outcomes.

NIH Research Projects · FY 2026 · 2024-07

1 This research proposal investigates the role of Myeloid Translocation Gene on chromosome 16 2 (MTG16) in regulating colon cell identity during homeostasis, regeneration, and dysplasia. 3 MTG16, a transcriptional co-repressor, plays a crucial part in stem cell function and lineage 4 determination in the hematopoietic system. Interestingly, we found that in the colon, MTG16 is 5 highly expressed in secretory precursors and goblet cells, implicating it in colonic goblet- 6 enteroendocrine (EE) cell allocation. Correspondingly, secretory lineages in the Mtg16-/- colon are 7 skewed toward goblet cells at the expense of enteroendocrine cells, positioning MTG16 at the 8 regulatory locus for goblet:EE allocation in the colon. This occurs through MTG16-mediated 9 repression of E protein transcription factors, key players in regenerative processes in numerous 10 tissues. Mtg16-/- mice also have increased sensitivity to colitis and colitis-associated dysplasia, 11 implicating MTG16 as an effector of colonic regeneration processes. However, just how MTG16 12 regulates these processes (i.e. genomic targets and repression complex composition) is largely 13 unknown, offering the potential for new therapeutic targets and interventions in IBD. Using yeast- 14 two-hybrid screens, we identified novel MTG16 interactors, including elongation-associated 15 factors, indicating transcriptional pausing as a new mechanism of MTG16-mediated gene 16 repression. Because MTG16 is expressed in both myeloid and epithelial cells, the observed gut 17 phenotypes could be caused by MTG16 loss in either population. We have observed that wild- 18 type bone marrow transplantation does not rescue Mtg16-/- colon phenotypes, and that these 19 phenotypes also persist in pure epithelial organoids. We hypothesize that MTG16 modulates 20 colonocyte identity during homeostasis, regeneration, and dysplasia by coordinating the 21 restructuring of epithelial transcriptional networks, thus promoting both stability and context- 22 dependent plasticity. Specifically, we predict that MTG16 enables the assembly of multi-protein 23 repression complexes to repress stem and enteroendocrine cell genes, and transcriptional 24 circuits, by modifying chromatin or pausing transcription, thus affecting colonic homeostasis, 25 regeneration, and dysplasia. We will test these hypotheses with three mechanistic, focused aims: 26 1) Define epithelial and/or myeloid MTG16’s contributions to homeostasis, regeneration, and 27 dysplasia; 2) identify context-dependent, colonic cell type-specific MTG16-mediated repression 28 targets; and 3) define colon-relevant MTG16 repression complexes. By unraveling MTG16's 29 molecular function and regulatory networks in colon biology, this project will provide pivotal 30 insights into the pathogenesis of IBD and colon cancer, offering potential therapeutic strategies.

NIH Research Projects · FY 2025 · 2024-07

PROJECT SUMMARY The fields of emergency medicine and hospital medicine deliver rapid diagnosis, treatment, and transitional care for the most common acute heart, lung, and blood disorders in the hospital setting. Despite being the foundation of hospital-based care, these fields are underrepresented in scientific career development efforts. These are complex conditions with systemic challenges requiring interdisciplinary approaches to engage patients and health system stakeholders, develop new knowledge, and translate this knowledge into practice. Building on Vanderbilt’s strong infrastructure and track record of training research fellows, we propose the Vanderbilt Interdisciplinary Hospital-based Systems of Care Research Training ProgrAm (VISTA). This two-year training program will train three postdoctoral investigators per year, with a focus on patient-oriented and health systems research for acute heart, lung, or blood disorders in the hospital setting. The program is rooted in the model of learning health systems, which are designed to “generate and apply the best evidence for the collaborative healthcare choices of each patient and provider, drive the process of discovery as a natural outgrowth of patient care, and ensure innovation, quality, safety, and value in healthcare.” We will provide junior investigators with role models and forums that demonstrate the intellectual productivity and practical benefits of multidisciplinary research in advancing human health. We endorse a team-based approach to filling knowledge gaps and translating discoveries into application. A robust and diverse pool of talented applicants is available, along with formidable research programs in emergency medicine and hospital medicine. We also have a thriving implementation science program; well-positioned Departments of Biomedical Informatics, Biostatistics, and Health Policy; expertise in stakeholder engagement; and diverse partners, including Meharry Medical College and Vanderbilt University School of Nursing. VISTA trainees will engage with faculty mentors with sustained federal funding and extensive mentoring track records. Each trainee will be guided by an individualized multidisciplinary team of experienced mentors with clinical expertise in hospital-based care of heart, lung, and blood disorders and methodological expertise in discovery, evidence translation, data science, policy and epidemiology, and operations research, with a focus on health equity. We will provide 1) advanced didactics, including degree program or focused coursework options; 2) mentorship to prepare trainees for K-level scholarship; and 3) experiential learning through research. Trainees will be supported by broad institutional resources for training and development, including multidisciplinary Work in Progress sessions, clinical and translational research seminars, career development seminars, and peer-mentoring activities. Taken together, these resources provide an optimal environment for developing the next generation of scientists to lead hospital-based research in NHLBI-priority areas.

NIH Research Projects · FY 2024 · 2024-07

The promise of genomic medicine to transform healthcare and improve health will not be fully realized until discoveries become relevant to and available for use by diverse populations and their clinicians. As part of the IGNITE II network, we are proposing two prospective randomized pragmatic genotype-guided clinical trials (GUARDD-US and ADOPT-PGx) to determine the impact of implementing genetic testing on hypertension, depression, and pain therapies. GUARDD-US: Chronic kidney disease (CKD) is associated with hypertension. People with African ancestry (AAs) have the highest risk of CKD and kidney failure, the highest prevalence of hypertension, and the lowest rate of blood pressure (BP) control. While this disparity is in part due to social determinants, ancestry has biological underpinnings and APOL1 high-risk genetic variants, nearly exclusive found in AAs, increase kidney failure risk 10-fold. We propose a genotype-guided trial to determine the effect of early vs. delayed knowledge of a positive APOL1 genotyping result on 3-month systolic blood pressure (SBP). The trial aims to recruit 5435 African Americans with hypertension, with or without CKD, randomized to immediate versus delayed return of APOL1 genetic testing. In those who are APOL1 negative, we will also conduct a pilot study to test the impact of pharmacogenetic (PGx) testing on SBP. Secondary outcomes include 6-month SBP, in CKD patients, on medications ordered, renal diagnosis and testing patient psycho-behavioral outcomes, cost effectiveness, and the effect of PGX guided hypertension management on SBP. ADOPT-PGx: Pain and depression are conditions that impact substantial proportions of the US population. The treatment of acute and chronic pain is challenged by the difficulty of finding effective therapies while minimizing the risk of adverse effects or opioid addiction. For depression, there are few clinically relevant predictors of successful treatment, which results in inadequate therapy for many patients. Both opioid and antidepressant prescriptions can be guided by PGx data based on existing guidelines from the Clinical Pharmacogenetics Implementation Consortium (CPIC). We propose a prospective randomized pragmatic genotype-guided clinical trial that tests the effect of genotype-guided therapy in three scenarios of patients: acute post-surgical pain, chronic pain, and depression. For each scenario, participants will be randomized to genotype-guided drug therapy versus usual approaches to drug therapy selection. Changes in patient reported outcomes representing pain and depression control using standard PROMIS scales define the primary endpoints. Secondary analyses include safety endpoints, changes in overall well-being, and economic impact represented by differences in healthcare utilization. We expect the successful results from these clinical trials will provide critical evidence needed to drive the implementation of genomic medicine across broad demographics of patient populations.