Vanderbilt University Medical Center

NIH Research Projects · FY 2025 · 2025-08

SUMMARY Diarrheal diseases are a leading cause of child mortality worldwide, causing approximately 800,000 deaths per year in children under five years of age, and prevalent morbidity in adults. For bacterial diarrheal infections, antibiotics are often the primary treatment; however, their heavy use disrupts beneficial microbial communities, which, in turn, exacerbates disease outcomes. A crucial approach to treat or prevent these infections involves restoring or modulating the gut microbiota with specific commensals that offer targeted protection against pathogens. Although fecal transplantation is one potential method, it is limited by the risk of transferring harmful pathogens to the recipients. Interestingly, commensal bacteria can influence the composition of intestinal metabolites, which may play a crucial role in either curbing or promoting pathogenicity. Therefore, manipulating these metabolites presents a promising therapeutic avenue to prevent severe diseases caused by intestinal pathogens. Research focused on identifying protective commensals and key metabolites is essential for developing effective prevention strategies against bacterial diarrheal diseases. In this application, we present compelling preliminary findings suggesting that the commensal Turicibacter sanguinis may protect against severe disease caused by the intestinal pathogen Citrobacter rodentium, an established model of attaching and effacing (A/E) bacterial infections in mice. While little is known about T. sanguinis, recent studies have shown that higher levels of this commensal correlate with healthier outcomes in children with diarrhea or acute gastroenteritis, hinting at a potential protective association against diarrheal diseases in humans. Consistent with these observations, our data show that severe disease from C. rodentium is linked to the absence of T. sanguinis and elevated intestinal levels of two specific metabolites: adenine and dioscoretine. Based on these findings, we hypothesize that adenine and dioscoretine create an intestinal environment conducive to severe C. rodentium infection, whereas T. sanguinis confers resistance by reducing these metabolites' abundance.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY The current paradigm of Idiopathic pulmonary fibrosis (IPF) pathogenesis implicates recurrent injury and dysfunctional repair of the alveolar epithelium which results in fibrotic lung remodeling and loss of functional blood-gas exchange units. Current IPF treatments modestly slow disease progression by attenuating collagen production by fibroblasts, but no available therapies stabilize disease nor facilitate functional lung repair. Our overarching hypothesis is that therapies modulating upstream disease mechanisms to promote functional alveolar repair could be transformative disease-modifying treatments for patients with IPF and other chronic lung diseases. The loss of normal alveolar blood-gas barrier forming Alveolar Type 1 (AT1) and surfactant- producing Alveolar Type 2 (AT2) cells has long been recognized in IPF and supported the concept that dysfunction of epithelial progenitor cells is a key aspect of disease pathogenesis. Several disease-emergent cell types identified in IPF (including KRT5-/KRT17+ aberrant basaloid cells) are abundant in areas of metaplastic epithelial remodeling and active fibrosis, but their role in IPF pathogenesis remains uncertain. Interrogating our single cell transcriptomic data, we identified significant enrichment of gene expression programs regulated by the hypoxia-inducible factor (HIF) family of transcription factors in KRT5-/KRT17+ aberrant basaloid cells. Our preliminary data using genetic and small-molecule based HIF2-targeting suggest that HIF2 inhibition specifically can attenuate experimental lung fibrosis and enhance alveolar repair and regeneration in recurrent injury. Additional studies using mouse and human derived alveolar organoid models demonstrate that HIF2- inhibition enhanced AT2 differentiation and suppressed the emergence of aberrant intermediates similar to disease-emergent cell states identified from IPF patients. Further, HIF2-biased activation in primary human organoids suppressed the TCA cycle, de novo fatty-acid biosynthesis, and promoted the emergence of aberrant intermediate markers. This leads us to hypothesize that HIF2 activation from chronic injury to the distal lung epithelium prevents AT2 cell regeneration from airway progenitors through epigenetic and metabolic modulation of key AT2-requisite biosynthetic functions. We will test this hypothesis by 1) determining how HIF2-activity modulates cellular fate and epigenetic programs during alveolar repair, and 2) delineating the metabolic processes underlying HIF2 suppression of AT2 cell differentiation in the distal lung. These studies will provide essential mechanistic insights in both murine and IPF patient-derived human models into the role of HIF2 in alveolar epithelial remodeling, how its modulation affects adaptive repair, and establishes foundational pre-clinical data for targeting HIF2 as a novel therapeutic strategy for IPF. The highly experienced mentorship team assembled, which includes both physician and basic scientists as well as external advisors, collectively brings expertise in lung epithelial biology, genome regulation, and molecular metabolism which is ideally suited to support my training and career growth as I develop my independent research program.

NIH Research Projects · FY 2025 · 2025-08

Patients with rare diseases (RDs) face tremendous physical, psychosocial, and economic suffering in their protracted journeys toward diagnosis and therapy. These journeys, known as diagnostic and therapeutic odysseys, are riddled with diagnostic delays and difficulties finding effective treatment strategies. The Undiagnosed Diseases Network (UDN) at the NlH was established to diagnose individuals who are living with the often-dire consequences of an RD. Despite UDN’s comprehensive diagnostic approach, 70% of patients remain undiagnosed, highlighting the need for novel diagnostic strategies. The diagnostic approach at the UDN currently relies on manual extraction of RD phenotypes from clinical notes in electronic health records (EHR), which is laborious and time-consuming. A promising alternative is to leverage natural language processing (NLP) models, which can automatically extract fine-grained RD phenotypes from clinical notes, to support timely diagnosis at the UDN. Existing general NLP models, however, are not suitable for supporting diagnosis at the UDN. Furthermore, NLP models have limited impact on diagnosis due to scarce infrastructure for delivering them to the clinic, highlighting the need to bridge the implementation gap between NLP and practice. Even after diagnosis, patients often undergo therapeutic odysseys. Despite advancements in gene therapy, evidence shows that genetics alone do not account for the wide diversity in RD phenotypes. Exposures also play a critical role, but less is known about how their causal effects vary across individuals. This knowledge gap underscores the need to elucidate the complex phenome-genome-exposome interplay on an individual-level basis, which is crucial in informing personalized disease management strategies. The overall objective of this proposal is to develop and implement advanced statistical machine learning (ML) methods aimed at shortening RD odysseys. Building on my K99 work, l will develop a novel NLP system to identify, standardize, and prioritize RD phenotypes for diagnosis (Aim 1) and implement it using REDCap at the Vanderbilt UDN to support diagnosis (Aim 2). l will leverage phenomic, genomic, and exposomic data from All of Us and build a causal inference framework that uses modern statistical ML techniques to estimate personalized causal effects of exposures on RD phenotypes (Aim 3). This proposal aligns with the Pl's expertise in statistical ML, artificial intelligence (Al), and causal inference. Overall, this project can help the Pl launch her independent research career in developing advanced statistical ML and Al methods to shorten RD odysseys.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY This proposal aims to advance our understanding of clonal hemopoiesis of indeterminate potential (CHIP) in the development of atherosclerotic cardiovascular disease (ASCVD). CHIP is a recently identified acquired risk factor for ASCVD. With aging, hematopoietic stem cells accumulate mutations that can lead to a proliferative advantage resulting in CHIP. Tet Methylcytosine Dioxygenase 2 (TET2) is a commonly mutated gene in CHIP and confers a 50% increased risk for incident coronary disease. How TET2 leads to ASCVD is in humans is not well understood and there is currently no ability to assess whether a specific TET2 mutation is high-risk. The central objective of this proposal is to (1) identify TET2 mutations that are high-risk for developing ASCVD to derive a comprehensive and clinically actionable risk score calculator and (2) identify the aberrant cell states and signaling pathways among TET2 mutated immune cells in the coronary vasculature. To identify high-risk TET2 mutations, the candidate will leverage a population-scale human genetics approach in >1 million people via BioVU and All of Us databases. To identify aberrant cell states and signaling pathways, the candidate will deploy their novel single cell lineage tracing protocol in coronary vascular tissue followed by validation experiments via population-based human genetic association studies. The candidate’s career goals are to become an independently funded physician scientist focused on developing new ways of treating ASCVD. In addition to the proposed science, the training activities outlined in the candidate’s career development plan are focused on the crucial skills and experiences necessary to enable an independent research program. Combined with the direct mentorship of Drs. Alexander Bick and Dan Roden, Vanderbilt University Medical Center represents an ideal environment for the proposed work and leverage some of the world-class strengths of the institution. The Bick and Roden labs have deep experience in the methods used in this proposal and are prepared to support the candidate throughout the entirety of the grant period. Overall, this NHLBI K08 proposal represents a set of innovative and timely scientific aims combined with a tractable career development plan that will meaningfully contribute to human health research and catalyze the candidate’s long-term career goal of developing into an independent investigator.

