Vanderbilt University Medical Center

NIH Research Projects · FY 2025 · 2025-09

ABSTRACT Alzheimer's disease (AD) disproportionately affects women, yet the underlying biological and genetic factors contributing to this sex disparity remain poorly understood. This proposal addresses this critical gap by focusing on the intricate interplay between sex-specific genetic factors, cerebrovascular disease (CVD), and AD pathogenesis. Building on our groundbreaking research revealing sex-specific genetic associations in AD- related endophenotypes, we aim to extend this paradigm to explore the role of genetics in the development and progression of CVD within the AD-affected brain and to investigate whether or not these relationships present in a sex-specific manner. Our research team, with expertise spanning statistical genetics, sex differences in Alzheimer's and related dementias, neuropathology, and neuropsychiatry, will harness the vast resources of the Alzheimer’s Disease Genetics Consortium and the Alzheimer’s Disease Sequencing Project. With autopsy data from over 9,600 well-characterized participants, including measures of CVD, amyloid and tau burden, and longitudinal cognitive scores, we are uniquely positioned to conduct the most extensive sex- specific genome-wide analyses of CVD endophenotypes in the context of AD to date. The specific aims of this proposal are threefold: [1] identify sex-specific genetic markers of autopsy measures of brain vessel disease (i.e., atherosclerosis and arteriolosclerosis), [2] identify sex-specific genetic markers of autopsy measures of vascular brain injury (i.e., macroscopic and microscopic infarction), and [3] characterize the degree to which known genetic drivers of CVD affect cognitive decline in a sex-specific manner. The outcome of this project will highlight new candidate pathways and begin the process of characterizing the mechanisms by which genetic variation among males and females affects the risk of CVD and clinical symptoms of AD. It also holds the promise of identifying novel therapeutic targets and of moving the field towards personalized interventions that consider an individual’s sex and neuropathological presentation.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Delirium occurs in about 50% of older hospitalized patients. This form of acute brain failure is associated with accelerated cognitive decline, leading to incident or worsening Alzheimer's disease and related dementias (ADRD). Psychotropic medications cause delirium in up to 42% of cases and represent an opportunity for intervention. However, deprescribing, which is stopping or reducing the dose of a medication, has not been shown to be effective in the treatment of delirium. This is because deprescribing relies on medication lists, which do not take into account drug toxicity. Novel approaches are needed to identify new medications for deprescribing to increase its efficacy. Incorporating serum psychotropic medication measurements using liquid- chromatography-mass spectroscopy (LC-MS) may identify new targets for deprescribing by uncovering supratherapeutic psychotropic drug levels (SPDLs) that usually go unrecognized. In our preliminary study of 158 older hospitalized patients, we found that 10% had SPDLs, and they were associated with longer delirium duration. The majority of SPDLs were selective serotonin and serotonin-norepinephrine reuptake inhibitors (SSRI/SNRIs) antidepressants, which are one of the most commonly prescribed psychotropic medications in older adults. Higher SSRI/SNRI levels were associated with prolonged delirium duration, particularly in patients with pre-existing ADRD. Because these were secondary analyses, we must confirm these findings. Assessing the patient's ability to metabolize a drug based on cytochrome P450 (CYP) genotypes may also identify additional deprescribing targets. Intermediate or poor metabolizers can have higher serum psychotropic drug levels, leading to delirium and accelerated cognitive decline. Medications that inhibit CYP (CYP-inhibitors) may also need to be deprescribed because they may cause genotype-phenotype conversion. This drug-drug interaction causes a genotype-predicted normal metabolizer into a phenotypic poor metabolizer, leading to higher serum psychotropic drug levels. Prior to incorporating these precision medicine tools into a deprescribing intervention, we must evaluate their clinical utility. Therefore, we propose this prospective cohort study of 600 older hospitalized patients with the following specific aims: Determine if serum concentrations of SSRI/SNRIs and other serum psychotropic medication classes measured at enrollment, 12-24 hours, and 48- 72 hours are associated with delirium duration (Aim #1) and 12-month global cognition (Aim #2) in older hospitalized adults. Evaluate how specific CYP polymorphisms affect serum concentrations of SSRI/SNRIs and other psychotropic medications (Aim #3). Explore how drug-drug interactions leading to poorer metabolizer genotype-phenotype conversion are associated with increased serum SSRI/SNRI concentrations (Aim #4). While SSRI/SNRIs are the focus, we will evaluate all psychotropic medication classes for Aims #1-3. This R01 will help develop a novel deprescribing intervention incorporating serum psychotropic drug measurements, CYP-genotyping, and CYP-inhibitor identification to be tested in a future randomized trial.

NIH Research Projects · FY 2025 · 2025-09

Project Summary: Pulmonary fibrosis (PF) is a chronic relentlessly progressive interstitial lung disease resulting in progressive loss of respiratory function leading to death of approximately 50,000 patients in the U.S. each year. Failure of normal epithelial repair processes is believed to play a central role in the development and progression of pulmonary fibrosis, leading to the loss of normal alveolar type 1 (AT1) and alveolar type 2 (AT2) and accumulation of alveolar epithelial cells that abnormally co-express genes associated with both AT1, AT2 and proximal airway epithelial cells. In order to understand how abnormal alveolar repair contributes to PF disease mechanisms, we must first determine the critical cellular and molecular mechanisms that facilitate normal alveolar repair and regeneration. Our prior studies and preliminary data indicate that the Hippo-Yap/Taz signaling pathway is an important regulator of alveolar development and promotes both AT2 proliferation and early AT1 specification during alveolar repair, but persistent and inappropriate activation of Yap/Taz signaling may prevent normal AT2/AT1 differentiation and underlie the dysfunctional epithelial repair seen in PF lungs. During adaptive repair of experimental fibrotic injury Yap is dynamically expressed in AT2 cells peaking at 7 days post-injury, while Taz is highest at 14 days post-injury in AT2 cells and readily expressed in most AT1 cells during homeostasis and repair suggesting distinct cell type- specific roles for Yap and Taz. Others have found that deletion of Taz in AT2 cells prevents AT1 differentiation and deletion of Yap/Taz in AT1 cells leads to a loss of AT1 cell identity. This leads to our over-arching hypothesis that dynamic, cell-type-specific, regulation of Yap and Taz activity is essential to guide adaptive alveolar regeneration. To test this overarching hypothesis will assess the concept that Yap and Taz have distinct and cell-type specific interaction partners that mediate transcriptional and epigenetic activity that guide normal lung repair. These concepts will be tested in 2 aims; 1.) To determine the mechanisms by which Yap regulates AT2 cell proliferation and transitional cell differentiation during alveolar repair, and 2.) To define the role of active Taz signaling in the differentiation, maturation, and maintenance of AT1 cells. To test these Aims we will use combinations of in-vivo genetic mouse models, in-vitro organoid models, and ex-vivo precision-cut- lung-slices to define the role of Yap and Taz during normal and pathologic repair. Successful completion of these aims will provide vital therapeutic strategies to guide adaptive repair and promote the delay or resolution of pulmonary fibrosis.

