Vanderbilt University Medical Center

NIH Research Projects · FY 2025 · 2020-04

Abstract Metastasis is a well-known driver of cancer-related deaths. Nevertheless, limited success has been achieved in targeting cancer metastasis because it is an exceedingly complex process driven by multiple, integrated mechanisms. Collaborative studies in the Zijlstra and Weaver laboratories studied two separate aspects of cell motility: a) the dynamics of cell-cell adhesion controlled by proteolytic shedding of adhesion receptor and b) the release of motility promoting extracellular vesicles (EV). Since these two events take place in the same cells and contributed to the same phenotype, we speculated that these two biological processes were coordinated. Indeed, preliminary studies demonstrated that syntenin-1, a key component of the EV biogenesis pathways, was part of a cell adhesion complex anchored by the IgG superfamily member Activated Leukocyte Cell Adhesion Molecule (ALCAM) and its companion-tetraspanin CD151. Altering the expression and/or shedding of ALCAM drastically impacted EV biogenesis, confirming our original idea that cell-cell adhesion could be coordinated with EV biogenesis. The hypothesis that this occurred through an intracellular link between ALCAM and syntenin is further supported by the ability of free intracellular domain to suppress EV biogenesis. Based on these observations and our published expertise in cell adhesion, EV biology and metastasis, we propose to investigate the integration between cell-adhesion and the production of motility-promoting EVs during cancer progression. Specifically, the proposed studies will investigate: 1) the mechanistic integration between cell-adhesion and EV biogenesis, 2) the consequences for cargo incorporated in motility-promoting EVs, and 3) the functional contribution to autocrine and paracrine communication. Moreover, the relevance of this biology will be tested in the context of bladder cancer where ALCAM shedding is an independent prognostic indicator of survival. For this purpose we have developed a novel ex vivo organotypic culture system for bladder urothelium and bladder cancer in which we can replicate the clinical phenotypes of both papilloma and carcinoma of the bladder. Considering that tumor cells have a large number of divergent mechanisms at their disposal by which they can enhance their malignant behavior, determining how mechanisms of cell adhesion and EV biogenesis integrate is not only an innovative way to deconvolve complex metastatic behavior, it will also have significant clinical impact. With findings from the propose studies, will provide novel avenues of intervention where a therapy may target a point of synergy and integration rather than a direct mode of action.

NIH Research Projects · FY 2024 · 2020-03

Project Summary Cognitive decline with aging, including Alzheimer’s Disease and Related Dementias (ADRD), is a public health imperative that impacts quality of life and disability. Survivors of acute surgical or medical illness contribute greatly to the crisis of cognitive decline. Hospitalization confers a 1.5-2-fold increase in the odds of new onset dementia. Surgery is common in older adults, but it (and its resulting hospitalization) is associated with significant cognitive decline. Individual interventions to reduce this decline have exhibited limited success. The COgnitive and Physical Exercise to improve Outcomes after Surgery (COPE-iOS) study is evaluating a program of cognitive and physical training throughout the perioperative period. The intervention consists of adaptive computerized cognitive training plus guided aerobic exercise sessions, whereas the active attention control consists of a non-adaptive control computer game and guided stretching sessions. Comprising both prehabilitation and rehabilitation, the two study arms participate in activities for at least 2 weeks prior to surgery and for 3 months after discharge and involve significant weekly interaction with our study team. The study assesses global cognition, disability, depression, and mechanistic pathways. Multiple additional factors, including social support, may influence postoperative recovery, and organized support groups empower patients are associated with improved outcomes after surgery. Throughout the COPE-iOS study, participants in both arms consistently engage with a core team of personnel and sessions are group-based, allowing participants to engage with and support one another. This design provides a much higher level of interaction with providers and peers facing similar circumstances than standard perioperative care. While the active attention control design is essential to the COPE-iOS study to evaluate the efficacy of the cognitive and physical exercise program, the active attention control may confer more benefit to patients than previously anticipated. The Investigating Functional Outcomes and Cognition thrU Surgery (InFOCUS) study is a prospective observational cohort measuring cognitive and physical outcomes after major surgery in older adults who are receiving usual care. The primary hypothesis of this proposal is that outcomes in usual care will be worse than both a combined cognitive and physical exercise program and an active attention control program with regard to global cognition (Aim 1) and disabilities and depression (Aim 2). The InFOCUS study will enroll 125 patients ≥60 years old awaiting major inpatient surgery and assess global cognition, activities of daily living, and depression at baseline and at 3 and 12 months after discharge to allow better understanding of the efficacy of the combined cognitive and physical exercise program and further our knowledge on potential contributions of enhanced systemic support around major surgery to improve outcomes when compared to usual care.

NIH Research Projects · FY 2025 · 2020-02

SUMMARY Tuberculosis (TB) is now the leading infectious cause of death globally, and it remains the #1 cause of death among people living with HIV (PLWH). The first-line regimen is long and burdensome to patients and programs, and drug-resistant TB typically requires treatment for 1-2 years with drugs that can cause severe or irreversible toxicities. The TB drug development pipeline is now robust, providing reason for optimism. To optimize current and new drugs, though, we must employ state-of-the-art drug development approaches (including best use of quantitative pharmacology), and it is imperative that new drugs or regimens be developed so that they can be used in all patients that may benefit from them, including PLWH, children, and pregnant women. Critical challenges and opportunities lie in using clinically pharmacology as a tool more effectively in TB and HIV therapeutics research, across the drug development and optimization spectrum. This is the context for this application for a K24 Mid-Career Development Award for Kelly Dooley, MD, PhD, Associate Professor of Medicine, Pharmacology, & Molecular Sciences in the Divisions of Clinical Pharmacology and Infectious Diseases at Johns Hopkins University, to provide protected time to mentor trainees in patient-oriented research in TB and HIV therapeutics. Dr. Dooley is one of the few Infectious Diseases specialists with training in Clinical Pharmacology working in the TB therapeutics field. She is a globally-recognized leader in TB and HIV- associated TB treatment research and has mentored (and is mentoring) multiple trainees in the field. Through the multiple independently-funded studies she is leading as well as those she is directing in her capacity as a member of the TB scientific leadership committees of the ACTG, TBTC, and IMPAACT networks, she is in a position to provide excellent opportunities to train the next generation of clinical researchers in patient-oriented research in TB and HIV. In addition, this K24 will allow her to expand her own knowledge in several key areas: quantitative pharmacology approaches, as applied to design and analysis in clinical trials of TB or TB-HIV treatment; biomarkers identification and use as well as understanding of drug delivery to hard-to-access compartments, for example in tuberculous meningitis; and a new area of critical unmet medical need, the treatment of nontuberculous mycobacteria (in patients with and without HIV). This K24 will allow Dr. Dooley to have the protected time to train the next generation of investigators in clinical pharmacology and clinical research, as applied to TB and HIV- associated TB, a critical shortage area; expand quantitative approaches in TB therapeutics work; and explore new areas of investigation. The protected time afforded by this award is essential to Dr. Dooley achieving these goals.

