Vanderbilt University Medical Center

NIH Research Projects · FY 2026 · 2024-06

PROJECT SUMMARY One of the biggest challenges facing the tuberculosis field is the heterogeneity of TB disease presentation. Only a small percentage of individuals infected with Mycobacterium tuberculosis go on to develop an acute infection. While several important tuberculosis co-morbidities have been identified (i.e. HIV co-infection, smoking, malnu- trition, diabetes), we are still unable to accurately predict whether a tuberculosis patient is at high risk for devel- oping severe disease. For decades, we have understood that the way in which Mtb-infected macrophages die plays a key role in dictating Mtb outcomes in vivo. Apoptosis, an “immunologically silent” form of cell death is generally considered anti-bacterial; apoptosis limits bacterial spread and does not release high amounts of im- munogenic DAMPs and PAMPs. Necrosis, an inflammatory form of cell death, promotes Mtb survival and spread and elicits harmful immunopathology. One would predict that a tuberculosis patient with macrophages that are prone to necrosis would be likely to experience severe inflammation in response to Mtb infection. Our preliminary data demonstrate that a common human SNP in a mitochondrial-associated gene called LRRK2 promotes a new hyperinflammatory type of necrosis in response to Mtb infection. This cell death was dubbed gasdermin D-mediated necroptosis, as it requires the pore forming protein gasdermin D and results in activa- tion of RIPK1/RIPK3/MLKL and cell death via necroptosis. This mutation (Lrrk2G2019S) promotes excessive mito- chondrial reactive oxygen species (mtROS) production and mtROS alone is sufficient to promote gasdermin D- mediated necroptosis. Building on these findings, this proposal will test the hypothesis that mitochondrial dysfunction and oxidative stress drive Mtb-infected macrophages to undergo inflammatory forms of cell death and constitute a new, important “co-morbidity” for tuberculosis patients. The goal of this proposal is to mechanistically define how oxidative stress promotes pathogenic cell death modalities during Mtb infection of macrophages and mice. Here, two models of high mtROS will be leveraged (exogenous mtROS via menadi- one treatment and the human disease-associated SNP Lrrk2G2019S) to mechanistically define how oxidative stress can repurpose cell death proteins in primary murine macrophages. Aim 1 will investigate the ability of LRRK2 kinase activity to directly activate necroptosome proteins and promote gasdermin D-mediated necroptosis. Aim 2 will define how various cellular stresses license N-GSDMD association with mitochondrial phospholipids to promote gasdermin D-mediated necroptosis. Aim 3 will examine the role of lipid oxidation in dictating cell death modality usage during Mtb infection. If successful, this proposal will define the cellular triggers of hyperinflam- matory cell death during Mtb infection of macrophages and identify novel points for therapeutic intervention that may be more efficacious to target in TB patients with underlying conditions or genetics linked to mitochondrial dysfunction and oxidative stress.

NIH Research Projects · FY 2025 · 2024-06

SUMMARY This proposal will elucidate how an understudied uropathogen – Pseudomonas aeruginosa – establishes acute infection and will determine whether age influences infection establishment and persistence. Urinary tract infection (UTI) is among the most prevalent urologic diseases. Pseudomonas aeruginosa accounts for ~3 million UTI annually, a number that matches Pseudomonas lung and wound infections. Yet, while the pathogenesis of Pseudomonas in the lung and wound have been – and continue to be – thoroughly investigated, there has been minimal study of the pathogenesis of Pseudomonas aeruginosa in the bladder. Moreover, Pseudomonas infections tend to occur in older individuals and afflict males and females equally. With this proposed work we aim to innovate by assigning a molecular signature that defines uropathogenic Pseudomonas and elucidating host and pathogen determinants that favor tropism of this pathogen to the aging population. Rationale and Hypothesis: All prior work on understanding Pseudomonas UTIs has been performed using model Pseudomonas strains isolated from wounds in the 1950’s. Given that the Pseudomonas genome is “open”, meaning that there is vast genomic variability among strains, we hypothesized that distinct pathogen genomic features exist in uropathogenic Pseudomonas isolates. Indeed, our isolation and sequencing of 96 uropathogenic isolates and subsequent genomic comparisons with a global cohort of 700 sequenced strains revealed specific genomic differences in one respiratory complex, ccoN between uropathogenic and other isolates. Based on preliminary data that demonstrate Pseudomonas enters the urothelial cell, we postulate that the identified ccoN mutations increase respiratory potential during acute infection. Moreover, we posit that host features in the aging bladder may influence uropathogenic Pseudomonas respiration, favoring its tropism for infecting older individuals. We propose two aims to test the posed hypotheses. Aims: Aim 1 will define how CcoN contributes to respiration within the bladder epithelial environment. In collaboration with the Dietrich group, we will create a series of specific mutations in CcoN in uropathogenic and respiratory Pseudomonas strains and compare their ability to adhere, invade and consume oxygen within the host cell cytosol. Aim 2 will determine the steps in pathogenesis followed by Pseudomonas in young versus old bladders. In parallel, differences in the immune response to infection will be measured in the old and young mice. Impact/How will the work change the field? These studies are the first to indicate a unique molecular signature that may be defining uropathogenic Pseudomonas. Evaluating the contribution of this signature to establishment and energy metabolism in vivo will provide significant insights into the kinetics of UTI caused by Pseudomonas. Understanding how pathogen genomic features may influence infection as a function of age, has the potential to change how Pseudomonas infections are mitigated in the elderly population, by guiding the development of quick diagnostic tools and identifying modifiable host factors that can be modulated to prevent or control infection.

NIH Research Projects · FY 2026 · 2024-06

Hypertension, a leading risk factor for death, impacts 40% of American women but is far more frequent after menopause. Postmenopausal hypertension is largely related to the pronounced decline in circulating estrogen associated with menopause, but the molecular mechanisms involved remain incompletely defined. In addition to activating the classical estrogen receptors (ER and ERβ), estrogen activates the G protein-coupled estrogen receptor 1 (GPER1), which elicits cardiovascular protective actions. Our preliminary data uncovered that (1) aged female global GPER1-knockout (GPER1 KO) mice have higher blood pressure than wild-type littermates do, and (2) GPER1 regulates renal endothelin-1 signaling and the activity of epithelial Na+ channel (ENaC), a major regulator of natriuresis and, thereby, blood pressure. To further investigate the GPER1-ENaC interaction, we generated mice with GPER1 deletion specifically in renal collecting duct principal cells (PC-GPER1 KO mice). Patch clamp electrophysiology experiments revealed greater ENaC activity in collecting ducts isolated from PC- GPER1 KO female mice. Conversely, pharmacologic activation of GPER1 downregulated ENaC activity in collecting ducts obtained from wild-type female mice. In aged GPER1 KO mice, prior pregnancy resulted in lower blood pressure, increased plasma E2 level and decreased adrenal production of aldosterone, which also regulates ENaC and blood pressure. In line with this finding, estrogen-mediated activation of adrenal ERβ has been shown to blunt aldosterone biosynthesis when GPER1 is silenced. Of note, most animal research with females utilizes virgin animals, which does not represent the overall female population, and the impact of uncomplicated pregnancy on later maternal blood pressure is unclear. Our preliminary data suggest GPER1 signaling may contribute to the later-in-life cardiovascular benefits of pregnancy previously observed in longitudinal studies of women. We hypothesize that GPER1 signaling and prior pregnancies elicit blood pressure -lowering actions in aged females by downregulating ENaC via regulation of ET-1 and aldosterone, respectively. AIM 1 of our study will determine whether GPER1 activation lowers blood pressure by downregulating collecting duct ENaC in aged female mice. AIM 2 will determine whether prior pregnancy lowers blood pressure in global GPER1 KO mice by improving ovarian function and downregulating aldosterone signaling. Simultaneously, using existing human genotyping, reproductive history and prospectively collected blood pressure data in BioVU, Vanderbilt University Medical Center's vast DNA repository, AIM 3 will examine the associations of candidate genetic variants of GPER1 and parity with blood pressure in postmenopausal nulliparous and parous women. Successful completion of the current studies will likely justify the development of antihypertensive therapeutics that target GPER1 for postmenopausal hypertension. Furthermore, the proposed studies will improve our understanding of the long-term effects of uncomplicated pregnancy on maternal blood pressure, which will consequently improve personalized cardiovascular care for nulliparous and parous women.