NIH Research Projects · FY 2025 · 2025-08

The 2022 Intersectoral Global Action Plan on Epilepsy (IGAP) established goals: by 2031 among the world’s people with epilepsy (1) 90% will know their diagnosis, (2) 80% will have anti-seizure medication (ASM) access, (3) 70% will achieve seizure control. At least 80% of the world’s people with epilepsy live in low- and middle-income countries (LMICs), such as those in Africa where epilepsy prevalence estimates vary (< 7 to > 70 per 1000), often with substandard methods, and where epilepsy diagnosis and treatment gaps are 60%-96%. Primary prevention of epilepsy is urgently needed in Africa’s LMICs where millions of people with epilepsy are untreated. Yet in Africa there are few epilepsy incidence studies, and few studies of modifiable risk factors for epilepsy across the lifespan, and even fewer studies of genetic risk factors for epilepsy. The Sahel Epilepsy Epidemiology and Genomics Study (SEEG) is a rural community-based study of epilepsy epidemiology across the lifespan, with case-control studies of potentially modifiable epilepsy risk factors, and genome-wide association studies (GWAS) to identify genetic modifiers of epilepsy risk. Using a previously validated epilepsy screening and seizure classification tool in English and the local language (Hausa), door-to-door epilepsy screening will be conducted by epilepsy-trained community health workers (CHWs) in malaria endemic rural Tudun Wada local government area, Kano state, Nigeria. In Year #1, 40,000-75,000 people will undergo epilepsy screening; people who screen positive for epilepsy will undergo clinical evaluations including electroencephalograms (EEG) using a point-of-care EEG-video system, with age- and gender-specific prevalence determination. The same GPS-located households screened in Year #1 will be screened again in Year #2 and again in Year #3 to identify new-onset epilepsy (incident cases) for determination of age- and gender-specific incidence rates. Among those diagnosed with epilepsy, the first 1000 people ages 6 months and older who provide consent will be enrolled in case-control studies and GWAS studies. About 1500 people (500 children, 1000 adults) who screened negative for epilepsy, and who have no evidence of epilepsy on clinical evaluation, including EEG, will be enrolled as controls in case-control studies of potential risk factors for potentially modifiable risk factors for epilepsy, including prior head trauma with loss of consciousness, HIV, history of cerebral malaria, and IgG evidence of prior parasitic infections (e.g., onchocerciasis, echinococcus, schistosomiasis). GWAS, with adult controls (> 30 years) from the local community to determine genomic modifiers of epilepsy risk among people with malaria, onchocerciasis and other common parasitic diseases will be conducted. SEEG will provide valuable insights into epilepsy epidemiology and genomics in the Sahel region of Africa and establish a valuable resource for the study of epilepsy epidemiology and genomics.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY / ABSTRACT Gastric cancer is one of the most common causes of cancer-related death worldwide. It develops in a sequential progression of a carcinogenic cascade from pre-cancerous metaplasia to cancerous dysplasia and adenocarcinoma. However, oncogenic drivers or master regulators which lead to carcinogenic transition between pre-cancerous and cancerous stages are uncertain. Previous investigations have noted that Kras activity is observed in up to 40% of patients with gastric cancer and have suggested that Ras activation in gastric cancer may promote the progression of metaplasia toward dysplasia and cancer. Our previous results described that Kras activation in chief cells can rapidly develop metaplasia and invasive metaplasia with dysplastic glands. These studies therefore imply that Kras activation might be a driving factor of gastric carcinogenesis and chief cells might be an origin of gastric cancer. However, there is a clear knowledge gap as to whether Kras activation is a critical oncogenic driver which controls the carcinogenic process of dysplasia to adenocarcinoma. Also, while roles of Sox transcription factor activation following the oncogenic Kras activation have been well-studied in other GI tract cancers, no studies have addressed whether such activities are important for metaplasia development or are associated with Ras activation in gastric carcinogenesis. We have therefore hypothesized that Kras activation is a driver of gastric carcinogenesis and metaplastic development and progression can be controlled by upregulation of Sox9 as a downstream effector of Kras signaling pathway. We propose two specific aims to elucidate a deeper understanding of cellular mechanisms and events of gastric carcinogenesis using a novel inducible driver mouse model, which is a stomach- and chief cell-specific driver mouse allele. First, we will define the oncogenic roles of Kras activation and the lineage contribution of active Kras-induced cells during gastric carcinogenesis. Second, we will assess functional roles of Sox9 transcription factor as a putative master regulator of metaplasia development and progression. Our proposed study will not only define the cells of origin for gastric cancer, but also determine the oncogenic potential and regulatory mechanisms of Kras activation during gastric cancer development. Consequently, our results from this proposed study would provide insights in pre-clinical information to design therapeutic interventions or to identify novel druggable targets by regulating transcriptional regulation of key factors in patients with gastric cancer.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY Neuroimaging, particularly for assessing salvageable tissue, is vital to modern stroke diagnosis and treatment decisions. It has been previously proved that pH/diffusion mismatch provides more accurate delineation of penumbra than the conventional perfusion/diffusion mismatch. This project aims to advance an MRI pH imaging technique, amide proton transfer (APT), for detecting penumbra. Despite APT's sensitivity to pH, quantifying its effect in tissues is challenging due to several confounding factors. Current techniques either fail to eliminate these contaminations or require lengthy scan times. As a result, although APT has showed potential in diagnosing stroke patients for a decade, it has not yet been adopted in clinical practice. Recently, machine learning (ML) has shown promise in improving the quantification of APT effects by identifying complex features that traditional methods often miss. However, ML often face issues such as insufficient training data and poor-quality ground truth when trained using in vivo data. This problem is exacerbated in acute stroke where obtaining large and high-quality training datasets is difficult. While fully synthetic data can address these issues, practical application remains challenging due to unidentified exchangeable pools and their parameter ranges. Our project proposes developing a new platform that generates partially synthetic chemical exchange saturation transfer (CEST) data for training ML models, addressing these challenges. Unlike a simple blend of measured and simulated CEST signals, the partially synthetic data integrates underlying components including CEST, direct water saturation, and magnetization transfer effects derived from either measurements or simulations to reconstruct CEST Z-spectrum. This approach balances simulation flexibility and fidelity. Recently, we published this novel concept of partially synthetic CEST data for ML training under the ideal condition of steady-state continuous-wave saturation achievable in preclinical MRI. Most recently, we published its application in an animal stroke model which outperformed traditional APT quantification methods and other ML methods trained on either in vivo or fully synthetic data in accurately and robustly detecting stroke. Additional experiments on healthy humans using steady-state pulsed saturation at 3T MRI demonstrate the method's transferability to human imaging. This proposal aims to further develop the method by extending it to the more complex non-steady-state pulsed saturation commonly used in clinical MRI, implementing it with interleaved acquisition and optimizing frequency offsets to shorten scan times, thus facilitating its translation to stroke patients. We will also validate its specificity and sensitivity through simulations and control phantoms in Aim 1, assess its ability to detect penumbra in an animal stroke model in Aim 2, and implement it at 3T MRI for a pilot study in human patients. Upon completion, this project will pave the way for the widespread adoption of APT imaging in identifying penumbra outside traditional treatment windows, significantly impacting healthcare.