NIH Research Projects · FY 2026 · 2019-12

ABSTRACT The goal of this UM1 proposal is to use the remarkable research infrastructure at Vanderbilt University Medical Center and collaborating sites (Washington University, University of Pittsburgh, and University of Pennsylvania) to conceptualize, design, implement, and analyze clinical research studies across a wide variety of pathogens, infectious diseases, and populations as a Vaccine and Treatment Evaluation Unit (VTEU). Vanderbilt University Medical Center was among the first VTEUs funded and has led pivotal studies of influenza, pertussis, pneumococcus, smallpox, and malaria vaccines. The Vanderbilt VTEU has a proven capacity to enroll healthy populations rapidly, including participating in two NIH- directed influenza pandemic responses since 2009, as well as expertise enrolling special populations such as pregnant women, infants and children, adults with underlying medical comorbidities, and the elderly. In the current application, we have expanded our ability to recruit across the lifespan and across multiple pathogens, including increased expertise in sexually transmitted infections, malaria, and novel approaches to conducting clinical trial visits in the home setting. The Vanderbilt VTEU has also led efforts to train the next generation of vaccinologists and clinical trial experts in infectious diseases, including the development of a vaccinology fellowship, participation of fellows and junior faculty in protocol teams and data safety committees, and encouraging concept development by junior faculty. The Vanderbilt VTEU is also committed to working collaboratively with the newly formed Infectious Diseases Leadership Group to articulate priorities for ID research.

NIH Research Projects · FY 2026 · 2019-12

Cognitive-communication disorder is a common and chronic consequence of moderate-severe traumatic brain injury (TBI) and a major source of disability that is associated with negative outcomes including reduced social participation, reduced employment, and reduced life satisfaction. Despite intensive research efforts, no significant reduction in TBI related disability has been documented over the past 20 years. This renewal application leverages our discovery in the prior award period of striking deficits in language processing in context to offer a new direction in the empirical study of cognitive-communication disorder in TBI. By determining the underlying mechanisms and timescale of these deficits, the proposed work will provide the necessary explanatory framework to support the future development of successful rehabilitation efforts. At the heart of the proposed work is the new understanding that the reach of cognitive communication disorder is more extensive affecting more aspects of language than previously appreciated and changing in magnitude over time scales not previously examined. In showing that cognitive-communication disorder extends considerably beyond deficits in communication (beyond the level of the utterance in discourse and conversation) to include deficits in the real- time processing of individual words, phrases, and sentences, the proposed work promises to afford a richer understanding of which language processing mechanisms are impaired in TBI. In showing that the magnitude of cognitive-communication disorder impairs the ability to learn from communicative experiences and that deficits grow over timescales of minutes to a week, the proposed work provides new insight into the implications of these impairments for a range of real-world interactions and into the challenges of their clinical management. Building on these discoveries and new methodological innovations developed in the prior award period, this proposal is organized around three specific aims: (1) To investigate the mechanisms of the language processing deficit in TBI; (2) To investigate the ability to learn and adapt from language experience and use in TBI; (3) To identify the predictors of language processing impairment at an individual level and to link impairment to functional outcomes. The results of this research will provide the explanatory framework necessary to set an agenda for future work developing new assessments for earlier identification and prediction of deficits and for development of empirically based interventions. This proposal is unique in the field and uniquely promising for understanding cognitive-communication disorder following TBI and, ultimately, improving communication outcomes and reducing disability.

NIH Research Projects · FY 2025 · 2019-12

SUMMARY Conventional wisdom says that antioxidants should lower cancer risk by neutralizing cell- damaging, cancer-causing oxidative stress. However, despite the compelling biochemical evidence that ties oxidative damage to carcinogenesis for in vitro systems, almost all large randomized clinical trials have shown that antioxidant supplementation provides no clear benefit and even increases cancer risk. These disappointing and seemingly contradictory results have puzzled the public and researchers for decades. Even more controversial is whether antioxidant supplementation is safe and effective for cancer survivors. An estimated 15.5 million Americans in 2016 were cancer survivors, and up to 81% of them used antioxidant supplements to promote healing. However, we do not understand whether and to what extent post-treatment oxidative stress is associated with cancer prognosis. We recently conducted a molecular epidemiological study of colorectal cancer (CRC). We found the first piece of evidence in humans that the association between oxidative stress and CRC risk was bidirectional, with both beneficial and deleterious effects. Moreover, these bidirectional effects were time-dependent. Specifically, in earlier phases of cancer development, high oxidative stress was associated with increased risk of CRC, whereas in later phases, it was associated with decreased risk. Correspondingly, we found that the association between antioxidant intake and CRC risk was also time- dependent and varied by baseline oxidative stress. In the pilot study, we found that among patients with more advanced cancer, their systemic levels of oxidative stress were actually lower. Furthermore, cancer patients with higher post-treatment levels of oxidative stress had odds of living longer, after comprehensively adjusting for clinical parameters. In this proposed study, we will conduct a large case-cohort study, building upon three Asian and European cohorts to determine whether our novel findings—the time-dependent and bidirectional effects of oxidative stress and antioxidants on CRC, first observed in Chinese women (discovery phase)—can be replicated in both sexes and in different ethnic populations (replication phase). Comprehensive assessments of oxidative stress in pre-diagnostic urine samples will be performed. We will also conduct a follow-up study of CRC cases from whom both pre-diagnostic and post-treatment urine samples have been collected. We will examine whether higher levels of systemic post-treatment oxidative stress are associated with better CRC survival, while comprehensively accounting for pre-diagnostic oxidative stress and other clinical parameters. We expect that this study, with its focus on the time-dependent and bidirectional association between oxidative stress and CRC, will provide novel insights into the role of oxidative stress in carcinogenesis, the first evidence linking oxidative stress and clinical outcomes of CRC, and much needed information for identification of population subsets for chemoprevention. Thus, this study will have high translational potential to lead to tailored strategies for CRC prevention and patient care.

