Vanderbilt University Medical Center

NIH Research Projects · FY 2025 · 2025-05

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

NIH Research Projects · FY 2026 · 2025-04

Psoriatic arthritis (PsA) is characterized by dactylitis, enthesitis, synovitis, and bone erosions, leading to significant morbidity and disability. Current treatment strategies targeting inhibition of TNF, IL-23, IL-17A, JAKs, or PDE4 inhibitors slow down but do not prevent, PsA pathogenesis. Similarly, treatment with the T cell targeted therapy cyclosporine has limited efficacy on PsA symptoms and progression. These findings suggest that other cell types or inflammatory proteins contribute to PsA pathogenesis. B cells are present in PsA patient synovial fluid and colocalize with T cells in PsA synovial tissue, consistent with ectopic lymphoid neogenesis. In this immune cell-dense region, B, T, and antigen-presenting cells interact to modulate and drive inflammation. PsA patients treated with rituximab, a B cell inhibitor, have improved arthritis clinical outcomes. Despite these observations, it remains unclear how B cells contribute to the pathogenesis of PsA. We recently engineered a mouse model of PsA (called Klk6+) that spontaneously develops a phenotype modelling human PsA, including dactylitis, enthesitis, synovitis, and radiographic erosive changes to the axial and appendicular skeletons. Klk6+ mice have decreases in anti-inflammatory IL-10+ Breg cells and increases in proinflammatory IL-6+ Beff cells that occur concomitant with increases in Th1 and Th17 cells, paralleling findings reported in PsA patients. Thus, the Klk6+ PsA mouse model represents a highly relevant model for studying B cell contributions to inflammatory arthritis and uniquely positions us to delineate the mechanisms by which this occurs. Using Klk6+ animals and samples obtained from PsA patients, we will test the conceptually innovative hypothesis that decreases in anti-inflammatory IL-10-producing Bregs and increases in proinflammatory IL-6- producing Beff cells promote Th17 cell inflammation and PsA development. Using a combination of innovative mouse molecular genetics approaches, cutting-edge single-cell sequencing and spatial transcriptomics, CyTOF, flow cytometry, and careful examination of improvement in individual PsA domains in mice, we will: 1. demonstrate that the PsA phenotype observed in Klk6+ mice is mediated by proinflammatory IL-6-producing Beff cell populations that promote Th17 and Th1 T cell inflammation and loss of the anti-inflammatory IL-10-producing Breg population; 2. elucidate the cellular and molecular mechanisms by which this occurs and 3. translate these findings to PsA patients. Collectively, our studies will identify B cells as new pathogenic contributors to PsA etiology and will identify the cellular mechanisms mediating B cell-T cell interactions that promote inflammatory arthritis. Our ability to translate and confirm our findings in PsA patients may lead to a paradigm shift in understanding PsA pathogenesis and the repurposing of existing FDA-approved drugs for treating PsA.

NIH Research Projects · FY 2026 · 2025-04

Our proposal addresses an urgent need to mitigate the long-term morbidities of cancer treatment. Breast cancer is the most common cancer in the US, with approximately 310,000 new cases diagnosed annually. Over half of all breast cancer patients undergo radiation therapy, which improves both local control and overall survival. However, radiation therapy, especially to the left breast, increases the incidence of ischemic heart disease. Patients receiving radiation therapy to the left breast have a 50% increased rate of major coronary events over the next 20 years. Cardiac toxicity from radiation therapy remains a major patient safety concern. Deep inspiration breath hold (DIBH) is a method used to extend the chest wall away from the heart during radiation therapy; this is achieved by coaching patients to hold a deep breath as radiation is delivered. DIBH can significantly reduce the mean radiation dose to the heart. Yet, it is challenging for patients and radiation therapy teams to execute consistently over a 3-to-5 week treatment course. DIBH variability leads to excessive cardiac toxicity as well as decreased patient and care team satisfaction. Currently, patients receive minimal training on DIBH. We propose to develop a personalized, patient-centered anatomy informed system, BReaTHS, to support optimal and consistent execution of DIBH. Patients will use BReaTHS to practice DIBH at-home and continue using the system during treatment to ensure reproducible DIBH. The system will include video display glasses to provide visual feedback and a respiratory sensor belt to measure real-time patient breath volume. The Specific Aims are: Aim 1: Refine and evaluate the personalized system using rigorous human-centered design methods. To optimize our existing prototype, we will conduct interviews, design sessions, and formative and summative usability testing. Throughout this process, we will engage breast cancer survivors who used DIBH during radiation therapy treatment to ensure the system is patient-centered. Aim 2: Pilot test the system’s effectiveness and acceptance with breast cancer patients and with radiation therapy teams. We will conduct a pilot randomized controlled trial with 24 left-sided breast cancer patients. Our primary outcome will be DIBH consistency and treatment duration. Secondary outcomes will be maximum and mean cardiac dose, duration of breath holds, patient anxiety, fatigue, and engagement throughout treatment, and patient and clinical team acceptance. We propose the development of a patient-centered, anatomy-informed training system can improve deep inspiration breath holds and reduce the long-term cardiac toxicities of radiation therapy. This work is aligned with NCI’s priorities outlined in the National Cancer Plan, including optimizing the delivery of care that is patient-centered and reduces the morbidity of cancer. Future work will include a multi-site randomized controlled trial to further evaluate the system’s effectiveness on patient care and outcomes.