NIH Research Projects · FY 2026 · 2024-06

PROJECT SUMMARY The immune system is an amazingly complex biological system characterized by rapid and precise cell-cell communication, danger signaling, migration, deployment of effector functions and resolution of inflammation to avoid self-harm. Yet despite its essentiality, the human immune system also displays remarkable inter-individual variability. Understanding what accounts for these inter-individual differences will set the stage for personalized therapies for chronic inflammatory diseases, which constitute a major medical and public health burden. Although it is clear many chronic inflammatory diseases have a strong genetic component, we still lack a precise understanding of how specific gene variants specify aberrant immune responses on an individual patient-by- patient basis. As a result, many patients receive broadly immunosuppressive treatments that do not address the root causes of their disease, may be ineffective or toxic, or lead to treatment-refractoriness. Most research on the genetic basis of inflammatory diseases has been performed using genome-wide association studies (GWAS) or single-gene knockout mouse models. However, both of these approaches are subject to important caveats: GWAS are predicated on an assumption of genetic homogeneity (e.g. disease is caused by common variants, shared by those affected); while human and murine orthologs of the same gene often control vastly different immunological phenotypes. To partially address this gap, my work combines unique capabilities in the analysis of large EHR-linked biobanks and rare cases of Mendelian disease, together with wet-lab approaches to discern the functional impact of novel variants on immune signaling pathways and cellular phenotypes. With these tools, my lab will identify genes and immune pathways that have large effects on inflammatory disease pathogenesis, and thus are strong candidates for therapeutic targeting. We identify genes and variants with strong impacts on disease through the in-depth study of rare patients with monogenic (Mendelian) inflammatory diseases. I have built a unique patient cohort along with a robust mutation discovery pipeline and used this tool to identify novel genetic variants in patients with severe pediatric inflammatory diseases. I have also developed wet lab capabilities to perform diverse molecular and cellular experiments to determine how each mutated protein causes immune dysregulation including the use of cutting-edge single cell assays in patient-derived samples. To determine how more common and non-coding variants in the same genes impact diverse inflammatory disease processes, I will use Vanderbilt's unique biobank of DNA from discarded clinical samples linked to de- identified electronic health records (EHR) to find new genotype-phenotype associations. Findings will be validated in two other independent large biobanks. The use of human genetic data, and especially insights gleaned from Mendelian genetic studies such as this, has a proven track record as an unbiased method to identify targets for intelligent drug design. Overall, this research program will clarify the basic mechanisms of chronic inflammatory diseases and point to therapeutically tractable targets.

NIH Research Projects · FY 2026 · 2024-06

Project Summary Sixty years of observational studies have consistently demonstrated an association between respiratory syncytial virus (RSV) lower respiratory tract infection (LRTI) and asthma, the two most common respiratory diseases of infancy and childhood, resulting in significant morbidity and mortality in the US and worldwide. However, we have demonstrated the problem with this approach, given confounding due to shared heredity. To overcome this, we have demonstrated in both retrospective and prospective studies that RSV infection, not only severe infection, during a susceptible age window increases the risk of asthma development, and that delayed primary RSV infection until after infancy is associated with a significantly decreased risk of developing childhood asthma. Our results along with human and experimental findings, provide the preliminary data to support that there is an age-dependent causal relationship between infant RSV infection and asthma. Key remaining unanswered questions include determining the critical susceptibility period/timing of RSV infection during which infection results in increased childhood asthma, establishing causality between RSV infection and asthma, and determining if new RSV prevention products impact long-term respiratory morbidity. We hypothesize that there is an identifiable age-dependent window during which RSV infection results in an enhanced risk of childhood asthma, and that prevention or delay in initial infection protects from asthma development. To test the hypotheses, we will assemble a population of over 4 million infants who were born and enrolled in a state Medicaid program and the Department of Defense Military Healthcare System from 2003-2028. We will address the questions using 1) an instrumental variable (IV) approach and 2) the “natural experiment” of the SARS-CoV-2 pandemic time period which resulted in more than a year during which there was almost no RSV circulation followed by an off-season summer RSV peak and an extremely early RSV season. The IV approach, designed to address causal questions using observational data, is a novel statistical method that has been successfully implemented in many health outcome studies. We will also address this question by taking advantage of the soon-to-be available RSV protection product(s) during the 2023-2028 RSV seasons to assess if they have an impact on long-term childhood respiratory morbidities including asthma. Establishment of an age-dependent causal relationship between RSV and asthma will be of enormous public health importance for asthma prevention, as there is currently no effective primary prevention strategy for asthma. Further, results of this study will be important in understanding required duration of protection during infancy to inform RSV prevention product recommendations. Lastly, demonstrating value added long-term benefit of RSV prevention strategies will certainly enhance the cost-benefit for uptake of RSV prevention products in low- and middle-income countries (LMICs), as well as individual acceptability and adherence to recommendations for RSV vaccines and monoclonal antibodies.

NIH Research Projects · FY 2026 · 2024-05

Summary Dysfunction of the intestinal barrier established by tight junctions between intestinal epithelial cells (IECs) is a critical issue for many diseases, including inflammatory bowel diseases and mucositis as a severe complication of chemotherapy. There is an unmet need in efficiently preventing dysfunction of the intestinal barrier. Observational evidence suggests that oligosaccharides in human milk are associated with beneficial effects in infancy and in adulthood. However, neither basic research nor clinical studies have revealed the exact biological functions or mechanisms of action of individual oligosaccharides during development or in adulthood. Thus, it remains largely unknown whether these oligosaccharides could become effective therapeutics. 2’- fucosyllactose (2’-FL) is the most abundant oligosaccharide in human milk but are not present in dairy milk. We have found a previously unrecognized role of 2’-FL in protecting intestinal barrier and ameliorating intestinal injury during colitis and mucositis in adult mice. Our preliminary studies have demonstrated that dysregulated microbial metabolic pathways in ulcerative colitis patients are regulated by 2-FL in adult mice. We have further found that 2’-FL promotes Bifidobacterium infantis to produce metabolites, such as pantothenate that protects the intestinal barrier against oxidative stress. Another important finding is that 2’-FL directly stimulates transactivation of a cell protective signaling, epidermal growth factor receptor (EGFR) in IECs. We will test the hypothesis that 2’-FL protects the intestinal barrier against injury during intestinal inflammation in adulthood through two mechanisms: by promoting the growth of beneficial bacteria capable of metabolizing 2’-FL, and by stimulating transactivation of EGFR in IECs in a microbially-independent manner. The mechanisms underlying protecting the mucosal barrier in intestinal inflammation by human gut microbiota consuming 2’-FL will be defined in Aim 1. We will define the impact of 2’-FL on the adult human gut microbial compositional balance, particularly growth of 2’-FL consuming bacteria, and metabolite production and determine the exact roles of 2’-FL-regulated microbial profile and metabolites, such as pantothenate, in protecting the intestinal barrier against injury in colitis and mucositis in adult mice. We will further identify 2’-FL-directed pathways that mediate growth and metabolism in B. infantis and B. breve. In Aim 2, we will determine the mechanisms by which 2’-FL directly stimulates cellular responses in IECs that ameliorate inflammation-induced disruption of the intestinal barrier through identifying novel targets of 2’-FL in IECs, including targets for EGFR activation, revealing protective cellular response through 2’-FL-stimulated EGFR signaling in IECs and further define these cellular programs at single cell resolution in the human intestinal epithelium, and defining the contribution of 2’-FL-stimulated EGFR signaling in IECs to preservation of the epithelial barrier and enhancement of epithelial regeneration in colitis and mucositis in adult mice. Results from this proposal will support 2’-FL as novel therapeutic strategies for diseases associated with impaired intestinal homeostasis.