NIH Research Projects · FY 2025 · 2025-07

Project Summary Respiratory viral infections are a key risk factor for asthma development in early life and the major trigger of asthma exacerbations across the lifespan. Impaired airway epithelium responses to viral infections are hallmarks of asthma and worsened by comorbid obesity. The rationale for the proposed research is that developing new therapeutic approaches for reducing viral-induced asthma exacerbations is critical for reducing asthma-related morbidity. The overall objective in this proposal is to establish proof-of-concept that dual glucagon-like peptide-1 receptor (GLP1R)/glucose-dependent insulinotropic polypeptide receptor (GIPR) signaling improve airway epithelial cell barrier function and anti-viral immune responses to respiratory syncytial viral (RSV) and improve clinical outcomes in patients with asthma. Our novel preliminary data in differentiated human bronchial epithelial cells showed that a GLP1R agonist, a GIP agonist, or the dual GLP1R/GIPR agonist, tirzepatide (Trz), preserved airway epithelial barrier function, reduced RSV viral load, and increased IFNB expression. Based on these data, our central hypothesis is that GLP1R and GIPR agonists decrease RSV-induced airway inflammation by increasing airway epithelial cell barrier function. We will capitalize on samples and clinical data available from patients with asthma initiating Trz therapy as part of standard care for management of obesity in distinct, but highly integrated specific aims. In aim 1, we will define how Trz increases airway epithelial barrier function and anti-viral response leading to reduced RSV infectivity and cytokine expression. We will differentiate nasal airway epithelial cells (NAECs) from donors with asthma prior to starting Trz therapy and overnight treat NAECs with a GLP1R agonist, a GIPR agonist, or Trz followed by RSV 01/2-20 infection. We will determine if Trz treatment (Aim 1a) increases airway epithelial cell tight junction barrier function and (Aim 1b) decreases viral load and increases interferons and/or anti-viral pathways. In aim 2, we utilize NAECs differentiated before and after Trz therapy and respiratory symptom scores collected at both time points to determine the effect of dual GLP-1R/GIPR signaling synergism on airway barrier function in patients with asthma pre- and post-Trz therapy. We will determine if Trz therapy (Aim 2a) increases NAEC barrier function and (Aim 2b) improves respiratory symptoms in patients with asthma. This fully human approach is innovative because no study has posited that GLP1R and/or GIPR signaling pathways directly regulate airway epithelial barrier function or enhance IFN responses to limit respiratory viral infections. This proposal is significant because it develops new therapeutic approaches for reducing viral-induced asthma exacerbations, critical for reducing asthma-related morbidity. This study will inform the mechanistic rationale and sample size estimates required to repurpose Trz to prevent respiratory viral infection-induced exacerbations in asthma and potentially other chronic respiratory diseases exacerbated by viral infections.

NIH Research Projects · FY 2025 · 2025-07

PROJECT SUMMARY Rotaviruses (RVs) are important pediatric gastrointestinal pathogens that can be released and infect in association with extracellular vesicles (EVs). EVs are membrane-bound structures released from ‘donor’ cells that transport cargo to ‘recipient’ cells. EVs vary by size, composition, and biogenesis, and they may differ by donor cell. Virus association with EVs can enable non-lytic virus egress, shield viruses from the immune system, and promote efficient multiparticle infection. Murine RV enclosure in EVs increases the number of cells infected and the severity and duration of disease in mice compared with free RV particles. Simian RV SA11 is released from human colonic epithelial Caco-2 and HT29 cells in association with EVs. Our results suggest that Caco-2-derived EVs fail to protect SA11 from neutralization, while EVs from SA11-infected HT29 cells confer protection. SA11 visually associates with EVs from Caco-2 and HT29 cells, in some cases through external adhesion. Small and medium EVs from HT29 cells aggregate with one another and RV particles. Addition of neuraminidase, which cleaves SA11 sialic acid receptors, reduces aggregation and RV association. EV-associated SA11 in Caco-2-derived small EVs and HT29-derived large and medium EVs can enhance multiparticle RV infection of recipient cells. While it is known that enclosure within EVs can enhance RV infection, our findings suggest that RV egress, shielding, and infection properties differ by donor cell, and RV adhesion to EVs may contribute to protection and infection efficiency. Due to tropism restrictions, human RV association with EVs is poorly characterized, and it is unclear which culture models are optimal for such studies. Although more studies of RV release in EVs have been conducted using Caco-2 cells, HT29 cells more closely resemble the targets of RV infection in humans. Human H69 cholangiocytes release RV non- lytically in EVs. Human intestinal enteroids, biopsy-derived cultures that differentiate into multiple cell types, are the most biological model for human RV infection. We will use Caco-2, HT29, and H69 cells and human intestinal enteroids to test the hypothesis that association with EVs, in some cases through external adhesion, differentially influences human RV egress, protection, and infection properties in a donor cell-specific manner. In Specific Aim 1, we will elucidate contributions of EVs to human RV egress and protection. In Specific Aim 2, we will elucidate contributions of EVs to human RV infection of recipient cells. Elucidating the complex interplay between human RVs and EVs will enhance an understanding of fundamental human RV biology and inform selection of culture models to study human RV egress and infection in the laboratory. This work also may generate new hypotheses regarding human RV pathogenesis mechanisms and prevention strategies.

NIH Research Projects · FY 2025 · 2025-07

PROJECT SUMMARY Dendritic cells (DCs) are professional antigen-presenting cells that initiate T-cell mediated inflammation or support tolerance to self- and environmental antigens. However, it remains unclear how DCs are programmed to choose between driving inflammation versus immune tolerance. During immune activation, DCs profoundly rewire their intracellular metabolic pathways to perform their functions and interact with T cells. However, the molecular mechanisms connecting metabolic changes in activated DCs to their immune functions are not completely understood. We propose that understanding the metabolic processes of DCs during antigen presentation offers an avenue for the discovery of novel mechanisms of inflammation and immune tolerance. Research from our group and others has shown that the metabolism of DCs regulates cytokine secretion and antigen presentation. We showed that DCs highly express the rate-limiting mitochondrial enzyme Glutaminase (GLS) that converts the most abundant circulating amino acid glutamine to glutamate. Our new data suggest that GLS is a metabolic checkpoint that controls DC maturation and activation and enhances antigen-presentation to CD4 and CD8 T cells. The central hypothesis of this project is that glutamine metabolism in DCs directly controls their choice during antigen presentation between activating pro-inflammatory T cells and priming regulatory T cells to establish tolerance. We will capitalize on novel mouse models of GLS deficiency in DCs and a combination of experimental and systems immunology approaches to identify molecular mechanisms of how Glutaminase-dependent metabolism in DCs controls inflammation and tolerance by following two complementary aims. In Aim 1 we will determine how GLS activity in DCs regulates antigen presentation and inflammation. To this end, we will decipher how GLS regulates intracellular metabolism, pro-inflammatory signaling pathways, gene expression and antigen processing and presentation in DCs during activation and maturation. In Aim 2 we will identify cellular and molecular mechanisms that connect GLS-expressing DCs to inflammatory diseases. We will determine how GLS and glutamine metabolism reshape the crosstalk between DCs and T cells in an antigen-driven model of atopic dermatitis and a genetic model of psoriasis. This project will identify new molecular mechanisms connecting metabolism to antigen-driven inflammation and direct novel interventions to target GLS in DCs to control pathological inflammation, allergy, and tissue damage.