NIH Research Projects · FY 2026 · 2025-04

PROJECT SUMMARY Interactions between the genome and environment can be assessed through examination of metabolic profiles. As the development of asthma is highly influenced by genetic and environmental factors, assessment of meta- bolic profiles can improve our understanding of disease pathogenesis. We have demonstrated that select me- tabolite concentrations at birth are associated with risk of early life wheezing and asthma. Further, we have identified genetic pathways linking birth metabolic profiles with childhood asthma. While these findings shed some light on biologic processes leading to asthma development, we do not understand intermediary pro- cesses, such as gene expression within specific tissues, that may identify and allow targeting of disease-caus- ing pathways. Placental changes have been shown to be associated with certain diseases in childhood. How- ever, very little is known about the impact of placental changes in the development of childhood asthma. Given the immunomodulatory and metabolic role of the placenta and its importance in mitigating adverse effects from the environment, this organ is likely to play an important role in asthma susceptibility and resilience. The overall objective of this proposal is to elucidate placental-specific transcriptomic pathways impacting the metabolome and underlying childhood asthma pathogenesis. The rationale is that identifying relationships be- tween placental-specific transcriptomic pathways, newborn metabolism, and childhood asthma will expand our understanding of the fetal programming of asthma, highlight an asthma-relevant tissue, and identify target genes for prioritization of future functional characterization. We will pursue the following specific aims: 1) deter- mine associations between predicted gene expression in human placenta and early life wheezing and asthma- related newborn metabolite concentrations, and 2) determine associations between placental predicted expres- sion and early life wheezing and asthma and estimate the effect of placental predicted expression on childhood asthma that is mediated through newborn metabolite concentrations. To achieve Aim 1, we will generate pla- cental gene expression data from an ongoing pregnancy cohort and regress predicted expression on metabo- lite concentrations using genotypes and targeted newborn metabolites from a prospective birth cohort. To achieve Aim 2, we will utilize placental expression data outlined in Aim 1 and wheezing and asthma summary statistics from large GWAS to determine associations between placental predicted gene expression and wheezing and asthma. We will then perform a mediation analysis using findings from our previous work and findings from Aims 1 and 2A to estimate the fraction of the effect of placental gene expression on childhood asthma that is mediated by newborn metabolite concentrations. Potential impact: Successful completion of the proposed research will provide important insights on the role of the placenta in the development of childhood asthma and identify potential targets for prevention. As asthma is among the most prevalent chronic diseases of childhood, development of effective prevention strategies could have enormous public health impact.

NIH Research Projects · FY 2026 · 2025-03

1 This research proposal investigates the role of Glutathione Peroxidase 3 (GPX3) in regulating 2 esophageal epithelial remodeling, subepithelial fibrosis, and eosinophil recruitment, all histologic 3 features characteristic of Eosinophilic Esophagitis (EoE). In order to maintain esophageal 4 epithelial homeostasis, reactive oxygen species (ROS) might be tightly regulated, and GPX3 is 5 crucial in this process as it catalyzes the reduction of ROS. We have demonstrated that in the 6 esophagus, GPX3 is expressed most highly in differentiated epithelial cells but is also expressed 7 by fibroblasts. In patients with EoE, GPX3 is reduced in these same cell types as compared with 8 non-EoE controls, and IL-13, which induces a large percentage of the epithelial transcriptional 9 changes in EoE, reduces GPX3 and glutathione peroxidase enzymatic activity in epithelial cells. 10 Consistent with these observations, the esophagus of Gpx3-/- mice exhibits histologic features of 11 EoE, including increased basal cell thickness, epithelial proliferation, expansion of transitioning 12 cells, and subepithelial fibrosis. Similarly, Gpx3-/- three-dimensional ex vivo esophageal organoids 13 phenocopy the same epithelial changes seen in mice. Additionally, we have shown that a 14 reduction in GPX3 results in increased susceptibility to activation of signaling pathways central to 15 EoE pathogenesis. Knocking down GPX3 in an esophageal epithelial cell line results in increased 16 activation of STAT6 after IL-13 treatment, suggesting that GPX3 dampens immunoactivation and 17 reduces eosinophil recruitment. Gpx3-/- esophageal organoids and fibroblasts both secrete 18 increased TGF-b1 as compared with wild-type (WT), and organoid culture media from Gpx3-/- 19 results in increased contraction of WT fibroblasts suspended in collagen. Collectively, these data 20 suggest that both epithelial and fibroblast GPX3 may contribute to subepithelial fibrosis through 21 activation of the TGF-b1 pathway. This is important not only because TGF-b1 is a significant driver 22 of fibrosis in EoE, but also because it suggests that the epithelium and subepithelium may be a 23 critical source of TGF-b1 in addition to immune cells. While it is clear that GPX3 is important in 24 regulating esophageal epithelial and subepithelial phenotypes, what is unclear is the mechanism 25 underlying how GPX3 alters these processes critical for EoE pathogenesis. Thus, the aims of this 26 proposal are 1) to determine the mechanism by which GPX3 regulates epithelial remodeling, 2) 27 to dissect how GPX3 regulates eosinophil recruitment and subepithelial fibrosis, and 3) to 28 leverage this information as a therapeutic for EoE. By uncovering a deeper understanding of the 29 molecular function of GPX3 and its regulatory networks, we will discover fundamental insights 30 into EoE pathogenesis, offering potential therapeutic strategies.

