Vanderbilt University Medical Center

NIH Research Projects · FY 2026 · 2026-06

Project Summary/Abstract The population of American adults is aging, leading to a growing number of adults experiencing both diabetes and cognitive dysfunction. Diabetes is a recognized risk factor for cognitive dysfunction and for progressing from mild cognitive dysfunction to dementia. Managing diabetes is a cognitively complex endeavor that requires understanding one’s condition, glycemic monitoring, adhering to medication regimens, and maintaining diet and exercise routines. Adults with cognitive dysfunction may struggle to meet these demands. This relationship may be reciprocal, with increased disease severity worsening cognitive dysfunction, which in turn impairs disease management and worsens severity over time. There is an urgent need to develop interventions that (1) integrate evidence-based rehabilitation methods to support diabetes management and (2) are scalable to reach the growing population of adults with diabetes and cognitive dysfunction. This proposal represents the first effort, to our knowledge, to leverage rehabilitation techniques to provide a technology- delivered self-management support intervention for adults with type 2 diabetes and cognitive dysfunction and their support persons. During this K01, the principal investigator (PI) will address these gaps in the extant literature while participating in a mentored training experience that will prepare her as an independent investigator who adapts interventions to the unique needs of people with cognitive dysfunction to support them in managing diabetes. Specific training goals include: (1) deepen content knowledge and experience in clinical diabetes management, (2) develop skills in mixed methods for intervention adaptation, (3) hone expertise in cognitive screening in primary care and community settings, and (4) lead a clinical trial and strengthen responsible conduct of research skills. The proposed research includes two specific aims. Aim 1: The PI will follow the ADAPT-ITT framework to iteratively adapt an existing technology-delivered intervention for adults with cognitive dysfunction based on end user feedback. Aim 2: The PI will conduct a pilot trial to determine feasibility and acceptability of the intervention and study design. Improvements, if needed, will be made prior to proposing a fully-powered clinical trial for a future R01. At the conclusion of this work, the PI will have robust preliminary data on an adapted self-management support intervention for adults with type 2 diabetes and cognitive dysfunction to inform an R01-funded clinical trial. This work is consistent with NIDDK’s strategic goals to (1) leverage technology to make healthcare more feasible and (2) take a precision medicine approach to support health across the lifespan. This K01 will accelerate the PI’s independent research career adapting interventions that incorporate evidence-based rehabilitation techniques with diabetes management and are scalable to support the growing group of adults with type 2 diabetes and cognitive dysfunction.

NIH Research Projects · FY 2026 · 2026-06

PROJECT SUMMARY/ABSTRACT Janus kinase inhibitors (JAK}---including tofacitinib, baricitinib, and upadacitinib-have emerged as promising oral treatment options for patients with rheumatoid arthritis who experience an inadequate response to conventional therapies. However, major safety concerns, including increased risk of cardiovascular events, venous thromboembolism, and serious infections, have prompted FDA black box warnings and remain major barriers to widespread use. These safety concerns largely stem from potential signals in integrated analyses of premarketing studies and the ORAL Surveillance trial, which reported a dose-dependent elevated risk of cardiovascular and thromboembolic events with tofacitinib compared to tumor necrosis factor (TNF) inhibitors. However, the ORAL trial has left some critical questions unanswered-specifically, whether the observed risk elevation is attributable to a specific JAK inhibitor toxicity, a protective effect of TNF inhibitors, or both; or how the safety profile of specific JAK inhibitors may compare to approved alternatives, such as interleukin-6 inhibitors. Approved JAK inhibitors have differences in selectivity and target binding affinity, which may translate into differences in adverse health outcomes. As a pan-JAK inhibitor, tofacitinib targets multiple JAK isoforms (JAK1, JAK2, JAK3), while newer agents such as upadacitinib and baricitinib exhibit greater selectivity for JAK1. The current FDA black box warning applies to all JAK inhibitor class members, but comparisons among specific class members are lacking. Moreover, all currenUy approved JAK inhibitors are metabolized via cytochrome P450 3A4 (CYP3A4), making them susceptible to clinically significant drug-drug interactions {DDls). Co-administration with moderate or strong CYP3A4 inhibitors, such as diltiazem, can substantially increase plasma JAK inhibitor concentrations, and potentially increasing the risk of adverse events. In this R01, we propose a comprehensive examination of the safety of JAK inhibitors among patients with rheumatoid arthritis. We will use the estimand framework and target trial emulation methods to compare cardiovascular, thrombotic, and infectious risks between JAK inhibitors and other commonly used therapies, overall and by agent. We will also evaluate how co-prescribed CYP3A4 inhibitors modify these risks. Our findings will directly inform clinical guidelines and prescribing decisions for patients with rheumatoid arthritis.

NIH Research Projects · FY 2026 · 2026-06

PROJECT SUMMARY/ABSTRACT There is a growing population of Medicare beneficiaries who are enrolled in Medicare Advantage (MA), an increasingly popular alternative to Traditional Medicare (TM) that administers Medicare benefits through private health plans. There are differences in benefit design between MA and TM, which create trade-offs in access to vs. affordability of cancer care. On the one hand, MA plans emphasize lower costs and provides supplemental benefits not covered in TM but employ utilization restrictions and selective networks to steer beneficiaries away from costly care. In particular, MA plans form selective provider networks that avoid larger, advanced cancer treatment facilities, such as NCI-designated cancer centers, that perform more complex and costly care. Such a risk-selection strategy can be used as a tool to avoid high-risk cancer patients. In comparison, TM imposes minimal restrictions on care but high cost-sharing, which may increase the financial burden of accessing care, especially for those without supplemental Medicare coverage. These trade-offs are consequential for patients with cancer, who experience pronounced care needs, but their impacts on cancer care delivery remain understudied. This early K99/R00 application proposes a comprehensive, mixed-methods study of cancer care quality in MA and TM, with a goal to establish Dr. Youngmin Kwon, PhD, as an expert investigator of MA policies and population-level cancer control in public insurance programs. Proposed training in MA encounter data, qualitative research methods, and clinical expertise in cancer care delivery will contribute to a successful execution of the study and support Dr Kwon’s transition to an independent investigator role. The K99 phase will leverage the Surveillance, Epidemiology, and End Results Program (SEER) cancer registries-linked Medicare data to assess acute care use (an outcome of poor care management) and specific cancer care process measures between aged MA and TM beneficiaries newly diagnosed with cancer (Aim 1). The aim will implement difference-in-differences and propensity-score weighted models to rigorously examine differences in acute care use and receipt of high-quality cancer care while controlling for predictors of plan selection. The R00 phase will focus on the role of selective MA networks (a critical feature of MA benefit design) and will encompass qualitative and quantitative components. Aim 2 will elicit the drivers of exclusion of NCI-designated cancer centers in MA networks through structured interviews of stakeholders at cancer centers and MA plans, which will identify challenges in ensuring adequate MA networks for cancer care delivery. This work will also inform Aim 3, which will formally quantify the impacts of MA networks on plan switching and cancer care quality by exploiting a significant drop in MA plans by health systems as an exogenous shock to plan networks. Together, these aims will provide novel evidence about the effects of MA coverage and plan networks on cancer care delivery, thereby informing proposals to reform the Medicare program and modifications to MA networks that can optimize cancer care delivery.