NIH Research Projects · FY 2025 · 2024-05

SUMMARY Zinc binding metalloproteins and metalloenzymes constitute ≈10% of the vertebrate metalloproteome and are essential for many cellular processes. Due to the critical importance of zinc to vertebrate physiology, zinc deficiency leads to numerous pathologies and is involved in the pathogenesis of many neurological disorders. In fact, zinc is one of the most prevalent metal ions in the brain where it serves important roles in neurogenesis, neuronal migration, and differentiation. Zinc deficiency constitutes a pervasive public health problem considering that approximately half of the world's population suffers from dietary zinc deficiency, now the fifth most important risk factor for mortality in developing countries. Despite the known importance of zinc cofactors to cellular function, the mechanisms by which zinc levels regulate tissue homeostasis remains poorly defined. Cellular zinc homeostasis is modulated by a specialized family of zinc trafficking proteins called metallochaperones. It is speculated that metallochaperones facilitate the hierarchical delivery of metals to their client proteins thereby regulating cellular and organismal homeostasis. We have identified the first vertebrate zinc metallochaperone, which we recently named Zinc regulated GTPase metalloprotein activator 1 (ZNG1). We demonstrated that vertebrate ZNG1 binds to and transfers zinc to metalloproteins to promote their enzymatic activity. Further, we identified numerous candidate ZNG1 client zinc metalloproteins in zebrafish and mice that are associated with brain function, including the zinc-finger transcription factors, ZFHX3 and ZFHX4. Collectively these findings suggest that ZNG1 is a regulator of brain development and function via interactions with specific Zn-requiring transcription factors, which will be tested by experiments proposed in this application. This work is expected to determine the impact of ZNG1 mediated zinc transfer on transcription factor activity in the brain (Aim 1) while defining the ZNG1-dependent ZFHX3 and ZFHX4 signaling pathways important for neuronal development, neuronal response to stress, and behavior (Aim 2). Completion of these aims has the potential to identify ZNG1 as a factor that modulates signaling in the brain in a manner that is dependent upon zinc bioavailability. These findings will shed light on the in vivo role of the first discovered zinc metallochaperone and will vertically advance our understanding of zinc homeostasis and contributions to the progression of human neurological disorders.

NIH Research Projects · FY 2026 · 2024-05

ABSTRACT Adolescents with pulmonary arterial hypertension (PAH) have impaired exercise capacity and reduced quality of life. Current therapies only modestly improve exercise capacity and are often prohibitively expensive, highlighting the need for additional, cost-effective interventions. Multiple studies have demonstrated that increasing physical activity is highly efficacious in adult PAH, resulting in six-minute walk distance (6MWD) improvement that exceeds the effect of medications. However, protocols require inpatient rehabilitation, making them impractical and poorly scalable to the adolescent PAH population. Moreover, cardiopulmonary rehabilitation is poorly reimbursed, and facilities are not easily available or accommodating of adolescents. Recently, in adults, we completed the first mobile health (mHealth) intervention in the PAH population, demonstrating the effectiveness of linking real time activity tracking with a “smart” behavioral coaching intervention, using personalized, encouraging content based in behavioral change theory (e.g. feedback loops and habit formation). After 12 weeks, the intervention arm took 1019 more steps per day than the control arm (adjusted for age, sex, functional class, and baseline step counts), with <5% dropout. In secondary analyses, we observed significant improvements in quality of life (QOL) and right ventricular function. But, adolescents may respond differently to remote real time activity monitoring and behavioral coaching, demanding optimization of our approaches. We hypothesize that a mHealth intervention specifically designed for the needs of an adolescent population with PAH is feasible and will increase daily step counts. We propose a randomized pilot trial of smart texts versus usual care for 12 weeks using personalized, adaptive step count targets and text messages that leverage age-appropriate behavioral psychology. Using a fully remote study without in-person visits, 50 participants will wear a Fitbit device and be randomized 1:1 to the mHealth intervention or usual care. Aim 1 will adapt our successful PAH-focused mHealth approach to the developmental needs and interests of adolescents. Participant, caregiver, and community feedback will be used to optimize our resource of smart text messages for study communication. In Aim 2, we will test the feasibility of a mHealth intervention to increase step counts in adolescents with PAH. Secondary endpoints will include measures of QOL for the adolescent and caregiver(s), activity duration and intensity, right ventricular function, as well as fidelity of text and data transmission. The goals of this proposal are to 1) develop and refine an adolescent-focused mHealth intervention for PAH and 2) obtain the feasibility and preliminary data needed to conduct a large, multi-center R01-funded trial across the U.S. with our Pediatric Network collaborators, which will be submitted for consideration during the last year of this award.

NIH Research Projects · FY 2025 · 2024-05

PROJECT SUMMARY This work proposes a multi-site study between Vanderbilt University Medical Center (VUMC) and Johns Hopkins University (JHU) that will apply novel neuroimaging and angiographic tools to test fundamental hypotheses regarding how biomarkers of stroke risk, vascular steno-occlusion, and cerebrospinal fluid (CSF) motion inform treatment candidacy and pathogenesis in North American patients with idiopathic moyamoya disease (MMD). MMD has unknown etiology and is characterized by steno-occlusion of the supraclinoid internal carotid arteries and proximal branches, subsequent development of collateral vessels, and more than a seven-fold risk increase of stroke. Importantly, once thought to be a rare condition affecting primarily females of Asian ethnicity, or more common as a syndromic complication of other disorders, MMD is being reported with increasing frequency in North America. While much work has increased our understanding of cerebrovascular disease treatments generally, MMD etiology remains unknown, animal disease models do not exist, biomarkers that may place patients at highest risk for stroke have not been conclusively established, and randomized treatment trials have not been performed. As randomized clinical trials of surgical revascularization vs. medical management are unethical owing to the benefits that revascularization surgery is believed to confer for many patients, there is now a need to accurately identify factors that underlie the North American phenotype and develop personalized signatures of tissue physiology that inform neurological impairment and treatment response in these patients. To address this need, Radiology, Neurology, and Neurosurgery faculty at VUMC and JHU have developed and applied magnetic resonance imaging (MRI) and angiographic tools, on similar MRI and digital subtraction angiography equipment, to help characterize the spectrum and hemodynamic origins of impairment in North American MMD patients undergoing these indirect surgical revascularizations. Here, we propose to extend these promising single center studies to evaluate generalizable and pre-surgical biomarkers of ischemic symptomatology, surgical response, and cerebral ischemia by leveraging overlapping imaging equipment, established investigators with ongoing collaborations, and two of the largest North American MMD treatment centers. Additionally, we will explore new directions in this field, whereby we will evaluate whether neuroimaging markers of aberrant neurofluid flow provide indicators of impaired cortical hemodynamics. Successful completion should provide new technologies that can expand the diagnostic and surveillance imaging infrastructure for the growing number of patients with idiopathic moyamoya disease.