NIH Research Projects · FY 2025 · 2025-09

Project Summary/Abstract Magnetic resonance-guided focused ultrasound (MRgFUS) neuromodulation is a groundbreaking, non-invasive therapeutic technique that combines real-time magnetic resonance imaging (MRI) with the precision of focused ultrasound (FUS). It offers a promising alternative to invasive brain stimulation methods for treating neurological -time MRI guidance ensures accurate targeting of brain regions, while MRI thermometry and Acoustic Radiation Force Imaging (ARFI) enable safe monitoring, and functional MRI characterizes the spatial and temporal neural responses to FUS stimulation. However, the effectiveness of MRgFUS neuromodulation is hindered by limitations in signal-to-noise ratio (SNR) or image quality in MRI. The objective of this project is to develop an innovative RF coil array specifically designed for MRgFUS neuromodulation applications. The proposed coil will overcome spatial constraints imposed by the FUS device and water bath, improving SNR and enabling high-quality imaging of human brain, especially deep brain structures such as the thalamus. Key innovations include the use of an imbalanced current/capacitor distribution and irregular coil geometry to maintain high receive sensitivity, even when the coil is displaced from the brain's center. These advancements will enhance the imaging quality of both structural and functional MRI, ensuring more precise and effective therapeutic interventions. The project will involve advanced electromagnetic simulations, the fabrication of coil prototypes, and performance testing. Successful implementation of this novel RF coil array will significantly improve imaging quality in MRgFUS neuromodulation, leading to better patient outcomes, improved patient comfort and expanded clinical applications of this non- invasive treatment for neurological conditions.

NIH Research Projects · FY 2025 · 2025-09

Severe trauma remains a leading cause of mortality and long-term disability worldwide. Patients who survive the initial injury face a continuum of complications, from early-phase multi-organ dysfunction syndrome (MODS) to late-phase post-injury syndrome (PIS). Despite extensive research, a critical knowledge gap remains in understanding how specific innate immune cells drive these adverse outcomes. This proposal aims to elucidate the dynamic interplay between the fibrinolytic system and inflammatory response, specifically neutrophil activation in early injury response, followed by sustained macrophage-driven inflammation in late-phase complications. Our central hypothesis posits that the spectrum of adverse outcomes stems from sequential immune cell responses to fibrinolytic dysfunction, centered on the management of the 'damage matrisome.' We propose a three-phase progression: 1) initial hyperfibrinolysis triggers neutrophil activation and DNAnet formation, 2) neutrophil-mediated fortification of the damage matrisome creates a fibrinolysis-resistant matrix that while initially protective, leads to organ inflammation and a hypofibrinolytic state within tissues, and 3) persistent hypofibrinolysis combined with chronic macrophage activation drives failure of tissue repair, degeneration and pain (PIS). To test this hypothesis, we will employ a clinically relevant murine model of severe trauma complemented by comprehensive flow cytometry-based immune cell phenotyping and tissue-specific transcriptomic analysis. Aim 1 will determine if early hyperfibrinolysis drives neutrophil activation and MODS by modulating fibrinolysis and assessing its impact on neutrophil phenotype and organ inflammation. Aim 2 will investigate whether activated neutrophils drive hypofibrinolysis both systemically and within tissues by manipulating neutrophil responses in both severe and non-severe injury models. Aim 3 will evaluate if modulating either fibrinolysis, chronic inflammation, or both can mitigate PIS. Important to the clinical relevance of this work, measures of PIS will include tissue fibrosis/calcification, musculoskeletal inflammation and degeneration, pain, and musculoskeletal function- all changes observed in severely injured patients. This research has the potential to revolutionize our understanding of trauma pathophysiology by defining how specific immune cell populations drive adverse outcomes. By elucidating these mechanisms, we aim to develop targeted, phase-specific interventions that address both immediate life-threatening complications and prevent long-term disabilities, ultimately improving outcomes for millions of trauma survivors worldwide.