NIH Research Projects · FY 2026 · 2026-06

PROJECT SUMMARY In this multi-site study, we will develop and validate the Communicating Needs with Care Partners (CONNECT) scale, which assess recovery of basic communication, a highly valued, but rarely measured milestone of severe brain injury recovery. Severe brain injury affects more than one million people worldwide each year. The most common cause of in-hospital deaths is withdrawal of life-sustaining treatment due to poor prognosis. There are no treatments proven to accelerate recovery from acute brain injury and no prognostic tools that can accurately predict outcome at the individual patient level. One factor contributing to these gaps is the imprecision of brain injury outcome assessment tools which rely on broad categories of global function to determine whether recovery is “favorable” or “unfavorable”. Multiple studies by our group and others indicate that the ability to communicate is a meaningful and desired outcome for persons with brain injury and their caregivers. Communication restores autonomy and provides a neuroanatomically-based target for intervention. Yet, there are no robust measures of communication that are designed for persons with brain injury. We developed a prototype of CONNECT and propose to finalize its content, assess its validity and reliability, and evaluate its Rasch measurement properties. CONNECT is administered to care partners as a structured interview that can be completed remotely. Assessment ranges from attempt to communicate at the floor to accurate expression of basic needs at the ceiling. First, we will work with clinicians, investigators, persons with brain injury, and care partners to finalize CONNECT items, establish content and face validity, and develop an administration and scoring guide. Then we will assess CONNECT’s concurrent validity, predictive validity, inter- rater reliability, test-retest reliability, and care partner variability in patients with brain injury enrolled at two acute care hospitals. We will use Rasch analyses to determine whether CONNECT is monotonic (i.e., rating scale options occur sequentially), hierarchical (i.e., items are arranged along a gradient of increasing difficulty), and unidimensional (i.e., items reflect the same underlying latent trait, recovery of communication). This study leverages an interdisciplinary team of neuroscientists, rehabilitation measurement experts, occupational therapists, and speech language pathology specialists, with expertise and experience in developing diagnostic and prognostic tools for patients with severe brain injury. CONNECT has the potential to accelerate treatment discovery, detect functional improvement and decline that would otherwise go undetected, and contribute to the development of precise prognostic models that inform decisions about withdrawing life- sustaining treatment after brain injury.

NIH Research Projects · FY 2026 · 2026-06

Adults diagnosed with colorectal cancer before the age of 50 years (early-onset CRC) are treated with a greater volume of cancer therapies compared to older-age patients with similar tumor features, which could damage reproductive organs and lead to infertility. Although this is a resounding concern for patients of reproductive age, at present there are no prospective data for us to understand whether modifiable behaviors-such as physical activity-can improve fertility after CRC. Given the unexplained rise in early-onset CRC incidence over the last decades, such evidence is now critical to guide clinical care management and surveillance for young CRC patients. Therefore, our proposal is designed to address this unmet, growing care need and achieve its overarching goal: to characterize the link between fertility and energy balance among young patients after CRC. To do so, we will utilize the Preserving Fertility After Colorectal Cancer (PREFACE) Study cohort that is actively enrolling 220 patients between ages 18 and 49 years who have been newlydiagnosed with CRC at Vanderbilt-Ingram Cancer Center. To characterize the potential contributions of physical activity and sedentary behavior on fertility across the CRC care continuum (Aim 1 ), we will prospectively collect physical activity, sedentary behavior and reproductive health validated questionnaires as well as capture one-week of accelerometry-assessed physical activity; at diagnosis, treatment and surveillance study timepoints. This will define whether and how patterns of frequency, duration, bouts, intensity and type of physical activity as well as sedentary behaviors change over time, and will also inform the highest physical activity concerns and needs-specific to reproductive age CRC patients along their cancer care journeys. We will then use fasting blood samples that are collected in parallel from patients at all three, uniform study timepoints to measure 39 circulating inflammatory and immune biomarkers (e.g., CRP, FGF, IL-1~, IL-6/8/10, IL-15, MCP-1/4, PIGF, SAA, TNF-am, VEGF-A/C/D) via validated multiplex assays. These biomarker levels, together with paired blood-based measurements for hormonal markers from our FDA-approved clinical immunoassays (for AMH, estradiol, FSH, SHBG, LH, DHEAS, inhibin B, testosterone, androstenedione, and DHT) and detailed clinical/treatment data, will be analyzed to investigate associations of gonadal function and energy balance in young CRC patients over time (Aim 2). Overall, this cost-efficient proposal augments existing PREFACE Study infrastructure to generate new data that is statistically-powered to inform clinical management guidelines on fertility and physical activity in early-onset CRC and, ultimately, to improve patient care and outcomes. Our findings may also lead to physical activity intervention studies for the design of effective, acceptable exercise prescriptions toward improving fertility after CRC in patients of reproductive age.

NIH Research Projects · FY 2026 · 2026-06

PROJECT SUMMARY The Vanderbilt Postdoctoral Education in Discovery and Systems Science (VPEDS) T32 Program is a new postdoctoral training program in child health research at Vanderbilt University Medical Center (VUMC). The VPEDS mission is to provide postdoctoral child health scientists with an immersive, interdisciplinary training experience in T3/T4 translational child health research within VUMC’s Learning Healthcare Systems research ecosystem. VUMC has invested deeply in establishing LHS infrastructure, and the VPEDS Program meaningfully extends the reach and impact of these investments by being the institution’s first program devoted to the development of LHS-enabled child health researchers. The program’s aspirational vision, training tomorrow’s child health scientists so all children may thrive, centers the mission on expanding discovery and accelerating innovation to improve health trajectories and lifelong opportunities for all children. The VPEDS Program accepts 2-3 new trainees annually for a 2-year, personalized, competency-based training experience that is nurtured by a vibrant community of mentors centered within VUMC’s Department of Pediatrics and interdisciplinary LHS partners from across the institution. To ensure alignment with the mission of NICHD, trainee-led research is conducted within one or more scientific priority areas outlined in the NICHD Strategic Plan 2025. All trainees receive mentorship from senior child health researchers in one or more of these areas along with institutional partners with T3/T4 methods expertise (pragmatic clinical trials, health policy, biostatistics, data science, implementation science). Trainees receive targeted career development in rigorous translational methods, core LHS principles, grant writing, and scientific communication. To maximize reach and impact of the training experience, trainees leverage institutional supports available through the Vanderbilt Institute for Clinical and Translational Research and the Centers for Health Services Research, Learning Healthcare, and Research and Innovation in Systems Safety, among others, as well as external partnerships locally (Meharry-Vanderbilt Alliance, The Nashville Collaborative, Tennessee Child Health Poll) and nationally (PCORNet Patient-Centered Clinical Research Network, Continuity Research Network [CORNET], Pediatric Research in Inpatient Systems [PRIS], and Children’s Hospital Association). The program is headed by senior child health researchers and experienced mentors and is further supported by devoted Steering and Advisory Committees, an exceptional cadre of child health researchers, systems scientists, and operational leaders; a mentor pipeline program; and sought-after clinical and academic programs amid superb research and training environments within the Department of Pediatrics and institutionally at VUMC.