NIH Research Projects · FY 2025 · 2019-09

We recently demonstrated that a critical infant adaptive social behavior -- looking into the eyes of an engaging caregiver -- obeys a fundamental biological principle of ‘entrainment’: Infant eye-looking entrains (or becomes time-locked) to the rhythmic social cueing of a caregiver during social musical interactions of infant-directed singing. Equally importantly, caregivers structure their own child-directed behavior to enhance this rhythmic cuing and facilitate the delivery and receipt of meaningful social information. These results inform basic mechanisms of typical social development as well as disruptions in social development in children with ASD. A common and lifelong neurodevelopmental disorder, individuals with ASD exhibit impairments in social and communicative functioning that require specialized support. In pilot data for the current proposal, we observe that toddlers with ASD show attenuated, though present, rhythmic entrainment to predictable child-directed singing. The current project builds upon our findings of rhythmic social entrainment during infancy to advance mechanistic understanding of rhythmic entrainment in social development in typically developing toddlers and those with ASD, as well as propose rhythmic entrainment as an active ingredient of music-based interventions for social communication in toddlers with ASD. In the R61, we first quantify the effects of rhythmic entrainment to child- directed singing in toddlers with and without ASD (R61 Aim 1) and examine predictability as a driver of this entrainment (R61 Aim 2). Successfully establishing rhythmic entrainment during predictable social musical engagement (Go/No-Go criteria) will provide strong evidence of a potential fundamental role of rhythm sensitivity in social entrainment. In the R33, we measure the extent to which individual levels of rhythmic entrainment in ASD are mechanistic predictors of response to music-enhanced and standard evidence-based naturalistic developmental behavioral interventions for ASD (R33 Aim 3). Establishing malleability in social rhythm sensitivity is a crucial step for identifying potential mechanisms of change for future investigations of music-based treatments for functional social communication outcomes in ASD. In alignment with RFA-AT-19-001, Promoting Research on Music and Health, this project will facilitate rigorous studies of child health and development and musical interventions. Through examination of the principles of social entrainment afforded by natural social musical interactions, this research has implications for basic mechanisms of disrupted interpersonal synchrony in ASD, while also identifying potential targets of active engagement for the development of music-based interventions.

NIH Research Projects · FY 2023 · 2019-09

PROJECT SUMMARY Advances in medical care have increased longevity for babies born with spina bifida, the most common permanently disabling birth defect in the United States. However, long-term health outcomes are limited, practice patterns vary, and best practices are not well defined. The Spina Bifida Program at Monroe Carell Jr. Children's Hospital at Vanderbilt (MCJCHV) evaluates over 250 patients with spina bifida each year. The neurosurgery, orthopaedics, and urology programs at MCJCHV have set the following goals for this study: 1) to approach each eligible patient in our program for enrollment, 2) to contribute longitudinal data on health status, clinical care, and outcomes for consented patients to the NSBPR over the five year study period, and 3) to evaluate NSBPR data to answer hypothesis-driven questions about outcomes in spina bifida. The PI along with the clinical research coordinator will ensure quality control of data submitted to the CDC. The PI and the Spina Bifida Program have a demonstrated record of productive research with the NSBPR and other national databases. Published results from this study will help to inform best practice clinical guidelines for spina bifida.

NIH Research Projects · FY 2023 · 2019-09

PROJECT SUMMARY Advances in medical care have increased longevity for babies born with spina bifida, the most common permanently disabling birth defect in the United States. The main goals of the urologist participating in the care or patients with spina bifida are: 1) to preserve normal renal function and 2) to ensure adequate bladder continence for enhancing self-esteem and independence. Despite these common goals, practice patterns vary, and best practices are not well defined. The Urologic Management to Preserve Initial Renal Function Protocol (UMPIRE) has been designed to evaluate outcomes on a standardized urologic protocol from the neonatal period to 10 years of age. The Spina Bifida Program at Monroe Carell Jr. Children's Hospital at Vanderbilt (MCJCHV) evaluates approximately 20 newborns with spina bifida each year. The pediatric urology division at MCJCHV has set the following goals for this study: 1) to approach each eligible patient in our program for enrollment, 2) to contribute longitudinal data on diagnostic studies and interventions as specified by the protocol, and 3) to evaluate data from UMPIRE to answer hypothesis-driven questions specifically about clinical predictors for hostile videourodynamics and decreased renal function. The PI along with the clinical research coordinator will ensure quality control of data submitted to the CDC. The PI has a demonstrated record of productive research UMPIRE. Published results from this study will help to inform best practice clinical guidelines for urologic management in the child with spina bifida

NIH Research Projects · FY 2025 · 2019-09

PROJECT SUMMARY There is increasing appreciation for the role of RNA binding proteins (RBPs) in shaping the transcriptome of specialized cell types and in helping cells respond to stress. Macrophages are innate immune cells that mount rapid and robust gene expression programs following detection of pathogen- and damage-associated molecular patterns (PAMPs and DAMPs). We know that this response is subject to post-transcriptional regulation at the levels of alternative splicing, alternative polyadenylation, RNA editing, etc. We also know that many of the RBPs that control post-transcriptional regulation of gene expression in macrophages are differentially phosphorylated downstream of PAMP and DAMP sensing. We hypothesize that post-translational modification of RBPs functionalizes them to coordinate the macrophage innate immune response. Tight regulation is essential for a functional immune response: a weak response may be insufficient to fight infection whereas a strong response risks cytokine storms, autoimmunity, and chronic inflammation. The role of RBPs in post-transcriptional regulation of innate immune gene expression remains an understudied feature of this important aspect of human health and disease. In the next five years, my lab will work to implicate new RBPs in the macrophage innate immune response and to define new paradigms through which macrophages reorganize their nuclei to activate innate gene expression. We have identified a cohort of RBPs in the SR/hnRNP families of splicing regulatory factors that are differentially phosphorylated in macrophages in response to PAMP/DAMP sensing. In the next funding period, we will work to uncover the molecular mechanisms through which each of these factors (hnRNP C, hnRNP F, RALY, and U2SURP) influence macrophage activation. We will study two complexes with the capacity to regulate many macrophage RBPs at once: the biomolecular condensate/suborganelle known as the nuclear paraspeckle and the nuclear RNA exosome. Our preliminary data demonstrate that the paraspeckle is dynamically up- and down-regulated over the course of early macrophage activation, can sequester specific RBPs in response to PAMP sensing, and is required for proper amplification of key inflammatory transcripts including Il6, Cxcl1, and Cxcl9. We found that the RNA exosome can control paraspeckle dynamics and is required to maintain normal homeostatic levels of antiviral transcripts in macrophages. Pursuing these lines of investigation will provide fundamental insights into how specific RBPs and ribonucleoprotein complexes control the ability of macrophages to sense and response to pathogens. By furthering our understanding of cellular stress responses and identifying novel nodes that control of innate immune gene expression outcomes, our work may contribute to efforts to develop therapeutics to help patients battling immune disorders and infection.

