Vanderbilt University Medical Center

NIH Research Projects · FY 2025 · 2017-09

PROJECT SUMMARY The rapid development and advancement of technologies and knowledge in molecular biology and genetics have led to major breakthroughs in cancer etiology research. The field of cancer epidemiology is moving rapidly toward a new era in which interdisciplinary and multidisciplinary collaborative research is the central theme. This necessitates a growth of workforce of scientists working at the interfaces of epidemiology, molecular biology, and genetics. The Vanderbilt Training Program in Molecular and Genetic Epidemiology of Cancer (Vanderbilt-MAGEC), launched in 2012 with NCI R25 funding and currently supported by a T32 grant, is designed to fill the gap with a goal of providing postdoctoral fellows from a variety of disciplines with the methodological tools, practical laboratory and survey-research knowledge, and hands-on research and grant writing experience necessary to launch an independent career in the molecular and genetic epidemiology of cancer. The specific aims of the Vanderbilt MAGEC program are: 1) To recruit ethnically-diverse candidates with strong backgrounds in epidemiology, genetics, and/or biology. 2) To deliver individualized didactic training tailored to complement each trainee’s prior training background and launch them into their desired career paths (molecular or genetic epidemiology of cancer). This training consists of courses, seminars, studios, journal clubs, conferences and research grant preparation. 3) To establish a multi-disciplinary mentor team for each trainee and integrate trainees into NCI-funded cancer epidemiology research projects. 4) To evaluate the impact of the Vanderbilt MAGEC program by tracking short- and long-term outcomes. Expected short-term outcomes for all trainees include publishing high-quality papers in peer-reviewed journals and submitting a grant proposal to an internal or external funding agency based on the NIH format. Long-term outcomes include cancer research career placements and NIH grant funding. The MAGEC program, built upon an outstanding research and education training environment; a pool of 31 excellent, well-funded researchers and educators; 100 ongoing, cutting-edge research projects; exceptional data/biospecimen and population resources; and a rich history of interdisciplinary training, has met remarkable success during the current grant cycle. During the last 4 years and 9 months, 12 fellows received or are currently receiving MAGEC training; of these, 2 graduated trainees obtained faculty positions, and both received K12 fellowship awards, and one received two additional career development awards. Another five graduated fellows are working in research-intensive settings. Trainees contributed to 56 publications, 30 as first author. The program is mature and is in an excellent position to continue growing. The renewal program will support 6 postdoctoral fellows. The expected training duration for the MAGEC program is 3 years. Continued support of the program is essential for sustaining its success and extending its impact on training a new generation of elite molecular and genetic cancer epidemiologists and leaders in the new era of precision medicine and prevention.

NIH Research Projects · FY 2025 · 2017-07

Project Summary/Abstract Adolescence, the developmental transition of juvenile social and cognitive processes to their adult forms, is a period of remarkable physiological, psychological, and social changes. During adolescence there is a significant increase in the risk for psychiatric disorders such that half of people who will suffer from mental illness have their onset by 14 years of age. Early research suggests that it is a pivotal transition for youth with autism spectrum disorder (ASD), a condition characterized by difficulty with social competence and change including developmental transitions. During the initial phase of the longitudinal study (MH111599), significant, clinically meaningful findings regarding autistic youth were revealed including: 1) dynamic and significant developmental effects of age on biobehavioral profiles, 2) advanced pubertal onset especially in autistic females, #3) elevated risk for depression emerging in early adolescence, 4) physiological dysregulation increasing with age and symptom severity and associated with depression, and 5) unique and complex profiles of sex and gender. These studies have provided the foundation and data for our competing renewal application, which is aligned with the NIMH Strategic Plan Goal 2 “…to examine mental illness trajectories to determine when, where, and how to intervene.” The overarching goal is on mental health risk (e.g., depression) and resiliency (e.g., coping) and potential moderating factors that may impact individual outcomes including diagnosis (autistic, neurotypical), development (age, puberty), sex (female, male) and gender (binary, non-binary) over adolescence. This research will help identify sensitive periods to reduce risk and prevent the onset of mental illnesses. Due to advanced pubertal timing in ASD and a significant rise in mental illness (e.g., depression) in early adolescence, studying the prepubescent period is essential. To examine developmental changes, the study will use a rigorous accelerated longitudinal design (ALD) corresponding with pre-, peri-, and pubertal development. Three cohorts will be enrolled at ages 8-9 (N=80), 10-11 (N=80) and 12-13 (N=80) followed over a four-year study period. Additionally, the previous cohort ages 15-17 (ASD N=64; TD N=60) will be followed providing a broad age span (8-17 years). The aims will address three areas. Aim 1: When: will examine the impact and unique contributions of adolescence and puberty on mental health profile based on diagnosis (ASD vs. TD) and Sex (Females vs. Males). Aim 2. Where: will examine social and emotional functioning during naturalistic interactions with peers. Aim 3. How: will examine physiological responses at the level of the central nervous system (event related potential), HPA axis (cortisol), and peripheral nervous system (heart rate variability) as plausible biobehavioral targets that predict risk and resiliency. An exploratory aim, Why: to explore key risk factors that impact mental health over adolescence and puberty to inform individual biopsychosocial profiles and treatment. The project will extend the MH111599 by focusing on mental health and key developmental, physiological, socioemotional, and demographic factors that confer risk or resiliency in youth with ASD or TD.

NIH Research Projects · FY 2026 · 2017-06

Alkaline diets and alkalemia have a profound impact on potassium homeostasis, but the underlying mechanisms remain poorly understood. Here we propose an innovative plan to close this significant knowledge gap, building on our recent discovery of a long sought-after electroneutral potassium transport pathway. Our data reveal that dietary alkaline loading stimulates the expression of the electroneutral KCl cotransporter, KCC3a (Slc12a6), in parallel with the Cl-/HCO3- exchanger, pendrin (Slc26a4), on the B- type intercalated cell apical membrane and the activation of the thiazide-sensitive sodium-chloride, NCC (Slc12a3), in the Distal Convoluted Tubule. Here we advance the overarching hypothesis that KCC3a is the long sought-after electroneutral potassium secretory pathway and propose the novel idea that coupling between KCC3a, pendrin, and NCC maintains potassium and acid-base balance in response to the consumption of alkaline and potassium-rich foods but drives potassium wasting in alkalosis. This new model will be rigorously tested by a multidisciplinary team of experts, combining state-of-the-art cellular biology and physiological phenotyping in novel genetically engineered mouse models. Aim 1 will test the hypothesis that KCC3a is activated in response to the consumption of alkaline diets and alkalosis to drive urinary potassium excretion. Intercalated-cell-specific KCC3 knockout mice will be investigated to a) test the contribution of KCC3 to potassium balance and b) to pendrin-mediated HCO3- secretion; c) elucidate the molecular mechanisms that underlie the regulation of KCC3 expression; c) test if KCC-specific inhibitors prevent the loss of K+ in alkalemia. Aim 2 will test the hypothesis that pendrin is co-activated with KCC3a to increase KHCO3 secretion. Pendrin knockout mice will be studied to determine: a) the contribution of pendrin to the regulation of KCC3a; and b) the physiologic consequences of uncoupling the transporters. We will also explore if KCC3a regulates pendrin through changes in pendrin transcription that involve changes in intracellular chloride. Aim 3 will test the hypothesis that alkalosis drives WNK-SPAK mediated phospho-activation of NCC to ensure electroneutral potassium bicarbonate secretion prevails over electrogenic potassium secretion. Newly developed DCT-specific loss and gain of SPAK mice and in vitro cell models will be examined to rigorously test this idea and explore the mechanism. In summary, this program of investigation should illuminate a new mechanism to explain how K+ and acid-base balance are preserved with the consumption of alkaline and potassium-rich foods, typical of the paleolithic and vegetarian diets. The investigation is also expected to change the textbook explanation of urinary potassium wasting in alkalosis, opening a new therapeutic horizon.