NIH Research Projects · FY 2026 · 2024-05

PROJECT SUMMARY Clinical disability in multiple sclerosis (MS) is largely determined by the accumulation of demyelinating lesions in the spinal cord (SC), but conventional magnetic resonance imaging (MRI) methods lack the sensitivity to assess the full extent of SC pathology including sub-radiological tissue damage that occurs beyond MRI-visible lesions. Recent studies have revealed that cervical SC pathology correlates with disability in MS and is independent from MRI measures of disease in the brain. However, a lack of evidence on disease in the lumbosacral spinal cord (LSC) has limited our ability to fully understand primary progressive MS (PPMS) pathology and how LSC lesions and diffuse damage impact clinical disability and autonomic function, which hinders the selection and evaluation of therapies for patients. Advancing multimodal MRI and developing imaging biomarkers of PPMS targeting the LSC will deliver more accurate assessments of disease progression, enabling and informing decisions regarding treatment with disease-modifying therapies or symptom management strategies. Our long-term goal is to develop MRI biomarkers of MS pathology for the complete SC. We predict that MRI measures of the entire spinal axis will better inform clinicians on the extent of disease, which will likely dictate therapy. Our project objective is to identify and validate quantitative MRI biomarkers in the lower SC that are associated with clinical disability in PPMS. Our previous work demonstrated that advanced MRI methods (diffusion tensor imaging, quantitative magnetization transfer MRI, and resting-state functional MRI) provide measures related to pathology in the cervical and lumbar SC in relapsing-remitting MS, and we will now study the extent of imaging abnormalities in the LSC by applying these advanced MRI methods in PPMS. We also extend advanced MRI to the conus and cauda equina to explore associations between imaging indices and autonomic dysfunction seen in PPMS patients. Our specific aims are: (1) Establish reproducibility and validate quantitative MRI indices in the LSC, (2) Characterize quantitative MRI biomarkers of disease pathology in the LSC for PPMS in relation to clinical disability, and (3) Optimize the resolution of quantitative MRI methods to extend their application to the conus medullaris and cauda equina. This research is technically innovative because it refines advanced MRI methods for application in the LSC; to our knowledge, this will be the first application of these methods to the conus and cauda equina. The resulting novel, quantitative MRI biomarkers of PPMS pathology in these structures will complement existing brain and cervical SC MRI in monitoring disease progression and treatment response. The results will improve our understanding of the pathological substrates of disability in PPMS, which is expected to have a significant impact on future studies of potential therapies. The MRI methods will also benefit studies of other neurological disorders, and this research aligns with NINDS’s mission to reduce the burden of neurological disease by developing imaging biomarkers that enable more precise assessment of disease biology.

NIH Research Projects · FY 2026 · 2024-05

Lack of reliable assessment tools is a major obstacle to validating novel treatments for chronic graft-versus-host disease (cGVHD), the leading cause of long-term morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HCT) to cure lifethreatening blood diseases. Skin erythema is a key cGVHD biomarker, but standard of care in-person evaluations are subjective, prone to error, and costly. We will validate artificial intelligence (AI) technology for accurate, efficient, and easily deployable measurement of cGVHD erythema from photographs in diverse patient populations. In our preparatory study, AI technology achieved human-level performance under controlled photography conditions. We propose to refine and validate this AI technology in a multicenter cGVHD patient cohort of unprecedented size, leveraging experts in dermatology, transplant medicine, medical imaging, artificial intelligence, biomedical informatics, and data science. A unique database of over 11,000 photographs and clinical information from ethnically and phenotypically diverse patients will be assembled from five major cancer centers: Fred Hutchinson Cancer Center, Mayo Clinic, the National Institutes of Health, University of Pennsylvania, and Vanderbilt University Medical Center. Accuracy to measure cGVHD erythema will be determined relative to expert dermatologist-level assessments. We will quantify and overcome potential biases for the AI including skin tone, biological sex, photography conditions, and disease severity. We will compare the prognostic value of AI and human assessments as biomarkers of mortality. Finally, we will prospectively benchmark the accuracy of AI measurements against standard in-person clinical trial assessments (NIH Skin Scoring) for patients recruited at all five cancer centers. The proposal could improve patient care and telemedicine through: consistent cGVHD scoring equivalent to specialist examination; visualizing cutaneous changes for quality assurance in observational and therapeutic studies; enabling frequent longitudinal monitoring at home or in clinic; and relieving the burden of time-consuming skin area assessment on patient care providers.

NIH Research Projects · FY 2026 · 2024-04

In the US, ~100,000 babies are born premature at <34 weeks gestational age (GA) each year, or ~2.7% of all live births. While infant preterm respiratory, pulmonary vascular, and systemic vascular diseases are common among those born preterm, many become asymptomatic in early childhood. Yet, emerging data point to subclinical abnormalities among adult survivors of preterm birth that may ultimately drive their increased rates of long-term cardiopulmonary complications including obstructive lung disease, pulmonary and systemic hypertension, and metabolic disease including diabetes, obesity and metabolic syndrome. Preterm-born young adults have systemic evidence of energy metabolism dysregulation, insulin insensitivity and oxidative stress. This application has four objectives: 1) Understand the cardiopulmonary phenotypic burden of disease among formerly preterm children (FPC) ages 5-12 years; 2) Evaluate for systemic evidence of metabolic dysregulation characterized by inflammation, oxidative stress, and insulin resistance in FPC; 3) Explore mechanisms by determining whether FPC have systemic molecular signatures of abnormal energy metabolism and inflammation; and, 4) Incorporate metrics of social determinants of health (SDOH), to understand how exposures interact with and modify the clinical condition as well as systemic and cellular features. There is a critical need to determine the burden of disease and mechanistic features during mid-childhood, when early interventions may change an otherwise predetermined lifespan trajectory toward chronic illness. We propose a strategy of dense clinical phenotyping paired with molecular studies and information about SDOH. We will leverage the clinical and research infrastructures built at our three centers over the past twenty or more years in the care and study of children born preterm. We hypothesize that school age FPC display systemic metabolic energy dysregulation, characterized by inflammation, oxidative stress, and insulin resistance, with associated cardiopulmonary abnormalities and suboptimal reactivity to stress challenge, and that these outcomes may be modified by social determinants of health (SDOH). Establishing a new human cohort of 100 FPC ages 5-12 years, matched by 50 formerly term healthy controls, we will pursue the following Aims: Aim 1: identify the clinical cardiopulmonary vascular features that characterize FPC; Aim 2: identify the biochemical markers in circulation that suggest metabolic dysregulation characterized by inflammation, oxidative stress, and insulin resistance; Aim 3: deeply explore mechanistic drivers by generating expression data from RNA Sequencing to determine the molecular variations that drive alterations in energy metabolism. In each Aim, we will integrate the phenotypic, biochemical, and molecular variations with socio-ecologic exposures. These studies will confirm the presence of cardiopulmonary irregularities among FPC in mid-childhood and connect these phenotypes with alterations in biochemical and expression markers, as well as SDOH, offering the foundation for future studies and a step toward personalizing care and surveillance guided by biologic data.