NIH Research Projects · FY 2025 · 2019-08

PROJECT SUMMARY The primary focus of this research proposal is the refinement and advanced optimization of the Non-Invasive Venous waveform Analysis for Heart Failure (NIVAHF) device, building upon the foundational achievements made under R01HL148244. This device represents a pioneering stride in the field of cardiology, offering the potential for accurate, non-invasive monitoring of volume status, which is paramount for heart failure patients. The advancements made in recent years have rendered a significant shift in our understanding of venous waveforms, leading to the development of this revolutionary monitoring tool--NIVAHF. This tool, at its core, employs an AI neural network algorithm to generate a NIVA Score, a pulmonary capillary wedge pressure (PCWP) equivalent value. This renewal looks to investigate and confront three major limitations found with venous waveform analysis in heart failure patients: tricuspid regurgitation (TR), those having undergone orthotopic heart transplantation (OHT), and those supported by a left ventricular assist device (LVAD). The prevalence of TR in heart failure patients, due to hemodynamic changes, makes it an essential marker of disease severity. Heart transplant recipients are particularly vulnerable, requiring continuous monitoring to detect early signs of graft dysfunction or rejection. Similarly, for LVAD-supported patients, consistent PCWP monitoring becomes a cornerstone for optimal care, as it helps in reducing complications and enhancing overall health outcomes. To address the complex challenges associated with venous waveform analysis, our research advances a multifaceted approach. Initially, we will delve into characterizing the intricate relationship between TR severity and the NIVA Score by harnessing an expansive database and analysis plan. This endeavor aims to recalibrate the device's precision for patients exhibiting different stages of TR. Concurrently, understanding the criticality of post-transplant surveillance, we will lay the groundwork for an OHT specific NIVAHF algorithm. This innovation will be pivotal in the early detection of graft anomalies, potentially amplifying survival rates and uplifting health trajectories for OHT beneficiaries. Lastly, as LVADs, especially the HeartMate 3, become indispensable in heart failure management, our focus sharpens on crafting an AI-driven neural network algorithm tailored for HM3 LVAD patients. The culmination of these targeted efforts will be to furnish a dependable, non-invasive PCWP monitoring device with NIVAHF to these vulnerable heart failure patients.

NIH Research Projects · FY 2025 · 2019-07

PROJECT SUMMARY/ABSTRACT: Overall This application is an A1 submission of the Vanderbilt-Ingram Cancer Center Gastrointestinal SPORE, which will focus on colorectal cancer, the second leading cause of cancer-related deaths in the United States. Our potential for success is high based on 1) productivity during the previous cycle of the GI SPORE, 2) exceedingly strong institutional support, 3) recruitment of talented investigators to the field of GI cancer through career enhancement and developmental research funding, 4) access to unparalleled resources for drug discovery and ex vivo models, 5) a blend of young and seasoned clinical investigators and basic scientists working together in a highly collegial environment, 6) a committed group of patient advocates now organized into a patient advocacy council and 7) multiple inter-SPORE, pharmaceutical, national and international horizontal and vertical collaborations. We narrowly missed being funded on our A0 submission and have been provided interim funding by NCI. We propose three projects and four supporting cores.

NIH Research Projects · FY 2024 · 2019-07

Project Summary Genetic factors play an important role in the etiology of both sporadic and familial breast cancer. Since 2007, common genetic variants in ~200 loci have been identified in genome-wide association studies (GWAS) in relation to breast cancer risk. However, it is often difficult to translate GWAS findings to disease prevention and treatment since causal genes in the large majority of GWAS-identified loci are unknown. Furthermore, a large fraction of breast cancer heritability remains unexplained. Recent studies suggest that nearly 80% of disease heritability can be explained by genetic variants regulating gene expression. Herein, we propose three well-powered transcriptome-wide association studies (TWAS) to systematically investigate the association of breast cancer risk with gene expression across the transcriptome of African, Asian and European descendants. In Aim 1, we will perform RNA sequencing and high-density genotyping assays using normal breast tissue samples and build race-specific gene expression prediction models using data from 1000 women of African, Asian and European descent. These models will be applied to the GWAS data generated from approximately 320,000 breast cancer patients and controls to impute gene expression for association analyses of predicted gene expression with risk of breast cancer overall and by estrogen receptor and HER2 status. In Aim 2, we will select the top 50 genes identified in Aim 1 for in vitro functional assays to assess their influence on major cell functions related to cancer biology. In Aim 3, we will evaluate whether TWAS-identified genes may express differently in normal breast tissues and breast cancer tissues collected from African, Asian, and European descendants to assess whether these genes may contribute to racial differences in breast cancer risk by molecular subtypes. With strong methodology and a large sample size, we believe that this proposed study should be able to identify and characterize a large number of novel genes related to breast cancer risk. Uncovering breast cancer susceptibility genes will greatly improve the understanding of the genetic and biological basis for breast cancer and accelerate the translation of genetic findings to disease prevention and patient care.

NIH Research Projects · FY 2026 · 2019-05

Pulmonary arterial hypertension (PAH) is a relentless disease characterized by vascular obliteration, right heart failure and death. Although there are ten FDA-approved therapies in three classes for PAH, none is curative and approximately 40% of patients are dead within 5 years of diagnosis. There is no established approach to identify patients who will respond to a specific therapy. The goals of this proposal are to improve outcomes in PAH using precision medicine concepts through an advanced genetics and “Omics” techniques. In unselected PAH patients, there are two subsets with striking responses to therapy. One is a small subset that has a marked reduction in PAH acutely in response to vasodilators and a dramatic long-term clinical response to calcium channel blocker (CCB) therapy. We previously published that RNA expression patterns and DNA variants in idiopathic PAH patients successfully identify patients that respond to CCB therapy. The second subset is patients that have marked improvement with parenteral prostacyclin (PP) therapy. Presently, there is little insight on how to select among the three FDA-approved PAH drug classes aside from clinical metrics of disease severity and little understanding of how PP therapy improves PAH. The first funding cycle of this grant has begun to address this unmet need by focusing on predicting responses to PP therapy. We have found two potential genetic associations with prostacyclin response, one is a polygenic risk score and the other is a variant in the complement 5 (C5) gene identified through a genome wide association study. Additionally, we prospectively enrolled 40 patients with PAH initiating PP to detect molecular predictors of prostacyclin response. In our early analysis, we have found changes in T cell phenotype in patients after PP, suggesting a more “tolerant” immune phenotype after PP. Others have published an important role for T cells in promotion of PAH, but the effect of PP therapy on T cell populations is unknown. This data was supported by a similar pattern of cytokine amelioration with PP (reduced IL-17A, IL-5). We found that IFN concentration at initiation could predict transplant-free survival, suggesting that these cytokines may be used to personalize treatment for PAH. We and others have extensively studied metabolic dysfunction in PAH, but the reasons underlying this phenomenon remain elusive. Here we found that in PAH patients requiring PP, plasma glucose directly correlated with IL-17A levels in the plasma, suggesting a potential link between metabolic disease and immune cell function in PAH. We hypothesize that immune phenotypes govern prostacyclin responses and are associated with metabolic changes in PAH. We propose the following specific aims to test this hypothesis: (1) Test the hypothesis that genomic phenotypes of prostacyclin response are common in all PAH subtypes, and are associated with poorer transplant-free survival in subjects treated with prostacyclins. (2) Test the hypothesis that inflammatory phenotype defines PAH prostacyclin response. (3) Test the hypothesis that PAH immune phenotypes are associated with metabolic dysfunction and ameliorated with prostacyclin therapy.