NIH Research Projects · FY 2025 · 2017-06

The goal of the Vanderbilt-Meharry Edge for Scholars Career Development Core is to inspire careers dedicated to interdisciplinary translational science and to produce leaders in the field who are optimally prepared to guide and participate in ground-breaking transdisciplinary teams. We have a record of excellence preparing early career scholars. Overall 93% remain in academics, 96% in research, and 81% are federally funded as PIs; 55% are site PIs or co-investigators with 50% or more of effort for research. Their careers are thriving. Current and prior awardees represent more than 20 disciplines and many clinical backgrounds including anesthesiology, chemistry, emergency medicine, hearing and speech, medicine, nursing, pediatrics, and thoracic surgery, with nearly even numbers of clinically trained and PhD-prepared scientists. We serve twelve trainees (6 grant; 6 internally funded). Program elements are purposefully designed for connecting, enlarging, and sustaining our community of translational scientists. Edge Scholars are grounded in the fundamentals of translational research, prepared to lead independent research programs, trained to effectively deploy innovative interdisciplinary approaches to attack and solve problems, and are committed to pursuing research that taps into the power of teams for driving breakthroughs. Scholars are selected by competitive review of applications from a scientifically diverse pool of early career faculty. Training is individually tailored to the investigator in the context of structured interdisciplinary mentorship and is overseen by the PI (Bastarache) and Co-Director (Gordon). The environment is further enriched by myriad institutional resources that ensure our researchers flourish. In this proposal we add a science communications initiative and extend Pathways to all Scholars. Pathways combine didactic, intensive, and experiential learning to consolidate competencies across many areas: Biostatistics & Epidemiology, Data Sciences, Clinical Context (for non-clinical scholars), Learning Healthcare System, Measurement Methods, and Technology Transfer & Innovation. Scholars form a mentor panel, participate in frequent work-in-progress groups and activities, receive formal evaluation each year, attend twice-monthly career development seminars with other K scholars, and are regularly exposed to case studies on responsible conduct of research, and rigor and reproducibility. Scholars access: 1) an array of cores; 2) biostatistics consultations; 3) manuscript groups; 4) technical editing; 5) studios with experts to vet scientific ideas, research designs, and aims; 6) robust intramural pilot and feasibility funding; and 7) grant writing resources including grant workshops, a library of funded grants, and mock study sections. Tools are in place to evaluate both scholars and mentors over time and to continuously enhance our program. Further oversight is provided by the Advisory Committee and external site reviewers and we extensively share with other CTSAs. Combined, these efforts assure we carefully foster excellence in the next generation of translational scientists.

NIH Research Projects · FY 2026 · 2017-06

The Vanderbilt-Meharry Edge for Scholars NRSA Core is an interdisciplinary, translational research training program invigorated by group activities that intentionally mix non-clinical and clinical trainees across disciplines and levels of training (TL1 and KL2). We offer a uniquely collaborative culture with a thriving research enterprise and our approach serves to connect, enlarge, and sustain our community of translational scientists. This model is responsive to calls for changing how the next generation of researchers is trained to drive translational endeavors and to excel in team science. Unlike traditional T32s, our selection of trainees is not constrained by discipline, graduate programs, or disease focus. Building on varied research backgrounds of trainees, we incorporate experiences to foster emergence of new interdisciplinary teams—which is proving effective. Pre- and postdoctoral trainees are selected by competitive review from a large pool of applicants. Training is individually tailored in the context of structured mentorship and progress is carefully monitored by the PI (Bastarache) and Co-Director (Edwards). Activities include interdisciplinary mentor panel meetings, work-in-progress groups, Bench-to-Bedside Rounds, near-peer mentoring, writing workshops, and pragmatic career development seminars. This program will serve 10 TL1 trainees, seven pre-doctoral and three postdoctoral, for up to five and three years respectively. In addition to conducting mentored research as part of an established transdisciplinary team and pursuing their academic course of studies if applicable, trainees will craft Pathways that combine 42 contact hours (not credits) of didactic, intensive, and experiential learning. These are anchored in several key areas: Biostatistics & Epidemiology, Data Sciences, Clinical Context (for non-clinical scholars), Learning Healthcare System, Measurement Methods, and Technology Transfer & Innovation. Individualized components of pathways build key translational competencies, yet are flexible and allow extensive individual tailoring to best match prior training and future career directions of the trainee. Our program benefits from integration within a CTSA hub in a medical center that ranks 5th in overall NIH funding, conducts cutting-edge research, provides top-flight graduate education, and has strong synergy across the TL1 and KL2 awards. We provide trainees an abundance of research cores and unique models for expert guidance like Studios, Biostatistics Clinics, REDCap Data Management courses, a library of funded grants, internal study sections, and much more. Tools are in place to evaluate both trainees and mentors over time and to continuously enhance the program. Oversight is provided by an Advisory Committee and external site visitors. We work extensively with other CTSAs and have built collaborative resources shared nationally. In summary, we foster excellence to inspire careers dedicated to interdisciplinary translational science and to prepare future leaders of high performing scientific teams.

NIH Research Projects · FY 2026 · 2017-06

The Vanderbilt Institute for Clinical and Translational Research (VICTR) is a highly functional and integrated clinical and translational (C&T) research infrastructure that has raised the quality and scientific rigor of the research conducted at Vanderbilt and longstanding partner Meharry Medical College. VICTR will contribute to the mission of the CTSA program while leveraging unique resources and expertise within VICTR’s Hub with these new aims: 1) Leverage VICTR's strong collaborative energy to enhance team science methodologies, integrate community engagement principles for all stages of research, and implement programs designed to support studies conducted representative of the population with the disease or condition and that are focused on health needs for all affected populations; 2) Develop and share multi-dimensional data organization methods and informatics tools to promulgate innovation, efficiency, quality, and promote studies that are focused on the health needs for all affected populations; 3) Ensure the translational science workforce is multi-disciplinary and has the skills, knowledge, and resources necessary to advance translation of discoveries; 4) Support the efficiency, quality, and impact of local studies and ‘raise the bar’ for acceptable scientific standards in research conduct; 5) Support the efficiency, quality, and impact of multi-site clinical trials by building and disseminating streamlining programs and promoting novel trial designs; and 6) Utilize unique institutional capabilities to enable the conduct of pragmatic trials during healthcare operations and repurpose existing drugs for new indications.