NIH Research Projects · FY 2025 · 2025-09

Abstract Aging is the biggest risk factor for the development of chronic disease and disability, including development of osteoporosis (OP) and osteopenia. These conditions affect more than 60 million Americans and are associated with great morbidity and mortality in the setting of fragility fractures. The number of people affected by these conditions will only increase as the population ages. Screening for OP and osteopenia is limited, facilitating intervention only in more advanced stages of bone loss. Limited studies have identified the potential of artificial intelligence (AI) and deep learning (DL) tools, as applied to opportunistically-acquired imaging, for the early identification of changes in bone structure that may herald the onset of OP. In addition, the growing field of epigenetics has facilitated assessment of aging and its comorbidities at a molecular and genetic level. Although one study suggested that bone mineral density (BMD)-associated loci discovered by genome-wide association studies could only explain up to 6% of BMD variation (Nat Genet 2012; 44:491-501), recent research has shown that methylation levels at five CpGs that differ significantly between healthy and osteoporotic women could explain 14% of BMD variation (Epigenetics 2017;12:674-687). Despite these promising findings, there is a lack of understanding of the connection between epigenetic modification of genes and imaged bone findings. This research area represents a crucial gap in existing knowledge that this project seeks to fill. This proposal aims to carry out a discovery-focused effort to identify epigenetic factors that cause early OP associated with imaging findings on CTs. The first aim of the study is to refine and to validate, in an American sample, DL approaches to measure BMD from opportunistically-acquired CT scans with a corresponding comprehensive electronic health record. The second and third aims are to identify quantitative markers of OP in CT scans that are associated with DNA methylation of genes implicated in OP, as assessed in blood (Aim 2) and bone (Aim 3) samples. Using these data, frailty and resilience will be quantified with reference to chronological and epigenetic age, through alignment of imaging-based quantitative metrics and molecular data. Knowledge and skills acquired and developed as part of this career award will involve AI/DL technologies, geroscience, epigenetic assessment, and advanced bioinformatics. Ultimately, this study will facilitate identification of early evidence of bony changes in younger patients, predating a disease state, which will allow for earlier intervention and identify targets for pharmacological intervention based on epigenetic patterns. Notably, a 13-year study recently demonstrated that reversal of epigenetic modification at set loci can reverse cellular evidence of aging (Cell 2023;186:305-326.e27). Building on this work, I seek to identify evidence of OP through DL/AI-mediated imaging findings and through epigenetic assessment at a time point when early intervention on factors affecting epigenetic pathways could halt, slow, or reverse progression of OP.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Rates of alcohol use disorder and alcohol associated liver disease requiring liver transplantation continue to rapidly rise. Return to alcohol use after liver transplant is associated with increased rates of liver transplant failure and mortality, but there is no evidence-based integrated intervention to address alcohol use disorder in liver transplant recipients. The goal of this K23 award application submitted by a liver transplant surgeon is to address a critical gap in knowledge and care for liver transplant recipients with concurrent alcohol use disorder by developing and pilot testing an integrated liver transplant and alcohol recovery program (ILTARP) consisting of an integrated community health worker supporting post-transplant alcohol relapse prevention, outreach, and care coordination. To address this knowledge gap, I propose three research aims. Aim 1 is to co-develop the ILTARP intervention with stakeholder and expert input though an iterative process of evidence gathering and stakeholder panels. Aim 2 will conduct a pilot feasibility study of the newly developed ILTARP intervention testing feasibility, acceptability, and potential effectiveness of ILTARP in the liver transplant clinical setting through a randomized control pilot trial (n=40). Aim 3 will assess barriers and facilitators of the ILTARP intervention through an integrated mixed methods approach to prepare the intervention for a future R01 application for a fully powered multisite Hybrid Type 1 effectiveness-implementation trial. My long-term goal is to be an independently funded researcher developing, testing and implementing interventions in solid organ transplantation integrating care of complex co-occurring health conditions. The research aims directly inform my three training goals: Goal 1 to gain advanced knowledge in alcohol use disorder treatment and addictions research; Goal 2 to acquire skills in intervention development and randomized trials of multi-component interventions; and Goal 3 to develop expertise applying implementation research frameworks and evaluating implementation outcomes through the use of mixed methods. The training plan includes guided reading, mentored research projects, monthly seminars, and selected coursework, planned research manuscripts, and frequent mentor meetings to review progress. The research project, the research environment, and the exceptional multidisciplinary mentorship team (Drs. Bartels, Kelly, Aschbrenner) and consultants (Drs. Cameron, Wakeman, Cheng) are ideally suited to my career development. Overall, this career development award will provide the opportunity for me to acquire the necessary research skills to advance my career goal to become a leading expert in intervention development and implementation research in solid organ transplantation integrating care of complex co-occurring health conditions. This formative work has the potential to result in a paradigm shift in liver transplant centers across the nation by broadly disseminating ILTARP to improve access, equity, and long-term outcomes for the growing number of patients suffering from alcohol use disorder and alcohol associated liver disease.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Long QT Syndrome (LQTS) occurs due to slowed cardiac repolarization, which is reflected as long QT intervals on patient electrocardiograms. This prolongation increase the risk of fatal cardiac arrhythmias. The voltage-gated potassium ion channel, KV11.1, comprises 25-40% of LQTS cases. Around 90% of loss-of- function KV11.1 variants cause reduced intracellular transport (trafficking) of KV11.1 protein, reducing its cell surface expression and causing LQTS. Currently, there are no clinically approved drugs that treat this mechanism. My high-throughput drug screens identified evacetrapib as a drug candidate that improves KV11.1 trafficking and activates the channels. For this project, I aim to 1) test evacetrapib for drug repurposing in trafficking-deficient KV11.1 variants and 2) identify targetable KV11.1 protein interactions that could improve trafficking and function. Aim 1 uses high throughput variant screening and human induced pluripotent stem cell cardiomyocytes (hiPSC-CMs) to assess KV11.1 variant trafficking and function. In collaboration with Brett Kroncke, this proposal uses published multiplexed assays of variant effect (MAVE) to generate more than 23,000 KV11.1 variants and identify variant-specific trafficking response to evacetrapib. Evacetrapib failed phase III clinical trials for high cholesterol, but patients tolerated the drug well, suggesting it could be repurposed to treat Long QT Syndrome. Thus, data from the MAVE will inform testing in translational hiPSC-CM models. Gene-edited or patient-derived HiPSC-CMs with responsive KV11.1 variants will be used to further confirm evacetrapib’s efficacy and facilitate the translation of the findings into clinical practice. Aim 2 explores KV11.1-protein interaction networks using established affinity-purification coupled with mass spectrometry protocols and high-throughput siRNA screening. This will identify KV11.1 interacting proteins and mechanisms that regulate KV11.1 trafficking. Dr. Egly will receive hands-on training in proteomics (instrumentation and analysis), which complements prior learning from courses and workshops. Dr. Christian Egly’s career goal is to establish an independent research lab focused on ion channel trafficking and finding new treatments for cardiac arrhythmias. The training plan highlights key areas for Dr. Egly’s growth including research independence in hiPSC-CMs (Aim 1) and proteomics (Aim 2), professional development, faculty development, and courses/learning of statistical analysis and bioinformatics. Mentors, Björn Knollmann, MD, Ph.D., and Lars Plate, Ph.D., have excellent track records in training students, fellows and early career investigators. Advisor Dan Roden, MD, offers decades of experience in cardiac electrophysiology and arrhythmia research and has trained multiple K awardees. Dr. Yaomin Xu provides biostatistical support to the project. Lastly, Vanderbilt University is an excellent environment with top-notch research facilities and investigators that will support Dr. Egly’s development towards independence.

NIH Research Projects · FY 2026 · 2025-09

PROJECT SUMMARY The overarching goal of this proposal is to leverage leading-edge technologies in bioengineering and vascular physiology to develop a human ductus arteriosus (DA) construct that mimics the response of native vessels to biomechanical and pharmacologic stimuli. In utero, the DA is an essential fetal artery connecting the pulmonary and systemic circulations, shunting blood away from the developing lungs. Circulatory adaptation at birth requires rapid constriction of the DA to facilitate proper perfusion of the newly inflated lungs. Failure to close postnatally results in a persistent left-to-right shunt, termed patent ductus arteriosus (PDA), which is associated with a myriad of debilitating morbidities and neonatal death. The occurrence of PDA is significant (0.05-0.2% of term infants, up to 80% of critically ill premature infants) but, to date, pharmacological therapies aimed at promoting vessel closure are quite limited in number and effectiveness. Current PDA drugs are non-specific and associated with significant off-target effects, including renal dysfunction, platelet abnormalities, spontaneous intestinal perforation, and necrotizing enterocolitis. Furthermore, they are ineffective in 30% of patients, exposing such infants to increased risk of adverse effects with no therapeutic benefit. Surgical ligation and catheter-based closure are effective alternatives, but these mechanical approaches come with their own risks and limitations. Studies have shown that some PDAs will spontaneously close over time, but it is not currently possible to accurately predict which cases will do so and which will require intervention. Advances in PDA management have been impeded by the lack of an appropriate model in which to identify PDA biomarkers and validate potential therapeutics. Animal models are poor mimics of the human DA transcriptome and morphology, and ethical concerns limit drug development efforts using human infants. Moreover, neither approach allows researchers to adjust physiological parameters in a controlled fashion to better understand DA biology. To overcome these critical limitations in predicting spontaneous PDA closure and in developing PDA therapeutics, we will utilize novel immortalized human DA smooth muscle and endothelial cell lines (SMCs and ECs) to develop a 3D engineered human DA construct capable of specifically responding to vasoactive agents in a biomimetic fashion. In Aim 1, we will use pulsatile flow to induce immortalized human DA SMCs embedded in a 3D tubular hydrogel to exhibit contractile phenotype and circumferential alignment (both of which are necessary for the initial vasoconstriction step of DA closure). Aim 2 will focus on establishing a functional DA-specific endothelium on the interior of the engineered vessel. In Aim 3, we will validate the ability of the engineered DA construct to specifically respond to known factors that regulate DA closure. This platform will have far-reaching benefits for the field of neonatology, providing a clinically-relevant testbed in which to develop new therapeutics as well as allowing researchers to control both physiological parameters and embedded cell genotype to explore how to predict spontaneous PDA closure in an effort to avoid unnecessary and risky therapeutic interventions.