NIH Research Projects · FY 2026 · 2026-06

Project Summary: Metabolic dysfunction-associated steatohepatitis (MASH), an advanced form of metabolic dysfunction-associated steatotic liver disease (MASLD), is a silent disease with little to no symptoms but is common in individuals who are overweight, diabetic, or genetically predisposed. The onset of fibrosis in MASH represents a critical inflection point in disease severity that progresses to portal hypertension, cirrhosis, liver failure and hepatocellular carcinoma. Liver transplantation remains the only treatment for cirrhosis. Liver fibrosis is the result of several integrated signaling networks that regulate the deposition of extracellular matrix, primarily collagens and fibronectin. The cascade of responses in hepatic stellate cells (HSCs) drives the activation and transition or normally quiescent HSCs into a myofibroblast-like phenotype that is contractile, proliferative and fibrogenic. In an effort to define the transcriptional networks underlying HSC activation in humans we applied genome-scale enhancer mapping (CUT&RUN) and bulk RNA- sequencing to an existing repository of human MASLD liver tissues with pathology ranging from normal to advanced fibrosis. This analysis nominated 125 candidate transcription factors (TFs) as potential regulators of collagen production. We employed a CRISPR screen in HSCs to test whether these TFs regulate collagen production using high content imaging readouts. We identified ZNF469 (Zfp469 in mice) as a modulator of collagen production in human HSCs. Both CRISPR and siRNA loss-of-function studies in human and mouse HSCs established the zinc finger domains in ZNF469 as critical for regulating collagen mRNA. Chromatin profiling revealed direct binding of ZNF469 at collagen gene bodies. In multiple mouse models of MASH Zfp469 expression was upregulated. Furthermore, ZNF469 expression correlated strongly with collagen expression in human livers with MASH. Our central hypothesis is that ZNF469 functions as a TF that positively regulates fibrosis in human liver through direct gene regulation of collagen in HSCs. To test this hypothesis we will pursue two Specific Aims: 1) determine the role of ZNF469 regulation of HSC activation in vitro; and 2) elucidate the HSC-specific role of Zfp469 in mediating fibrosis in experimental models of MASH. This project has the potential to establish ZNF469 as a novel transcriptional regulator of liver fibrosis with potential for therapeutic translation.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY / ABSTRACT Type 1 diabetes (T1D) is caused by T-cell mediated destruction of insulin-producing pancreatic beta cells. While notable progress has been made in predicting and delaying onset of T1D, our limited understanding of the factors that initiate and maintain this autoimmune attack continue to act as a major barrier to further progress. Increasing evidence points to the pancreas itself, including endocrine cells, exocrine cells, and the extracellular matrix, as possible contributors to the pathogenic immune activation. One factor that is known to contribute to immune cell activation, and that is altered in other pancreatic disease including cancer, is protein N-glycosylation, wherein complex carbohydrate chains called glycans are enzymatically attached to specific asparagine (called N-glycans) residues as proteins transit the endoplasmic reticulum and golgi complex. Glycosylation patterns influence protein stability, localization, and receptor binding, which can dramatically alter cell function and intercellular communication. Though the pancreatic glycome has been studied in pancreatic cancer, very little is known about how the glycome changes in diabetes pathogenesis, partially owing to the relative scarcity of appropriate human tissues to study and to the complexity of analysis methods required to measure protein glycosylation. While single cell transcriptomic data shows that expression of many of the enzymes involved in glycosylation are altered in T1D, it remains unknown how the pancreatic glycome changes during T1D pathogenesis, and whether altered glycosylation contributes to changes in pancreatic structure, cell composition, or immune cell infiltration. I hypothesize that N-glycosylation in the pancreas is altered as type 1 diabetes progresses, contributing to changes in immune cell localization and phenotype. I will employ two state-of-the-art imaging technologies to test this hypothesis in pancreas tissues from donors without diabetes, with positive auto-antibodies, or with recent-onset or long-standing T1D: 1) Imaging mass spectrometry will allow comprehensive quantitation of different N-glycans across entire tissue sections and at single-cell resolution, and 2) Multiplex immunofluorescence microscopy (CODEX) will be used to define pancreatic regions of interest and to quantify cell types and subtypes across the same tissue section. In Aim 1, I will test the hypothesis that the pancreatic N-glycome quantitatively changes throughout T1D progression. In Aim 2, I will test the hypothesis that regions of altered N-glycome signature are associated with changes in cellular composition and immune cell phenotypes. Completion of these aims will identify high level changes to post-translational protein processing signatures as T1D progresses. These results will lay the groundwork for future studies into mechanisms responsible for glycomic changes, identification of specific proteins that are affected, and definition of novel glycoprotein signatures that may be promising biomarkers or drug targets.

NIH Research Projects · FY 2026 · 2026-05

Project Summary / Abstract With effects on multiple cellular mechanisms of aging – including systemic inflammation, cellular senescence, and DNA damage – HIV infection is a recognized biological model of age acceleration. Indeed, people living with HIV (PWH) experience higher risk and earlier onset of a number of aging-related conditions, including cardiovascular disease, frailty, and cognitive and physical function decline. Addressing the excess burden of comorbidities, including geriatric syndromes, experienced by PWH is an NIH and public health priority. Objective measures of accelerated aging are urgently needed for mechanistic, clinical, and interventional investigations to improve aging-related outcomes of PWH. Epigenetic age acceleration (EAA) has been proposed as one such measure, which is based on calculating differences between chronological age versus biological age predicted from DNA methylation patterns. Previous studies have shown, using whole-blood samples, that the epigenomes of PWH on antiretroviral therapy look 5 years older than expected based on their chronological age. Expansion of the use of EAA into studies of aging biology and interventions has been limited due to the high cost of the assay and our incomplete understanding of differences in EAA among cell types, including immune cell types most affected by HIV infection. The overall objective of this study is to examine differences in EAA across immunologic cell profiles in people with and without HIV. Using cryopreserved PBMC samples and existing detailed cellular and clinical outcome data of younger (n=35; 30-39 years) and older (n=105; ≥50 years) individuals with and without HIV, Aim 1 of the study will examine whether bulk-PBMC EAA measures predict changes in clinical (frailty, cognitive performance, comorbidity) and immunologic aging profiles (CD4 and CD8 subpopulation measures of activation, senescence, and exhaustion) in people with and without HIV using a novel, cost-effective DNA methylation assay. Aim 2 will examine effects of HIV infection and aging on EAA measures of sorted immune cell populations, namely naïve and memory T cell subsets, B cells, monocytes, and NK cells. Our overarching hypothesis is that HIV infection will be associated with increased and more varied EAA among immune cell populations and that measures of EAA will predict accelerated measures of adaptive immune senescence. Results of this study will provide critical evaluation of epigenetic clock performance in PWH and will provide novel insights in the cellular populations driving accelerated aging outcomes in this population. Led by a multidisciplinary team of experts in clinical epidemiology of HIV and aging, evolutionary biology and genomic science, and the immunology of HIV, our team will leverage powerful genomic, HIV, immunologic institutional research resources for the efficient and successful execution of this 2-year, innovative R21 study of epigenetic age acceleration, immunology, and HIV.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY Sepsis, the systemic inflammatory response of a host to a pathogen, is a leading cause of death in modern intensive care units. It induces significant vascular dysfunction that manifests as altered vascular tone, leading to hypotension and capillary leak, leading to edema and acute respiratory distress syndrome. Therapies that target vascular pathophysiology in sepsis are lacking, and clinical care remains primarily supportive. We have found that leucine-rich repeat containing 8 A (LRRC8A), the required isoform for all volume-regulated anion channels (VRACs), significantly modulates both the endothelial cell (EC) and vascular smooth muscle cell (VSMC) response to multiple acute inflammatory challenges. Our data demonstrate that LRRC8A, in partnership with another specific isoform, LRRC8C, functions as both regulators of superoxide (O2-•) production by NADPH oxidases (NOXes), and a portal for O2-• influx. Movement of O2-• into the cytoplasm sets off a series of intracellular redox signals that enhance vascular contraction, impair relaxation, reduce endothelial barrier function, and cause significant alterations in metabolism. Mice with VSMC-specific knockout of LRRC8A have preserved vascular reactivity and LRRC8A knockdown EC cells have reduced permeability in response to inflammatory challenges. Importantly, our data also suggests that FDA-approved LRRC8 inhibitors administered after infectious challenge can reduce EC inflammation, indicating LRRC8 blockade may serve as a post-infectious rescue. In this proposal, we will test the central hypothesis that LRRC8A/C channels regulate vascular inflammation during infectious challenge. O2-• influx alters Rho GTPase-mediated regulation of the cytoskeleton, leading to impaired metabolism and altered cellular contractility. Further, we hypothesize that blocking LRRC8 channels with known FDA-approved pharmaceuticals after the onset of sepsis can improve vascular function and outcomes. Aim #1. Influx of O2-• controls VSMC and EC cytoskeletal function via LRRC8-dependent signaling. We will define mechanisms by which NOX/LRRC8/O2-• drives inflammation-induced changes in VSMC vascular contractility and EC barrier function via a multi-protein complex that controls small GTPases. We will further assess how O2-• bioavailability affects the composition and function of this complex, alters inflammatory signaling, and regulates the cytoskeleton. Aim #2. O2-• influx alters metabolism to promote inflammation-induced vascular dysfunction. The impact of O2-• on inflammation-induced changes in metabolism (Seahorse, 13C-labelling) will be correlated with vasomotor and barrier function (wire myography, transendothelial resistance). Aim #3. Impaired vascular function in sepsis is abrogated by reduced LRRC8-dependent signaling. Vasculopathy, as examined by wire myography and indices of capillary permeability, will be assessed in murine models of sepsis to determine if genetic or pharmacological impairment of LRRC8 channels improves outcomes. These integrated aims will increase our understanding of fundamental mechanisms that cause infection-mediated vascular dysfunction and assess the potential of targeting LRRC8 channels for the treatment of patients with sepsis.