NIH Research Projects · FY 2026 · 2025-03

Unnecessary antibiotic prescribing is a potentially avoidable source of iatrogenic harm, particularly in unscheduled outpatient care settings. Urgent outpatient care visits for acute upper respiratory infections (URIs) account for approximately 40% of all outpatient antibiotic prescribing, contributing to the high rates of antibiotic- associated adverse events and the global threat of antimicrobial resistance. Seen in emergency department (ED), retail clinic, and walk-in clinic settings, an estimated 23%–51% of all outpatient antibiotic prescriptions for URIs are unnecessary. Despite the recognized effectiveness of interventions based on audit and feedback and clinical decision support systems embedded in electronic health records for improving clinician behavior, existing antimicrobial stewardship programs are hampered by frequent underperformance and lack of sustainability of multifaceted, complex interventions because of the time-pressured nature of urgent clinics, lack of patient continuity, failure to consider clinician workflow, lack of usability of electronic tools, and inability to scale successful interventions. Our interdisciplinary team of experts in emergency medicine and infectious diseases, human factors engineering, biomedical informatics, clinical trials, biostatistics, and implementation science employed user- centered design to develop and pilot the Care, Review, Assessment and Feedback Tool (CRAFT) to provide automated feedback on patient outcomes and clinical processes of prescribing in urgent outpatient care settings as part of a Department of Veterans Affairs (VA)-funded grant. In addition to automated feedback, the intervention included clinician education through academic detailing, leadership engagement, clinical champions, and non-financial incentives. In the proposed CRAFT-IAR (CRAFT bundle In Acute Respiratory infections) study, we seek to adapt this intervention to a new healthcare system outside the VA, add electronic clinical decision support, and examine the effectiveness of the CRAFT bundle on antibiotic prescribing in a hybrid type 1 randomized clinical trial in a total of 31 EDs, retail clinics, and walk-in clinics across a single non-VA healthcare system in Middle Tennessee with over 90,000 annual acute URI visits and a potentially inappropriate prescribing rate of 27%, pursuing the following Aims: 1) Engage EDs, retail clinics, and walk-in clinics to understand workflows and implementation climate. 2) Adapt, refine, and implement the CRAFT bundle. 3) Examine the effectiveness and implementation of the CRAFT bundle vs. usual care antimicrobial stewardship on antibiotic prescribing and implementation outcomes for patients with acute URIs in unscheduled outpatient clinic visits. The advanced development and scalability of the previous iteration of the CRAFT bundle, our team’s expertise in clinical decision support development, and the engagement of operational leaders makes this important and minimal risk trial highly feasible and ready for evaluation in a real-world environment.

NIH Research Projects · FY 2026 · 2025-02

PROJECT SUMMARY Glaucoma is the world’s leading cause of irreversible blindness, which evolves from degeneration of retinal ganglion cells (RGCs) and their axons which form the optic nerve. Glaucoma is characterized by sensitivity to intraocular pressure (IOP), with susceptibility increasing with age. Current treatments lower IOP to relieve stress to RGC axons, but many patients continue to lose vision. Thus, an unmet clinical need is a treatment that addresses RGC degeneration directly. Our long-term goal is to probe the mechanisms of RGC degeneration in glaucoma to identify novel therapeutic targets to protect and potentially restore vision. The objective of this proposal is to investigate the potential role of the cyclic nucleotide guanosine monophosphate (cGMP) in countering RGC degeneration in glaucoma. Glaucoma involves complex pathogenic processes in the retina and optic nerve. These include interactions between RGCs, astrocyte glia, and microvascular elements, which is our focus here. cGMP is a vasoactive second messenger produced by the nitric oxide (NO)-sensitive enzyme soluble guanylate cyclase (sGC, referred to in this proposal as GC1), which relaxes vascular smooth muscle tissue to increase blood flow. Longstanding evidence suggests that cGMP signaling is impaired in glaucoma. Patients show decreased ocular cGMP, while polymorphisms in genes encoding GC1 lead to increased incidence of glaucoma with early paracentral visual field loss. Our published work demonstrates that aberrant cGMP signaling induced by global knockout of GC1 (GC1-/-) leads to gross morphological abnormalities in retinal astrocyte and vascular networks that precede age-related RGC degeneration. Finally, increasing cGMP with a PDE-5 inhibitor (tadalafil) protects RGCs in multiple murine models of glaucoma. Based on these findings, this proposal will test the central hypothesis that disrupted cGMP signaling in glaucoma degrades astrocyte-vascular networks, leading to RGC metabolic stress and subsequent axon degeneration. As a corollary, we will test whether increasing cGMP signaling specifically in either astrocytes or RGCs slows progression. This hypothesis is supported by preliminary data that show aging GC1-/- mice exhibit (1) reduced retinal glucose uptake coincident with decreased glucose transporter-1 (GLUT1) and mitochondrial proteins and (2) increased RGC oxidative stress and RGC degeneration. Here we will discern age vs. IOP-dependent effects of cGMP signaling by combining cell-specific transgenics and viral-targeted gene disruption with imaging, electrophysiology, and visual function testing in our microbead occlusion model in mice. In Aims 1 and 2 we investigate how cGMP signaling alters astrocyte and vascular cellular connectivity, and RGC mitochondrial function and oxidative stress. In doing so, these experiments will reveal novel cell-specific roles of cGMP in the retina that may be targeted therapeutically to preserve vision in glaucoma by abating RGC degeneration, possibly by boosting mitochondrial function and reducing metabolic stress – in Aim 3 we test this possibility.