NIH Research Projects · FY 2026 · 2024-04

Project Summary Abstract To address the increasing demand for research in precision medicine in Africa, the proposed Vanderbilt- Nigeria Research Ethics Training Program (V-NET) is an innovative research ethics training program that involves the creation of a Master of Science (MSc) in Research Ethics degree program. V-NET will integrate curricular development, didactic coursework, skills development, mentoring, and practicum experiences to build capacity for the ethical design, conduct, and oversight of genetic and genomic research in Nigeria. V-NET builds upon long-standing and successful collaborations between leading research institutions in Nigeria and the United States - Aminu Kano Teaching Hospital/Bayero University Kano (AKTH/BUK) and Vanderbilt University Medical Center (VUMC). The V-NET team includes experienced educators from the VUMC Center for Biomedical Ethics and Society, the Vanderbilt Institute for Global Health, AKTH/BUK, and the National Health Research Ethics Committee of Nigeria. We will create the first master’s degree program in research ethics in northern Nigeria at BUK and train 15 MSc students (in total) through didactic training and mentored research. We will integrate genomics-focused ethics into the annual 1-month long Vanderbilt Institute for Research Development and Ethics (VIRDE) faculty enrichment program at VUMC, benefiting 8 Nigerian researchers over a 5-year period. We will also host an annual 3-week practicum at VUMC’s Center for Biomedical Ethics and Society for 12 Nigerian Institutional Review Board (IRB) members to strengthen their skills in protocol review and administration. We will offer annual 5-day research ethics workshops for IRB and Community Advisory Board members at AKTH in Nigeria on protection of human subjects in research, ethics of genetic and genomic research, and review of genomic research protocols (~150 trainees in total). To sustain and expand the impact of the V-NET program, we will: 1) create, curate, and distribute a curricular toolkit in ethics of genetic and genomic research tailored to Nigerians and other African IRB members and research ethics educators, and 2) coordinate 16 quarterly online research ethics webinars presented by global ethics experts to African researchers. Through V-NET, a skilled cohort of Nigerian academics, researchers, and healthcare professionals will emerge, providing leadership in the ethical design and review of genetic and genomic studies in Nigeria's rapidly evolving research landscape.

NIH Research Projects · FY 2026 · 2024-04

PROJECT SUMMARY The objective of this training program is for Vanderbilt-Vietnam Genetic Epidemiology Training Program (V2- GENE) will join efforts across Vanderbilt University (VU) and low-middle income country (LMIC) partners Hanoi Medical University (HMU), and Vietnam National Cancer institute (VNCI) to train scholars in the genetic epidemiology of NCDs. Non-communicable disease (NCD) is the leading cause of death globally, accounting for about 71% of the 56.9 million deaths that occurred worldwide in 2016 and 74% in 2022. With a population over 96 million, Vietnam ranks as the 14th most populous country in the world. Vietnam, a LMIC. The goal of the program is to develop a team of researchers and educators prepared with the necessary training and expertise to lead genetic epidemiology research of non-communicable diseases (NCD) across the lifecourse in Vietnam and to enhance engagement of US-based researchers in low- and middle-income countries (LMIC). We build upon existing partnerships across VU and HMU/NCI as well as the substantial expertise in genetics and genomics research in NCD and research training in LMICs from investigators in the Vanderbilt Epidemiology Center and the Vanderbilt Genetics Institute. We will leverage Vanderbilt’s robust and existing infrastructure that provides training for faculty, postdoctoral fellows, and PhD graduate students to lead this program. Integrating our training with these existing resources will ensure the success of the trainees supported through our program. Specifically, the V2-GENE program seeks to: 1. Train leaders and trainers in genetic epidemiology research. We will target three visiting faculty members from HMU and VNCI for one-year appointments who have existing and complimentary expertise in epidemiology and molecular genetics research. They will receive mentorship and grant writing training during their visit to VUMC. 2. Train scientists and future leaders in genetic epidemiology research. This will be accomplished through combined US- and Vietnam-based training activities (three predoctoral PhDs [three-year appointment], three MPH students [two- year appointment], and one postdoctoral fellow [two-year appointment] from Vietnam) that include didactic courses and mentored research activities. 3. Guide our training with activities that ensure a long-term impact. Our approach of training the trainers and building training infrastructure within Vietnam will provide sustainability for the program. The long-term follow-up of alumni will also foster collaborations and continued support beyond the duration of the training period. Direct outcomes of this training program will be expanded workforce and development of future leaders in genetic epidemiology research within Vietnam and further engagement of US researchers in global health research. This synergistic partnership across VU and Vietnam as part of the V2-GENE program will significantly enhance the research and training capacity for genetic and genomics of NCD within Vietnam. This program will build the necessary workforce within Vietnam to lead the next-generation of genetics researchers.

NIH Research Projects · FY 2026 · 2024-04

South Africa has made progress towards their 95-95-95 goals, yet a substantial proportion of the population do not test regularly. In South Africa, people of low socioeconomic status, men, people in rural areas, and those who distrust the health system have higher rates of HIV stigma and are less likely to receive an HIV test. These individuals are also more likely to see a traditional healer for their health care needs, making healers an ideal group to bridge the health care utilization divide. To reach people who otherwise may avoid testing, our team trained 15 traditional healers to conduct HIV counseling and testing in their own indumbas – a hut or room by their home where they provide care to their patients (R34MH122259-01, PI Audet). Over six-months, with no advertisement or community events, healers offered HIV counseling and testing to 463 individuals who visited them for unrelated services. Fifty-four (11.7%) self-reported a positive HIV status. Of the 409 eligible participants, 316 (77%) agreed to test, and 20 (6.3%) tested positive- 95% were linked to HIV care and treatment services. In collaboration with the Department of Health and Kukula, the local healer’s organization, we propose to build on our successful pilot to test an expanded Healer-Initiated HIV Testing and Linkage to Care intervention with the following testing and linkage to care components. Healers will provide three testing services: (1) Advertise the availability of free healer-initiated counseling and testing for their clients; (2) Offer partner-based testing services at their facilities or client homes; and (3) Provide monthly community-based testing outreach activities at local events (e.g., sporting events, fairs). In addition to testing, healers will support linkage to care and treatment adherence, offering clients accompaniment to their first clinical appointment, ongoing adherence support/counseling in person or via WhatsApp, and a nurse/healer WhatsApp group to facilitate more technical support if needed. We propose a cluster randomized controlled trial (comparing standard of care testing options vs. standard of care + enhanced testing with support of traditional healers) at 42 clinical catchment areas to evaluate the impact this intervention. The Specific Aims of this study are to: (1) Compare rates of HIV testing in healer-initiated HIV counseling and testing communities vs. control communities via a cluster randomized controlled trial in rural South Africa; (2) Assess adoption, implementation fidelity and maintenance of healer-initiated HIV testing; and (3) Evaluate the cost-effectiveness of healer-initiated HIV counseling and testing compared to standard of care. Our team has a proven record of engaging traditional healers to improve patient outcomes, conducting research to evaluate and address mistrust in the health system, HIV stigma, and developing interventions to increase HIV testing uptake. We believe that traditional healers are an untapped resource with the potential to reach those who historically avoid HIV testing and they have the potential to help South Africa reach their 95% testing targets.