NIH Research Projects · FY 2026 · 2026-05

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease affecting ~1–4% of the population, characterized by inflamed nodules, abscesses, and pus-discharging tunnels in the axillary, inguinal, gluteal, and perianal regions. HS profoundly impairs quality of life and is associated with systemic comorbidities such as metabolic syndrome, type 2 diabetes, cardiovascular disease, inflammatory arthritis, inflammatory bowel disease, and depression. Despite its impact, the pathogenesis of HS remains poorly understood, limiting effective treatment options. HS has a strong genetic basis, with heritability estimates as high as 80%. Recent GWAS and meta-analyses have identified KLF5 and SOX9 as risk factors. While their causal roles remain unclear, both genes are closely linked to hair follicle biology, underscoring the central role of this structure in disease. The goal of this proposal is to define the causal roles of HS-associated genes in pathogenesis. Our single- cell RNA-sequence data show increased KLF5 and SOX9 expression in keratinocytes (KCs) from HS lesional skin, with immunohistochemistry confirming higher protein levels in affected hair follicles and tunnels. Whether these increases directly contribute to disease is unknown, a fundamental gap this project aims to address. We will use mouse molecular genetics, lentiviral delivery, human KC bioassays, and RNA sequencing to test the hypothesis that synchronized upregulation of KLF5 and SOX9 in hair follicle KCs drives structural changes that recruit immune cells and sustain HS pathogenesis. Successful completion of this project will advance understanding of how coordinated KLF5 and SOX9 expression in KCs modulates hair follicle biology and promotes inflammation. It may also establish a new preclinical model of HS, enabling exploration of disease pathogenesis, host-microbe interactions, genetic drivers, and novel therapeutic targets.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY/ABSTRACT Children and adults in the US are increasingly seeking treatment in Emergency Departments (EDs) for suicide ideation (SI) and suicide attempt (SA), and suicide is a leading cause of death across age groups. The ED setting has become a critical point of intervention to prevent suicide in the US. In spite of this demonstrated need, most EDs lack resources to address suicide risk, and there is an urgent need to identify strategies to improve evidence-based care for the high-risk and vulnerable individuals who seek ED care due to suicidal ideation or suicide attempt. There is increasing interest in the use of technology to address provider shortages and related gaps in care. Tele-mental health, hereafter “telehealth,” relies on technologies including video- and audio-conferencing with remote clinicians and use of shared electronic health records to improve access to remote mental health specialists. To date, little is known about how EDs use telehealth, and specifically how telehealth services integrate suicide prevention practices for patients at high risk of suicide. The objectives of this project are to gain a comprehensive picture of whether telehealth increases access to treatment and improves treatment outcomes, to understand which patients benefit most from telehealth and which elements of telehealth are most beneficial, and to gather information relevant to understanding the mechanisms by which telehealth influences outcomes. The study team will link data from a previous NIMH-supported survey about EDs’ use of telehealth with health care claims from national samples of individuals insured by Medicaid and Optum private payers to examine relationships between patient receipt of care via telehealth and patient outcomes of post-ED visit connection to follow-up mental health care within 30 days and ED or hospital revisit within 90 days. The team will conduct semi-structured interviews with a subset of ED leaders, clinicians, and mental health consumer advocates around the country to understand facilitators and barriers to telehealth implementation within EDs and mechanisms by which telehealth influences patient outcomes.

NIH Research Projects · FY 2026 · 2026-05

Transforming growth factor (TGF)-β promotes inflammatory and fibrotic responses via activation of the serine/threonine kinase receptor TβRII and consequent activation of SMAD3. In the kidney, TGF-β is activated in acute kidney injury (AKI) and is associated with proximal tubule epithelial cell (PTEC) responses that lead to the development of and progression to chronic kidney disease (CKD). To this end, PTECs produce inflammatory cytokines, extracellular matrix, and stimulate differentiation of fibroblasts into myofibroblasts, the major producers of extracellular matrix and drivers of fibrosis. Although a role for TGF-β in AKI and CKD has been established, anti-TGF-β therapy has not yet translated into successful treatment in CKD patients. A possible explanation is that TβRII can be activated in a ligand-independent manner which potentiates low dose TGF-β signaling. We showed that the cytoplasmic tail of TβRII contains several tyrosines which can be phosphorylated in a TGF-β independent manner, leading to SMAD3 activation and fibrotic responses in kidney cells. We found that the tyrosine kinase EPH receptor B2 (EphB2) forms a complex with and phosphorylates TβRII. EphB2 is expressed by PTECs and it contributes to organ injury by promoting inflammation and fibrosis. However, the contribution of EphB2 to AKI-to-CKD progression and the cells responsible for its deleterious effects have not been investigated. Using a model of AKI that progresses to CKD, we show that pYEphB2 and pYTβRII are evident in the acute and chronic phases of kidney injury. Ephrin B1-mediated activation of EphB2 leads to pYTβRII and enhances TGF- β-induced SMAD3 activation and epithelial-to-mesenchymal transition. Mice treated with a novel EphB2 inhibitor showed reduced tubular injury, inflammation, collagen production as well as pYEphB2 and pYTβRII following ischemia/reperfusion-induced AKI. Interestingly, we found that macrophage inhibitor factor (MIF), a cytokine that contributes to inflammation following kidney injury, is produced by PTECs when stimulated with Ephrin B1, but not TGF-β. Thus, there is a canonical EphrinB1/EphB2 as well as a non-canonical EphrinB1/EphB2/TGF-β axis in PTECs that can contribute to inflammation and fibrosis in AKI and its progression to CKD. We hypothesize that EphB2 expressed by PTECs contributes to inflammation and fibrosis following AKI and its progression to CKD by inducing the secretion of MIF and by potentiating TGF-β signaling via phosphorylation of TβRII. In this grant, we will: Determine the contribution of PTECs in EphB2-induced kidney inflammation and fibrosis (Aim 1). Determine the mechanisms whereby EphB2 contributes to inflammation and fibrosis (Aim 2). Determine whether the EphB2 small molecular weight inhibitor is beneficial in AKI and its progression to CKD (Aim 3). This study will identify a novel mechanism whereby EphB2 and TβRII interact; how EphB2/TβRII-mediated fibrotic signaling can be modulated in kidney disease; and devise new therapeutic interventions aimed to prevent EphB2 activation and function in kidney disease.