NIH Research Projects · FY 2025 · 2025-02

Viruses are responsible for significant morbidity/mortality at the heart of most of global pandemics of the 21st century. Recent developments in technical and bioinformatic capabilities to address viral sequence diversity in a high-throughput context alongside integrated host responses have ushered in the potential for investigating viral presence and consequences at epidemiologic scale. Here, we establish the Vanderbilt-coordinated Virus Characterization Center (V2C2) to respond to RFA-RM-23-019 to address the central call of the Human Virome Program (HVP)—to provide a comprehensive, annotated, host-contextualized virome. The central theme/hypothesis of V2C2 is that unrecognized eukaryotic/prokaryotic viruses in human ecology (1) exhibit important interactions with host biology and flora, with prevalence of viral persistence or integration related to variation in biologically relevant phenotypes in healthy individuals (e.g., obesity, inflammation). To address this hypothesis, we will study (1) ≈2250 Hispanic/Latinx individuals at the US-Mexico border (ages 8-90; 1750 with 2 serial samples already collected with up to ≈20 years follow-up; 500 with 3 serial samples to be prospectively collected over ≈4 years); (2) ≈200 children (ages 0-5, CANOE-VU) with serial samples (some already collected). We propose a broad sampling scheme for prospective samples, spanning ocular, nasal, oropharyngeal, plasma, blood (extracellular vesicles, PBMCs, platelets), urine, and stool samples, and accompanying placental and breast milk samples (pediatric cohort), and will prioritize plasma (all samples) and 3 additional sample types (prospective only) based on consortium discussion. Our host-contextualized viral characterization approach (Aim 1) will include viral whole metagenomic/metatranscriptomic sequencing (to assess viral presence, function) with targeted capture-based confirmation. With other HVP members (e.g., Functional Interaction awardees), we will study host-viral interactions (Aim 2) via (1) host genomics (for integration); (2) viral tropism studies (using single cell and in vitro infection studies); (3) host response characterization (at the cellular and organism-wide level with proteomics/transcriptomics). In Aim 3, we will establish a repository of harmonized metadata and molecular information for data sharing in an ethically responsible manner to allow multi-omic connections between longitudinal phenotypes and host-viral characteristics. We will execute this vision collaboratively within the HVP via (1) a core structure (led by administrative) that addresses biospecimen collection, assay, data analysis/submission, and ethical/legal/social implications that (2) follow a pre-determined series of milestones (predicated on establishing consortium-wide protocols in the initial 6 month planning phase). V2C2 leadership has (1) published expertise in large sample viral characterization/biological discovery, with extensive preliminary data bearing directly on HVP; (2) cohort epidemiology; (3) extensive consortium experience in NIH, CDC, and Common Fund initiatives. The effectiveness of V2C2 is augmented by strong community engagement (CCHC), institutional support, and program management staff with experience at the scale of HVP.

NIH Research Projects · FY 2026 · 2025-01

PROJECT SUMMARY Drug reaction with eosinophilia and systemic symptoms (DRESS) is a life-threatening severe cutaneous adverse drug reaction (SCAR). Vancomycin is the first-line treatment for multidrug-resistant gram-positive bacteria and is the most common drug associated with DRESS in the United States (US). Vancomycin DRESS is strongly associated with HLA-A*32:01, and approximately 20% of patients carrying HLA-A*32:01 develop DRESS after more than 2 weeks of vancomycin exposure. This underscores a vital knowledge gap that exists for all HLA- associated SCAR: what co-morbidity, genetic, and other multi-omic risk factors that interact with and without HLA confer susceptibility or resistance. By leveraging electronic health record (EHR) linked DNA biobanks, this project will discover co-morbidity, genetic, multi-omic, and other risk factors for vancomycin DRESS through an innovative translational bioinformatics approach to inform mechanisms of drug hypersensitivity and tolerance. In this K08 proposal, I will undertake critical training for my long-term career goal of bringing precision medicine to SCAR and other allergic/immunologic conditions by developing and applying expertise in allergy/immunology, immunogenomics, and translational bioinformatics. The project will be completed under the guidance of my primary mentor Dr. Elizabeth Phillips, and a Research Advisory Committee of experts in bioinformatics and immunogenomics. By integrating targeted immunogenomic typing, including HLA, KIR, and ERAP and GWAS- level genotyping, I will discover epistatic interactions of HLA/KIR/ERAP and multi-omic variation in vancomycin DRESS, which has the potential to apply to other allergic and immune-mediated diseases such as cancer, autoimmune and infectious diseases. My mentored research project has two specific aims: Aim 1: Develop EHR phenotyping algorithms to identify DRESS cases and utilize machine learning on routine laboratory values to develop predictive models for earlier diagnosis. Aim 2A: Confirm the association of HLA-A*32:01 and vancomycin DRESS in a large prospective cohort; discover additional genetic variation outside of HLA through GWAS and targeted immunogenomic typing; and, importantly, assess the generalizability of the HLA-A*32:01 association to diverse populations in other EHR biobanks. Aim 2B: Perform multi-omic analyses and causal discovery methods to test the hypothesis that genetically regulated transcriptomic, proteomic, and metabolic traits vary between vancomycin DRESS cases and vancomycin-tolerant controls. Through the skills and mechanistic insights gained by this career development award, I will develop a research niche to design and implement future studies on SCAR and other allergic/immunologic diseases that leverage translational bioinformatics in diverse EHR biobanks, such as the NIH’s All of US cohort, eMERGE Network and others across the US and globally. Through this career development award, I will gain the foundation to independently lead a multi-disciplinary research team in future R01 proposals to bring precision medicine approaches to SCAR that will translate to strategies for prevention, earlier diagnosis, and targeted therapies.