NIH Research Projects · FY 2026 · 2025-07

PROJECT SUMMARY/ABSTRACT Gestational weight gain has profound consequences for mothers and their children. However, roughly 70% of pregnant women in the United States do not fall within the recommended range for gestational weight gain. Despite the significant public health burden of insufficient or excessive gestational weight gain, intervention strategies have had limited success and are often difficult for individuals to adhere to outside of clinical trials. Additional opportunities for prevention, early modification, and/or reduction of adverse outcomes may be gained with a better understanding of the causal pathways leading to and resulting from gestational weight gain. Novel research approaches, adding biological and clinical perspectives, delving further into upstream determinants, and dissecting periods of gestational weight gain that affect later outcomes, are necessary to curb the multigenerational adverse effects of gestational weight gain outside of recommendations. The research objective of this proposal is to discover novel risk factors and biologic pathways underlying gestational weight gain as well as outcomes associated with patterns of weight gain during pregnancy; thereby enabling targeted interventions and further refinement of current guidelines. We will pursue the following specific aims: 1) apply machine learning models to electronic health records (EHRs) to predict excessive and inadequate gestational weight gain, 2) examine the causal effect of prepregnancy glucose on gestational weight gain using Mendelian randomization, and 3) investigate the impact of gestational weight gain trajectories on risk for adverse pregnancy and maternal outcomes using longitudinal latent profile analysis. To achieve these aims, we will utilize data from individuals with documented pregnancies in Vanderbilt University Medical Center’s (VUMC) Synthetic Derivative, a large EHRs database, as well as a DNA DataBank linked to deidentified EHRs at VUMC (BioVU), and publicly available summary statistics from a genome-wide association study of gestational weight gain. The proposed research will advance clinical care by identifying modifiable prepregnancy risk factors, characterizing at-risk individuals prior to pregnancy, and pinpointing concerning patterns of GWG, resulting in increased opportunities for prevention and intervention. This research is part of a K01 award for Dr. Elizabeth A. Jasper, Ph.D. Through a comprehensive career development plan, under the guidance of an exceptional mentor panel, and with access to unique resources, Dr. Jasper will gain training in biomedical informatics and advanced epidemiologic and statistical methodologies. Dr. Jasper will acquire the knowledge, skills, and resources necessary to achieve her long-term career goal of becoming a leading maternal-child health genetic epidemiologist who focuses on identifying the prepregnancy, prenatal, and perinatal origins of adverse health outcomes.

NIH Research Projects · FY 2025 · 2025-07

Summary / Abstract This is an application to obtain a whole body 3 Tesla MRI scanner to support research at Vanderbilt University Medical Center. In the past year we performed over 5,300 research scans on human subjects on 2 existing 3T scanners, but still many less than were requested by investigators. This applications seeks to (i) add a third scanner that will increase our capacity for research studies, especially needed given the growth of brain imaging of neurodevelopment and neurodegeneration; (ii) provide next-generation scanner performance, especially in the capabilities of ultra-high performance gradients for diffusion imaging; and (iii) provide insurance against the failure of our current scanner, which has been in use for research full-time for 18 years. Our current scanners are heavily used by over 82 active investigators with NIH funding who rely on high quality MRI and MRS data for diverse research applications. Many of these users require advanced neuorimaging studies that include functional and structural MRI of the brain and spine, and increasingly exploit the power of diffusion MRI to assess white matter tracts and microstructure. We aim to enhance our current capabilities by installing a 3 Tesla Siemens Cima.X scanner equipped with advanced Gemini gradients that can achieve 200 mT/m strength, >3 times stronger than any gradient system we currently use and capable of dramatically increasing the types and quality of diffusion studies possible. The new gradients will provide several major specific advantages including [1] higher gradient b values in diffusion MRI, which will allow shorter echo times, shorter diffusion times, higher signal to noise ratio, faster acquisitions and higher spatial and angular resolution in diffusion tractography of white matter; [2] stronger gradients will allow enable decreases in the effective spacing between echoes in echo planar imaging, reducing geometric distortions arising from long readouts, and allowing increased resolution in functional MRI acquisitions. In addition, the new scanner has multiple enhancements over our current, aging scanners (e.g. larger number of receivers and coil elements, powerful AI-aided reconstructions, and shorter exam times) that will ensure our users remain state-of-the-art for the next several years. Our vendor selection also ensures we will be able to participate more fully in multi-site imaging programs that are dominated by Siemens installations. In this application we highlight 16 selected Major Users, who are PIs on 40 funded grants, all of whom are experienced users of the current 3T scanner. We also illustrate 4 Minor Users who are representative of 23 others listed who hold 51 NIH grants that require MRI. The projects of the Users described herein would require approximately 76% of the useable time available. The scanner will be housed and managed within the Vanderbilt University Institute of Imaging Science, and will be supported by a relatively large group of expert MRI scientists and staff. A comprehensive plan has been developed for the financial support of the system as well as for its management, and the system is assured of strong institutional support, including $3 million towards the purchase and installation.

NIH Research Projects · FY 2025 · 2025-07

PROJECT SUMMARY/ABSTRACT Nearly 1 in 4 Americans will experience heart failure (HF) during their lifetime, with at least 50% classified as HF with preserved ejection fraction (HFpEF). Exertional intolerance is a key clinical feature of HFpEF. While cardiac dysfunction is one aspect of this condition, limitations to exertion have increasingly been ascribed to age-related pathobiological processes in multiple organs outside the heart (e.g., muscle, vascular, adipose). Indeed, ≈60-90% of people with HFpEF are considered “frail”—a systemic condition defined as “impaired metabolic resilience to physiologic stress”—and frailty itself strongly and independently predicts both cardiac and non-cardiac morbidity in HFpEF. Efforts to combat frailty and restore multi-organ “resilience” in HFpEF through physical activity, rehabilitation, and metabolic interventions (e.g., SGLT2 inhibition) have shown promise, but the mechanisms by which rehabilitation alter outcomes in HFpEF remains unclear. The central hypothesis of this K23 application is that proteins linked to quantitative, multi-organ frailty phenotypes in HFpEF will specify prognostic pathways of disease to inform future targeted surveillance or therapeutic studies. In this application, the PI (Dr. Andrew Perry) will measure associations between the human proteome and detailed hemodynamic and physiologic measures of multi-organ function in HFpEF in a hospital-based referral sample with invasive hemodynamic cardiopulmonary exercise measures (Aim 1). Dr. Perry will then identify and prioritize reversible pathways of multi-organ system impairment in HFpEF by measuring a circulating proteome before and after an already conducted, NIH funded randomized clinical trial intervention in HFpEF (REHAB-HF; Aim 2). He will finally conduct a pilot prospective study of home-based rehabilitation using a mobile application in HFpEF, supported by a larger NIH-funded effort (Aim 3). Dr. Perry has assembled a comprehensive mentoring team to aid his career development and scientific aims, including NIH funded investigators in exercise physiology in HFpEF using prospective studies (Shah, Lewis, Nayor), frailty and HFpEF (Kitzman), and high-dimensional molecular characterization and statistics (Shah, Below). The scientific aims are embedded within a synergistic training/research program focused around exercise physiology, multi- omics, advanced statistical techniques, and human patient-oriented studies, including completion of a Master of Science in Clinical Investigation. He is also supported by a rich institutional environment within Department of Medicine and Cardiovascular Medicine, including Vanderbilt’s VICTR CTSA. Successful completion of the scientific and training objectives in this K23 will provide Dr. Perry with the requisite skills to take the next, formative independent step in his long-term goal of leading a patient-oriented translational research program studying mechanisms of functional improvement in patients with advanced cardiovascular disease.