NIH Research Projects · FY 2026 · 2026-05

Title: Bacterial membrane fusion sustains commensal resilience during enteric pathogen infection Project Summary: The trillions of commensal microbes in the human gut, collectively known as the microbiota, play a pivotal role in host health by regulating immunity and defense against pathogens. Perturbations such as enteric infections can trigger severe intestinal inflammation, which destabilizes the microbial ecosystem and drives it towards dysbiosis, a state linked to disease exacerbation. Commensal resilience, or the ability of beneficial microbes to withstand or recover from such perturbations, is therefore essential for sustaining gut homeostasis and overall health. Yet, the molecular mechanisms underlying this resilience remain poorly understood. One critical challenge that arises during infection is the activation of a host process known as nutritional immunity, which restricts microbial access to essential metals like iron and poses a significant threat to commensal survival. While the enteric pathogen Salmonella Typhimurium (S. Tm) overcomes iron limitation by producing high-affinity iron chelators, or siderophores, how commensals such as Bacteroides vulgatus adapt to iron limitation remains largely unknown. Our preliminary findings reveal that B. vulgatus does not utilize free or protein-bound siderophores; instead, it depends on outer membrane vesicle (OMV) fusion to access siderophores produced by S. Tm, a mechanism distinct from classical siderophore uptake. Using genome-wide forward genetics, we identified key determinants of OMV fusion, notably enzymes involved in peptidoglycan remodeling. Our data show that cell wall remodeling is essential for OMV-bacterial membrane fusion, and that mutants defective in this process display impaired iron acquisition. Building on these strong preliminary data, this proposal aims to define how OMV fusion orchestrates commensal iron acquisition and resilience in the inflamed gut. Specific Aim 1 will determine how OMV fusion facilitates iron uptake and supports B. vulgatus fitness during gut inflammation, using reductionist in vitro systems and murine models of infectious colitis. Specific Aim 2 will elucidate the molecular and structural basis of OMV fusion, focusing on the contribution of peptidoglycan remodeling. This work is innovative because it leverages a unique bacterial behavior and integrates high-throughput genetic screens, live-cell imaging, and high-resolution cryo-electron tomography to provide a mechanistic understanding of OMV-mediated nutrient acquisition in commensal bacteria. While membrane fusion is a well-established process in eukaryotes, its mechanisms and physiological significance in prokaryotes remain almost entirely unexplored. The impact of this research lies in uncovering peptidoglycan remodeling as a critical component of membrane fusion and commensal resilience during gut inflammation, presenting a new frontier in microbial physiology. Ultimately, this work has the potential to transform our understanding of how beneficial microbes survive and adapt within the inflamed intestine, laying the groundwork for rational interventions to bolster the gut microbiota in patients with inflammatory disease.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY/ABSTRACT There are growing concerns with the increased use of metformin during pregnancy beyond the treatment of maternal diabetes, given the evidence of reduced offspring birth weight and increased risk for childhood adiposity, insulin resistance, and hyperglycemia. Exposure to maternal metformin (mMET) may directly affect developing fetal cells and tissues since metformin accumulates in maternal and fetal blood at similar concentrations, and fetal tissues, including pancreatic islets, express metformin transporters. Using a clinically relevant non-human primate model, we have found that islets from fetuses exposed to mMET have reduced insulin content and alterations in mitochondrial oxygen consumption and that exposure to maternal Western style diet (WSD) results in inappropriate insulin hypersecretion and increased mitochrondrial fragmentation. The overall objective of this proposal is to determine whether mMET, with or without maternal WSD consumption, disrupts offspring islet development, metabolism, and function to potentially increase offspring diabetes risk later in life. We will use a highly translational Rhesus macaque model whereby pregnant females receive metformin at a clinically relevant dose and are fed either a control (healthy) or WSD to mimic dietary differences present in pregnant women using metformin. Our approach will identify developmental effects of mMET, with and without WSD, on offspring islet beta-cell mitochondrial health and function, gene regulation and expression, cell identity and metabolism, and insulin secretion. These studies leverage detailed maternal-offspring phenotyping and biological samples collected through the parent R01 (DK128187). Our primary hypothesis is that metformin exposure reduces oxidative metabolism in developing tissues, and alters developmental programming, independent of maternal diet., leading to defects in offspring beta-cell maturity and function. In Aim 1, we will determine the functional impact of mMET on offspring pancreatic islets, examining mitochondrial health and fuel utilization and glucose-stimulated insulin secretion. In Aim 2, we will determine the impact of mMET on beta-cell morphology, identity, and maturity. In Aim 3, we will characterize mMET-dependent transcriptional and metabolic responses that potentially impact offspring beta-cell function. Our results will determine the impact of mMET on offspring islet function and metabolism and identify mechanisms of action within islets and beta cells. In contrast to the potential beneficial effects of metformin in the mother, we expect that mMET exposure will disrupt offspring islet oxidative metabolism and affect developmental programming leading to persistent changes in beta-cell gene regulation, metabolism, and function, leading to deleterious effects in the offspring. These results will inform clinical practice on the benefits and risks of maternal metformin use for mothers and offspring.

NIH Research Projects · FY 2026 · 2026-05

Abstract /Summary: Malignant pleural effusion (MPE) affects 200,000 individuals in the United States annually and lung cancer is the most common cancer to metastasize to the pleura. Unfortunately, cytologic examination of the pleural fluid (PF) obtained during thoracentesis only has a diagnostic sensitivity of ~50% with marginal increase upon serial sampling and limited by the need to detect malignant cells which are sparse in the PF. More invasive procedures such as thoracoscopic pleural biopsy are often required, but these procedures are associated with potential complications, hospital stay and delayed diagnosis and treatment. There is an urgent need to develop novel approaches to complement PF cytology. To address this need, we examined the potential of tumor cell products, specifically extracellular vesicles (EVs) and non-vesicular particles, for MPE diagnosis. In previous studies, we have detected and characterized EVs in PF and have identified and validated distinct EV microRNA (miRNA) signatures discriminating cytology-positive (C+) lung adenocarcinoma induced MPE (LA-MPE) from non-malignant pleural effusion (non-MPE). Additionally, because epithelial-derived surface markers are not native in the pleural space, we analyzed the expression of epithelial cell adhesion molecule (EpCAM), in cell- free PF of LA-MPE to identify tumor-derived EVs. We showed significantly higher EpCAM expression in (C+) LA-MPE compared to non-MPE. An essential next step is the evaluation of extracellular miRNA and proteins within the cytology-negative (C-) MPE populations, where current tests fail or are highly invasive. To Accomplish this goal, we will leverage samples from a diverse PF biorepository (current n=313) including (C+) and (C-) MPE and non-MPE with 35% African/Black participants and detailed tumor-specific and clinical data. Specific Aims will: 1) identify differentially expressed extracellular miRNA among patients with (C-) LA-MPE and non-MPE and validate the identified miRNA signature in an independent validation cohort, 2) identify differentially expressed extracellular proteins (particularly epithelial-derived proteins) among patients with (C-) LA-MPE and non-MPE. In addition, we will identify protein expression in (C+) and (C-) MPE due to breast cancer and compare protein expression among groups. We will evaluate the combined discriminating role of protein and miRNA expression among (C-) LA-MPE and non-MPE. Development of a diagnostic classifier, using a cell-free biofluid enriched with tumor-cell products that requires drainage and is underutilized is paradigm shifting and a crucial missing step in our MPE management which will be addressed through our proposal. Most biomarkers to date are examined in (C+) MPEs of heterogeneous populations and lack reproducibility or confirmation in (C-) MPE groups. We aim to close this gap and focus on (C-) LA-MPE populations where our findings could be clinically relevant and practice changing. This work will lead to an R01- level grant focusing on PF tumor-derived EVs and EV cargo in diagnosis, disease monitoring and prognosis of metastatic cancers of varying tissue type to the pleura.