NIH Research Projects · FY 2026 · 2025-01

ABSTRACT The proposed K23 Career Development Award will enable Dr. Colin Orr to become an independent physician- researcher with expertise in food insecurity and childhood obesity prevention. Dr. Orr is a general pediatrician whose long-term goal is to design, test, and implement interventions to address food insecurity and promote optimal nutrition and healthy weight gain in children. His strong methodologic background, combined with his experience and knowledge of health disparities among racial and ethnic minority groups, makes him an ideal candidate to conduct the proposed research. Dr. Orr’s preliminary work has described the cross-sectional impact of food insecurity on parent feeding behaviors and child health outcomes. Dr. Orr’s research will contribute to the science of obesity prevention by examining the longitudinal relationships, if any, between food insecurity, parental feeding behaviors, and childhood obesity. Specifically, his proposed research has the following aims: 1) To examine the association between change in food insecurity and change in parental feeding behaviors in a cohort; 2) To assess parents’ knowledge, attitudes and understanding of feeding behavior and food insecurity, and how these relate to childhood obesity; and, 3) To develop the NCCARE360+Peer Parent Coach (PPC) intervention and conduct a pilot randomized controlled trial (RCT) that evaluates the intervention’s feasibility and acceptability. The pilot study will serve as preliminary data for a subsequent R01. To conduct this research, Dr. Orr has assembled a team of mentors and collaborators who will guide him in accomplishing the following training goals: 1) Learn casual inference, longitudinal analysis, and qualitative methods to examine how food insecurity influences child health over time and acquire the skills to design and execute qualitative studies to guide intervention development; 2) Learn behavior change theories to inform development of a peer support intervention; and 3) Gain training in implementation science to guide implementation of interventions. Dr. Orr’s mentorship team will meet with him regularly, provide additional content expertise in writing manuscripts and R01 and equivalent grants, and will ensure his progress toward his research aims and training goals. Dr. Orr’s career development will be supported by coursework at the Gillings School of Global Public Health at the University of North Carolina at Chapel Hill. Dr. Orr’s work aligns with the National Institute of Diabetes and Digestive and Kidney Diseases Strategic Plan to support research that aims to prevent chronic diseases, such as obesity and diabetes, in racially and ethnically diverse patient populations. His proposed research has high potential for public health impact, given the high prevalence of food insecurity and childhood obesity and the urgent need for well-designed interventions to address these problems in racial and ethnic minority populations. The proposed K23 award will enable Dr. Orr to take important next steps in his career development and position him as an independent investigator with expertise in testing, implementing, and evaluating innovative solutions to address food insecurity and obesity in children.

NIH Research Projects · FY 2026 · 2025-01

Alzheimer's Disease and Related Dementias (AD/ADRD) are common progressive conditions that damage critical mental functions, causing significant emotional, physical, and financial burdens. Currently, there is no cure for AD/ADRD, nor a drug to delay the onset of the disease. New drugs targeting AD/ADRD have had a 99% failure rate, largely attributable to incomplete biological knowledge, an emphasis on testing single therapies, a lack of predictive validity in animal models, and unacceptable adverse effects. Drug repurposing--identifying new uses for existing drugs--offers an alternative approach that can reduce the time, costs, and risks of failure associated with new drug development. Indeed, genetic research and large biobanks have accumulated a wealth of relevant data for AD/ADRD drug repurposing efforts. However, given the complexity of AD/ADRD pathogenesis, standard efforts to identify and prioritize drug repurposing candidates for downstream analyses have not yielded success; these repurposing efforts generally arise from basic science or clinical observation and result in a one-at-a-time approach focused on candidate validation in clinical trials. Such efforts ignore the opportunities provided by big data (e.g., genetics and electronic health records) for identifying and validating candidates. The lack of standardized approaches to systematically screen and validate drug repurposing candidates represents a critical barrier to the success of leveraging existing public knowledge and clinical data to advance AD/ADRD treatment. We propose integrating genetics, transcriptomics, literature, and clinical data with advanced informatic technologies and computational capabilities to develop and share tools which systematically screen, prioritize, and validate drug repurposing candidates and their combinations for AD/ADRD. The proposal responds to PAR-22-093, incorporating several emphases highlighted in related notices of interest (e.g., NOT-AG-21-045, NOT-AG-21-033, and NOT-AG-21-050). In Aim 1, we will systematically screen and prioritize drug repurposing candidates for AD/ADRD via both virtual transcriptome and Mendelian randomization, validating the candidates in multiple large clinical datasets. In Aim 2, we will identify, assess, and validate candidates from the literature. In Aim 3, we will evaluate and validate combinations of drug repurposing candidates. For all validations, we will assess the candidate drug/drug pair’s benefits for prevention (i.e., pre-morbidity exposure) and treatment (i.e., post-morbidity exposure), including analyses stratified by dose, sex, and race. In Aim 4, we will make our findings, including deployable tools and codes, broadly available on the AD Knowledge Portal and related websites to facilitate future research.

NIH Research Projects · FY 2026 · 2025-01

Summary: The heme metabolite unconjugated bilirubin is toxic at high levels, but also has beneficial effects when slightly elevated within the normal range as seen in Gilbert’s syndrome, with benefits including protection from diabetic kidney disease and chronic kidney disease. These benefits had been attributed exclusively to the antioxidant properties of bilirubin, however several lines of evidence suggest not all bilirubin effects can be explained by antioxidant effects, and bilirubin can trigger receptor-mediated events. Thus, it remains unclear how bilirubin elicits beneficial effects protecting from kidney diseases. We recently discovered unconjugated bilirubin activates Liver Receptor Homolog-1 (LRH-1, NR5A2), a nuclear receptor expressed in the adult human liver and kidneys. A clear role for this new bilirubin-LRH-1 axis has not been established, and LRH-1 functions in the kidney remain almost completely uninvestigated. We hypothesize LRH-1 directly senses bilirubin levels to mediate specific beneficial effects of mildly elevated levels of bilirubin in the human liver and kidneys. A novel approach recently developed by our group permits studying LRH-1 in any human model, including primary human cells. After developing this powerful approach, we now seek to apply it to study diabetic and chronic kidney disease, and in pioneering studies of LRH-1 function in the kidney, which is almost completely uninvestigated. The first aim determines how toxic levels of bilirubin are sensed in primary human hepatocytes to activate basolateral bilirubin efflux pumps, a process that induces jaundice in human patients. The second aim determines how beneficial levels of bilirubin are sensed by human kidney organoids, and will be the most comprehensive analysis of LRH-1 function in the kidney to date. The final aim will determine how nuclear receptors mediate these responses in the liver and the kidneys at the molecular level. Together, this proposal will elucidate how both the toxic and beneficial levels of bilirubin regulate liver and kidney function in primary human cells and organoids, using unique approaches our group has previously developed, and now seek to apply to understanding LRH-1 function in the kidney.