NIH Research Projects · FY 2026 · 2024-04

Abstract Prenatal exposure to viruses and toxins places a developing fetus at risk for neurodevelopmental, motor, and sensory deficits that may directly or indirectly impact language ability. To date, most research on prenatal exposure effects have focused on clearly identifiable sequelae (e.g., microcephaly, hearing loss) that can be detected shortly after birth. This approach omits the much larger group of children with a history of prenatal exposure who appeared asymptomatic at birth or during infancy. We have demonstrated that children exposed to the Zika virus (ZIKV) who were asymptomatic at birth exhibit a slower rate of communicative than cognitive development during infancy that cannot be explained by nonverbal cognitive delays or peripheral hearing loss. Our more recent data from exposed and not exposed children during the preschool age indicate group differences in language and communicative skills. The central hypothesis of the proposed study is that prenatal viral exposure can result in altered language development in the absence of peripheral hearing loss or nonverbal cognitive disabilities, that these characteristics become more apparent later in childhood, and can be predicted by well-selected, sensitive behavioral and physiological measures. Children born during the ZIKV pandemic in Brazil in 2015-2017 present a unique cohort with objectively documented exposure status. We have begun study of this well-characterized cohort to evaluate language characteristics and identify auditory neural markers. This application proposes to characterize the impact of prenatal virus exposure on the development of language by addressing these specific aims: Specific Aim 1: To comprehensively characterize language development in school-age children with prenatal exposure to ZIKV. Studies typically have followed exposed children only through toddlerhood and utilized limited language measures. Emerging data suggest that language difficulties increase as these children get older despite normal peripheral hearing and typical cognitive skills. Specific Aim 2: To characterize auditory neural function in children with prenatal ZIKV exposure. Studies of auditory function to date have focused on peripheral hearing sensitivity, which is rarely abnormal, and have not systematically examined auditory neural processing, particularly for speech stimuli. Specific Aim 3: To construct a model that describes concurrent and predictive relationships between language ability, biological, cognitive, and environmental factors in children with prenatal ZIKV exposure. The proposed research facilitates collaboration among researchers in the USA and in Brazil who follow some of the largest cohorts of ZIKV-exposed children in the world. The opportunity to study this well-defined cohort of children will improve understanding of the impact of prenatal virus exposure on language development and auditory neural function, inform future studies investigating the effects of prenatal and postnatal factors on language outcomes, and provide auditory markers for earlier identification of those at risk for language difficulties.

NIH Research Projects · FY 2026 · 2024-04

PROJECT ABSTRACT Mozambique has made considerable strides in its national HIV response, specifically in its progress towards the lofty UNAIDS 95-95-95 goals. Yet, despite this progress, significant gaps persist, including numerous incident infections, large numbers of persons living with HIV (PLWH) unaware of their status, and challenges in achieving viral load suppression in certain groups. Further, the country is yet to optimally leverage newer data- driven and genetics-based approaches for personalized HIV care, and for molecular epidemiology of the disease. To address these gaps, Mozambique must build its biomedical informatics (BMI) research capacity. BMI focuses on using computational and information sciences approaches in biology (primarily genomics and proteomics) and health disciplines (primarily clinical & public health). Leveraging proven leadership and expertise as Mozambique’s lead HIV Strategic Information partner and highly successful partnerships between Universidade Eduardo Mondlane (UEM) and Vanderbilt University Medical Center (VUMC), we propose the Vanderbilt-Mozambique Biomedical Informatics (VM-BMI) Training and Research program. The VM-BMI is designed to sustainably equip Mozambican scientists with skills to advance progress towards HIV epidemic control through high-quality BMI-based research that is relevant to the country. To build such capacity and accomplish this objective, we propose the following three Specific Aims: 1) Train six Mozambican faculty fellows in BMI to build UEM’s capacity for a self-sustaining HIV-focused BMI research portfolio. This multi-faceted BMI training will occur during Year 1 and Year 2 of the program. 2) Develop and implement a BMI track within the existing master’s in informatics program at UEM. Given that this is a new program and faculty expertise and capacity needs to be established/expanded, implementation and enrollment of students into this new BMI track will begin in Year 3 of the program. 3) Conduct annual HIV-related BMI workshops and bootcamps at UEM to provide BMI research training and practical experience addressing HIV-relevant research questions in Mozambique (targeting 20 individuals per year for each workshop and bootcamp for a total 200 trainees in five years). To our knowledge, this will not only be the first BMI training program in Mozambique, but also the first in all Portuguese-speaking (Lusophone) countries in Africa, training upwards of 216 trainees. At the end of the 5- year VM-BMI program, we will have equipped UEM to: (a) lead a fully-fledged BMI-based HIV research portfolio, (b) support a full BMI master’s program, and (c) better address the HIV epidemic in the country.

NIH Research Projects · FY 2026 · 2024-04

PROJECT SUMMARY Dr. Aileen Wright, MD, MS, is an Instructor in the Department of Biomedical Informatics and Department of Medicine at Vanderbilt University Medical Center (VUMC). Her long-term goal is to become an independent physician scientist bridging the gap between artificial intelligence (AI) and healthcare. To this end, Dr. Wright seeks a mentored career development award to develop an AI-assisted clinical decision support (CDS) tool for diabetes care. Hypoglycemia is the most common complication of insulin therapy, and has been associated with increased risk of acute coronary syndrome, stroke, falls, length of stay, and mortality. Due to the severe consequences of hypoglycemia, insulin therapy is on the Institute for Safe Medication Practices’ list of high-risk medications and insulin-induced hypoglycemia has been designated a “never event”. Models to predict hypoglycemia in hospitalized patients have been developed, and could be implemented as CDS tools to improve the safety of insulin therapy. However, published models could benefit from improvements in accuracy. Furthermore, these models have not yet translated to tangible clinical outcomes as they have not been integrated into the electronic health record (EHR). For AI-assisted CDS tools to be effective, they must be developed with clinician input throughout the design process to ensure tools are utilized, fits into the clinician workflow, and reduce clinical workload rather than increasing cognitive burden. CDS which is not accurate and fits poorly into the clinician workflow, can contribute to ‘alert fatigue’, user dissatisfaction with the EHR, and clinician burnout. The objective of this proposed study is to use state-of-the-art machine learning methods and human-centered design processes to develop a high performing AI-assisted CDS tool for preventing hypoglycemia in hospitalized, non-critically ill adults. The specific aims of this proposal are to 1) validate and extend existing inpatient hypoglycemia models, 2) expand feature space and apply deep learning to hypoglycemia prediction, and 3) integrate and prospectively validate prediction models for diabetes care. Dr. Wright is a practicing general internal medicine physician who has completed a fellowship in biomedical informatics. During the award period, Dr. Wright’s research and career objectives include broadening her methodological foundation in machine learning to include deep learning techniques, gaining experience integrating clinical prediction models into the EHR, and forging new collaborations in informatics and clinical medicine. These objectives will be met through a combination of didactic coursework, mentored research, and career development activities. This award will facilitate Dr. Wright’s transition to an independent investigator who develops, implements, and evaluates AI-assisted CDS tools to transform healthcare, preventing harm for patients with diabetes and lifting burdens for clinicians.

NIH Research Projects · FY 2026 · 2024-04

PROJECT SUMMARY/ABSTRACT Childhood adversity (CA) is one of the most potent risk factors for psychopathology across the lifespan, largely due to enduring disruptions in the body’s stress response system. Further, the cascade of molecular and neurobiological transformations following CA distinguishes patients from non-exposed counterparts, spurring a more pernicious course of illness, greater symptom severity, more comorbidities, and less favorable response to treatments. Thus, there is an urgent need to identify transdiagnostic mechanisms of risk. This proposal facilitates the long-term goal of identifying intervention targets, guided by evidence that adolescence is a period of vulnerability to stress that is accentuated by prior CA exposure. To date, investigations of neural, physiologic, and behavioral stress response deficits following CA have been conducted in relatively separate literatures, and the majority of these studies have taken a cumulative risk approach (i.e., “total adversity”) without attention to shared features among certain types of CA. Further, investigations of regulatory processes have generally examined either broad-level dysregulation or honed in on only regulatory strategy (e.g., reappraisal), neglecting to account for the dynamic nature of stress responsivity. This proposal addresses a critical gap in current research by examining a comprehensive set of stress responses, including emotion reactivity, emotion regulation (ER), and ER flexibility, each of which is a malleable target for intervention, spanning multiple units of analyses. Specifically, this study will examine CA characterized by threat (e.g., abuse, witnessing domestic violence), physiologic reactivity across multiple systems (i.e., HPA axis, parasympathetic and sympathetic branches of the autonomic nervous system), and neural activation during an fMRI paradigm that allows for an assessment of initial stress reactivity as well as ER strategy selection, implementation, and flexibility (i.e., evaluation and modification of a strategy based on the stressor/context). The sample will be comprised of 100 adolescents, aged 14-16 with varying levels of threat exposure. In addition to the initial assessment, participants will complete a six-month follow-up to measure prospective psychopathology symptoms, addressing a secondary focus of this proposal linking stress response patterns to internalizing and externalizing pathology. Employing a multi-unit analysis of acute stress responses will facilitate the characterization of precise CA-related decrements in reactivity and regulation that confer psychopathology risk during a crucial developmental period.