NIH Research Projects · FY 2026 · 2026-05

ABSTRACT Late-life depression (LLD) is a heterogeneous neuropsychiatric disorder that can take a chronic and recurrent course. Executive dysfunction (i.e., difficulties with complex mental tasks and planning) is prominent in recurrent LLD, persists despite remission of depressive symptoms, and corresponds with increased risk of cognitive decline and transition to dementia. Past work demonstrates executive function deficits are related to changes in the underlying structure and function of the brain’s executive control network (ECN). Combining targeted cognitive-enhancing interventions aimed at promoting neuroplasticity may strengthen the underlying ECN, thereby improving executive function performance. Multi-modal approaches using cognitive training and non- invasive neuromodulation (i.e., transcranial direct current stimulation; tDCS) support cognitive benefits in older adults. However, previous research used more general executive function-based cognitive training, while the current study proposes a targeted cognitive training (TCT) intervention that was created to specifically address executive function deficits found in LLD. Combining this with tDCS applied to the frontal lobes may help to maximally engage and benefit executive function-based cognitive and neural functions. The proposed study aims to identify cognitive and neural changes elicited by a multi-modal cognitive- enhancing intervention using a randomized clinical trial pilot study design. Sixty non-demented older adults presenting with executive dysfunction and recurrent LLD will undergo a 4-week daily intervention contrasting the effects of three conditions (bifrontal active tDCS+TCT, sham tDCS+TCT, and sham tDCS+non-targeted control cognitive training (CT)) on measures of executive functioning and ECN brain connectivity pre- and post- intervention. Specific aims are to determine whether stepwise ECN engagement across randomized groups (active tDCS+TCT > sham tDCS+TCT > sham tDCS+control CT) results in progressively greater benefit to executive functions (Aim 1) and functional connectivity between ECN regions (Aim 2). We will also explore whether intervention-related changes in ECN relates with executive function performance (Exploratory Aim) and changes in depressive symptoms. Resultant data will enhance understanding of mechanisms underlying this multi-modal cognitive-enhancing intervention in recurrent LLD and inform a more definitive randomized, mechanistically-focused clinical trial via an R01. This K23 will support my career development goals of building expertise in 1) delivery and optimization of multi-modal non-pharmacological interventions to enhance cognition, 2) functional connectivity neuroimaging analysis in LLD, and 3) clinical trials development, implementation, and management. Study results will establish the necessary groundwork for my development as an independent investigator focused on multi-modal targeting of the ECN (via TCT, tDCS) to enhance brain and cognitive functions in LLD, with goals of understanding mechanism, personalizing treatments, and altering the trajectory of cognitive decline to reduce dementia risk.

NIH Research Projects · FY 2026 · 2026-05

Project Summary Nearly half of adults have hypertension, a major risk factor for cardiovascular disease. Despite treatment with multiple drugs, 30% of hypertensive patients remain hypertensive. There is an urgent need for new therapies. We discovered a novel role of mitochondrial cyclophilin D (CypD) in vascular dysfunction and hypertension. CypD is a new "master" regulator of mitochondrial function, however, its specific mechanism of action remains unclear. We propose CypD acetylation as a pathogenic "gain-of function" driving mitochondrial and vascular dysfunction, hypertension and end-organ-damage. Global CypD depletion alters metabolism, and clinical trials revealed off-target effects of CypD blockers. In this proposal we will test a novel paradigm that CypD acetylation leads to switch from homeostatic to pathogenic gain-of-function, and targeting CypD acetylation reduces vascular dysfunction and hypertension. Our preliminary data showed that human hypertension is associated with CypD-acetylation, CypD-K166 acetylation is driven by GCN5L 1 acetyltransferase which is increased in hypertension, and mitochondria targeted scavenger of cytotoxic isolevuglandins mito2HOBA reduces CypD acetylation and attenuates hypertension. In the proposed studies, we will take this work forward by defining the cell specific pathogenic mechanisms of endothelial and smooth muscle CypD-K166 acetylation in hypertension and vascular dysfunction, testthe therapeutic potential of new CypD blockers, GCN5L 1 depletion and novel scavengers of mitochondrial isolevuglandins after onset of hypertension to reduce CypD acetylation, rescue vascular function, reduce hypertension and end-organ-damage. AIM 1. To test the hypothesis that endothelial CypD acetylation promotes endothelial dysfunction, and depletion of endothelial GCN5L 1 rescues endothelial function and reduces hypertension. We will use endothelial specific CypD-K166Q knock-in acetylation mimetic EccypD·K1••0 and tamoxifen-inducible endothelial specific GCN5L 1 knockout male and female mice in angiotensinll and DOCA-salt models of hypertension. AIM 2. To test the hypothesis that smooth muscle CypD acetylation promotes vascular dysfunction, and blocking the smooth muscle GCN5L 1 improves vascular function and reduces end-organ-damage. This will be tested in smooth muscle specific CypD-K166Q knock-in acetylation mimetic (Smccypo-1<1••0j, smooth muscle specific GCN5L 1 knock out male and female mice and using mitochondria-targeted mitoTEMPO and mito2HOBA. AIM 3. To test the hypothesis that pharmacological inhibition of CypD acetylation and CypD blockers after onset hypertension rescue vascular metabolism and function. We will study therapeutic effect of new mitochondria targeted mito2HOBA-C1/C10 (A) and new CypD blocker NV556 (B) in hypertensive mice, and ex vivo treatment of human resistance arterioles from hypertensive patients to rescue vascular metabolism and function. We are in an ideal position to perform these studies. We have unique CypD mouse models, access to human vascular tissue, unique expertise in oxidative stress, mitochondria-targeted treatments, human vascular studies, and hypertension. Our data strongly support novel pathways, and this work has the potential to make a major impact.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY Most common diseases including diabetes, hypertension, and coronary artery disease present in a polygenic nature. This means that an individual’s risk for the condition is due to genetic variation across numerous genes. Polygenic risk scores (PRSs) are genetic instruments designed to quantify this genetic liability by summing the effect size estimates for these various risk alleles of a given disease. A great deal of work has gone into developing PRSs for various diseases. As of January 2025, the PGS catalog contains more than 5,000 published PRSs. Just as common diseases present with risk due to variation in multiple genes these conditions also present with a myriad of comorbid conditions. Many of these comorbidities may reflect the underlying genetics with a specific combination of genetic risk alleles included in PRS for a given disease. Therefore, the systematic evaluation of comorbidity patterns associated with a given PRS may improve our understanding of these common complex diseases. Phenome-wide association studies (PheWASs) are one such tool to systematically evaluate clinical disease across multiple biobanks and in various populations. PheWASs use phecodes, aggregates of clinical billing codes, to represent clinical disease. Then the association between a genetic predictor, such as a PRS, and the various phecodes are assessed using regression analyses. In Aim 1 we will perform PheWAS analyses of the published PRSs (PRSxPheWAS) in the PGS catalog in All of US, eMERGE, BioVU, and UK Biobank. These analyses will be adjusted for standard covariates that reflect differences in patient demographics and hospital utilization. The results from these biobanks and others will be meta- analyzed using AnVIL. In Aim 2 the analyses of Aim 1 will be repeated but the population will be separated by electronic medical record reported sex to identify potential differences in clinical disease presentation and risk. All produced workflows, data visuals, and results will be made available for public access via AnVIL. PheWASs of individual PRSs can identify shared comorbidity structures and risk patterns that may reflect underlying biology, environmental/behavioral patterns, or phenotypic convergence. Further, the creation of a robust catalog of phenotypic relationships to individual PRSs across multiple biobanks, the end product of this award, can improve our understanding of comorbidity patterns for common polygenic diseases.