NIH Research Projects · FY 2025 · 2017-04

PROJECT SUMMARY/ABSTRACT The focus of this renewal remains colorectal cancer (CRC), the 2nd leading cause of cancer mortality worldwide. During the last cycle of funding, seminal advances were made related to early and late events in colorectal neoplasia, utilizing cutting-edge technologies and uncovering paradigm-shifting concepts applicable to other solid tumors. In the next cycle, we will concentrate on microsatellite stable (MSS) CRC, which accounts for 85% of CRC and does not respond to immune checkpoint blockade (ICB) in marked contrast to microsatellite unstable (MSI-H) CRC. As MSS tumors are derived from a stem/progenitor epithelial cell population, we propose studies involving the identification of a novel marker for a quiescent stem cell population, Tob2, as well as determining the nonredundant roles of Lrig1 and Lrig3 in colonic tumor formation as they are critical regulators of intestinal homeostasis. In separate studies using a novel NSC-seq platform, we have identified Tob2 that is expressed early in mouse embryogenesis and marks a population of quiescent stem cells that will be probed for its ability to impact colonic tumor formation as well. Also, we have discovered a 4-gene immune-exclusion (IEX) score in MSS CRC that impacts clinical outcome. Three of the genes encode secreted proteins (DDR1, TGFBi, DPEP1) that may be responsible for IEX and are therapeutically tractable. A clinical trial has already started combining a neutralizing antibody to DDR1 and ICB. A major area of investigation has been small extracellular vesicles (sEVs) and an amembranous nanoparticle, termed supermeres, which we recently discovered. Remarkably, DPEP1 and TGFBi are the two most abundant proteins in CRC sEVs and supermeres, respectively; DDR1 is also enriched in supermeres. Of note, these proteins are markedly increased in the respective plasma-derived fractions of CRC patients versus healthy controls so they may serve as CRC biomarkers. We propose mechanistic studies to determine the function of these proteins, including that of a novel isoform of DPEP1 whose overexpression results in tumor formation in mice. Our discovery of supermeres has opened the possibility for new biomarkers and ways to target tumor progression through cell-cell communication, which we will explore through understanding supermere biogenesis and determining supermere function in immunomodulation of the CRC tumor microenvironment. In this renewal, we intend to continue to make paradigm-shifting discoveries that impact the ways of thinking about cancer, its origins, how it progresses, as well as implementing practice- changing strategies to diagnose and treat MSS CRC.

NIH Research Projects · FY 2025 · 2016-09

PROJECT SUMMARY Substance use disorders (SUDs) remain a medical and societal burden with a relative paucity of prevention and treatment options. The nucleus accumbens (NAc) is an essential hub integrating cognitive, contextual, sensory and affective information into behavioral outcomes. Changes in excitatory (glutamatergic) synaptic function in the NAc is a leading molecular mechanism by which illicit drug exposure leads to the behavioral manifestations represented by SUDs. However, a gap in the input specificity, temporal dynamic, mechanism(s) and consequences of plasticity and drug-induced plasticity onto parvalbumin expressing fast spiking interneurons (PV-FSIs) remains. The long-term goal is to understand the mechanisms by which NAc circuits mediate reinforced behaviors. The overall objective of this application is: (1) to define input-specific plasticity mechanisms controlling excitatory synaptic strength onto PV-FSIs, (2) to elucidate mechanistic contributions of these synapses to reinforcement behavior, and (3) to determine contribution of NAc PV-FSI AMPA receptors to cocaine-evoked plasticity of MSN excitatory synapses. The central hypothesis is that functionally-distinct corticolimbic and thalamic synapses onto PV-FSIs in the NAc support cocaine-evoked adaptations in reinforcement behavior and circuit function. Aim 1 is designed to determine mechanisms of stimulus and cocaine-evoked synaptic plasticity of specific excitatory inputs onto NAc PV-FSIs. Aim 2 will determine the role of glutamatergic signaling onto NAc PV-FSIs in modulating reinforcement behavior in an input specific manner. And, Aim 3 will elucidate the contribution of NAc PV-FSI AMPA receptors to cocaine-induced plasticity of MSNs. The rationale for the proposed studies is that they will provide a detailed understanding of the functional organization of NAc PV-FSI microcircuitry, revealing synaptic mechanisms by which PV-FSIs adapt to stimuli and support reinforcement behavior as well as influence cocaine-evoked reorganization of output circuits. To accomplish these aims a combination of whole-cell patch clamp electrophysiology, Drugs Acutely Restricted by Tethering (DART) pharmacology, optogenetics, reinforcement behavior and transgenic mice will be used. The proposed research is innovative because it represents a new and substantive departure from the status quo by shifting focus to the modulation of PV-FSI feedforward inhibition as a master regulator of NAc function and thus reward-related behavior. Completion of the work in this proposal will: (1) establish plasticity mechanisms at specific excitatory inputs onto PV-FSIs. (2) Establish a causal relationship between NAc PV-FSI AMPA receptors and reinforcement behavior and (3) demonstrate that NAc PV-FSI AMPA receptors are necessary for cocaine- evoked plasticity of MSN excitatory synapses. Completion of this work is expected to have a positive translational impact by examining an understudied but integral component of the reward system and will provide a launching point for the development of novel strategies to prevent and treat Substance Use Disorders.

NIH Research Projects · FY 2025 · 2016-07

This application seeks to renew the Vanderbilt Genomic Medicine (VGM) training program at Vanderbilt University Medical Center (VUMC). VGM fellows are trained in data science, bioinformatics, laboratory science, and genomic discovery; the program also instructs fellows on the practice of genomic medicine. VGM builds on decades-long strengths in critical enabling resources and infrastructure within VUMC including: 1) BioVU, the largest biobank linking DNA samples to electronic medical records (EMRs) at a single academic institution (now >244,000 subjects), 2) Participation in three NHGRI-funded networks: the Electronic Medical Records and Genomics (eMERGE) network and eMERGE coordinating center, the Implementing Genomics in Practice (IGNITE) Network, and the Undiagnosed Disease Network (UDN), 3) the Pharmacogenomic Resource for Enhanced Decisions In Care and Treatment (PREDICT) project which embeds pharmacogenomic testing within electronic health records (EHRs) to guide drug and dosage choices 4) a Precision Oncology program that applies tumor genome sequencing to identify actionable mutations in cancers and to personalized target therapy, and 6) the largest Department of Biomedical Informatics in the country, with strong research, education, and support programs in clinical information technology. The program has 35 highly collaborative and well-funded faculty preceptors who team up to provide both basic and clinical research opportunities to Ph.D.-level and M.D.-level postdoctoral fellows. Fellows will participate in rotations, seminars, journal clubs, and retreats and interact with other clinical and research fellows and faculty. Under Vanderbilt’s Biomedical Research Education and Training (BRET) Office, the program will provide Responsible Conduct in Research (RCR) training, high-standard Individual Development Plans (IDP), and Career Development programs with the goal of developing fellows to be next-generation leaders in genomic medicine. A Scientific Advisory Committee and an External Advisory Committee provide valuable advice on VGM program development and enhancement. The program actively seeks candidates from different professional and research backgrounds. Our fundamental model is to enhance multidisciplinary training through a curriculum tailored for each trainee based on prior experience, coupled to paired mentoring with both clinical and methodological expertise.