NIH Research Projects · FY 2026 · 2024-04

PROJECT SUMMARY/ABSTRACT Cardiac allograft vasculopathy (CAV), a form of chronic rejection, is a leading cause of late graft failure and mortality after heart transplantation (HT). It is characterized by diffuse intimal thickening of the entire coronary tree, including the epicardial coronary arteries and microvasculature. Currently, therapies are initiated after identification of epicardial CAV on coronary angiography. However, they have limited efficacy once epicardial disease is detected. There remain substantial unmet needs in CAV prevention and treatment, due in part to a lack of fundamental understanding of the mechanisms early in CAV pathogenesis. The PI’s long-term career goal is to develop into an independent physician-scientist leading a patient-oriented research program in heart transplant biology. The PI has previously shown feasibility of performing single-nuclear RNA sequencing (snRNA-seq) on endomyocardial biopsies (EMBs) collected routinely during post-HT clinical care. The central hypothesis of this proposal is that unique and dynamic gene regulatory networks define early and progressive CAV. The Specific Aims of the proposed research are (1) To define dynamic cell-specific transcriptional programs in individuals with new and progressive epicardial CAV within the first-year post-transplant; (2) To characterize longitudinal changes in cell-specific chromatin accessibility in individuals with progressive epicardial CAV during the first-year post-transplant; and (3) To identify transcriptional signatures that precede CAV in PBMCs and compare relative expression to myocardial tissue. Identified genes will be highly relevant to clinical CAV, whether serving as biomarkers preceding CAV or influencing progressive disease, and will be prioritized for functional and clinical utility studies in the next phase of the PI’s career (i.e., R01). This work is supported by primary co-mentors, Dr. Jane Freedman and Dr. Ravi Shah, and a multidisciplinary research advisory committee comprising of experts in clinical heart transplantation, RNA sequencing, immunology, bioinformatics, and multi-omics. The PI will leverage the highest-volume heart transplant center in the world over the past three years, Vanderbilt University Medical Center, to accomplish the proposed Aims. During this award, the PI will also complete a Master’s in Clinical Investigation and select courses in immunology, advanced statistics, and machine learning to augment his research experience. Through the studies outlined in this proposal, an exemplary mentorship team, and a well-defined career development plan, the PI will (1) obtain a foundation in patient-oriented translational research, (2) develop state-of-the-art CAV molecular phenotypes, (3) gain expertise in immunology and advanced statistical modeling of high-dimensional data, and (4) refine professional development and scientific communication skills to successfully transition into an independently-funded physician-scientist.

NIH Research Projects · FY 2026 · 2024-04

This proposal aims to explore the metabolic advantages and mechanisms of glucagon-like peptide-1 receptor agonists (GLP-1Ra) in individuals with stage 2 type 1 diabetes (T1DM) undergoing treatment with teplizumab, an immunomodulatory therapy. Stage 2 T1DM represents a critical juncture where interventions could potentially slow β-cell decline, delay the need for exogenous insulin therapy, and improve long-term outcomes. Our study seeks to address current knowledge gaps concerning the role of GLP-1Ra in modifying the disease progression of T1DM. We are particularly interested in understanding how the insulinotropic and glucagonostatic effects of GLP-1Ra can rectify metabolic derangements during this early stage in T1DM. Our study's significance lies in challenging the current treatment paradigm, primarily centered on immunomodulation, by proposing an innovative combination of GLP-1Ra and teplizumab in stage 2 T1DM. The capacity of GLP-1Ra to enhance glucose-dependent insulin secretion and suppress glucagon release could present beneficial metabolic outcomes for T1DM patients, especially when combined with teplizumab. Addressing the current knowledge gaps about this combined therapy could pave the way for the development of more effective and personalized treatment strategies. Our proposal introduces several novel elements in the treatment of early-stage T1DM and the understanding of disease mechanisms. The research explores a new use of GLP-1Ra in early-stage T1DM, repurposing a treatment initially developed for T2DM. By investigating the potential benefits of combining these therapies in a population where their combined effects have not been fully explored, our study contributes to shifting the prevailing paradigm of early-stage T1DM treatment. To achieve our objectives, we have designed a randomized, double-blind, placebo-controlled, mechanistic crossover study. We will quantify postprandial hyperglycemia, disposition index, and nitric-oxide mediated endothelial function during mixed meal tolerance test studies. We will recruit volunteers from Vanderbilt's Type 1 Diabetes Immunotherapy Clinic. The goals of this study will yield novel insights into GLP-1Ra’s insulinotropic and glucagonostatic effects and their individual contributions to improving metabolism outcomes in stage 2 T1DM patients. As a pilot and feasibility study, this research will provide key information and experience for the design of a future, fully-powered study. This includes refining the recruitment process, optimizing the study design, and generating preliminary data to inform the full-study’s data analysis plan. Our findings will help address the Dual Derangements of diminishing insulin secretion and detrimental hyperglucagonemia present in stage 2 T1DM, guiding the development of more effective, personalized treatment strategies. Thus, our research will lay the groundwork for future therapies and significantly contribute to the broader field of T1DM management.

NIH Research Projects · FY 2026 · 2024-04

ABSTRACT Sudden cardiac death (SCD), a major public health problem in the US and worldwide, is often caused by a triggered arrhythmia, such as ventricular tachycardia (VT) evolving into ventricular fibrillation. VT is often preceded and maintained by spontaneous extra beats that do not originate from the sinus node. Those are thought to occur at the cellular level: Under pathologic conditions of excessive Ca load in the intracellular Ca stores (sarcoplasmic reticulum, SR) and/or malfunctioning ryanodine receptors (RyR2), Ca is released from the SR during diastole. This induces a transient inward current (Iti), consisting mainly of Na/Ca exchanger (NCX) current moving Ca out of the cell. Iti depolarizes the cell membrane, generating a delayed afterdepolarization (DAD). If the DAD is large enough to reach the Na channel activation threshold, an ectopic action potential (AP) occurs, which then can propagate and cause a triggered arrhythmia on the tissue level. Such diastolic Ca releases and associated triggered beats are hallmarks of inherited catecholaminergic polymorphic ventricular tachycardia (CPVT) and are also found as an acquired defect after myocardial infarction (MI). Yet, it remains unclear how NCX can generate enough current to trigger an AP in intact tissue, where ventricular myocytes are electrically coupled and thus effectively stabilized by a large current sink. Non-selective large-conductance (200-500 pS) ion channels (LCCs), activated by several mechanisms, including increase in intracellular Ca ([Ca]i) and/or extracellular ATP ([ATP]o), have been previously reported in the plasma membrane of ventricular and atrial cardiomyocytes. The molecular identity of these LCCs remains controversial, with number of candidates being proposed, including RyR, transient receptor potential (TRP), pannexin (Panx) channels, and connexin (Cx43) hemichannels. Our preliminary data from Casq2-/- mice (calsequestrin knock-out model of CPVT) strongly points toward Panx1 channels as the major candidate, although Cx43 hemichannels also may be contributing to LCC activity. Our central hypothesis to be tested in current application is that rapid simultaneous activation of Panx1 in certain pathophysiological conditions may serve as a significant amplifying and/or synchronizing factor for the Iti elicited by spontaneous diastolic Ca release, making AP triggering possible and in this way critically contributing to arrhythmia and SCD. The proposed experiments will investigate if activation of Panx1 by [ATP]o via paracrine signaling pathway increases the incidence of triggered AP in single cardiomyocytes from Casq2-/- and WT mice and in vivo (Aim 1), test if increased Panx1 expression in cardiac Purkinje cells contributes to their arrhythmogenicity (Aim 2) and study the effect of Panx modulation on arrhythmia risk using mouse model of acquired (MI, coronary ligation) triggered arrhythmia pathology. Accomplishing these aims may reveal a new mechanism of arrhythmia triggering in cardiac pathologies associated with diastolic Ca release and provide a new target for their therapeutic treatment.