NIH Research Projects · FY 2026 · 2026-04

Each year, urinary tract infections (UTI) affect over 400 million people worldwide, such that nearly half of all women will have a UTI within their lifetime. However, the exponential rise in antibiotic resistance of uropathogenic bacteria profoundly threatens our ability to treat UTI. Thus, it is imperative that measures are quickly taken to reduce the rise of resistance and develop alternative strategies to treating UTI. The goal of this proposal is two- fold: develop a point-of-care diagnostic which can rapidly detect UTI and develop a novel treatment for UTI via in situ commensal microbiome engineering. 1) Conventional diagnostic strategies for UTI (e.g., urine culture) are insensitive, non-specific, and/or time consuming. As a result, antibiotics are primarily prescribed before diagnostic results are received, which can result in unnecessary antibiotic use and in turn, contribute to the rise of resistance. To address this, I will combine padlock probes and in vitro transcription and translation systems to detect pathogenic bacteria and antibiotic resistance genes in urine in less than an hour at the point-of-care. This should reduce unnecessary antibiotic use by providing rapid and accurate UTI diagnoses. 2) Commensal urobiota have been shown to decrease the pathogenicity of UTIs. However, attempts to modulate the microbiome via probiotics have seen inconsistent efficacy in the treatment of UTI, which may be due to poor colonization. To address this, I will engineer the urinary microbiome in situ to downregulate UTI pathogenicity. Briefly, phages will be engineered to deliver therapeutic genes to diverse strains common to the urinary microbiome. These phages will be validated to work in in vitro and in vivo models of UTI. In total, this proposal will enable a novel diagnostic and therapeutic approach for the clinical care of UTI which could be leveraged for a variety of microbiome-based urological and kidney diseases.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY Influenza virus is a significant pathogen in solid organ transplant (SOT) recipients, including lung transplant recipients. Compared to other solid organs, patients with lung transplants experience more severe influenza disease, including respiratory failure, acute cellular rejection, antibody-mediated rejection, and chronic lung allograft dysfunction. Inactivated influenza vaccines (IIVs) are recommended for all immunocompromised individuals six months and older to mitigate severe influenza illness. However, lung transplant recipients respond poorly to standard dose (SD)-IIV due to the high levels of maintenance immunosuppression required to prevent allograft rejection. Recent studies have investigated two strategies to overcome attenuated immune responses to SD-IIV in SOT recipients: administration of one high-dose (HD)-IIV or two doses of SD-IIV in the same influenza season. However, these studies were conducted during the late post-transplant period (e.g., >1 year) and lacked crucial information from the early post-transplant phase when SOT patients are most vulnerable to influenza. Additionally, prior studies had limited representation of lung transplant recipients, a population at greater risk for influenza-related morbidity and mortality compared to other SOT recipients. We are conducting an NIH-sponsored clinical trial comparing two doses of HD-IIV to two doses of SD-IIV administered within the same season to lung transplant recipients 1-35 months post-transplant (DMID protocol number 22-0014). However, our current study does not address whether two doses of IIV are necessary for the subsequent influenza season and, relatedly, the required dose level (standard vs. high) to confer safe and sufficient protection in the subsequent season. The proposed research will compare the immunogenicity and safety of two doses of HD-IIV to two doses of SD-IIV in lung transplant recipients over two consecutive influenza seasons, elucidate cellular immune phenotypes and responses to vaccination, and define cellular immune predictors and correlates of influenza vaccine antibody responses in repeatedly vaccinated lung transplant recipients. The central immunogenicity hypothesis of our proposal is that within each vaccine group, the hemagglutination inhibition (HAI) geometric mean titer (GMT) following one vaccine dose in the repeater year will exceed the HAI GMT following two doses in the first year. To test this hypothesis and address critical knowledge gaps outlined above, lung transplant patients at Vanderbilt University Medical Center enrolled in DMID protocol number 22-0014 during the 2024-2025 and 2025-2026 influenza seasons will be enrolled the following season (2025-2026 and 2026-2027, respectively) in the proposed study and receive either two doses of HD-IIV or two doses of SD-IIV by replicating their respective first-season dose assignments. Results of this study will provide comprehensive insights into humoral and cellular immune responses in adult lung transplant recipients and guide long-term vaccine recommendations. Moreover, our findings will inform optimal vaccine strategies in other SOT populations.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY/ABSTRACT Traumatic brain injury (TBI) is a major cause of death and disability in the U.S. and beyond. More than half of TBI deaths occur in the context of acute withdrawal of life-sustaining treatment (WLST). The decision to continue towards neurorehabilitation versus transition to WLST hinges on predictions of recovery. Predicting recovery, however, is challenging. Recovery predictions drive care decisions, but even seasoned clinicians cannot make reliable predictions. The stakes are high: surrogates overwhelmingly view a persistent vegetative state after severe TBI as worse than death. Yet, late recovery and functional independence may be possible for many. Among those who die after WLST, up to one third may have recovered to functional independence. Correctly identifying those patients in the intensive care unit could equate to up to 10,000 lives saved annually with good functional recovery by preventing premature WLST. We must move beyond prognostic uncertainty. A potential diagnostic tool is available: the injured brain’s response to anesthesia reveals its likelihood to recover, and this response is measurable with electroencephalography (EEG). Anesthesia can induce distinctive patterns of brain network reconfiguration. In patients with disorders of consciousness, detection of these brain network reconfigurations in response to propofol anesthesia may allow us to correctly identify patients with the capacity to recover consciousness. In our preliminary work, we quantified the reconfiguration of high-density EEG network hubs and directed functional connectivity before, during, and after propofol anesthesia to obtain an index of propofol-induced network reconfiguration. This index discriminated with high accuracy between patients who did or did not later regain consciousness. This work was limited to 10 patients with disorders of consciousness after acquired brain injury, of which 2 had acute TBI. This tool has the potential to apply to acute TBI patients. To address this evidence gap, this R21 proposes to enroll 30 unresponsive acute TBI patients from our intensive care unit, both isolated and polytrauma TBI, in a prospective study with two Specific Aims: (1) to develop a novel propofol-induced index to predict recovery of consciousness after acute TBI in the intensive care unit; and (2) to quantify the added value of this novel index for TBI prognostication. We will use high-density and clinical-grade EEG to measure the brain’s response to the neurophysiological perturbation of propofol anesthesia and then calculate the accuracy of this novel index to predict recovery of consciousness 6 months later. This project leverages our high-volume, high-acuity trauma center with a large pool of severe TBI patients. This interdisciplinary team science collaboration leverages the diverse skillsets of four female investigators: a trauma surgeon intensivist, a neurologist specializing in critical care EEG, a neuroscientist focused on recovery of consciousness, and an engineer focused on consciousness and neuroprognosis. Eventually, this pragmatic, bedside prognosticator for unresponsive, acute TBI patients may provide hope of recovery and prevent early inappropriate WLST.