NIH Research Projects · FY 2025 · 2016-07

This application proposes continuation of the Southern Community Cohort Study (SCCS), a large, prospective cohort study tracking the cancer and other disease experience of a cohort of nearly 86,000 adults age 40-79 at cohort entry. By design, most of the cohort members were recruited from communities in the US Southeast that experience high cancer risk or high cancer mortality rates. Recruitment took place during 2002-2009 across 12 southern states mainly at Community Health Centers (CHCs), institutions providing basic health and preventative services. Our recruitment strategy resulted in the SCCS comprising a segment of the American population at elevated cancer risk seldom if ever enrolled in large numbers in other cohorts including Southern, low-income, rural, and African American participants. Associating with CHCs also facilitated creation of the unique SCCS Biospecimen Repository, with bloods obtained and stored for approximately 40,000, mouth cells for 39,000, urines for 24,000 and DNA available for nearly 90%. No other cohort has a collection of baseline blood, buccal cell, and urine specimens from African Americans as comprehensive as the SCCS. Herein, we seek funding to continue the operational aspects of this highly successful study. The SCCS is poised to produce even greater benefit in the coming years as the cohort matures, and larger numbers of cancer events occur. We propose to continue both passive (via linkage with national mortality, Centers for Medicare and Medicaid Services, state cancer registries and other health record databases) and active (via questionnaire survey) follow up of the cohort. The Repository has been exceptionally important to date in genetic and molecular studies, since the SCCS provides one of the few resources available for discovery-stage analyses and for independent replication of findings in a US South population. Continuation of the SCCS will enable full utilization of the investment made thus far in this unique national resource and enhance its richness. The follow up of the cohort will accrue additional cancer and other disease outcomes enabling critical hypothesis-driven research (to be funded separately) into the causes of cancer in the US Southeast and nationally, especially in communities with high cancer risk.

NIH Research Projects · FY 2025 · 2016-07

PROJECT SUMMARY Breast cancer is the most diagnosed malignancy in the United States. Genetic factors play an important role in breast cancer etiology, but known genetic factors explain only a small fraction of breast cancer heritability, particularly in women of African ancestry (AA). In collaboration with investigators from >25 studies we established the African-ancestry Breast Cancer Genetic Consortium (AABCG) in 2016 to address a significant racial disparity in breast cancer genetic research that includes primarily women of European ancestry (EUR). In AABCG, we conducted genome-wide association studies (GWAS) and related analyses using data from ~18,000 breast cancer cases and ~22,000 controls and reported significant novel findings to begin filling knowledge gaps. By analyzing whole genome sequencing (WGS) data from a smaller number of AA women (~1,340 cases and ~670 controls), we provided promising preliminary data in strong support of the important role of structural variants (SV) and low-frequency and rare single nucleotide variants (SNV) in the etiology of breast cancer. In this competitive renewal application, we propose a large study including both AA and EUR women with a major focus on investigating SVs and low-frequency/rare SNV that carry larger effects than common variants but cannot be adequately studied in GWAS. We plan to expand the AABCG by conducting deep whole genome sequencing (WGS) in 8,000 AA breast cancer cases and harmonize existing WGS data from other studies, which will allow us to expand the AABCG’s sample size to approximately 13,800 AA breast cancer cases and ~80,400 AA controls with deep WGS data. We also will harmonize existing WGS data from several studies to build a resource containing WGS data from ~27,400 EUR cases and ~534,200 EUR controls. Using these data, we propose to 1) systematically evaluate low frequency and rare variants, including both coding and non-coding variants, across the genome to identify novel breast cancer susceptibility variants and genes, and 2) search the whole genome to identify SVs (both common and rare) associated with breast cancer risk. We will also evaluate racial differences in the frequency and type of breast cancer associated SNVs and SVs and the strength of their associations with breast cancer risk. This study will be built upon the success of the AABCG and leverage large amounts of existing data to substantially enhance the national resources for genetic research of breast cancer in an extremely cost-efficient manner. With strong methodology and unique data sources, this study will generate critically needed data that will improve the understanding of breast cancer genetics, biology, and etiology. This will, in turn, facilitate the translation of genetic findings to cancer prevention and treatment.

NIH Research Projects · FY 2026 · 2016-05

PROJECT SUMMARY The substantial time and effort required to harmonize data for global multi-cohort collaborations can lead to research delays, particularly given heterogeneity in data, data management capacity, and data sharing regulations. The goal of the Harmonist project is to develop data standards, software, and methods that help HIV observational research consortia to coordinate multiregional research projects and apply data management best practices more effectively and efficiently. To promote reusability, Harmonist tools are built (when feasible) as shareable External Modules for the widely used Research Electronic Data Capture (REDCap) software, which is in use at over 4,450 institutions in 138 countries as of mid-2020. The initial Harmonist suite of tools includes the Harmonist Hub, a platform for scientific project and portfolio management, and the Data Toolkit, a web-based system for data quality checking and secure data exchange. The Harmonist project aims to (1) strengthen data harmonization and consortium support for the International epidemiologic Databases to Evaluate AIDS (IeDEA) consortium, including providing a new data framework for IeDEA prospective studies, (2) expand support to the Regional Prospective Observational Research for Tuberculosis (RePORT) International consortium, which studies TB in the context of HIV, and (3) support bi- directional mentorship and sharing around Harmonist tools, data management best practices, and data standards. This proposal is a collaboration among research informatics experts at Vanderbilt University Medical Center, all seven regional networks of IeDEA, and RePORT International. These partnerships ensure that all components of Harmonist address real-world user needs in a practical manner and provide the tools with a dedicated user base. We believe that these research tools can reduce the time and effort needed for critical data management and administrative tasks that underlie the role of observational HIV cohorts studying the global epidemic. The modular infrastructure we have designed can adapt to diverse research settings and expand to include new data types and sources as the understanding of HIV evolves. The resulting shareable software and mentoring resources will provide tangible immediate and long-term benefits to IeDEA, RePORT, and the broader HIV research community.

NIH Research Projects · FY 2025 · 2016-02

PROJECT SUMMARY (ABSTRACT) Helicobacter pylori is a Gram-negative bacterium that colonizes the human stomach. H. pylori colonization of the stomach results in chronic gastric mucosal inflammation and is a strong risk factor for gastric cancer and duodenal or gastric ulceration. Gastric cancer is the third leading cause of cancer-related death worldwide, and H. pylori has been classified as a type I carcinogen by the World Health Organization. The H. pylori CagA protein is secreted through a type IV secretion system (T4SS), enters gastric cells, and causes alterations in cellular signaling associated with malignant transformation. CagA and components of the Cag T4SS are encoded by genes within a chromosomal region known as the cag pathogenicity island (PAI), which is present in some H. pylori strains but not others. The incidence of symptomatic gastroduodenal disease (gastric cancer or peptic ulceration) is higher among individuals infected with cag PAI-positive strains than among those infected with cag PAI-negative strains. The molecular architecture and protein composition of the H. pylori Cag T4SS differ substantially from corresponding features of T4SSs found in other bacterial species. The overarching long-term goal of this research is to develop a better understanding of the molecular mechanisms by which H. pylori causes gastric disease. During the previous funding period, we isolated a transmembrane core complex of the Cag T4SS containing five proteins encoded by the cag PAI, described three main structural features of the complex (outer membrane cap, periplasmic ring and stalk), and built partial models of three proteins within the complex. The aims of the current proposal are i) to build a complete structural model of the five Cag T4SS core complex components; ii) to define structure-function relationships for CagY (a core complex component predicted to span from the inner membrane to the outer membrane), elucidating its role in CagA recruitment and T4SS activity; and (iii) to define actions of the Cag T4SS in vivo. Methods will include single particle cryo-electron microscopy analysis of the T4SS core complex, specialized techniques for genetic manipulation of H. pylori, cell culture- based assays of Cag T4SS activity, and an animal model of H. pylori-induced gastric cancer. These studies will provide important advances in our understanding of the molecular mechanisms by which H. pylori infection can lead to gastric cancer and other gastric diseases. On a broader scope, these studies will increase our understanding of bacterial secretion systems and the delivery of bacterial virulence factors into host cells, as well as molecular mechanisms underlying microbe-induced carcinogenesis.