NIH Research Projects · FY 2026 · 2019-03

Abstract The Vascular Endothelial Growth Factor (VEGF) family of proteins has been implicated in protection against Alzheimer’s disease (AD) and includes exciting and emerging targets for intervention in Alzheimer’s disease and related dementias (ADRD). Research from our team and others has led to the nomination of FLT1 as a top target for intervention in the Agora platform. This renewal seeks to expand representation in the molecular characterization of the VEGF family while providing the cellular resolution needed to move this family toward therapeutic intervention. Our data suggest that there are clear and expected changes in endothelial cells for a number of protein targets, and that microglial cells are equally relevant for our top target FLT1. Unfortunately, both of these cell types are poorly represented in most single nucleus datasets, presenting a pressing need to expand our work to improve cellular resolution. This renewal will leverage advanced vascular isolation protocols and state-of-the-art spatial proteomic and transcriptomic techniques to provide unprecedented cellular resolution. Additionally, there is an opportunity to expand our analysis of this critical family of proteins to a cross-national brain bank to improve representation and ensure our findings generalize to the global population. The overarching goal of this work is to move multiple targets within the VEGF family of proteins toward therapeutic intervention leveraging deep molecular analysis in human brain. We hypothesize that VEGF effects rely on distinct ligand/receptor combinations that act in a cell-specific manner that can be pharmacologically manipulated. Uncovering the mechanism and cellular context of VEGF ligand/receptor combination associations with ADRD will provide selective targets for therapeutic intervention aimed at reducing the detrimental effects of the VEGF signaling malfunction. We are uniquely positioned to characterize the effects of VEGF using advanced multi-omic tools within three cohort studies from Rush University including the Pathology Alzheimer's and Related Dementias Study (PARDoS), a longitudinal cohort study in Brazil led by Rush. This renewal has the bold and important goal of expanding representation in molecular characterization of Alzheimer’s disease brains, while moving from molecular observation to nominated and well-characterized targets for intervention. The results of this work will provide a comprehensive characterization of each VEGF family member including the cellular context of effects, clinical stage at which intervention may be most beneficial, and a set of biomarker candidates that could facilitate participant identification and tracking for future interventions. All data will be shared in accordance with the open data science policies of the Accelerating Medicines Partnership AD project (AMP-AD), facilitating deep vascular characterization of the AD brain from groups around the world.

NIH Research Projects · FY 2026 · 2019-03

PROJECT SUMMARY/ABSTRACT Vanderbilt-Ingram Cancer Center (VICC) is a matrix cancer center within Vanderbilt University Medical Center (VUMC). VICC has been part of the cooperative group system for over 30 years, and a Lead Academic Participating Site (LAPS) since the inception of the National Clinical Trials Network (NCTN). Throughout the years, we have integrated our physicians into leadership roles and our basic science into investigator-initiated trials, as well as enrolled patients onto clinical trials. Additionally, VICC has a long track record of leadership, both scientific and administrative, within the cooperative groups, and mentoring junior faculty in clinical trial development. VICC brings great strengths to the NCTN, including two SPORE grants, an EDRN grant, eight highly funded scientific programs, and an Early Therapeutics Clinical Trial Network (ETCTN) grant. Our Precision Oncology Program is dedicated to matching the appropriate therapy to the genomic alterations that are driving the growth of cancers, with an active research component investigating mechanisms of resistance to targeted therapies. VICC clinicians and scientists are academic leaders in their respective disciplines and will continue to significantly contribute to the NCTN goals with the objective to improve the outcomes for cancer patients. Kristen Ciombor, MD, MSCI, serves as Principal Investigator and leads the efforts of the institution to integrate its scientific, academic, and patient resources into the NCTN. She has been involved extensively in the cooperative groups/NCTN in conduct of clinical trials, including leadership roles and receipt of expert mentorship. In recognition of her active engagement and leadership in NCI-funded collaborative clinical trials, she was named a recipient of the 2021 National Cancer Institute Cancer Clinical Investigator Team Leadership Award. Dr. Ciombor will leverage this experience and continue to successfully lead our NCTN program at VICC. To assist Dr. Ciombor with the conduct of this grant, VICC created two advisory boards, Internal Advisory Board (IAB) and NCTN Executive Committee (NEC), whose membership includes a broad representation of medical disciplines and disease interests across VICC and VUMC. The IAB assures the optimal use of the grant, such as budget review, assurance of multidisciplinary involvement, and participation throughout the NCTN. The NEC implements operational functions, such as trial opening, accrual and mentoring. Operationally, the NEC has actively managed NCTN trial opening, accruals and participation across disciplines and groups, including identification of barriers for timely activation of NCTN trials. Both the IAB and NEC work to integrate VICC science into the NCTN. The VICC Clinical Trials Office and its NCTN team ensures that regulatory, biospecimen, radiology, and data submissions are timely and highly accurate. This grant details the expert leadership and mentorship that VICC faculty have provided to the NCTN cooperative groups.