NIH Research Projects · FY 2025 · 2025-09

ABSTRACT Gastric cancer is the 4th leading cause of cancer-related death worldwide and it most commonly develops within a carcinogenic cascade from pre-cancerous metaplasia to dysplasia and adenocarcinoma. Metaplasias first arise as a response to injury through the chief cell transdifferentiation into spasmolytic polypeptide- expressing metaplasia (SPEM) cells. While this initial process is possibly reversible, oncogenic gene activation or chronic inflammation can activate SPEM cell plasticity, which promotes SPEM cell progression to intestinal metaplasia (IM) and dysplasia. This neoplastic process may also lead to transcriptional and epigenetic changes, and incite cell lineage conversion, where multiple intermediate cell types are produced that can evolve into cancerous cells, including dysplastic stem cells which may arise during the neoplastic transition. Furthermore, the oncogenic gene mutation burden may be associated with the cell lineage conversion and diversification of the dysplastic stem cells to cancerous cells. However, it is not clear whether the SPEM cell plasticity is responsible for the cell heterogeneity and evolution of pre-cancerous metaplasia to incomplete IM, which carries a higher risk of patient progression to dysplasia and what mechanisms are involved in the carcinogenic process. We therefore hypothesize that SPEM cells are key gastric cancer precursor cells, which display functional properties and cell lineage conversion capacity to drive metaplasia progression to dysplasia. Our overarching goal is to define mechanisms that control the cell lineage conversion of reparative SPEM cells towards incomplete IM and more cancerous cell lineages, which display a higher mutational burden. To address these questions directly, we have established novel in vivo transgenic mouse models and in vitro metaplastic or dysplastic organoid models derived from transgenic mouse stomachs following induction of active Kras or from human patient samples with metaplasia or dysplasia. Using these novel models, we will assess critical SPEM cell lineage derivation and define cell populations that account for the key transcriptional and epigenetic changes arising during metaplasia progression. We will pursue three specific aims: First we will assess functional properties of SPEM cells during mucosal recovery or neoplastic progression following mucosal injury. Second, we will examine regulatory mechanisms of cell lineage diversification and conversion during metaplasia progression. Third, we will investigate molecular mechanisms driving cell linage diversification and clonal evolution of dysplastic stem cells to adenocarcinoma. Our studies will define critical transition points which lead to neoplastic transitions for SPEM cells as the origin of gastric carcinogenesis. An understanding of regulatory mechanisms in cell plasticity and the ability to reverse such transitions could lead to therapeutic interventions to prevent gastric cancer.

NIH Research Projects · FY 2025 · 2025-09

The goal of this application is to create a new T32 mentored training program, Pediatric Cardiorespiratory Research Training Program: Childhood origins of diseases across the lifespan for Pediatrics fellows and PhD scientists who possess both the aptitude and passion to become a new generation of basic, translational, and clinical scientists. The overarching goal is to provide a nurturing mentored environment for fellows for 2 years (with an optional 3rd year) of highly rigorous research training to facilitate successful transition to a subsequent appointment as tenure track faculty. The ultimate goal is to expand the pipeline of those achieving independence as clinician-scientists. Each fellow investigator participates in workshops, may complete a Master’s program (MSCI,MPH, MSACI), and leverages VUMC societies for clinician-scientist development, and will develop and complete a mentored research project in an area of focus consistent with the missions of NHLBI. Investigation may be basic, translational, clinical, or population health. This training program will have 2 training slots per year at any given time to support fellows for a minimum of 80% protected research time for at least 2 years. There is a formal program selection process to identify the most competitive applicants. The program will provide intense scientific mentorship and personalized career development. The fellows will have access to a cadre of >26 carefully selected preceptors with sustained NIH funding coupled with successful track records of mentoring early career scholars. Each fellow will have a personalized Scholarly Oversight Committee to assist in achieving program goals, to provide independent evaluation of their progress, and to develop, advise on, and track their career development plan. Assessment of fellows includes competency-based milestone assessments. There will be equally rigorous mentor and program assessments. Key outcomes for the program include: Academic productivity (presentations, peer-review publications, grants and rates (and success) of appointment to early career academic faulty positions, and applications for initial individual K career development awards. Long-term follow-up of all fellows will be performed using FlightTracker and through personal contact. The Department Pediatrics is fully integrated into the Vanderbilt School of Medicine and Medical Center and consistently ranks in the top 10 in NIH funding. All departments, hospitals, research laboratories and core facilities reside on a single campus offering an integrated research environment for early career clinician-scientists. Our proposal is consistent with the NHLBI’s current Strategic Vision Statement.

NIH Research Projects · FY 2025 · 2025-09

Project Summary Aging is associated with increased mortality and the prevalence of diseases such as cancer, cardiovascular, neurological, and respiratory diseases. One fundamental mechanism of aging is acquiring DNA mutations, which can lead to clonal hematopoiesis of indeterminate potential (CHIP), frequently driven by mutations in in DNMT3A, TET2, and ASXL 1. We seek to identify and re purpose existing medications or investigational therapeutics to decrease or eliminate the CHIP clone as a way to address multiple agingrelated diseases. We will leverage single cell machine learning foundation models, human genetics, and electronic health records (EHR). We propose a two-phase approach: In the UG3 phase, we will utilize single cell foundation models to perform virtual screens as well as genetic and EHR data to identify existing medications to reverse CHIP pathology. In the UH3 phase, we will experimentally validate drug candidates in in vitro and in vivo CHIP models. Successful execution of this work will rapidly translate findings into the clinic by repurposing FDA-approved medications to mitigate CHIP and its related aging diseases.