NIH Research Projects · FY 2026 · 2025-01

PROJECT SUMMARY Altered reward signaling plays a key role in multiple Parkinson’s disease nonmotor symptoms including depression, apathy, and impulsive and compulsive behaviors. Moreover, therapies for Parkinson’s disease including dopaminergic medication and deep brain stimulation have been associated with both pathologic increases and decreases in reward guided behaviors. Unfortunately, symptoms of altered reward signaling such as depression, apathy, and impulsive and compulsive behaviors lack effective therapies. A better understanding of the neural signaling underlying reward signaling is crucial to developing better treatments for these disorders. This proposal for a mentored clinician scientist research career development award for Dr. Sarah Bick capitalizes on access to human intracranial recordings in neurosurgical procedures to characterize reward signaling neurophysiology in the subthalamic nucleus and dorsolateral prefrontal cortex. Dr. Bick has previously demonstrated that subthalamic nucleus and dorsolateral prefrontal cortex beta power increase during reward and that dorsolateral prefrontal cortex reward related power is associated with depression and apathy. The specific aims of the present study are to 1) characterize neurophysiology correlates of reward signaling in subthalamic nucleus and its connectivity with dorsolateral prefrontal cortex, 2) determine how acute subthalamic nucleus stimulation perturbs reward signaling, and 3) determine how chronic STN stimulation alters reward signaling. Dr. Bick’s long-term goal is to develop improved neuromodulation strategies for cognitive and psychiatric disorders such as Parkinson’s disease nonmotor symptoms. To accomplish this, her objectives during the period of this award are: 1) to develop expertise in advanced computational techniques such as machine learning to apply to neurophysiology analysis, 2) to gain experience with neurophysiology connectivity analysis, and 3) to learn analysis methods for MRI structural connectivity. VUMC is the ideal environment to foster her development into an independent investigator studying the neurophysiology of cognitive and psychiatric processes in order to develop novel neuromodulation techniques. The environment includes a strong team of NIH funded mentors and advisors with expertise in neurophysiology, advanced computational techniques, structural connectivity, engineering, and Parkinson’s disease, a high clinical volume of the patient population needed to recruit study subjects, and strong institutional resources to support career development of physician scientists. The project will thus provide a platform for Dr. Bick to establish preliminary data and critical research skills to launch an independent research career.

NIH Research Projects · FY 2026 · 2025-01

PROJECT SUMMARY The overall objective of this work is to apply innovative neuroimaging methods of cerebrospinal fluid (CSF) production, transport, and resorption in patients with Huntington’s disease (HD) to test fundamental hypotheses regarding the sequelae of aberrant neurofluid circulation in HD participants. New intrathecally administered ASOs have gained great interest as a disease-modifying treatment in HD, and yet in HD, these interventions have resulted in increases in neurofilament light protein (NfL) levels, and greater ventricular volumes. Importantly, post-hoc data indicates some may benefit from these interventions, and new trials are being developed. Heterogeneity in treatment response may be explained by CSF flow dysfunction. The recent proposal of the glial-lymphatic system has highlighted the importance of neurofluid circulations. For instance, the current paradigm describes CSF circulation as a combination of perivascular, interstitial, and bulk flow pathways. The CSF is produced by the choroid plexus (ChP) complexes, traverses the brain parenchyma along peri-arterial and peri-venous pathways, and exits the brain along parasagittal dural (PSD) space, cranial nerves and through dural venous sinuses. We have established a collaborative effort between neurologists, imaging scientists, and neuroradiologists to investigate quantitative changes in neurofluid circulation in the setting of neurodegeneration. These investigations provide a more comprehensive perspective on neurofluid production and flow and allow for sequential assessments of choroid plexus (ChP) perfusion, CSF flow and velocity, and volumetric assessments of the parasagittal dural space (PSD), with established relevance in neurofluid egress. Using these approaches, we have characterized age-related declines in ChP perfusion and net CSF flow, and increases in ChP and PSD volume, across the healthy lifespan in 80 healthy adults, demonstrated that a subset of these markers including PSD hypertrophy directly correlate with proteinopathy extent in 24 older adults with neurodegenerative proteinopathies, and, in preliminary data motivating this project, that these same trends persist in 29 patients progressing from pre-manifest to manifest stages of HD on a more accelerated timescale. We propose to apply these methods for the first time to characterize the range of neurofluid aberrations more fully across HD stages; to differentiate choroid plexus pathology, characterize CSF movement through the cerebral aqueduct and brain cisterns, and peri-sinus space anatomy with the quantification of PSD across HD stages. Data collected during this project are intended to further inform our understanding of HD pathophysiology and provide biomarker ranges that will be required to rigorously inform a future trial based on personalized signatures of hypothesized responsiveness.