NIH Research Projects · FY 2025 · 2025-07

Severe cutaneous adverse reactions (SCAR), including both Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS), are immunologically-mediated, life-threatening, and typically drug-induced diseases affecting adults and children that result in significant morbidity and mortality. Survivors of SCAR are often left with long term-disabilities that can affect their quality of life and a lifelong fear of taking any new, even if unrelated, drugs. SCAR reactions are often associated with drugs used to treat diseases of public health importance globally such as tuberculosis and leprosy. Even though SCAR is rare, it is often severe and requires effective care across different populations globally, including highly coordinated teams of multiple disciplines that are comprised of dermatologists, critical care specialists, ophthalmologists, allergists and immunologists, pharmacologists, infectious diseases, and mental health specialists. For the first time, and to further the success of our DRESS 2022 meeting and previously NIH-funded SJS/TEN meetings in 2017, 2019, 2021, and 2023, we are proposing to hold “SCAR 2026: Stronger together,” a joint meeting planned for 2026. SCAR 2026 will be in-person to catalyze progress in improving prevention, early diagnosis, and treatment of SCAR. The scheduled 2.5-day meeting will include plenary and patient and community-focused sessions on the first day, followed by keynote and scientific breakout sessions the subsequent two days. Topics covered will be both overlapping and distinct to individual SCAR. Community engagement will once again be a key theme of the meeting. “SCAR 2026” will showcase new science from both diseases in addition to understanding and translating knowledge within and between diseases. The meeting will again provide a rich training environment of networking and interactions for early investigators. We will focus on understanding SCAR mechanism (both shared and separate) through research and continue our community and patient-focused sessions to bring the patient voice into all of these important discussions.

NIH Research Projects · FY 2025 · 2025-07

Project Summary Helicobacter pylori is a Gram-negative bacterium that colonizes the stomach in about 50% of the human population (i.e. over 4 billion people). Without antibiotic therapy, H. pylori can persist in the stomach for decades. Over time, H. pylori can lead some infected individuals to develop severe diseases including peptic ulcers or gastric cancer, the third leading cause of cancer-related death worldwide. This has led the World Health Organization (WHO) to classify H. pylori as a type I carcinogen. The effectiveness of therapeutic approaches is becoming increasingly compromised by the growing incidence of antibiotic resistance, leading WHO to declare H. pylori a priority pathogen for development of new antimicrobials. Bacterial lipoproteins are modified by acylation to anchor them to the inner or outer membrane in Gram-negative bacteria where these proteins carry out a variety of essential functions. The proteins responsible for lipoprotein synthesis and proper subcellular localization are emerging targets of antimicrobial development. In previous studies, we identified the enzymes responsible for lipoprotein synthesis in H. pylori. Although the H. pylori proteins only exhibit 20-40% amino acid identity to their E. coli counterparts, each was able to complement an E. coli mutant strain. In the current proposal, we hypothesize that inhibitors of H. pylori lipoprotein synthesis would interfere with the ability of H. pylori to survive in the stomach. This hypothesis is based on the following. First, we found that five proteins required for lipoprotein synthesis and localization (biogenesis) are essential for H. pylori growth in vitro. Second, we found that a sixth lipoprotein biogenesis protein (not essential in vitro) is essential for the ability of H. pylori to colonize the stomach. The current proposal aims to develop assays suitable for high-throughput screening to identify inhibitors of lipoprotein synthesis in H. pylori. In Aim 1, we will develop complementary assays to monitor both acylation of a synthetic peptide by recombinant H. pylori prolipoprotein diacylglyceryl transferase (Lgt) and a byproduct of the acylation reaction. In Aim 2 we will develop an assay to monitor signal peptide cleavage by recombinant H. pylori lipoprotein signal peptidase (LspA). In Aim 3, we will develop complementary assays to monitor both acylation of a synthetic peptide by recombinant H. pylori apolipoprotein N-acyltransferase (Lnt) and a byproduct of the acylation reaction. The assays developed in this R21 Exploratory/Developmental proposal will provide the foundation for the future identification of inhibitors of H. pylori lipoprotein biogenesis using computationally driven virtual screening, fragment-based lead discovery, and traditional high-throughput screening. We will then optimize the activities of identified compounds, determine whether the inhibitors are specific to H. pylori or are active against other bacteria, and test the effectiveness of inhibitors using established animal models of H. pylori infection.

NIH Research Projects · FY 2025 · 2025-06

Founded in 1965 as one of the original Intellectual and Developmental Disorders Research Centers (IDDRC), the Vanderbilt Kennedy Center (VKC) IDDRC serves as the central nexus across Vanderbilt for interdisciplinary research, communication, and training in intellectual and developmental disabilities (IDD). The VKC IDDRC serves as a cross-institutional institute that brings together over 200 faculty from 38 departments in 10 schools at Vanderbilt. The VKC’s mission to facilitate discoveries that inform best practices to improve the lives of people with IDD and their families. This mission is met by leveraging our outstanding institutional resources and support, partnering with disability communities, and capitalizing on synergistic interactions across the VKC’s federally designated centers: the VKC IDDRC, a University Center of Excellence in Developmental Disabilities and a Leadership Education in Neurodevelopmental Disabilities program. The IDDRC as the centerpiece of the VKC is the foundational organizing structure that creates a “Center culture” wherein research and discovery permeates the VKC’s broader training and service activities, thus enhancing the translational research goals of the IDDRC. Demonstrable IDDRC success includes 976 investigator- authored publications (2015-2020) and robust NIH funding to Vanderbilt to support IDD-related research ($52.6M in FY20). Harnessing and leveraging this cross-institutional strength to focus on unique challenges in IDD, the overarching goal of the next phase of the IDDRC is to develop precision care for IDD by providing infrastructure and scientific leadership to enable rapid translation of basic discoveries into high-impact IDD interventions and treatments. Three global Aims guide the IDDRC’s work. Aim 1 provides core services to enable and disseminate impactful research on individualizing treatments based upon the causes, mechanisms, and contributing co-morbid sequelae of IDD; Aim 2 focuses on incorporating innovative methods and approaches to enhance multidisciplinary IDD research; and Aim 3 proposes to conduct a signature research project to improve the precision use of antipsychotic medication in people with autism. Across these Aims and five Cores supported by the IDDRC (Administrative, Clinical Translational, Translational Neuroscience, Behavioral Phenotyping, and Data Sciences), three themes permeate our work: (1) recruitment of highly-skilled researchers not currently conducting IDD research; (2) enhancing participation of people with IDD into research studies that currently do not involve IDD; and (3) incorporation of novel scientific approaches and methods. Our IDDRC is ideally posed to enable rapid discovery of precision care approaches by supporting 50 investigators leading 70 research projects (15 from NICHD), and, as highlighted by the Signature Research Project, to promote and implement generative, novel, and impactful research directions, thus meeting the NICHD’s vision of applying newly evolved technologies and approaches to rapidly accelerate the prevention and/or amelioration of IDDs.