NIH Research Projects · FY 2025 · 2025-09

ABSTRACT Dr. Stephanie DeMasi is an academic physician-scientist in the Department of Emergency Medicine at Vanderbilt University Medical Center. Her focus is improving care for patients receiving time-sensitive interventions in the emergency department (ED) and intensive care unit (ICU). To achieve her long-term career goal of becoming an expert acute care clinical trialist, her career development goals are to [1] learn rigorous pragmatic randomized trial design, [2] become an expert in exception from informed consent (EFIC), waiver, and written informed consent processes, [3] develop expertise in the collection and analysis of long-term functional and psychological outcomes after critical illness, and [4] build leadership skills to effectively lead multicenter randomized trials. Research Proposal Summary: Each year in the United States, millions of adults undergo emergency tracheal intubation (placement of a breathing tube). Nearly one quarter of patients undergoing tracheal intubation in an ED or ICU experience hypoxemia, which more than doubles the risk of death. The most common approach to intubation of critically ill adults involves the administration of a sedative followed by neuromuscular blockade (paralysis). The alternative approach of using only sedation for intubation has not been widely used historically because neuromuscular blockade was often needed for the person doing the intubation to see the vocal cords. In the current era, with video laryngoscopy and other advanced techniques, the patient’s muscles do not need to be as relaxed for the vocal cords to be easily visible on the video screen. Therefore, patients may not need to be paralyzed during intubation to achieve adequate visualization of the vocal cords. Avoiding neuromuscular blockade would allow patients to breathe spontaneously during intubation, potentially preventing hypoxemia. No randomized trial has ever compared tracheal intubation using only sedation vs using sedation and neuromuscular blockade among critically ill adults. This career development award application proposes to leverage our group’s research infrastructure to conduct the INtubation with Sedation Only to Preserve Independent Respiratory Effort (INSPIRE) trial, a single- center pragmatic randomized trial comparing the effect of emergency intubation using sedation only versus sedation plus neuromuscular blockade among 228 critically ill adults undergoing emergency intubation on the incidence of hypoxemia (Aim 1a), failure to intubate on the first attempt (Aim 1b), incidence of awake immobility (Aim 2a), and symptoms of PTSD at 90 days (Aim 2b). This application proposes a career development program that will (1) examine a fundamental treatment received by adults with acute respiratory failure, (2) provide the mentored learning for Dr. DeMasi to become a leader in the design and conduct of randomized trials in emergency care, and (3) ideally position Dr. DeMasi to lead subsequent multicenter trials of emergency interventions to improve care and outcomes of critically ill adults going forward.

NIH Research Projects · FY 2025 · 2025-08

The kidney remains understudied as a target organ for in vivo gene transfer leading to a lack of effective gene therapies for kidney disease. Chronic kidney disease (CKD) is estimated to affect 13% of the population worldwide with high mortality and morbidity rates. Many kidney diseases have underlying genetic etiologies that may be amenable by gene therapy or genome editing, underscoring the crucial unmet need for effective and safe kidney-targeting gene delivery vehicles. Cystinuria is a common kidney inborn error of metabolism with existing mouse and canine models providing an ideal disease model for preclinical gene replacement strategies. With the approval of five AAV-based products by the FDA for treating ocular, hematological and neuromuscular disorders, there ~200 completed or active gene therapy trials. However, little progress has been made to date in achieving effective therapeutic gene transfer to kidneys due to the intrinsic filtering function, diverse cell types, complex physiology, and species differences. We have recently demonstrated successful evolution of cross-species compatible AAV capsids. The approach involves iterative evolution in multiple animal models and such new AAV variants could enable better predictive preclinical modeling and improve the therapeutic window of AAV gene therapies in humans. Here, we present promising preliminary results successfully adapting this robust approach to tackle the problem of efficient gene transfer to the kidney in multiple species. The current proposal hinges on understanding the biology of new AAVs in kidney cell types and further engineering features that can improve kidney tropism and decrease liver sequestration, thereby improving kidney targeting and safety (Aim 1). We will also develop these new kidney-tropic AAV vectors for gene transfer to phenotypically correct cystinuria in in vivo mouse models and human kidney organoid models (Aim 2). Using a battery of assays, we will evaluate the ability of gene transfer to prevent disease onset as well as treat the disease phenotype in mouse models. We will also evaluate the ability of new AAV variants and optimized vector cassettes to correct the cystinuria disease phenotype in human induced pluripotent stem cell (hiPSC) derived kidney organoids. Overall, this collaborative proposal between Vanderbilt University Medical Center and Duke University has the potential to be transformative for gene therapy of kidney disorders.

NIH Research Projects · FY 2025 · 2025-08

Modified Project Summary/Abstract Section: Human Immunodeficiency Virus (HIV) infection remains a significant public health problem in the United States (US). Despite the availability of safe and effective HIV treatment (antiretroviral therapy, ART) and prevention (pre-exposure prophylaxis, PrEP), there remains a significant proportion of people living with diagnosed HIV who have not achieved viral suppression and a significant proportion of people at risk for HIV acquisition who have not accessed PrEP. The application of rigorous implementation science (IS) research is needed to address gross inequities across HIV-related outcomes. Effective implementation of HIV diagnosis, treatment, prevention, and response services will allow the US to reduce new HIV infections by 90% by 2030 by enhancing reach, adoption, and maintenance of EBIs. Implementation chasms persist in the HIV prevention and care continuum, in part, because few HIV scientists were adequately trained in, or supported with, real-time IS technical support when conducting complex, multi-sectoral implementation studies. In 2022, both the Emory Center for AIDS Research (CFAR) and Tennessee CFAR were awarded IS Hubs, Directed by Dr. Jessica Sales (MPI) and Dr. Carolyn Audet (MPI), respectively. In this application, our teams have partnered to create the proposed Southeast Regional HIV-IS Consultation Hub. We have assembled an outstanding team consisting of clinic and community training, IS research mentoring, and dissemination experts, making us exceptionally well-prepared and qualified to support the entire academic-community/implementing partner Ending the HIV Epidemic (EHE) grantee team’s needs, support capacity-building around dissemination and transition planning, and collaborate with Hubs and the Coordinating Center (CCDMC) to advance HIV IS science and progress towards EHE goals. We propose to achieve these goals via four aims: (1) Provide needs assessment, consultation, technical assistance, and practical support to EHE funded research projects to bolster successful implementation, dissemination, and transition planning to maximize sustainability and EHE impact. (2) Develop technical support resources to facilitate sustainable IS research capacity. (3) Promote the professional development and capacity-building of stakeholders essential to ending HIV in the US, and (4) Engage in cross-Hub collaborations to collectively advance HIV D&I science to achieve EHE goals. Our innovative focus is to support the IS capacity building needs of the entire EHE grantee team- the academic, community, and clinical implementing partners- to facilitate implementation during the grant period, allow for the creation of a transition toolkit to improve implementation sustainability, and ensure dissemination of successful strategies across the US. These efforts will reduce the “implementation to practice” gaps, resulting in the reduction in health disparities across the entire HIV prevention and care continuum.