NIH Research Projects · FY 2026 · 2024-12

PROJECT SUMMARY/ABSTRACT Liquid biopsies are currently in clinical use for many cancers. The majority of liquid biopsies are measuring and identifying naked, cell-free DNA (cfDNA) molecules in the blood that are shed from all cells into the circulation. When cancer cells shed their DNA into the bloodstream, this is known as circulating tumor DNA (ctDNA), but a major impediment to maximizing the utility of liquid biopsies is the fact that the percentage of ctDNA is relatively small in a patient’s blood, even those with metastatic disease and/or a heavy tumor burden. Improvements in technology have pushed the limits of detection such that even one ctDNA molecule in a million normal cfDNA molecules can be identified from blood. However, it is often not feasible to obtain even thousands of cfDNA molecules from a single blood draw, thus limiting the clinical sensitivity of liquid biopsies. Therefore, even though there are currently commercial tests available for testing minimal residual disease after curative intent therapies for early stage cancers, as well as tests for detecting cancer in asymptomatic persons as a primary cancer screening tool, none of these tests have a high enough negative predictive value (NPV) to safely say that a negative test truly means the individual is without cancer. The overarching goal of this research program is to increase the clinical sensitivity of ctDNA liquid biopsies, such that they could truly distinguish between patients with and without cancer. To do so, will require a better understanding of the mediators of cfDNA biogenesis. Despite years of research on cfDNA and ctDNA, there is still a paucity of knowledge regarding how cfDNA is released from cells, and factors that influence its degradation. If such knowledge were discovered, then new drugs could be developed to increase the amount of ctDNA from cancer cells thus vastly improving the sensitivity and NPV of liquid biopsies. In this proposal, these unmet needs will be addressed based upon new preliminary data via the following specific aims: Aim 1): Elucidating the role of the RNA binding protein Sam68 in mediating cfDNA release, Aim 2): Pharmacologic optimization of cfDNA release and stability for increasing ctDNA detection and Aim 3): Identifying genetic mediators of cfDNA release influenced by the local microenvironment. The completion of these aims will yield new insights and knowledge regarding how ctDNA is regulated at the cellular level, as well as how extrinsic factors including local tumor microenvironments affect ctDNA’s half-life. Moreover, these studies will leverage existing and new knowledge that will ultimately enable us to increase ctDNA levels for diagnostic purposes. By improving the sensitivity of current ctDNA tests, liquid biopsies might one day be able to determine if patients are cured of their disease. Additionally, a negative liquid biopsy screening test would also be able to determine with high confidence that an individual truly is without cancer. This would a represent major step forward in our ability to utilize ctDNA for the management of patients with cancer.

NSF Awards · FY 2024 · 2024-12

The broader impact of this I-Corps project is the development of a real-time billing tool to support accurate coding for smoking cessation services within healthcare systems. The solution addresses missed coding and billing opportunities that compromise data integrity and public health insights, impacting quality metrics and population health assessments. For example, gaps in data can make it unclear if smoking cessation care occurred but was not billed or if the care was overlooked entirely. By automating the identification of eligible encounters directly within clinical workflows, this solution enhances both the financial viability and transparency of preventive services like smoking cessation. Broad adoption of this solution could bolster health systems’ capabilities to provide, track, and bill for essential preventive care, aligning clinical actions with public health priorities. This I-Corps project utilizes experiential learning coupled with a first-hand investigation of the industry ecosystem to assess the translation potential of the technology. This solution is based on a machine learning model that analyzes clinical notes in real-time to identify billing-eligible smoking cessation counseling. By directly integrating with electronic health records, the solution ensures immediate, accurate billing and correct data capture from clinical notes during patient encounters, addressing the dual challenge of missed billing and incomplete data. Initial testing demonstrates high predictive accuracy, establishing a foundation for scaling this solution across healthcare systems. This project aims to bridge gaps in automated healthcare billing, advancing clinical informatics, and enhancing data-driven public health outcomes. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2024-12

Project Summary/Abstract Cellular plasticity, a feature associated with epithelial-to-mesenchymal transition (EMT), contributes to tumor cell survival, migration, invasion, and therapy resistance. Across human cancer, tumors that are high grade, poorly differentiated, and have undergone EMT carry a worse prognosis with a high likelihood of metastasizing to distant organs. EMT is a common feature associated with tumor progression and is thought to be critical to cancer cell dissemination in some tumors. Despite significant evidence that EMT directly contributes to tumor progression, several studies have suggested EMT is not required for the metastatic spread of PDA and breast cancer. For example, most metastatic lesions are known to exhibit epithelial features, an observation that seems to be at odds with EMT as a prerequisite for metastasis. As such, the importance of EMT in cancer biology has been questioned. I hypothesize that the chronic activation of an EMT program within a tumor may depend on paracrine signals within the tumor microenvironment, dictating whether the tumor cells undergo EMT or MET. Because these cells exist in a plastic state, it is possible that these tumor cells readily revert their phenotype based on a microenvironment-specific context and factors. Additionally, current in vivo lineage-tracing technology has not settled the debate between the importance of collective migration and/or EMT for metastatic dissemination. During my postdoctoral research, I aim to investigate this hypothesis in two aims: 1) Decipher genetic changes required for cellular plasticity using a novel patient-derived organoid lineage tracing model, live-imaging and single cell analyses. 2) Investigate extracellular cues for cellular plasticity and EMT by evaluating the role of the immune system in EMT and metastasis. These aims will allow the field to better understand epithelial plasticity in an oncogene- and tissue-specific manner. Understanding this process will aid in the development of effective metastatic cancer therapies and will direct future research directions in metastasis.