NIH Research Projects · FY 2025 · 2019-03

Sudden cardiac death due to ventricular arrhythmias is a major public health problem, accounting for 10-20% of all deaths in adults in the US. Current predictors can identify patient subsets at high risk, but unfortunately sudden death is the first manifestation of heart disease in up to half the victims. Costly implantable defibrillators in high-risk patients are the only real therapeutic option at present. Conventional anti-arrhythmic drug therapy targeting membrane ion channels has either no survival benefit or even increases mortality. Thus, a key challenge in the arrhythmia field is to understand fundamental mechanisms in order to find better ways to predict and treat ventricular arrhythmias. Since the pharmaceutical industry has all but abandoned drug development for cardiac arrhythmia, in 2018 there are fewer antiarrhythmic agents available for clinical use than 20 years ago. Hence, another key challenge for academia is to improve the efficacy of existing antiarrhythmic drugs and find new compounds that could be developed therapeutically. The overall vision of my R35 research program is to better understand molecular and cellular mechanisms responsible for arrhythmia and to use this knowledge to improve the care of patients with arrhythmia disorders. To accomplish this vision, the proposed research program will build on our prior accomplishments (e.g, finding new treatments for catecholaminergic polymorphic ventricular tachycardia or developing human induced pluripotent stem cells as better tools for arrhythmia research) to pioneer discovery in three areas: (1) Discovery of new arrhythmia mechanisms; (2) Discovery of new antiarrhythmic treatments; and (3) Development of new approaches to individualize care of patients with arrhythmia disorders. Accomplishing these goals will provide major conceptual advances for our understanding of the pathophysiology and treatment of acquired and inherited arrhythmia syndromes.

NIH Research Projects · FY 2024 · 2019-02

PROJECT SUMMARY/ABSTRACT: This application is being submitted to PA-20-272 in accordance with NOT-OD-22-137. We propose to leverage the infrastructure of the parent study (R01 AI143710), a large population-based birth cohort of over 3,000 individuals with Down syndrome (DS), an experienced study team, to study all-cause respiratory morbidity during the pandemic time of individuals with DS. This application is eligible for the Administrative Supplement award as it proposes to address “Component 2: Assembly of a large cohort of individuals with Down syndrome across the lifespan to perform deep phenotyping and study co-existing conditions” of the INLCUDE project (Investigation of Co-occurring conditions across the Lifespan to Understand Down syndromE). Individuals with DS will be followed through 2023 to study the respiratory burden during the pandemic, a priority of National Institute of Allergy and Infectious Diseases (NIAID) for the INCLUDE project. The underlying immunologic, anatomic, and physiologic abnormalities of DS make individuals with DS susceptible to respiratory viral infections and less responsive to immunizations. During the pandemic, studies have shown that individuals with DS are at increased risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and more severe SARS-CoV-2 infections. On the other hand, the implementation of non-pharmaceutical interventions (NPIs) such as hand washing, social distancing, and face masking has resulted a dramatic global reduction in the incidence of common respiratory virus infections during the pandemic. Respiratory burden resulting from these viruses in individuals with DS might be reduced. The overarching objectives of the study are to determine the burden of respiratory morbidity in individuals with DS during the pandemic time. Building upon the parent study of a population-based birth cohort of 3,051 children with DS who were born in 1995-2019 and enrolled in Tennessee Medicaid Program and Department of Defense Military Healthcare System, we propose to 1) expand the cohort to include individuals with DS who were born during the pandemic (born 2020-2023, estimated N=705) and 2) extend the follow-up period of the current subjects (born 1995-2019) to 2023 to study all-cause respiratory morbidity during the pandemic time. We will determine the rates and quantify the severity of COVID-19 related and unrelated respiratory healthcare encounters. Respiratory morbidity, including healthcare encounters for COVID-19, pneumonia, otitis media, croup, wheezing, asthma, bronchitis, bronchiolitis, respiratory failure, tympanostomy tube, and other respiratory related morbidity, will be examined. Public Health Impact. Results of the study will provide a better understanding of the overall prevalence and burden of COVID-19 related and unrelated respiratory morbidity, and provide important information to inform the usage of subsequent vaccines, protection products, and therapeutic strategies in individuals with DS, an important goal of the INCLUDE project and part of our research team’s long-term interest.

NIH Research Projects · FY 2026 · 2018-09

PROJECT SUMMARY Staphylococcus aureus is a major human pathogen that causes significant morbidity and mortality in both hospital- and community-acquired infections. The appearance of multidrug-resistant strains has compounded this problem, galvanizing efforts aimed at identifying new therapeutic targets. Staphylococcal infections are characterized by the formation of tissue abscesses which represent the primary site of interaction between a bacterial microcolony and the innate immune response of the host. We have discovered that the staphylococcal abscess exhibits remarkable molecular heterogeneity, challenging efforts focused on designing therapeutics or vaccines for the treatment and prevention of S. aureus infections. In this proposal, we will address this challenge through the development of a cutting-edge multi-modal imaging platform that will define the molecular inventory of the S. aureus abscess and reveal the contribution of host antimicrobials to the molecular composition of this infectious interface. This proposal combines our expertise in immunology, infection biology, mass spectrometry, small animal imaging, machine learning, and computer vision to develop an integrated multimodal visualization method for studying microbial communities and tissue abscesses. Our unique approach will reveal the proteins, lipids, small molecules, and transcripts that define the staphylococcal abscess. Through genetic inactivation of critical innate immune effectors, we will uncover how the host response to infection drives alterations in these lesions. These experiments will test the hypotheses that exposure to environmental stresses encountered within the host have a powerful effect on molecular abundance and distribution within the staphylococcal microcolony, and that the molecular environment of the abscess is highly variable and changes according to the stage of abscess development. Taken together, our next-generation imaging capability will (i) map molecular heterogeneity within microbial communities in response to environmental stressors, (ii) define molecular heterogeneity in tissue abscesses, and (iii) determine molecular profiles and discover spatio-molecular host and microbial factors that define the lifecycle of the staphylococcal abscess. These studies will uncover new targets for therapeutic intervention against this important human pathogen, and the techniques developed as a result of this proposal will be broadly applicable to all physiologically relevant processes, profoundly impacting biomedical research.