NIH Research Projects · FY 2026 · 2026-04

Half of the global human population harbors the gastric bacterial pathogen He/icobacter pylori. This bacterium induces chronic gastritis that progresses through a histologic cascade and ultimately results in gastric cancer in 1- 3% of all those infected. In addition, 10-15% of infected individuals will develop peptic ulcer disease. Antibiotics do not uniformly eradicate the infection and resistance to the most commonly used antibiotics for H. pylori infection is a major health problem worldwide. Therefore, rational alternative therapies that can limit the infection and/or increase the eradication by antibiotics are needed. We have recently discovered that two compounds initially developed to inhibit enzymes of the mammalian reverse transsulfuration pathway (RTP), namely aminooxyacetic acid (AOAA) and propargylglycine (PAG), inhibit the growth of H. pylori in vitro. Of particular relevance, we have generated multiple H. pylori isolates from an ongoing clinical cohort, including a strain that we have found to be resistant to metronidazole, a common clinical problem. The cytotoxic effect of the RTP inhibitors also occurs in the antibiotic-resistant strain, increasing the potential importance of these compounds for future human studies. Using targeted and untargeted metabolomics, we found that cystathionine, a main metabolite of the H. pylori RTP (HpRTP), accumulates in H. pylori treated with AOAA or PAG, suggesting that these inhibitors can also target this metabolic pathway. Further, we found that stomach colonization and gastritis are inhibited when H. pylori-infected mice are treated with AOAA. Altogether, these data indicate that the HpRTP is essential for H. pylori survival in vitro and in the stomach and is therefore a rational therapeutic target. We hypothesize that commercially available molecules that inhibit the HpRTP result in bacterial killing and represent a novel treatment strategy to reduce H. pylori colonization and associated diseases. This entirely new concept for H. pylori treatment will be studied through two Specific Aims. 1) In vivo: To test if the compounds AOAA and PAG reduce H. pylori-induced diseases. A) We will determine colonization and gastritis in H. pylori-infected C57BL/6 mice treated or not with AOAA or PAG; we will also determine the mucosal immune response, the metabolomic signature of the gastric tissues, and the composition of the gastric microbiota. B) We will investigate the effect of these compounds on colonization, development and extension of dysplasia/carcinoma, and oncogenic signaling in dysplasia-prone FVB/N mice overexpressing the human gastrin gene (INS-GAS). C) The combination of antibiotic therapy with AOAA or PAG will be tested on antibiotic-susceptible and resistant clinical isolates. 2) In vitro: To delineate the molecular mechanisms by which AOAA and PAG affect H. pylori. A) We will use an approach combining metabolomics with classical microbiological and biochemical investigations to identify the enzyme(s) of the HpRTP inhibited by both compounds. B) We will determine whether AOAA/PAG influence the transcriptome of H. pylori, including the expression of the main virulence factors. Together, these studies are expected to provide new insights that can be translated to future investigations in humans with H. pylori infection, to limit infection burden and related diseases.

NIH Research Projects · FY 2026 · 2026-04

This supplement to our renewal application seeks continued support for the Vanderbilt Child Health Research Career Development Award (K12) – a program designed to prepare early-career pediatric physician-scientists to become future leaders in basic and translational research. The K12 program provides 80% protected time for mentored research, structured oversight, and individualized career development for up to three years. The Vanderbilt K12 pathway has produced a strong pipeline of pediatric physician-scientists, with substantial return on investment. Among the 11 scholars in the first funding cycle, 73% (8/11) secured individual NIH K awards, and 63% (5/8) of those K-award recipients transitioned to R01-level funding. Program alumni have secured independent research grants and assumed leadership roles in academia, underscoring the program’s impact. Both current K12 Training Directors are products of a Department of Pediatric physician-scientist training pathway (one a former K12 scholar and one a former pediatrics T32 fellow), underscoring our commitment to developing outstanding Vanderbilt Pediatric physician-scientists from fellows through late careers. A central feature of our program for the last 10 years has been the Vanderbilt K12 Club. This monthly forum brings together current scholars, alums, training directors, and multiple PIs to foster peer mentoring, professional development, and knowledge sharing. The program’s mentorship model is tiered and multidisciplinary. Each scholar is guided by a team of senior investigators and “Next Generation” near-peers, including former K12 recipients and mentors, ensuring both expert guidance and relatable peer support. We intentionally align our approach with Social Cognitive Career Theory, which emphasizes how self-efficacy, outcome expectations, and environment influence career development. This theoretical framework underpins our Individual Development Plan process and mentoring strategies, reinforcing scholars’ confidence and persistence. We also added a new mandatory Precision Medicine Research Rotation (1 day/week for 6 months). VUMC’s BioVU links DNA to de-identified electronic health records datasets (Synthetic Derivative, Research Derivative) for genotype–phenotype discovery and validation. Led by Dr. Jennifer Sucre (former K12 scholar and current K12 training director), scholars will build phenotypes, merge genomic and clinical data, and conduct phenotypic and genotypic analyses with bench validation. Additionally, Vanderbilt’s CTSA (Clinical and Translational Science Award) program has supported our scholars by providing infrastructure for clinical research translation, including a biorepository. Collectively, these resources, mentors, and our track record of success provide evidence that the K12 supplement will continue to support the pathway for physician-scientists committed to improving child health.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY/ABSTRACT This K23 proposal aims to provide Dr. Jonah Garry with the skills and experience required to lead a patient oriented translational research program focused on pulmonary vascular disease and right ventricular (RV) function. Through mentored research and career development, he will gain skills in: 1) Advanced statistical methods for high-dimensional molecular data, 2) Human genomics, 3) Prospective cohort study design and execution, and 4) Scientific oral and written communication. This proposal is focused on right ventricular (RV) dysfunction in heart failure-associated pulmonary hypertension (HF-PH). RV dysfunction is a leading cause of morbidity and mortality in HF-PH, a condition that affects 2.4-5.6 million Americans. Despite its clinical significance, the molecular drivers of RV dysfunction in HF-PH remain unknown. The candidate’s preliminary data suggest that dysregulated fatty acid (FA) metabolism plays a key role, aligning with prior findings in pulmonary arterial hypertension. If confirmed, this would suggest shared molecular mechanisms of RV dysfunction across PH subtypes, potentially broadening the applicability of FA metabolism-directed treatments across PH etiologies. This animates the central hypothesis of this proposal that dysregulated FA metabolism drives RV dysfunction in HF-PH. Notably, Sodium Glucose Cotransporter 2 Inhibitors (SGLT2i), which modulate FA metabolism, are already used in HF-PH and provide an ideal opportunity to study the effect of modulating FA metabolism on RV function. The research proposal includes three independent, integrated aims. In Aim 1 the candidate will assess whether FA metabolism-related proteins associate with RV dysfunction in HF-PH. Using a biorepository of plasma samples from HF-PH subjects with independent discovery and internal validation cohorts (both n=250 subjects), the candidate will determine whether a pre-specified set of 50 FA metabolism related proteins associate with RV dysfunction. In Aim 2 the candidate will assess whether the genetic determinants of FA metabolism are associated with RV dysfunction in HF-PH. He will use whole genome sequencing data from Vanderbilt’s de-identified biobank BioVU (n=6,368) and the Veterans Administration Million Veterans Project (n=~10,000) to determine whether validated genetic risk scores for FA metabolism protein expression associate with RV dysfunction. In Aim 3 the candidate will enroll a prospective observational cohort of HF-PH subjects (n = 40) who have recently been prescribed an SGLT2i. Participants will undergo clinical assessment, echocardiogram, cardiac magnetic resonance imaging and measurement of targeted metabolomics at the time of SGLT2i prescription and after 6 months. The candidate will determine whether SGLT2i therapy improves RV function and if changes in RV function correlate with improved FA oxidation and reduced myocardial lipid content. Completing these aims will provide fundamental in vivo, human subject insights into the mechanisms of RV dysfunction and may identify molecules of therapeutic interest.