NIH Research Projects · FY 2023 · 2025-08

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY The overall goal of the Intersection of Immunity and Cardiovascular Disease (IICD) Program Project Grant is to understand how immune cells are activated and contribute to target organ damage in hypertension and autoimmune diseases. Our overarching hypothesis is that activated immune cells promote renal and vascular dysfunction and damage, promoting vascular and renal disease, blood pressure elevation and worsened autoimmunity. Robust experimental and clinical data indicate that Isolevuglandins (IsoLGs) formed in these conditions alter enzyme and transcription factor function and form antigens that stimulate T cell activation and autoantibody formation. Project 1 director Dr. Harrison has identified specific peptide antigens, and characteristics of class 1 human leukocyte antigens (HLAs) that present these antigens. He will identify T cells and T cell receptors common to experimental hypertension, SLE and psoriasis. The ability of HLAs to present IsoLG-adducted peptides will be evaluated and an unbiased assay will be employed to discover peptides that can activate T cells in human hypertension. In project 2 Dr. Annet Kirabo’s team will examine how salt stimulates IsoLG formation in human salt sensitivity and in the hypertension associated with SLE. She will characterize salt sensitivity using a well-accepted inpatient protocol, and then randomize subjects to a trial of 2-hydroxybenzamine (2-HOBA) for 4 weeks to determine if this improves salt sensitivity and vascular function in these subjects. Dr. Kirabo has developed an innovative animal model involving adoptive transfer of peripheral blood mononuclear cells from humans with SLE to immunodeficient mice, which leads to blood pressure elevations and albuminuria. Preliminary data indicate that salt feeding exacerbates disease in this model, and she will determine if scavenging IsoLGs is protective in these animals and in humans with salt sensitivity. Dr. Michelle Ormseth, the director of Project 3, will conduct a 20-week randomized, placebo-controlled, double-blind, cross-over proof-of- concept phase II study to determine the effect of scavenging IsoLGs with 2-HOBA in humans with SLE. Our early-stage investigator (ESI) and director of Project 4, Dr. Matthew Alexander, has found a marked renal accumulation of granulocytes in a mouse model of psoriasis that is associated with increased cutaneous IL-17A, renal damage and blood pressure elevation. He will define the role of interleukin 17A, IsoLG formation and granulocytes in the hypertension and renal disease observed in these animals using tools employed by other IICD investigators. A major goal of the IICD is to ensure success of our ESI, and we have created a mentoring plan and set aside funding that will enhance his scientific development. The IICD PPG will be supported by an administrative core (Core A), which will also provide biostatistical guidance for all projects, and an Analytical and Biochemical core (Core B) that will provide essential assays and reagents for all projects. Overall, this IICD PPG will provide new understanding of the molecular mechanisms of inflammation in hypertension and autoimmune conditions and identify new therapeutic targets to reduce morbidity and mortality in these devastating illnesses.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY Glioma represents a significant health concern, characterized by alterations in multiple macromolecules and metabolites within the tumor microenvironment. Non-invasive imaging of these molecular profiles could provide invaluable diagnostic insights. Chemical exchange saturation transfer (CEST) is an emerging molecular imaging technique that offers enhanced sensitivity and provides complementary information to magnetic resonance spectroscopy (MRS), with the ability to reflect various molecular compositions within tissues. Amide proton transfer (APT), a primary variant of CEST that reflects mobile proteins, has demonstrated substantial potential for glioma diagnosis. However, despite FDA approval for APT imaging in glioma in 2018, it has not yet been integrated into clinical practice. A clinical trial aimed at differentiating gliomas using APT imaging was halted due to poor image quality, likely resulting from the inaccuracy of existing CEST quantification methods and the inherently low signal-to-noise ratio (SNR) of CEST imaging. Machine learning (ML) has the potential to identify complex features that traditional methods often miss. While ML has been applied to quantify CEST, it faces challenges such as insufficient training data and poor-quality ground truth data when trained using measured in vivo data. Fully synthetic data can mitigate these issues, but practical application remains challenging due to unidentified exchangeable pools and their parameter ranges in tissues. Our project aims to develop a novel platform to generate partially synthetic CEST data for training ML models, thereby addressing these challenges. Preliminary data suggest success in accurately quantifying APT in animal models in preclinical MRI using an ideal steady-state continuous-wave saturation. In Aim 1, we will translate this approach to human imaging at 3T by extending it to the more complex non-steady-state pulsed-CEST imaging typically used in clinical MRI. We will also expand it beyond APT to include amine (glutamate), guanidine (creatine), and nuclear Overhauser enhancement (NOE) effects (large proteins, phospholipids), enabling more generalized CEST imaging of molecular profiles. In Aim 2, we will develop a novel autoencoder-based denoising technique, coupled with an innovative dual-power data preparation strategy, to improve SNR. This strategy leverages the high SNR of higher saturation power and the enhanced peak resolvability of lower power, ensuring effective noise suppression while preserving molecular information. This will make the technique more suitable for low-power applications, which are preferred for imaging multiple CEST effects at 3T. In Aim 3, we will integrate these two ML-based techniques and evaluate their performance in glioma patients. By the completion of this project, we aim to overcome current challenges in CEST imaging, facilitating its widespread clinical adoption and significantly enhancing healthcare outcomes.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY / ABSTRACT As genetic testing becomes more common in medical care, an increasing number of individuals will discover that they carry a pathogenic variant. For some, this result will explain current symptoms and aid in diagnosis. For others, the future health impacts of a pathogenic variant may be less clear, causing uncertainty but also presenting an opportunity to prevent or mitigate serious health outcomes in the future. This uncertainty arises from incomplete penetrance and variable expressivity. Whether a symptom manifests in a carrier depends on numerous individual factors (only some of which are known), creating a dilemma for practitioners regarding whether and how to intervene. Using what we can learn from past clinical experience in variant carrying individuals captured in a growing number of resources like biobanks, we can address this clinical dilemma by creating a machine learning / artificial intelligence (ML/AI) tool that predicts the likelihood a pathogenic variant carrier will develop disease. Building on our extensive experience in creating computable and portable phenotypes from data in the electronic health record (EHR) that accurately represent clinical trajectories in pathogenic variant carriers, we propose to refine our understanding of disease prediction by modeling factors affecting variant expressivity and using longitudinal patient trajectories to identify early, often subtle, phenotypic indicators of disease progression. Finally, we will use a Bayesian transfer learning approach to synthesize multimodal data for generating individualized predictions of risk of key clinical outcomes in the context of a given pathogenic variant. To develop a viable model for clinical translation that addresses the significant risks and challenges associated with developing ML/AI tools, we will employ a knowledge-guided framework that incorporates input from Ethical, Legal and Social Implications (ELSI) experts, clinicians, statisticians, geneticists, and informaticians at every stage of the design process, from defining key clinical outcomes, selecting and engineering model inputs, and developing approaches to communicate predictions to patients and providers. Our framework will allow us to synthesize current knowledge of pathogenic variants with the patterns mined from real-world data while addressing the significant ELSI concerns inherent in ML/AI tool development. Our proposal brings together a transdisciplinary team of experts in informatics, ethics, machine learning, cloud computing, genomics, and clinical medicine, and leverages exceptional local data resources to bring the potential of ML/AI genomic medicine. With this innovative proposal, we aim to create resources that will enable the development and validation of valuable genomic medicine tools for the future.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY: Approximately every fifteen minutes, a child is born in the United States with a congenital heart defect (CHD). The severity of the defect can vary widely, but children will often require invasive surgery for correction of their heart defects. While survival after complex CHD surgery has greatly improved over time, there remains a significant portion of children who do not survive. Reasons for this are multifactorial, but one notable cause is due to the development of severe, life-threatening infections, known as sepsis. Within the postoperative population, there is a subset of patients who have immunological dysfunction that predisposes them to infections. These patients often have persistent inflammation, immunosuppression, and catabolism syndrome (PICS) and are characterized by having a low absolute lymphocyte count (ALC), low albumin and an elevated c-reactive protein as well as a prolonged intensive care unit (ICU) stay. Utilizing an institutional database, we have previously investigated the impact of PICS on all culture-positive sepsis mortalities within a high-volume, single- center children’s hospital over the past 20 years. While a PICS phenotype occurred in nearly one-half of all culture-positive sepsis-related deaths institution-wide, it occurred in nearly three-quarters of the sepsis mortalities in the cardiovascular ICU (CVICU). Based on these findings, we will perform a deeper analysis in two institutional databases to assess the timing and risk of developing PICS with sepsis in the CHD postoperative period. These databases are based on a searchable electronic medical record (EMR) within a single institution stretching back over 25 years. Data comes in the form of structured data points, such as billing codes and encounter dates, semi-structured data such as laboratory results, or unstructured data such as progress reports. Extracted data will be analyzed with the intent of understanding baseline risk and time-to-event analysis of key characteristics and outcomes of the PICS phenotype. Aim 1 will determine the relationship of clinical and genetic variables in CHD patients with PICS postoperatively. Specifically, the association of genetic polymorphisms to postoperative ALC, as well as assessing the general prevalence of PICS within the CHD surgical population and identifying clinical and demographic risk factors associated with phenotype development will be determined. In Aim 2, known risk factors associated with postoperative PICS and sepsis will then be coupled with machine learning (ML) to identify new, previously unidentified risks. Aggregate risk factors will be used to generate prediction models of PICS after CHD surgery that can be embedded within an EMR. The overall goal of these pursuits is to create a better understanding of what features potentially lead to PICS and postoperative sepsis in CHD patients and create a practical clinical prediction tool that offers guidance to researchers and clinicians alike. With a clearer understanding of who might develop PICS in the postoperative period, targeted research questions and proactive treatment modalities can be employed to temper the effect of immune dysfunction in this critically ill and vulnerable population.