NIH Research Projects · FY 2026 · 2025-06

VANDERBILT ALZHEIMER’S DISEASE RESEARCH CENTER – OVERALL PROJECT SUMMARY - REVISED We aim to establish the Vanderbilt Alzheimer’s Disease Research Center (VADRC) as a world-class interdisciplinary center in Nashville, Tennessee. With high regional burden of Alzheimer’s disease (AD) and related dementias (ADRD) as well as vascular risk factors, there is a pressing need to understand the complexities underlying the intersection between vascular risk and ADRD. Vascular risk factors, the majority of which are modifiable, are linked to ADRD risk and highly prevalent in our region. The VADRC’s mission is to characterize how vascular burden intersects with ADRD pathogenesis, manifestation, prevention, and treatment at the cellular, systems biological, and population levels. This effort will capitalize on the scientific strengths of our campus-wide investigators, expansive and collaborative institutional resources, and foundational work completed over the last several years. The Administrative Core will serve as the hub for all local ADRD research activities and coordinate and integrate all Center interactions and collaborations. The Outreach, Recruitment, and Engagement Core will build upon existing community partnerships to bring awareness of ADRD and relevant vascular risk factors to the community. The Outreach, Recruitment, and Engagement Core team will recruit participants with a vascular risk profile reflective of our local community into our Clinical Core alongside outreach in the community. The Clinical Core will enroll, deeply phenotype, and annually follow 400 participants, capturing clinical, neuropsychological, cardiac imaging, neuroimaging, and biofluid data in collaboration with the Biomarker Core. The Neuropathology Core will obtain post-mortem brains and biofluids from participants, allowing for complete post-mortem characterization of ADRD and vascular pathologies. Our Data Management and Statistical Core will ensure all data collected is properly stored in an integrated informatics infrastructure, is shared with national repositories, and is readily accessible to other investigators via our web-based data sharing platform. Finally, the VADRC will foster professional development for the next generation of ADRD clinicians, scientists, and leaders, with a particular focus on supporting early career faculty scholars through the Research Education Component. The VADRC is exceptionally well positioned to become the first center of its kind in Tennessee and serve a growing population suffering from ADRD.

NIH Research Projects · FY 2026 · 2025-06

PROJECT SUMMARY/ABSTRACT Pulmonary Fibrosis (PF) is a progressive, fatal lung disease. Two FDA-approved treatments modestly reduce functional decline but are poorly tolerated and do not relieve symptoms. A major barrier to developing new and better treatments is that the primary endpoint in clinical trials, change in the forced vital capacity, varies significantly and is not suitable for early-stage disease. To gain a more complete understanding of progression across the entire disease development history, the Familial Pulmonary Fibrosis (FPF) Registry was established. The Registry enrolls proband with clinical (symptomatic) PF and their asymptomatic relatives, who are “At-Risk” to develop FPF. At-risk relatives participate in an ongoing, prospective study to screen for progressive subclinical PF. In a preliminary analysis of FPF Registry data, collectively representing early subclinical through advanced PF, the progressive decline in several pulmonary function tests (PFTs) was evaluated after disease stage alignment using a Bayesian approach. Counter to the prevailing view that PF progression is individual-inherent, our data suggests that the rate and timing of progression on various PFTs is conserved across individuals and highly stage-specific. The diffusion capacity of lung for carbon monoxide begins declining 10 years before clinical disease onset, while forced vital capacity is normal initially but declines precipitously 5 years after clinical disease onset. Notably, no PFT parameter declines uniformly across the disease development history, so any trial whose analysis ignores disease stage will be inherently inefficient. A Bayesian approach can also be used to conduct a treatment efficacy analysis, measuring the proportional treatment effect on progression of one or more endpoints, after accounting for disease stage. Experience with other rare, slowly progressive diseases suggests that this approach can have a huge impact on trial efficiency. Our hypothesis is that patients with PF experience a conserved, sequenced, and stage- specific progression trajectory. Specific Aim 1) Fit and validate a Bayesian disease progression model defining the conserved progression in PF. Domains on which progression is evaluated will include physiological (PFTs), anatomical (quantitative lung imaging), and biological (circulating biomarkers). Aim 2) Test the utility of incorporating a Bayesian approach to PF trial design. The results of Aim 1 will be used to design trials with stage-specific population selection criteria, stage-appropriate endpoint(s), and/or a Bayesian statistical approach to account for disease stage. The operating characteristics (trial size, type 2 error) will be simulated and compared to traditional trial designs. Trial designs applicable in both subclinical and clinical disease will be simulated. These transformative results will ultimately lead to more effective therapy for this devastating disease by: 1) proposing novel trial designs that substantially improve trial efficiency; 2) enabling disease prevention trials; and 3) providing a template to understand the optimal timing of treatment initiation, ultimately supporting earlier diagnosis of PF.

NIH Research Projects · FY 2025 · 2025-06

Glaucoma is a leading cause of irreversible blindness due to neurodegeneration of retinal ganglion cells. Previously, we discovered a mutation in the gene encoding the matrix metalloprotease, ADAMTS10, that causes Primary Open Angle Glaucoma (POAG) in a colony of Beagle dogs. This mutation results in a glycine- to-arginine substitution at amino acid 661 (G661R) in the cysteine-rich domain that may disrupt a protein interaction surface. Our discovery was verified with the finding of an A387T mutation in the catalytic domain of ADAMTS10 that causes POAG in Norwegian Elkhounds. To investigate the pathogenic mechanisms of glaucoma-causing ADAMTS10 mutations, we created mouse lines carrying either the G661R or the A387T mutation of Adamts10. We found that mice homozygous for the G661R mutation displayed reduced TGFβ signaling in the developing inner retina of postnatal day 10 mice which was associated with increased apoptosis. This correlated with reduced RGC axon number and attenuated retinal function in adult mice. These findings suggest the hypothesis that glaucoma-causing mutations of Adamts10 reduce neuroprotective TGFβ signaling in the developing retina resulting in optic nerve and retinal pathology in the adult. We also discovered direct interaction between ADAMTS10 and the latency associated peptide of TGFβ, suggesting the hypothesis that ADAMTS10 directly regulates TGFβ. A similar direct regulatory mechanism has been shown for two other ADAMTS family members, ADAMTS1 and ADAMTS16. In this mechanism, interactions between the cysteine rich domain of the ADAMTS and the latency associated peptide of TGFβ allow interaction of TGFβ and its receptor, activating TGFβ signaling. We will make use our mutant Adamts10 mouse lines to accomplish the following: Specific Aim 1: Define the mechanism by which ADAMTS10 promotes TGFβ signaling. Our finding of direct interaction between ADAMTS10 and TGFβ-LAP suggest a direct regulatory mechanism as has been shown for ADAMTS1 and ADAMTS16. The mechanism of promoting TGFβ signaling and the effects of glaucoma-causing mutations of ADAMTS10 will be investigated by cell culture transfection approaches. Specific Aim 2: Test the hypothesis that reduced TGFβ signaling results in development of fewer optic nerve axons in adult G661R and A387T mice. Glaucoma-causative mutations of Adamts10 reduce TGFβ signaling in developing ganglion cell layer of the retina which results in reduced RGC function and axon number in adult mice. TGFβ signaling in the ganglion cell layer of the retina in P4 – P10 mice will be experimentally reduced by disruption of ADAMTS10/TGFβ-LAP interaction and by treatment with losartan of postnatal mice. Mice will be matured to adults and RGC function and optic nerve axon counts determined. Significance: Confirmation of our hypotheses would suggest that direct regulation of TGFβ signaling is a common feature of the ADAMTS family. Since this interaction can be manipulated by exogenous peptides, this may offer novel approaches to alter TGFβ signaling as a treatment for glaucoma and other diseases.