NIH Research Projects · FY 2025 · 2016-02

ABSTRACT / SUMMARY This proposal aims to continue our research to identify and characterize resting state functional MRI signals within the grey matter of the spinal cord, and to validate the interpretation of resting state functional connectivity (rsFC) networks in the spine that appear to reflect specific, behaviorally-relevant functions. In the current funding period we have found resting state networks within the cord exhibit more complex connectivity than previously reported, both within and across segments, including significant correlations with the intermediate region and grey commissure that are relevant for autonomic functions and left-right coordination. Importantly, by implementing a dorsal column injury to the cervical spine in a non-human primate, we have confirmed that the strengths of connectivity within these networks are in general related to functional performance, and changes in the networks correspond to behavioral changes in, for example, skilled hand use. We next aim to fully characterize the sub-components of rsFC and relate them to more specific functions. We will acquire sub-millimeter, multi-parametric MR images at high field (9.4T) in squirrel monkeys and address three main aims. (1) We will identify and differentiate rsFC networks within spinal cord using selective lesions and pharmacological interventions to determine which components and network connectivities are affected by specific disruptions of normal sensory or motor pathways. We will isolate circuits affected by (a) reversible block of motor or sensory inputs with pharmacological agents; (b) permanently ablating the drive of motor neurons from primary motor cortex in ventral horn; and (c) disrupting sensory signals to dorsal horn neurons by sectioning dorsal spinal nerve roots. We will follow the evolution of each injury using CEST and DTI to measure the extent and severity of the injury, and DTI and qMT to validate injury severity and quantify changes in axonal integrity and myelination. (2) We will validate the rsFC measures from MRI by comparisons with electrophysiology, micro-stimulation and tract-tracing histology. We will (a) directly stimulate specific nodes while monitoring down-stream activity with electrophysiology and fMRI; (b) perform longitudinal fMRI and microarray recordings of electrical coherences in each monkey subjected to specific interventions (Aim 1); and (c) determine whether regions which appear to be functionally connected by fMRI also show strong anatomical connections by injecting tracers and performing histological assessments post mortem. (3) We will determine the functional and behavioral relevance of rsFC by disrupting each circuit, identifying corresponding changes in rsFC, and relating these changes to performance of skilled hand sensorimotor behavior. By the completion of the study, we will validate rsFC measurements as indicators of spinal cord functions, and establish the fine- grained intrinsic architecture of intra-spinal circuits. These studies will provide new information on the neural organization of the spinal cord, validate the interpretation of BOLD measurements of connectivity, and provide a roadmap for the use of fMRI for studying human spinal cord functions.

NIH Research Projects · FY 2026 · 2015-09

Project Summary Congenital ocular malformations such as microphthalmia, anophthalmia and coloboma are prevalent in 1 in 3- 4,000 individuals and are the cause for over 25% of childhood blindness worldwide. Defective closure of the optic fissure (coloboma) alone may account up to 10% of childhood blindness. Therefore, it is vitally important to understand the molecular mechanisms underlying ocular development. While several causative genes are identified, more effort is required to define the downstream targets and events underlying eye morphogenesis. In our previous project, we showed that Porcn signaling needs to be tightly regulated during optic cup formation and optic fissure closure. The Rho GTPase Cdc42 is critical for optic vesicle invagination and growth of the optic cup, as well for optic fissure closure. Higher resolution Airyscan imaging revealed the presence of actin-rich, filopodia-like extensions in the closing fissure. Important gaps in our understanding are how the fissure margins make contact during the closure process and how growth of optic cup domains is coordinated. The molecular, unconventional motor Myosin X (Myo10) can induce filopodia formation and is a novel candidate gene for microphthalmia in humans. Our preliminary data shows that Myo10 mutant mice can exhibit coloboma and microphthalmia. In Aim 1 of this renewal application, we propose to investigate the role of Myo10 in ocular tissues using inducible conditional inactivation. Furthermore, the Hippo signaling pathway is a novel key regulatory pathway controlling distinct processes during mammalian eye development. We discovered an early role of the upstream regulator neurofibromin 2 (Nf2) in restricting retinal pigment epithelium (RPE) proliferation in the invaginating optic cup, critical for proper optic fissure closure. In Aim 2, we propose to examine how Nf2 disruption causes extended RPE proliferation in the early optic cup. In addition, our preliminary data shows an early effect on ocular growth by modulation of Hippo signaling in ocular and periocular tissues. In Aim 3, we will analyze the precise role of Yap/Taz and Nf2 during early optic cup morphogenesis. The studies proposed here will be a critical step toward an understanding of the cellular and molecular mechanisms controlling eye morphogenesis and important for advancing treatment and regenerative efforts of ocular diseases.

NIH Research Projects · FY 2025 · 2015-04

Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. Revised Abstract Section Overall Decades of HIV research have generated knowledge and tools with the potential to end the epidemic, but reality falls far short of this goal. The Tennessee Center for AIDS Research (CFAR) is located in the Southeastern United States, the region with the greatest number of new HIV acquisitions, and of persons living with HIV. The CFAR continues its four-way partnership between Vanderbilt University Medical Center (a research-intensive institution), Meharry Medical College (a burgeoning academic health sciences center), Tennessee Department of Health (an academically engaged state health department), and Nashville CARES (a sophisticated HIV community-based organization), all of which are located in Nashville. Leveraging complementary strengths of the partner institutions, the CFAR has had immense impact that includes 1) a remarkable expansion in the size and scope of the NIH-funded HIV research portfolio across the CFAR, 2) the successful career development of early-stage investigators such that many have advanced to leadership positions in the CFAR, and 3) considerable progress in community-engaged research that permeates the CFAR. Given the critical importance of community-engaged implementation science strategies to end the epidemic in both urban and rural areas, the CFAR will add an Implementation Science Core. The CFAR has also established a formal collaboration with the University of Memphis School of Public Health, located in Shelby County, which, in 2023, had the second-highest incidence of HIV among all metropolitan areas nationwide. This CFAR's vision is to have a transformative impact that spans from local to global. Guided by this vision, our mission is to coordinate institutional and community resources to develop evidence-based strategies that reduce the burden of HIV and can be scaled and disseminated to help end the epidemic. To fulfill our mission, The CFAR will pursue four specific aims: 1) To support multidisciplinary HIV research that leverages the highly collaborative local environment to build impactful team science among the partner institutions and beyond; 2) To nurture and support the career development of early-stage investigators to grow the next generation of HIV researchers; 3) To expand HIV research opportunities through increased collaborations across partner institutions and resources throughout the CFAR; and 4) To continue to grow a broad emphasis on HIV-focused community-engaged research that permeates the CFAR, strengthened by implementation science. The work of this CFAR aligns with NIH priorities for NIH/AIDS research.