NIH Research Projects · FY 2025 · 2025-08

Project Summary Within the clinical research arena, investigators are increasingly expected to share their research data. Enhanced data sharing can enable collaboration and reuse to achieve more scientific goals from the same or decreased funding. Harmonizing disparate datasets can be a challenging and time-consuming process for investigators. Therefore, applying a common data standard as part of the data sharing process can have downstream benefits and efficiency gains. Additionally, investigators conducting regulatory clinical trials must submit study data to the Food and Drug Administration (FDA) following the Study Data Tabulation Model (SDTM) data standard developed by the Clinical Data Interchange Standards Consortium (CDISC). Transforming data from case report forms into a common data standard, such as SDTM, is a resource- intensive process. Up until recently, SDTM dataset preparation has been performed mostly by industry sponsors and clinical research organizations who have sufficient resources to be able to handle this work. However, a growing number of investigator-led studies have FDA submission or National Institutes of Health Data Sharing Policy requirements. Researchers at academic medical centers are finding themselves in a position where they have neither the expertise, nor the resources to prepare SDTM datasets. REDCap is an electronic data capture system that is available at no cost to academic and non-profit institutions and is in use at over 7600 organizations around the world. Since REDCap is already used by academic researchers for data collection and dataset preparation, we hypothesize that a method to map REDCap case report form fields to SDTM data elements will increase the accessibility and uptake of SDTM among academic research organizations by greatly reducing the associated burden. Through the REDCap Standards Mapper (REDSTAMP) project, we aim to 1) develop a coding structure and user interface for researchers to associate REDCap fields to SDTM, and 2) apply the REDSTAMP method to existing International Maternal Pediatric Adolescent AIDS Clinical Trial Network (IMPAACT) studies and CDISC foundational case report forms. We will demonstrate the effectiveness of this method by comparing the SDTM datasets generated by REDSTAMP with those originally produced for those studies by traditional methods. Both the REDSTAMP software and the case report forms with embedded SDTM mapping will be published and shared through REDCap Consortium platforms where researchers can import both directly into their projects. By developing a method where researchers are guided through preparation of a SDTM dataset and can share the mapping with other researchers, this project can promote awareness and expertise for clinical trials data standards. The collective ability to map data to standards will improve the efficiency of regulatory submission and the interoperability and reuse of shared clinical trials data.