NIH Research Projects · FY 2025 · 2025-05

Summary / Abstract This is an application for funding to purchase a new, integrated MRI-PET scanner for animals that will replace two obsolete, separate systems, an MRI and a microPET scanner. Our 4.7T Varian/Agilent MRI scanner has been in continuous use for 19+ years, while our Siemens Inveon PET scanner is >11 years old. The current electronics and console of the Varian MRI are no longer state-of-the-art, their limited capabilities are affecting productivity, and the system is no longer supported by the manufacturer (Varian/Agilent). The PET system would replace an obsolete Siemens Inveon PET/CT scanner that is also no longer supported by the manufacturer and which is highly unreliable in use and can no longer perform CT imaging. For both systems there have been no software upgrades for several years, replacement parts are scarce as the vendors are no longer in the animal scanner business, and overall the reliability and capabilities no longer meet the demands of our core users. The current 4.7T magnet would be replaced by a 7T magnet, with an accompanying gain in overall signal to noise ratio, greater spectral dispersion (e.g. for MRS and CEST), increased sensitivity to BOLD effects, and improved image quality. The new magnet would not use cryogens, so there would be considerable savings in operating expenses, and we would be insured against shortages of liquid helium. The PET insert would have an axial FOV of 80 mm, large enough to accommodate small, non-human primates and large rodents. The integrated scanner will be capable of simultaneous MRI and PET acquisitions, allowing new types of studies to be performed with accurate co-registration between modalities. PET studies will benefit from the availability of a large range of radiotracers obtainable from our research-dedicated cyclotron and radiochemistry laboratories. The device will be used by at least 22 established investigators, all of whom are already experienced users of animal imaging, in over 30 NIH-funded research applications and training programs. These research projects include applications in cardiac physiology; neuroscience (including studies of the architecture and functional organization of the brain and spine in non-human primates, as well as the actions of novel pharmaceuticals); cancer (including the study of tumor biology and treatment effects); lung disease (especially the detection of fibrosis); bone disorders; and basic imaging science. The projects of the 16 Major Users would require approximately 65% use of the availability of the instrument, the 6 Minor Users and two Center Core programs would require 16%, and the remaining time available would be used for exploratory research and new directions. The scanner will be housed and managed within the Vanderbilt University Institute of Imaging Science, and will be a primary research resource for a large number of experienced imaging scientists and trainees. The instrument will be supported by an established group of imaging experts and support staff. A comprehensive plan has been developed for the financial and technical support of the scanner as well as for its management, and the system is assured of strong institutional support and oversight.

NIH Research Projects · FY 2026 · 2025-05

Summary: Phospholipids and inositol phosphates are two classes of small molecules with well-known functions in the cytoplasm, but poorly defined roles in the nucleus. The goal of my diverse group is to understand the structural biology and functional genomics of these two classes of small molecules. We also take chemical biology approaches to develop new small molecules to interrogate nuclear functions, which informs therapeutic development for several human diseases. Nuclear lipids are enigmatic molecules because they are found outside membranes, within the nucleoplasm and have metabolic and signaling properties distinct from membrane lipids. However, we do not understand fundamental aspects of the structure or function of nuclear lipids, which are ubiquitous, well conserved signaling molecules. Funding over the past 3.5 years has used the NR5A nuclear phospholipid receptors as models to address these questions. Those studies informed new approaches to small molecule screening for full-length NR5A2, the results of those screens revealed new molecules that regulate these receptors in new ways, which we build on here. Over the next five years, our studies will reveal the structures of ceramide, sphingomyelin and sphingolipid bound NR5A receptors, as well as new small molecules and genes that regulate nuclear lipid signaling through NR5As, enabling further progress. Nuclear inositol phosphates are soluble signaling molecules made by the nuclear kinase “inositol polyphosphate multikinase”, or IPMK. Work from several groups has established IPMK kinase activity regulates gene expression, however specific cellular mechanisms have remained unclear. Funding over the past 3.5 years used genetics in human cells to show IPMK-generated inositol phosphates specifically activate HDAC3 to regulate histone acetylation, further progress has been hampered by limitations inherent to these genetic knockout/complementation approaches. To overcome this, we helped develop the first selective chemical inhibitors of IPMK, which have revealed novel aspects of inositol phosphate signaling. Over the next five years, we can now use these inhibitors to ask questions not previously possible, defining how IPMK regulates transcription. Our group is uniquely positioned to address these diverse problems because we focus on two model systems: the NR5A nuclear phospholipid receptors and IPMK. We have developed novel chemical and genetic tools that give us unique ability to interrogate these difficult questions. Our work will reveal how phospholipids and inositol phosphates control gene expression, with potential to impact cancer, diabetes and the metabolic side effects of anti-psychotic drugs.

NIH Research Projects · FY 2026 · 2025-05

Project Summary/Abstract Principles of open science often clash with requirements of data privacy laws and organizational policies, especially with respect to sensitive health data. This conflict has become particularly evident in HIV research, which provides critical information guiding health decisions and clinical care guidelines in the United States. HIV research relies on observational cohort data from outside of the US because of the large numbers of people living with HIV whose data are more readily available and because these data reflect care in resource-constrained settings that are similar to rural regions of the US. Currently, researchers cannot publicly share HIV cohort data (e.g., post on a publicly available website) and therefore many of the benefits of open science cannot be realized, such as enabling the reproducibility of published findings and creating opportunities for a larger number of people to study the data and contribute scientific discoveries. Synthetic data generated by computer simulation offer a desirable solution as they can resemble the characteristics of the original data while severing the linkage between records and real people. Though synthetic data can never fully replace the original data, they can benefit science. However, existing methods for generating synthetic data are insufficient to generate synthetic HIV cohort data that closely resemble the original data. In this project, we will adapt and apply state-of-the-art artificial intelligence methods for generating synthetic data that are tailored to longitudinal observational HIV cohorts. We will apply these methods to create synthetic data intended to mimic data from two multinational HIV cohorts in the International epidemiology Databases to Evaluate AIDS (IeDEA-EA) consortium. These cohorts are composed of hundreds of thousands of people living with HIV and contain important data for studying HIV in the United States. We will evaluate the quality of our synthetic data using both intrinsic (e.g., proportions, distributions, correlations between variables) and extrinsic comparisons to the original data. Extrinsic comparisons will be performed by a research advisory board who will select comparative HIV studies independent of the data generation process. We hypothesize that the synthetic data will be useful for hypothesis generation, and these extrinsic comparisons will provide evidence supporting or refuting this hypothesis. We will also study potential ethical, legal, and social barriers to sharing synthetic HIV cohort data through qualitative studies among people involved in HIV cohort studies. Finally, we will develop software toolkits so that others can generate synthetic HIV cohort data.