NIH Research Projects · FY 2026 · 2014-12

PROJECT SUMMARY Glaucoma blinds through degeneration of retinal ganglion cells (RGCs) and their axons in the optic projection through sensitivity to intraocular pressure (IOP). Many patients continue to lose vision despite efforts to manage IOP. Thus, an unmet clinical need is a treatment that addresses RGC degeneration directly. Our long-term goal is to identify new therapeutic targets based on neuronal repair, protection, and restoration. In the previous grant cycle, we leveraged transgenic mouse strains to discern interplay between RGC dendritic pruning, axon degeneration, and astrocyte glia. We discovered two novel forms of adaptive remodeling that boost and preserve RGC signaling and slow progression. With unilateral IOP elevation, metabolic redistribution transfers metabolites from the unstressed optic nerve to the retina and nerve challenged by IOP elevation through astrocyte networks. Conditional knock-out of the gap junction protein connexin 43 (Cx43) uncouples this network and prevents redistribution. Finally, for individual RGCs exposed to elevated IOP, enhanced excitability amplifies the light response, even as dendritic complexity diminishes, through reorganization of voltage-gated sodium channels (NaV) in the unmyelinated axon segment. Both phenomena occur early and are transient, as are their protective effects. Our objective in this competitive renewal is to build upon these important results to discern how enhanced excitability and metabolic redistribution mechanistically relate to axonal and dendritic degeneration and whether they can be enhanced to extend RGC survival. As a corollary, we will test whether the transient nature of both forms of adaptation arises from metabolic and oxidative stress to the astrocyte network and if boosting resources exogenously reduces this stress and extends visual function. This hypothesis is supported by new preliminary data showing a dietary metabolite (pyruvate) increases astrocyte glycogen in the optic nerve and enhances nerve excitation in response to elevated IOP, suggesting that the two forms of adaptive remodeling may be linked. In our inducible glaucoma models, we will utilize a cross-disciplinary approach that combines electrophysiological, cellular and in vivo imaging, and transgenic tools. Aim 1 will determine the dependence of adaptive remodeling on axonopathy and dendritic pruning. Aim 2 will characterize the interdependence between metabolic redistribution and enhanced excitability and whether metabolic redistribution through astrocyte networks maps retinotopically to spatial sectors of intact RGC axon and dendritic function. Finally, Aim 3 will test whether boosting metabolic resources reduces astrocyte stress, extends adaptive remodeling, and slows progression in mouse and non- human primate models of glaucoma. Building from results in the prior grant period, our innovative strategy will elucidate how two novel, intrinsically compensatory adaptive processes utilize metabolic resources to promote RGC survival in glaucoma. By translating results to our non-human primate model, we will test the therapeutic value of targeting enhanced excitability and metabolic redistribution as clinical interventions.

NIH Research Projects · FY 2025 · 2014-09

PROJECT SUMMARY Undiagnosed Diseases (UD) are constellations of clinical findings evaluated specialists see over time without determining their cause(s) and for which diagnostic procedures and tests have been exhausted. The NIH NINDS Diagnostic Centers of Excellence for the UDN provides an exciting opportunity to increase the reach of UDN to a broader patient population in an efficient manner utilizing a tiered evaluation approach combined with iterative data analysis with an overarching goal of improving the diagnosis, care, and understanding of patients with UD. To this end, we propose establishing the Vanderbilt Center of Excellence in Undiagnosed Diseases (VCEUD). We formed our VCEUD by leveraging 1) a strong clinical team of Pediatricians, Internists, Endocrinologists, Psychologists, Immunologists, Rheumatologists, Neurologists, and Geneticists; 2) institutional strengths in bioinformatics, phenomics, structural biology, and artificial intelligence (AI) approaches such as Large Language Models (LLM) and Natural Language Processing (NLM); 3) institutional resources such as the BioVU DNA databank and its experts, PheWAS, MedWAS, VICTR-Studios, and REDCap database system, 4) VUMC’s Recruitment Innovation Center (RIC) to establish mutually beneficial relationships with community collaborators that serve populations with health disparities, 5) education and training of the next generation of physicians that will help sustain our program over the long-term, and importantly 6) significant institutional funding. The goal is to improve community engagement, efficiency, diagnostic rate, and development and dissemination of novel methods. We will increase our outreach efforts to populations facing health disparities. We will consider genetic and non-genetic etiologies and evaluate cases in our tiered diagnostic pipelines. For the genetic diagnostic stream (GDS), we analyze genomic data using a multi-omics approach to generate clinical and gene hypotheses and merge them to identify concordant disorders that cause undiagnosed diseases and discover new diseases. For the non-genetic diagnostic stream (NGDS), we leverage our VICTR-Studios to generate refined clinical hypotheses that are then tested by an in- depth clinical workup. We hypothesize that novel approaches in AI, phenomics, genomics, bioinformatics, structural biology, and experimental validation can be leveraged to more efficiently identify undiagnosed disorders that have proven difficult to solve with standard approaches. To do this, we will, 1) Increase recruitment, especially for populations with health disparities, by building a network of diverse community partners and equipping those partners with tools and resources, 2) Optimize efficiency and effectiveness of clinical evaluation of individuals with UD, 3) Determine the causes of challenging UD cases by integrating novel analytic and bioinformatics strategies with current methods into an efficient tiered iterative pipeline.

NIH Research Projects · FY 2025 · 2014-07

The training program, open to MDs, typically at the end of their residency training is designed to provide 2 years of research training in perioperative science. The major goal of this training program is to provide the highest caliber research training to residents and postdoctoral fellows in four Specific Themes originating from existing strengths of our faculty within Anesthesiology and at Vanderbilt University Medical Center: 1) Mechanisms and Management of Pain; 2) Perioperative Stress Biology and Outcomes; 3) Perioperative Health Services and Translational Research; and 4) Personalized Medicine and Pharmacogenomics. Each of these themes directly relates to the overarching aim of the program – to train the next generation of scientists to create new knowledge and translate it into best evidence for personalized perioperative care and pain management at a population level. The training faculty will consist of an exceptionally strong collection of physician-scientists and basic scientists who offer superb interdisciplinary research training opportunities in 7 different academic departments. The training program will accept two new trainees per year (staggered, maximum of 4 participants per year). Clinicians who show exceptional aptitude for successfully pursuing an academic research career and occasional PhDs who demonstrate best aptitude to develop towards independence will be considered for participation. Each participant will commit to a 2 year basic science, clinical and/or translational research project with 75% effort and will receive over the 2 year period in addition to their research project training, coursework training in research related processes such grant writing, publications, ethics, and responsible conduct of research. This training will prepare them to utilize the skills they acquire in the pursuit of future academic research careers.