NIH Research Projects · FY 2026 · 2024-04

Plasminogen (Plg), well-known for its fibrinolytic role in clotting, has emerged as a multi-functional protein that transports lipids and small non-coding RNAs (sRNA) as a lipoprotein-like particle in circulation. Extracellular sRNAs have been demonstrated to be transported by classical lipoproteins and extracellular vesicles; however, a large fraction of extracellular sRNAs are likely carried by currently unknown small lipid-bearing ribonucleoproteins. In preliminary studies, size-exclusion chromatography and lipid-binding agents were used to isolate lipid-based ribonucleoprotein complexes for their identification by mass spectrometry proteomics. Strikingly, Plg was identified and subsequently confirmed as ribonucleoprotein with moderate binding affinity towards single-stranded microRNAs and viral sRNA fragments. Preliminary studies based on sRNA-sequencing demonstrated that the Plg-sRNA profile a) includes both host and non-host sRNAs, b) is distinct from other lipoproteins, and c) is altered in hypercholesterolemia. We also observed that Plg has the capacity to delivery sRNAs to recipient macrophages and potentially facilitate intercellular communication between myeloid cells. Plg treatment of immune cells elicits strong gene expression and cytokine changes, and we hypothesize that Plg regulates macrophage gene expression, functions, and sub-phenotypes through extracellular sRNA transfer and ligand-receptor activation. To test this hypothesis, we aim to define the mechanisms and impact of Plg-sRNA cargo on macrophage phenotype and intercellular communication. We will confirm Plg-sRNA uptake across myeloid cell types and assess selectivity in Plg-sRNA transfer to macrophages. We will define the role of receptor-mediated endocytosis for Plg-sRNA uptake and determine the necessity of Plg/Pla protease activity for sRNA delivery to macrophages. We will assess the roles of known Plg receptors, as well as identify novel Plg- sRNA receptors and binding proteins, for macrophage sRNA uptake and storage. We will assess the impact of sRNA cargo on classic Plg functions, including inflammation through quantifying changes to cytokine gene expression and secretion from recipient macrophages. We aim to establish macrophage mediated Plg-sRNA intercellular communication between myeloid cells. Furthermore, we aim to define the impact of hypercholesterolemia and post-transcriptional modifications (PTxM) on Plg-sRNAs and their regulation of macrophage polarization and functions through ARM-seq, LC-MS/MS, and Nanopore-based direct sRNA- sequencing. Successful completion of these aims and objectives will open an entirely new direction for hematology research and advance the status quo for multiple fields.

NIH Research Projects · FY 2026 · 2024-03

PROJECT SUMMARY/ABSTRACT This application is in response to RFA-AI-22-076 to establish a Clinical Research Center at Vanderbilt University Medical Center for the Consortium of Food Allergy Research. The goal of this application is to establish the infrastructure for a CRC that will then successfully, efficiently, and rigorously conduct both CoFAR-wide clinical studies along with advancing the science and understanding of the food allergy syndrome related to alpha-gal. These goals will be pursued via the following specific aims: Specific Aim 1: Establish infrastructure for the VUMC CoFAR CRC, which is capable of rapidly implementing and executing single site and multi-center clinical trials, with high quality and fidelity, focused on the prevention and management of patients with food allergy, supplemented by studies to better elucidate the mechanisms underlying food allergies and, in particular, alpha-gal syndrome. This CRC will serve as an opportunity for New and Early-Stage Investigators to contribute to these projects and advance their independent research careers. Specific Aim 2: Develop and conduct a consortium-wide, multi-center, non-inferiority clinical trial to evaluate the comparative effectiveness of early peanut introduction with once weekly peanut feeding (low weekly peanut protein dose, 2 gm) versus thrice weekly peanut feedings (standard weekly peanut protein dose, 6 gm) in the prevention of peanut allergy in at risk infants. Specific Aim 3: Based upon the concept that alpha-gal syndrome (AGS) is clinically manifest as a wide spectrum of clinical presentations, we aim to better understand (1) why some patients in tick-endemic areas develop clinically evident AGS after a bite, while others do not, and (2) why the clinical expression of AGS is variable amongst patients and changes over time.

NIH Research Projects · FY 2026 · 2024-03

PROJECT SUMMARY Only 17% of adolescents with type 1 diabetes (T1D) meet the recommended target for hemoglobin A1c, placing them at high risk for acute and long-term complications of T1D. Thus, there is a critical need for novel approaches to improve diabetes management in adolescents with T1D. Insufficient and poor-quality sleep decrease insulin sensitivity, worsen glycemic outcomes and compromise executive function in adolescents, reducing their ability to effectively manage T1D. In other populations, sleep disturbances are linked to reduced brain matter integrity and to novel cerebrospinal fluid glymphatic flow. The glymphatic system is a recently characterized brain-wide interstitial fluid drainage pathway that enables metabolic waste clearance from the brain, particularly during sleep. Glymphatic clearance occurs through a network of perivascular spaces, and dysfunction is associated with cognitive impairment. White matter integrity and perivascular fluid, a marker of glymphatic flow, can be measured through quantitative magnetic resonance imaging (MRI) methods to assess, for the first time, how disordered sleep may impact brain health in adolescents with T1D. Aim 1. Building on our pilot work in this population, we will evaluate the effects of a sleep-promoting intervention for adolescents (age 11-17) with T1D on sleep duration and timing via a randomized controlled trial. Our central hypothesis is that adolescents randomized to the Sleep Coach intervention will exhibit significantly longer sleep duration and reduced sleep variability as compared to those who receive enhanced usual care. Aim 2: We will evaluate the effects of a sleep-promoting intervention on executive function and glycemic outcomes (HbA1c, Time in Range) and diabetes management. Hypotheses: adolescents randomized to the Sleep Coach intervention will demonstrate improved executive function, improved HbA1c and Time in Range and better diabetes management, as assessed by validated measures, compared to those who receive enhanced usual care. Aim 3: We will explore whether brain glymphatic flow, assessed via quantitative diffusion tensor imaging along perivascular spaces with MRI, increases among adolescents with T1D in parallel with increased sleep duration. We will also assess whether adolescents with increased glymphatic flow exhibit improved executive function skills. This exploratory aim will aid in understanding of the mechanisms by which disrupted sleep may impair cognitive function in T1D. Our multidisciplinary team includes a pediatric psychologist, a pediatric neurologist, a pediatric endocrinologist, and a pediatric neuroradiologist, an imaging physicist and a pediatric sleep expert. Our Children’s Diabetes Program serves a large, diverse population of children with T1D with a strong history of clinical research leadership and participation of youth with T1D and their families. This project has the potential to influence standards of clinical care for adolescents with T1D by rigorously studying a behavioral sleep intervention to improve diabetes management and executive function and elucidate mechanisms by which sleep may improve brain health and ultimately T1D outcomes.