NIH Research Projects · FY 2025 · 2025-08

People with HIV (PWH) have a two-fold excess risk of cardiovascular disease (CVD) as compared to those without HIV. Some of this excess risk is due to heavy alcohol consumption. Presently, few therapies exist that effectively reduce alcohol consumption or mitigate alcohol’s harmful effects. Our overarching objective and theme are to conduct clinical trials and observational studies that inform new clinical trials to reduce alcohol consumption or mitigate alcohol’s harmful effects among PWH who are at risk for CVD. Informed by our prior clinical trials and cohort studies, the Southeast Translational Alcohol and HIV Research (STAHR) Center proposes three inter-related projects focused on alcohol, gut dysbiosis and its derived metabolites, glucagon like peptide 1 (GLP-1), inflammation, and CVD risk among PWH. Project 1, GEM HIV, will examine the association between alcohol, gut dysbiosis and dysbiosis derived metabolites, biomarkers of inflammation, gut permeability, CVD risk and endogenous GLP-1 and determine whether a probiotic can increase endogenous GLP-1 levels among PWH who are heavy drinkers. Project 2, GUT CVD HIV, will determine the association between dysregulation of tryptophan catabolism and its metabolites (Kynurenine/Tryptophan, KYN/TRP ratio) and alcohol, senescent T cells, vascular inflammation, and CVD and whether a probiotic can reduce the KYN/TRP ratio, T cell senescence, and vascular inflammation among PWH who are heavy drinkers. Project 3, GL1DER HIV RCT, proposes a randomized clinical trial that will test whether a GLP-1 receptor agonist (semaglutide) versus placebo decreases alcohol consumption, cigarette smoking and CVD risk among PWH. This trial will be conducted at the Tennessee Center for AIDS Research at Vanderbilt University Medical Center (VUMC). Projects 1 and 2 will be ancillary studies to our ongoing META HIV CVD RCT (P01AA029542, PIs Freiberg, Barve). Project 2 will also use Veterans Aging Cohort Study (VACS) data. All projects will be supported by our Administrative (Admin) and Dissemination Cores at VUMC, and the Resource Core at the Norton Research Institute in conjunction with the Integrated Metagenomics and Metabolomics Core at the University of Louisville Alcohol Research Center which is part of the ongoing META HIV CVD RCT. The Admin Core will be responsible for coordinating all study projects and cores, and the Resource Core will provide a unified analytical platform to meet all the technical needs for the data acquisition, generation, management, analysis, and storage needs across the three projects. The Dissemination Core will connect the STAHR Center faculty, staff, and our research with (1) the global scientific community, (2) trainees and health care professionals and (3) the PWH community. IMPACT: This research will advance our understanding of alcohol’s effect on CVD among PWH. If our hypotheses are correct, endogenous GLP-1 and tryptophan metabolites may serve as targets for future RCTs designed to reduce alcohol’s harmful effects on CVD while GLP-1 receptor agonists may ultimately revolutionize care by reducing alcohol and CVD risk among PWH.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY / ABSTRACT Respiratory syncytial virus (RSV) is one of the most common respiratory viruses resulting in significant morbidity and mortality in infants and young children globally. Recent approvals of the world's first maternal vaccine and infant extended half-life monoclonal antibody mean that for the first time, all infants born in the US in 2023 and later will have immunization options for protection from RSV-associated severe illness. The two currently available prevention products differ in target recipients, timing of administration, biologic mechanism of action, and duration of infant protection. As these products have become part of recommended maternal and infant vaccine schedules, key questions needed to inform policy include determining: 1) the real-world comparative effectiveness, 2) the cost-effectiveness of these products, 3) safety of maternal vaccine, and 4) impact on other acute and long-term respiratory outcomes. To address these questions, we propose to assemble a population of over 735,000 mother-child dyads including infants born 2023-2029 utilizing the diverse populations represented by the Tennessee Medicaid Program and Department of Defense Military Health System. The overarching objectives are to determine optimal RSV prevention strategy(ies) taking into consideration infant date of birth relative to RSV circulation, infant risk for RSV LRTI, maternal- child characteristics, and the effectiveness and cost-effectiveness of RSV prevention products in reducing the risk of RSV LRTI, other acute respiratory illness, and later childhood all-cause respiratory morbidity. We will determine the uptake, adherence to policy recommendations, and characteristics of those who receive the approved RSV prevention products (Aim 1), the real-world effectiveness and comparative effectiveness in reducing the risk and severity of RSV LRTI and other acute respiratory morbidities (Aim 2), the effectiveness on reducing later childhood all-cause respiratory morbidity (Aim 3), and the cost-effectiveness in reducing RSV LRTI and childhood all-cause respiratory morbidity (Aim 4) of these RSV prevention products. Socioeconomic associated health disparities at the individual and neighborhood levels in vaccine uptake (Aim 1) and effectiveness (Aims 2 & 3) will be determined. With supply chain limitations affecting the availability of infant extended half-life monoclonal antibody, the 2023-2024 respiratory season presents a unique opportunity to evaluate these disparities in the setting of the initiation of a large nationwide medical intervention. Results of the study will inform public health expectations and policy recommendations for RSV maternal vaccines and extended half-life monoclonal antibodies, and more importantly, identify and quantify any value-added long- term benefits of RSV LRTI prevention during infancy on later childhood respiratory morbidity. We anticipate that this will in turn increase public acceptability, promote uptake of RSV prevention products in the US, and provide data to support the acute and longer-term benefits of these prevention products worldwide, promote uptake of these products worldwide and particularly in low- and middle-income countries.

NIH Research Projects · FY 2025 · 2025-08

Project Summary Positron Emission Tomography (PET) is an imaging modality that can be used to visualize and quantify functional changes and the distribution of molecular markers in the body. PET utilizes molecules that are labeled with positron-emitting isotopes (radiotracers), which are typically produced via automated synthesis modules. Carbon-11 (11C) is a particularly important PET radionuclide, as virtually all organic molecules contain carbon atoms. Because 11C has the same properties as carbon-12, labeling with 11C is extremely useful as a radionuclide for exploration of molecules as PET radiopharmaceuticals for exploration of their in vivo properties (metabolism, binding, pharmacokinetics, etc.). Furthermore, the short half-life of 11C (20.3 min) allows for the possibility of multiple molecular imaging studies on the same day, simplifying the logistics and recruitment for clinical research studies. Traditionally, 11C is installed with either [11C]Mel or [11C]MeOTf as synthons due to their straightforward production from cyclotron-produced [11C]CO2. Recently, researchers have begun to use [11C]CO2 directly to form ureas and carbamates, but exploration into use of [11C]CO2 for methylation has been extremely limited. In this proposal we will: 1) Develop and optimize direct use of [11C]CO2 reductive methylation method for heteroatoms using a silicon-hydride reduction system. It is expected that this approach will provide facile and rapid access to 11C-radiopharmaceuticals with a broad substrate scope; 2) Develop a site-specific labeling method using iminophosphorances and [11C]CO2 that will allow for 11C-methylation in the presence of multiple reactive sites; 3) Extend this direct [11C]CO2 methylation methodology to carbon-nucleophiles to allow for direct carbon methylation using [11C]CO2. Development of these radiosynthesis methods will allow for more reliable and straightforward 11C-labeling strategies, reducing the development timeline for new 11C-radiopharmaceuticals and improving the radiochemical yields.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY: The Centers for Disease Control in the US reports that more than 15% of adults over the age of 18 suffer from hearing loss, making it the third most prevalent chronic disease, more common than diabetes or cancer1. While hearing aids and cochlear implants are available, they do not always provide benefit to patients, and they fail to reverse the underlying pathology of hair cell loss. Much of what is known about the inner ear’s molecular architecture is based on animal models. Key unanswered questions remain about the genetic architecture and molecular mechanisms of transcriptional control within the adult human inner ear. Unlike any other organ in the body, the human inner ear cannot be biopsied in living individuals without making the organ completely non-functional. While there are established temporal bone laboratories throughout the US focused primarily on temporal bone histopathology, there remains a large gap in access to living inner ear samples. In this proposal, we have established a collaborative team of surgeons, scientists, and surgeon- scientists to create a molecular and physiologic biorepository of the human inner ear at unprecedented scale. This will include primarily inner ear tissues that are comprised of the cochlea and the vestibular apparatus. We will also collect non-invasive physiologic data such as otoacoustic emissions. The purpose of the study is to identify the normal physiology and molecular architecture of the human inner ear. Our ultimate goal is to determine whether what we know about mammalian inner ears from animal models is true in humans and identify potential therapeutic targets for patients with hearing loss and vestibular disorders. Specific Aim 1: Establish pipeline of human vestibular epithelia for in vitro modeling. We will establish a pipeline from the operating room to the laboratory to collect utricles, saccules, and ampullae. Two sources will be utilized: patients undergoing ablative therapies of the inner ear and lateral skull base, and organ donor tissues. Our experiments will consist of histology, single cell transcriptomics, spatial transcriptomics, and in vitro cultures for perturbations. Specific Aim 2: Characterize the physiologic and molecular composition of the human cochlea. The adult human cochlea remains one of the most inaccessible organs. While there are many samples in the archives of established temporal bone laboratories comparing audiometry and histopathology, to the best of our knowledge, there is currently no direct physiologic and molecular measure of the human cochlea. We aim to establish a pipeline for performing otoacoustic emissions on organ donors followed by harvesting the cochlea. Histologic, single cell transcriptomic, and spatial transcriptomic characterization of the cochlea will be directly correlated with physiologic measurements. By creating a biorepository of human inner ear tissues, this project will enable a range of studies that can dramatically advance our understanding of the molecular mechanisms at work in the adult human inner ear.