NIH Research Projects · FY 2025 · 2014-06

Project Summary/Abstract Aphasia is one of the most common and debilitating consequences of stroke. Fortunately, most individuals with aphasia experience some degree of recovery of speech and language function over time. However, there is great variability in terms of the extent of recovery, which has historically been poorly understood. The overall goals of this R01 program are (1) to describe the nature of recovery from aphasia in the first year after stroke; (2) to identify neuroimaging, behavioral, and patient-related predictors of recovery; and (3) to characterize the neural correlates of recovery using functional and structural imaging. In previous cycles, we have recruited 380 individuals with aphasia and built an unprecedented longitudinal dataset of speech/language evaluations and multi modal neuroimaging. We have comprehensively documented trajectories of recovery from aphasia and their dependence on lesion location and extent, shown that this information can be used to explain much of the variance in recovery patterns, and revealed the critical role of surviving core language regions in language processing in people with aphasia. In the present renewal application, we propose to address several remaining knowledge gaps and pursue opportunities for clinical translation. We will extend our ongoing longitudinal study of aphasia recovery, recruiting 240 new individuals with acute post-stroke aphasia over the next 4 years. We will use this expanded dataset to determine what functional changes underlie the robust recovery that we have observed, investigating two hypotheses: (1) that reorganization may be highly specific to individual patterns of brain damage and behavioral variables; and/or (2) that the neuroplastic changes supporting recovery may take place primarily within surviving language regions. In Aim 1, we will identify longitudinal changes in the functional organization of language regions associated with recovery from aphasia, using validated semantic and phonological adaptive language mapping paradigms, and models that incorporate information about both structural damage and behavior. In Aim 2, we will characterize longitudinal changes within surviving language regions in terms of their representational capacity, using a new naturalistic functional imaging paradigm and state-of-the-art language encoding models. Even as we continue to explore the mechanisms that support recovery, we are also ready to develop tools and resources to allow clinicians to make use of the information we have already gained. In Aim 3, we will translate our findings for real-world clinical applications by creating a fully automated aphasia recovery prediction tool and a multimodal data portal. Our project will inform ongoing research into behavioral and neuromodulatory interventions, and will support clinicians in developing realistic goals for rehabilitation, optimizing allocation of treatment resources, and providing individualized education to individuals with aphasia and their caregivers and families.

NIH Research Projects · FY 2025 · 2014-06

The central theme of our PPG is that HDL function is a critical determinant of atherogenesis and cardiovascular risk in chronic human disease. The goal of our research is to define the mechanisms for HDL functional loss in diseases associated with increased risk for atherosclerotic cardiovascular disease (ASCVD): Familial Hypercholesterolemia (FH), Chronic Kidney Disease (CKD) and Rheumatoid Arthritis (RA). A major hypothesis of the PPG is that dysfunctional HDL contributes to the residual inflammatory risk of cardiovascular events. Reactive dicarbonyls including MDA, IsoLG, and ONE are highly reactive species that rapidly adduct to apoAI and HDL phospholipids impairing HDL function. A major recent advance by our PPG is the discovery that two different small molecule dicarbonyl scavengers, 2-HOBA and PPM, improve HDL function, reduce LDL oxidation, and dramatically reduce atherosclerosis in Ldlr-/- deficient mice, a model of FH, in the absence of changes in plasma lipid levels. The atherosclerotic lesions showed a dramatic decrease in necrosis and inflammation and had evidence for reduced efferocytosis. Projects 1 and 4 will both explore the hypothesis that reactive carbonyl- induced HDL dysfunction will impair macrophage efferocytosis. Project 1 will test the hypothesis that dicarbonyl scavengers promote remodeling of established atherosclerosis with resolution of inflammation. These studies will set the stage for a translational proof of concept study to test the hypothesis that the dicarbonyl scavenger 2-HOBA will inhibit modification of apoAI and HDL and improve HDL functions in humans with heterozygous FH and subjects with CAD without FH. Interestingly, we have recently discovered that lipoproteins are highly- enriched with small RNAs derived from bacterial and fungal species in the microbiome and environment (msRNA). Another major theme is that msRNA carried by HDL influence HDL function and atherogenesis. Project 2 will examine the hypothesis that CKD increases mesenteric lymphatic output and apoAI harboring harmful bioactive substances (IsoLG, miRNA, msRNA) that contribute to the increased risk of ASCVD. Importantly, microbial sRNAs are present in human and mouse atherosclerotic lesions. Project 3 will examine the hypothesis that HDL removes microbial sRNAs from lesion macrophages and suppresses pro-inflammatory gene expression through retro-endocytosis and msRNA acceptance. In addition, we will target macrophage TLR7/8 activation in vivo using non-targeting locked-nucleic acids (ntLNA) to inhibit atherosclerosis progression and promote regression. Project 4 will elucidate mechanisms whereby dicarbonyl modified lipoproteins potentiate inflammation and cell death in macrophages and determine if these alterations contribute to reduced efferocytosis. Overall, the proposed studies will advance our understanding of the role of HDL function in human disease and identify new therapeutic approaches for the treatment of ASCVD. There are 4 Cores: Core A. Administrative and Biostatistics; Core B Lipoprotein and HDL Function; Core C Chemical Synthesis and Lipid Peroxidation Analytical Core; and Core D Non-Coding RNA and Bioinformatics.

NIH Research Projects · FY 2026 · 2014-05

In the stomach, metaplasia arises in the setting of parietal cell loss or oxyntic atrophy. Two types of metaplasia occur in the human stomach: intestinal metaplasia (the presence of intestinal goblet cell lineages in the stomach) and Spasmolytic Polypeptide-Expressing Metaplasia or SPEM (the presence of deep antral gland type mucus cells in the corpus of the stomach). Investigations over the past decade have led to the recognition that SPEM lineages are substantially derived from transdifferentiation of protein secreting chief cells into mucus-secreting SPEM lineages. In addition, increasing evidence suggests that SPEM represents a physiological local repair lineage that is meant to promote local restitution and then be replaced by normal lineages. Importantly, the induction of SPEM from chief cells is orchestrated by release of IL-13 from ILC2 intrinsic mucosal immune cells. Elimination of ILC2s blocks the development of SPEM following acute parietal cell loss. In the setting of chronic injury and inflammation, in addition to alterations in the inflammatory cells within the metaplastic milieu, there is a resculpting of the stromal fibroblasts that likely supports the altered metaplastic stem cell niche. We have identified the relocalization of telocyte fibroblast populations to the bases of metaplastic glands following acute oxyntic atrophy in mice. In addition, we have identified four distinct populations of fibroblast in the normal and diseased human stomach. Together these findings suggest that intrinsic mucosal inflammatory cells and fibroblasts within the parenchyma of the metaplastic niche may promote the maintenance of metaplastic cell lineages as well as their progression to more proliferative and intestinalized pre-neoplastic lineages. We have hypothesized that intrinsic immune cell populations and altered fibroblasts promote a remodeled tissue milieu that promotes progression towards neoplasia in the stomach. To evaluate this hypothesis, we will examine two specific aims: First, we will determine how expansion of ILC2s promotes metaplasia and its progression. Specifically, we will examine the effects of IL-13 and or ILC2- co-culture with metaplastic gastroids to promote progression of metaplasia. Additionally, we will define the transcriptional regulation initiated by IL-13 mediated activation of STAT6 that accounts for induction of metaplasia progression. Second, we will define specific fibroblast populations that promote the development of an altered pre-neoplastic milieu in the gastric mucosa. We will assess the dynamics of telocyte populations in the establishment of the metaplastic milieu in mice and evaluate their ability to promote metaplastic progression in vitro in co-culture. We will further isolate fibroblast sub-populations from regions of normal, metaplastic, and cancerous human gastric mucosa to define alterations in fibroblast sub-populations that may promote a pre-neoplastic niche in the metaplastic mucosa. These studies will establish in greater detail how immune cell and fibroblast populations contribute to the development of a pre-cancerous milieu in the stomach and will allow the identification of strategies that can arrest or reverse progression from metaplasia to cancer.