NIH Research Projects · FY 2025 · 2025-05

PROJECT SUMMARY / ABSTRACT Candidate: Kelly Watson, PhD is Assistant Professor in the Department of Neurology and a clinical psychologist who provides a specialized, evidence-based behavioral therapy to adolescents with Tourette syndrome (TS). Dr. Watson strives to establish an independent program of patient-oriented research, with an emphasis in social and cognitive processes in TS. She earned her PhD in clinical psychological science from Vanderbilt University where she then completed her research-focused fellowship on an NIMH T32 training grant. In her early career, Dr. Watson has served as a co-I on extramural grants, was awarded an internal KL2 grant, and has co-authored numerous scientific publications. Her background demonstrates strong potential for a productive research career translating key findings into the development, evaluation, and dissemination of psychosocial interventions in TS. Research Project: TS is a neurodevelopmental disorder characterized by motor and vocal tics with a prevalence of 1% in adolescence. While current treatments focus on tic reduction, patients commonly report clinically distressing social problems. Yet, limited research in adolescence has focused on risk factors that contribute to social problems or examined the impact of these problems on social isolation. The aims of the proposed study are to: (1) quantify the prevalence of social isolation in TS adolescents; (2) assess explicit social cognition in TS adolescents; (3) apply eye-tracking techniques to assess implicit social cognition in TS adolescents; and (4) determine the contributions of social cognition to social problems in TS adolescents. Fifty adolescents with TS and 50 age- and sex-matched controls will be recruited, along with their parents, to complete a multi-method assessment battery. Results have the potential to inform psychosocial interventions to improve quality of life. Career Development: The training in this career development award will support Dr. Watson to achieve her goal of becoming an independently funded clinician scientist in TS focused on social and cognitive processes. Her goals include advanced training in: 1) social cognition, 2) eye-tracking methods, 3) longitudinal study design and analysis, and 4) professional development. She has developed a career development plan that includes coursework, workshops, webinars, conferences, and individualized training from an exceptional interdisciplinary mentorship team with expertise in cognitive neurology (Dr. Daniel Claassen), social cognition (Dr. Blythe Corbett), eye-tracking methodology (Dr. Alexandra Key), and quantitative methods (Dr. Kristopher Preacher). Environment: Vanderbilt University Medical Center (VUMC) is an optimal academic environment for cultivating Dr. Watson’s development into an independently funded clinician-investigator specializing in patient-centered research in TS. The institution has an exceptional track record for fostering productive and independently funded clinician-scientists. VUMC offers a wealth of resources to support this work, including a specialty clinic with a large population of adolescents with TS; VUMC is one of only 23 Tourette Association of America Centers of Excellence in the country and the first in Tennessee to receive this designation.

NIH Research Projects · FY 2026 · 2025-05

PROJECT SUMMARY Hypertension is a leading modifiable risk factor for global mortality and a key driver of atherosclerotic cardiovascular disease (CVD). Despite aggressive lowering of cholesterol and blood pressure, up to 50% of patients still suffer recurrent cardiac events. While this “residual risk” is likely due to chronic inflammation, what drives inflammation once hypercholesterolemic and hypertensive stimuli have been resolved is poorly understood. Recently, a phenomenon known as trained immunity—in which innate immune cells form long- lasting memory—has been described. In training, an initial stimulus rewires the epigenome (i.e. enhancers) of myeloid precursors thereby maintaining them in a primed state so that their mature progeny mount an augmented response to a wide range of subsequent stimuli. We propose the novel concept that hypertension results in trained immunity that predisposes to inflammation and atherosclerosis independent of blood pressure. We have new preliminary data in support of this concept: 1) transplant of hematopoietic stem and progenitor cells (HSPCs) from angiotensin (Ang) II-induced hypertensive mice into irradiated Western Diet-fed low-density lipoprotein receptor deficient (Ldlr-/-) mice accelerates atherosclerosis, as compared to HSPCs from normotensive mice; 2) cellular metabolism and epigenome organization in monocytes differentiated from these HSPCs remain altered months after exposure to Ang II; 3) in vitro Ang II-trained myeloid cells have an augmented pro-inflammatory cytokine response and increased signaling downstream of Dectin-1 — a non-canonical receptor for Ang II implicated in other forms of trained immunity; 4) blocking Dectin-1, but not the canonical Ang II type 1 receptor (AT1R) prevents the Ang II-training phenotype in vitro; 5) polymorphisms in the gene for Dectin-1 associate with atherosclerotic and inflammatory vascular diseases in a human phenome-wide association study. Thus, we hypothesize that hypertension induces trained immunity by epigenetically rewiring immune progenitors via a Dectin-1 pathway, contributing to chronic unresolved inflammation and the long-term increased risk of atherosclerotic CVD associated with hypertension. We will address this hypothesis through the following specific aims: Aim 1. Determine how hypertension-induced training of myeloid progenitors rewires the mature monocyte epigenome to promote a pro-atherogenic cell state and enhanced T cell activation. Aim 2. Determine whether hypertension-induced trained immunity and augmented atherosclerosis are specific to Ang II. Aim 3. Establish the mechanism by which Ang II promotes trained immunity in myeloid cells.

NIH Research Projects · FY 2025 · 2025-05

Project Summary The purpose of this proposal is to acquire advanced equipment – Terumo CDI ® Blood Parameter Monitoring System 550 – to benefit the users of the S.R. Light Surgical Research Laboratory. The S.R. Light Laboratory is a core facility managed under the Section of Surgical Sciences at Vanderbilt University Medical Center (VUMC). The core is directed by Dr. José Diaz MD, Research Associate Professor of Surgery and Director of the Division of Surgical Research. The S.R. Light Laboratory provides hands-on preoperative, intraoperative, and postoperative support for surgical experiments in various animal models including dogs, goats, pigs, and sheep. Vanderbilt University Medical Center is a world-renowned institution for organ transplantation, and its preclinical research programs also have a strong clinical focus on organs, including advanced techniques for ex-vivo organ preservation and recovery, and artificial organ therapies including extracorporeal membrane oxygenation. These clinical interests have also been reflected in the investigations that are supported by the S.R. Light Laboratory. However, the current monitoring equipment offered by the S.R. Light Laboratory lags state-of-the-art equipment used for clinical transplantation and artificial organ therapies. To continue meeting these growing research needs, the S.R. Light Laboratory will need to expand its capability to not only provide direct technical hands-on support, but also to provide access to such state-of-the-art equipment. Across these ongoing projects, they all share the need for continuous hemodynamic and perfusion monitoring to acquire blood data on pH, pCO2, pO2, hemoglobin, potassium, and other critical measures of health. Currently, the investigators rely upon manual blood draws and analyses to measure these parameters to ensure animal health. Not only are manual blood draws cumbersome and labor-intensive, but they also add financial cost due to the rising cost of disposables to obtain blood gas measurements. The new equipment Terumo CDI will provide continuous readings of blood gases, meaning that there is no added monetary cost after the first set up, and real-time measurements will better inform surgical and clinical decisions during animal experiments. The new shared equipment from Terumo will therefore bring the current NIH-funded research programs up to a clinical standard of perfusion monitoring. For projects that span over multiple days, the CDI system will be beneficial by providing longitudinal trends, and the equipment will also support research and innovation into automated control of circuits. Furthermore, this equipment will also stimulate the start-up of research projects by new faculty who are seeking new funding and would greatly benefit from this equipment. The S.R. Light Surgical Laboratory will be able to continue supporting this growth of Vanderbilt’s organ research.