NIH Research Projects · FY 2025 · 2018-08

Cardiometabolic diseases (CMD), including obesity, dyslipidemia, type 2 diabetes, and hypertension, are the leading cause of disease burden in the world. In the first funding period of our project, The Hispanic/Latino Lipid Consortium (HLLC), our efforts centered on discovering genetic factors impacting serum lipid levels, obesity, and T2D in self-identified Hispanic/Latinos (HL), population with high rates of genetic admixture and significant CMD health disparities. This highly impactful research, which has resulted in 39 published papers to-date, leveraged extant genetic data as well as new genetic data generated for the project in >63k participants to identify multiple new CMD loci. We also characterized the regulatory mechanisms influencing lipid levels using a new resource of whole blood (WB) gene expression profiles in 880 HL participants. Yet, the mechanism of action of most GWAS signals and the molecular pathways disrupted in metabolic tissues are still not well understood. As such, in the second funding period of the HLLC, we propose to build on our remarkable success and experience generating and analyzing transcriptomic data in HL. Here, we aim to investigate the role of multi-tissue gene expression (WB and subcutaneous adipose tissue [SAT]) and changes in WB expression over time with the goal of identifying key modifiable molecular signatures associated with CMDs in an even larger sample of admixed individuals. Specifically, we propose to: first, identify multi-tissue transcriptomic patterns associated with CMD and related traits (obesity, type 2 diabetes, dyslipidemia, hypertension measures) in recently acquired WB RNA sequencing data from 14k admixed participants as well as in 300 SAT tissue specimens from participants recruited for the present application; second, identify longitudinal changes in WB transcriptomic data associated with changes in CMD-related risk factors in participants from the HLCC (1500 RNA measures from 750 participants with an average of 5 years between the two RNA sequencing measures for each person); and third, conduct integrative analyses of genetic and transcriptomic data to establish causality via Mendelian Randomization and characterize existing genomic findings with functional evidence. Our aims are entirely independent, exceptionally well powered, and designed to answer critical questions about the causal pathways underlying observed transcriptomic differences in CMD. This work will result in creation of a publicly available resource of eQTL information for metabolic tissues in HL and identify novel targets for early prevention and pharmaceutical intervention. Significantly, by addressing CMD risk our work contributes directly to the NIH’s mission to promote disease prevention and treatment.

NIH Research Projects · FY 2025 · 2018-08

The overall goal of the Vanderbilt Oncology Training Program (VOLT) is to prepare hematology and oncology fellows and other trainees for careers conducting impactful cancer-related clinical, translational, and population science. The objectives of VOLT are 1) to identify and recruit trainees to become top-tier junior investigators in hematology and oncology by providing an advanced training experience, and 2) to develop skills that support this career, including communication, resiliency, team building, and grant management. VOLT will accomplish this by mentored clinical research in oncology and tailored didactics including Master’s degree programs. Through regular meetings with the Program Directors, peer trainees, and mentorship committees, annual retreats, as well as preparation of Individual Development Plans and structured Progress Reports, VOLT trainees gain the skill set required for a successful oncology research career. VOLT has identified an outstanding group of 43 committed, experienced mentors across cancer-related disciplines. Trainees conduct mentored research in three areas: 1) molecular oncology, 2) therapeutic development, tumor immunology, and immunotherapy, and 3) bioinformatics, big data, and cancer outcomes. Trainees are recruited from medical and pediatric hematology and oncology, or other cancer-related disciplines. VOLT is led by two physician scientists, a medical oncologist who conducts translational research and a pediatric oncologist who conducts population science and clinical research. An Internal Advisory Committee representing the range of VOLT research evaluates prospective trainees, and monitors the progress of individual trainees and the program’s success. Metrics for trainee and program evaluation include program completion, retention in research-focused careers, funding success, publication, and impact. An External Advisory Committee, composed of four physician-scientists, provides input into the scientific direction of program, ensures it is meeting national workforce needs and cancer priorities, and monitors progress, accomplishments, and trajectory to further programmatic advancement. Ongoing program evaluation has led to improvements in trainee evaluation and changes in advisors and mentors to reflect greater breadth of research expertise. Our 10 trainees have published 28 manuscripts since their appointment to VOLT. Four have received peer-reviewed grant support, and an additional three have applications under review. Of the five trainees who have graduated, four continue in research-intensive careers. In its first cycle, VOLT has been successful in developing trainees who will lead cancer research and advance cancer care and is well poised to continue this trajectory.

NIH Research Projects · FY 2025 · 2018-07

Unprecedented opportunities exist for the treatment of a broad spectrum of neurological disorders. These are being driven by rapidly accelerating advances in neuroscience. Over the last six years, the Network of Excellence in Neuroscience Clinical Trials (NeuroNEXT), a coordinated, efficient, and vibrant network of clinical sites, has rapidly implemented innovative trials in response to disease-specific opportunities. Vanderbilt University Medical Center remains ideally positioned to continue our involvement as a clinical site within NeuroNEXT. The Principal Investigators and their co-investigators have participated in a multitude of diverse disease-oriented networks and multicenter trials, and have a strong track record of developing and participating in innovative trials with NIH (including NINDS), industry, and foundation support. The Vanderbilt NeuroNEXT site team will leverage the many strengths of the collegial, multidisciplinary environment for clinical and translational research on our campus. These include the Vanderbilt Institute for Clinical and Translational Research (CTSA-funded entity with overmatching funding by Vanderbilt), which includes the "Center for Innovative Trials in Children and Adults" (Trial Innovation Network Center or TIC) and "Improving Clinical Trial Education, Recruitment and Enrollment at CTSA Hubs" (Recruitment Innovation Center or RIC). We also have an unmatched genomics team and genetics institute to assist in future gene therapy trials. Furthermore, we have an established partnership with Meharry Medical Center to optimize diversity within our site. Our Specific Aims include: (1) To fully engage our collaborative leadership team in continuing to develop a transformative neuroscience network site that is agile and responsive to the needs of NeuroNEXT. The Principal Investigators, their two key co-investigators, and a cadre of collaborators and advisors bring to NeuroNEXT their complementary experience in trials and disease-specific networks involving both adults and children, funded by NIH, other federal agencies, industry, and foundations. (2) To leverage the abundant institutional resources of the Vanderbilt research enterprise, including the TIC and RIC, the undiagnosed disease network, Meharry Medical Center, our research cores, and our expanding Vanderbilt health-affiliated network to strengthen our participation in NeuroNEXT trials. This will provide NeuroNEXT with deliverables including high enrollment and retention of diverse study participants, with an emphasis on quality and data integrity. We will seamlessly apply our expertise from ongoing trials to new trials and continue to refine our practices throughout the funding period. (3) To provide mentorship and educational opportunities in neurological clinical trials to early career investigators, leveraging our institutional resources along with the abundant opportunities within NeuroNEXT. While focused on early career investigators, we are uniquely poised to provide education in clinical trials at all levels of education, including students, residents, fellows, and faculty (including established investigators changing the direction of their research careers), and research staff.