NIH Research Projects · FY 2026 · 2014-04

PROJECT SUMMARY The Cooperative Human Tissue Network (CHTN) has played an important role since 1987 as a source of human tissues for biomedical research. To this end, the overarching goal of the Western Division of the CHTN at Vanderbilt University Medical Center (CHTN-VUMC) is to continue to serve the scientific community by procuring and distributing adult biospecimens, utilizing a stringent quality management program to maintain a highly efficient and productive biorepository operation. Key aspects of this goal are the prospective customized collection of high-quality solid tissues and biofluids with clinical annotation and the application of a rigorous Quality Management System to all aspects of the program. Services include blood and biofluid collection (whole vacutainers) including investigator-supplied tubes and specialized procurement of fresh tissue for Tumor Infiltrating Lymphocytes (TILs) in response to changing investigator needs are proposed. In addition, preneoplastic and rare lesions will be banked to facilitate research in tumor progression. The CHTN-VUMC will adhere to rigorous ethical standards for protection of human subjects and patient confidentiality and will partner with the VUMC advocacy program to engage patients and provide opportunities for participation in research. We also propose to serve as the Informatics (IT) trans-network Coordinating Center responsible for the second version of the “Investigators IT” system (TQII), utilizing web services (AWS hosted) and a strong modern technologically advanced platform and ensuring adherence to IT security best practices. In its divisional IT strategy, CHTN-VUMC will develop and integrate new business models and novel informatics strategies to improve operational efficiency. Marketing efforts will include initiatives to increase awareness of CHTN in the scientific community, including enhanced use of social media, and CHTN-VUMC will actively contribute to biorepository science and education through leadership in societies such as the International Society for Biological and Environmental Repositories. CHTN-VUMC’s leadership in network IT development makes the division uniquely qualified to continue serving as the central IT coordinating site. A robust track record of specimen procurement and distribution, with 57,977 specimens shipped to 734 investigators over the past 5 years, highlights the capabilities of the existing CHTN-VUMC infrastructure. CHTN-VUMC goals in the next funding period include building upon these foundational achievements to improve efficiency and communication within the network, investigators and scientific community.

NIH Research Projects · FY 2026 · 2013-08

Following the immediate injury to intrinsic kidney cells induced by ischemia/reperfusion, we and others have demonstrated an important role for innate immune cells in both propagation of injury and subsequent recovery. There is an initial renal influx of neutrophils after ischemic injury, followed a few hours later by accumulation of proinflammatory monocytes and activation of resident renal macrophages. Within days after the injury, the majority of renal macrophages shift from a proinflammatory to an anti-inflammatory and pro- resolution phenotype, which is essential for effective repair and resolution of the injury. Meanwhile, with moderate ischemic injury, neutrophil numbers in the injured kidney progressively decrease, and relatively few neutrophils remain after 72 hours. Although neutrophil apoptosis and efferocytosis by macrophages is an important mechanism of neutrophil clearance, in addition, in other tissues, studies have shown that intact neutrophils may also exit the tissue through “reverse migration”. Mechanisms underlying the resolution of inflammation are an area of active investigation. The question of what mediates resolution of inflammation, and specifically what mediates the resolution of the inflammation resulting from ischemic AKI, remains unresolved. Cyclooxygenase (COX) is the rate-limiting enzyme that metabolizes arachidonic acid to prostaglandin G2 and subsequently to prostaglandin H2, thereby serving as the precursor for subsequent metabolism by prostaglandin synthases. More than 20 years ago, Gilroy et al. reported a paradox in sterile inflammation. Pharmacologic COX-2 inhibition at the early phase (2h) accelerated recovery while the same pharmacologic inhibition prevented recovery when applied 24h later, suggesting that COX-2 may have different roles in neutrophils and macrophages in inflammation resolution. We have recently we have reported that COX-2 expression increased in renal macrophages following ischemic injury, and selective deletion of COX-2 or the PGE2 receptor subtype 4 (EP4) with myeloid-specific Cre recombinases delayed recovery, resulting in persistent inflammation in the post-ischemic kidney and subsequent tubulointerstitial fibrosis. In our new preliminary results, we now surprisingly find that selective deletion of neutrophil COX-2 expression results in decreased injury in response to an ischemic insult. We propose that the macrophage COX-2/PGE2 axis promotes recovery from AKI, but the neutrophil COX-2/PGE2 axis has the opposite effect and is important for the initial injury induced by neutrophil infiltration. The goal of our proposed studies is to further our understanding of mechanisms of resolution from AKI by characterizing the disparate roles and mechanisms played by the COX-2/prostaglandin system in neutrophils and macrophages following acute ischemic kidney injury. We have two specific aims: Specific Aim 1 Determine the role of the macrophage COX-2-PGE2-axis in recovery from ischemic AKI Specific Aim 2 Determine the role of COX-2 in neutrophil function in response to ischemic AKI

NIH Research Projects · FY 2026 · 2013-01

PROJECT SUMMARY Acinetobacter baumannii is an important nosocomial pathogen that causes a range of diseases, including respiratory and urinary tract infections, meningitis, endocarditis, wound infections, and bacteremia. In fact, A. baumannii is now responsible for up to 20% of all intensive care unit infections in some regions of the world with pneumonia being the most common presentation. The clinical significance of A. baumannii has been propelled by this organism’s rapid acquisition of resistance to virtually all antibiotics. The identification of novel targets for therapeutic intervention is critical to our ability to protect the public health from this emerging infectious threat. A promising area of therapeutic development exploits the idea that all bacterial pathogens require nutrient metal to cause infection. This approach mimics host-mediated metal sequestration, which is a potent defense against infection in a process termed “nutritional immunity”. Paradoxically, dietary restriction of metal exacerbates infection underscoring how alterations in metal abundance can profoundly impact the outcome of host-pathogen interactions. The host protein calprotectin (CP) is one of the most important contributors to immune-mediated metal restriction and CP protects against infection through the chelation of nutrient metals, including zinc (Zn). Using CP as a probe, we have uncovered a genetic locus within A. baumannii that is important for survival during conditions of CP-dependent Zn starvation. This locus encodes a member of the conserved COG0523 family of GTPases that we have named Zur-induced GTPase A (ZigA). We have also found a second COG0523 member within the A. baumannii genome that we refer to as 0934. ZigA and 0934 have biological properties consistent with metallochaperones that insert Zn into client proteins. Our preliminary data indicate that 0934 and ZigA bind and regulate client metalloenzymes involved in cell wall synthesis and recycling. Based on these fundamental discoveries, we hypothesize that A. baumannii colonization of the lung leads to massive accumulation of CP which starves A. baumannii for nutrient Zn. We further hypothesize that ZigA and 0934 regulate cell wall remodeling during Zn starvation to accommodate insertion of nutrient Zn transporters into the cell envelope that are necessary to combat host- or dietary-imposed Zn starvation. To test this central model, we propose a series of experiments aimed at understanding the mechanism and pathophysiological consequence of the A. baumannii response to dietary and host-imposed Zn deprivation during pneumonia. In these studies, we will (i) define the molecular interactions of ZigA and 0934 with their metalloprotein clients, (ii) interrogate the physiological function of ZigA and 0934 in A. baumannii, and (iii) determine the importance of ZigA and 0934 in response to Zn starvation during the pathogenesis of pneumonia. This research will establish a new paradigm for how bacteria respond to dietary- or immune-mediated Zn restriction during infection through metallochaperone-dependent regulation of cell wall homeostasis.