NIH Research Projects · FY 2024 · 2018-07

PROJECT SUMMARY The learning healthcare system is 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.” Vanderbilt is committed to continuing in the development of a cadre of scientists formally trained and well versed in best methods for integrating scientific discovery, evidence implementation, and evaluation of health policies within the learning healthcare system. We have a strong track record of training fellows and improving patient outcomes. We propose to renew the Vanderbilt Patient, pRactice Outcomes and Research in Effectiveness and Systems Science (PROgRESS) Program to cross train post-doctoral investigators with a focus in the learning healthcare system's three core disciplines: 1) Patient Centered Outcomes Research - To determine which strategies are most effective for patients; 2) Implementation Science - To implement and evaluate those effective strategies into practice; and 3) Health Policy/ Community Health - To influence policy to benefit all patients and improve health of the population and community. By cross training researchers, we will draw together groups of trainees and mentors to model team science. We provide role models to junior investigators and 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 that leads to improvement in the populations' health. A robust and diverse pool of talented applicants is available with more applicants each year than spaces available in the program. We have a thriving Implementation Science program, a well- positioned Department of Health Policy, and diverse partners including Meharry Medical College and Vanderbilt University School of Nursing. PROgRESS trainees will continue to access faculty mentors with sustained federal funding who have an extensive track record of mentoring trainees. Each trainee's Scholarship Oversight Committee (SOC) will draw from an experienced pool of mentors in the three areas of focus: Patient Centered Outcomes Research, Implementation Science, and Health Policy/Community Health. The program will continue to provide: 1) advanced didactics, including a degree program or focused classwork; 2) formal mentorship that prepares trainees for K-level training; and 3) experiential learning through the conduct of a research project. Trainees will be supported by a broad array of institutional resources for training and development, including: Work in Progress, Clinical Quality and Implementation Research Scholarly Series and journal clubs, Biostatistics Seminars, clinical and translational seminars, and peer-mentoring activities. Taken together, these resources provide an optimal environment for developing the next generation of learning health system scientists.

NIH Research Projects · FY 2026 · 2018-01

PROJECT SUMMARY/ASBTRACT Electronic health record (EHR) and other routinely collected data are often used as cost-effective data sources for HIV/AIDS research. These data sources, however, are known to be prone to errors, typically across multiple variables, which can lead to biased study results and misleading conclusions. In addition, EHR data sources often lack gold-standard measurements that are needed to clearly define the presence or absence of co-morbidities (e.g., liver fibrosis). To address limitations of EHR data sources, researchers can validate or collect additional data on a subsample of their patient records. By combining the rich, but error-prone EHR data on all study subjects with the gold-standard / validated data collected on a subsample of subjects, researchers can improve study estimates. Specifically, researchers can eliminate the bias of estimates had they only used the EHR data, and they can improve the precision (e.g., narrower confidence intervals) of study estimates had they only used the subsample with gold-standard / validated data. In earlier research, we developed statistical methods and software to combine EHR data with validated sub-samples of data. We developed optimal, multi-wave designs for targeting records for data validation. Importantly, we applied these methods to multiple HIV studies using retrospective observational data from the International epidemiology Databases to Evaluate AIDS (IeDEA). However, in our applications, we have encountered additional challenges that have not yet been addressed. In particular, there is great potential in combining expensive, prospectively collected, gold-standard data that are sparsely measured (e.g., once per year) on a sub-sample of patients with EHR data that are collected much more frequently on a larger number of patients. We will develop methods to handle this setting, and we will develop statistical designs to better select which participants should be approached for prospective data collection and which patient records should be validated. We will also develop statistical methods to address other challenges encountered with using EHR data, including how to incorporate validation data into studies when inclusion in the study is error-prone, and methods to address more complex types of data (e.g., interval censored data), for which there are a lack of techniques to handle error-prone data. Our methods and designs will focus on extensions of multiple imputation, maximum likelihood, and generalized raking techniques. Open source tools and tutorials will be developed to help researchers to implement these novel methods and study designs. The methods and designs will be applied to data from the IeDEA network to estimate the incidence of and risk factors for liver fibrosis/steatosis and frailty among people living with HIV in East Africa and Latin America.

NIH Research Projects · FY 2025 · 2017-09

An excess burden of chronic kidney and end stage renal disease is experienced by Black Americans. Risk variants in the apolipoprotein-1 (APOL1) gene, found almost exclusively in individuals of African ancestry, are associated with several forms of non-diabetic kidney disease in Black Americans, including focal segmental glomerulosclerosis, HIV-associated nephropathy, and hypertension-related kidney disease. These APOL1 risk variants explain up to 70% of the excess risk in Black Americans with these kidney diseases. However, presence of these risk variants does not guarantee development of kidney disease, with secondary genetic or environmental hits required. This along with lack of targeted therapies makes the value of genetic screening for APOL1 risk variants unknown. The impact of APOL1 risk variants in kidney transplantation, for both donors and recipients, is understudied. It is unknown if living kidney donors with APOL1 risk variants are at increased risk for development of kidney disease post donation. For recipients, initial studies have suggested that recipients who receive donor kidneys with two APOL1 risk variants may have worse graft outcomes. Due to both biological and social-economic factors, Black Americans have been historically disadvantaged in receiving kidney transplants, and the theoretical practice of APOL1 genetic screening and excluding donors with risk variants could further disadvantage this population. These multiple questions highlight the need to thoroughly examine the impact of APOL1 risk alleles on transplant outcomes. The NIH- sponsored APOL1 Long-term Kidney Transplantation Outcomes Network (APOLLO) is addressing this important question by uniting transplant centers, organ procurement organizations (OPOs), and the United Network for Organ Sharing (UNOS) to enroll donors of African ancestry and their kidney recipients, then follow their transplant outcomes. In Phase 1 of APOLLO, we have functioned as an ideal clinical center in direct response to original request for application by enrolling 154 qualifying deceased donor recipients, living donors, and living donor recipients through partnerships with 8 transplant centers in addition to our primary Vanderbilt University Medical Clinical Center, providing DNA, biospecimens, and essential longitudinal clinical data. Our aligned transplant centers include large academic programs as well a small community programs to strive for the goal of universal enrollment. We have worked seamlessly with the other Clinical Centers and the SDRC, as well as partnered with OPOs and UNOS, to build a strong foundation for APOLLO. For Phase 2, we will continue the important work of the APOLLO Consortium through accomplishment of several aims. In Aim 1, we will prospectively collect long-term follow-up data on all APOLLO participants and enroll additional living donors. In Aim 2, we will provide detailed clinical data and biospecimens on APOLLO participants as well as kidney transplant biopsy slides from our Clinical Center. In Aim 3, we will facilitate return of APOL1 genotype results. Once completed, these Aims will advance our knowledge of APOL1 in kidney transplantation.