NIH Research Projects · FY 2025 · 2024-09

Untested penicillin allergies, or “labels”, are highly prevalent, and they adversely impact healthcare quality by limiting use of guideline-recommended first-line antibiotics, thereby increasing treatment failures, drug resistance, and opportunistic infections. 10-15% of the US population carries a penicillin allergy label (PAL), but only 1 in 20 of PALs are verified as accurate after allergy testing. In previous work we developed, validated, and implemented risk-stratified management for low-risk penicillin allergy delabeling at our institution 99% NPV (95%CI 96.4, 99.9) with more than 400 patients delabeled by non-allergists to date. We now seek to extend this work using the ADAPT-ITT framework with an impact on outpatient antimicrobial stewardship by 1. measuring efficacy, barriers and facilitators of outpatient antibiotic allergy assessment for surgical, transplant and obstetric patients, 2. designing and piloting patient-centered penicillin allergy self-assessments, and 3. implementing penicillin allergy assessment in the outpatient pre-surgical environment. We hypothesize that 1. There may be additional barriers and adaptations to implement penicillin allergy risk assessment and challenges across different settings that can be overcome, leading to a model for optimal outpatient implementation of penicillin allergy risk assessment 2. That a patient performed risk-stratification questionnaire is sufficient to identify low-risk penicillin allergies and impact obstetric referrals for testing, and 3. That routinely performed penicillin allergy risk assessment will improve use of first line surgical prophylaxis. Completion of these proposed research aims would create new tools for penicillin allergy assessment delabeling efforts, new models for optimal implementation in the outpatient setting, and augment our platform for delivering drug allergy services at the points of care where they are needed most. Our multidisciplinary team is uniquely positioned to ensure the success of this undertaking.

NIH Research Projects · FY 2024 · 2024-09

Alzheimer's Disease and Related Dementias (AD/ADRD) are common progressive conditions that damage critical mental functions, causing significant emotional, physical, and financial burdens. Currently, there is no cure for AD/ADRD, nor a drug to delay the onset of the disease. New drugs targeting AD/ADRD have had a 99% failure rate due to the incompleteness of biological knowledge, the emphasis on testing single therapies, the lack of predictive validity in animal models, and the emergence of unacceptable side effects. Drug repurposing--identifying new uses for existing drugs--offers an alternative approach that can reduce the time, costs, and risks of failure associated with new drug development. Indeed, genetic research and large biobanks have accumulated a wealth of relevant data for AD/ADRD drug repurposing efforts. However, given the complexity of AD/ADRD pathogenesis, identifying and prioritizing drug repurposing candidates for downstream analyses remain a challenge. Standard repurposing efforts generally arise from basic science or clinical observations, resulting in a one-at-a-time approach via candidate validation in clinical trials. Such efforts ignore the opportunities provided by big data (e.g., genetics and electronic health records) for identifying and validating candidates. The lack of standardized approaches to systematically screen and validate drug repurposing signals represents a critical barrier to the success of leveraging existing public knowledge and clinical data to advance AD/ADRD treatment. We propose integrating genetics, transcriptomics, literature, and clinical data with advanced informatic technologies and computational capabilities to develop and share tools which systematically screen, prioritize, and validate drug repurposing candidates and their combinations for AD/ADRD. The proposed project directly responds to PAR-20-156’s challenge to "combine large-scale genotypic and phenotypic data, and use established or develop novel computation approaches to investigate new uses of FDA-approved drugs or drug combinations." In Aim 1, we will systematically screen and prioritize drug repurposing candidates for AD/ADRD via both virtual transcriptome and Mendelian randomization, validating the candidates in multiple large clinical datasets. In Aim 2, we will identify, assess, and validate candidates from the literature. In Aim 3, we will evaluate and validate combinations of drug repurposing candidates. For all validations, we will assess the drug/drug pair’s benefits for prevention (i.e., pre-morbidity exposure) and treatment (i.e., post-morbidity exposure), including analyses stratified by dose, gender, and race. In Aim 4, we will make our findings, including deployable tools and codes, broadly available on the AD Knowledge Portal and related websites to facilitate future research.

NIH Research Projects · FY 2025 · 2024-09

ABSTRACT The broad, long-term objectives of the grant are to increase our understanding of the mechanisms underlying the gene x environment interactions that link developmental manganese (Mn) exposure, dopamine (DA) dysregulation and increased frequency of ADHD diagnoses. Through the use of both sexes and varied genetic backgrounds in our testing models (mice and human iPSC lines) we use a rigorous approach to deepen our understanding of the role of genetics on the strength of the mechanisms under investigation. Strong epidemiological and correlation evidence points to a relationship between overexposure to metals, including Mn, and development of childhood and adolescent neuropsychological disorders. We will use oral exposures to mimic exposure to Mn through poorly filtered water such as that obtained from wells, at levels relevant to known human exposures in N. America. We will support our behavioral studies with comprehensive analyses of dopaminergic (DAergic) function including post-mortem analyses of brain tissues, electrophysiology approaches in live brain slices and in vitro study of human induced pluripotent stem cell (hiPSC)-derived DA neurons. Our first Specific Aim is to Determine the role of sex and genetic background on Mn exposure- induced behavioral change and DAergic transport deficits. Three background strains have been selected for their baseline differences in DAergic function, Mn metabolism and locomotor activity. Mice will be exposed to control, moderate or high Mn through water from weaning to assess the impact of sub-toxic (i.e. no expected cell death) Mn levels in brain during development. We will use a range of behavioral outcomes that are representative of changes observed in ADHD as well as variation observed in the general public. We will study DA metabolism and release/reuptake kinetics through neurochemistry, post translational protein modifications, RNA and electrophysiology approaches. In Specific Aim 2 we will Test whether Mn modifies pharmacological modulation of DA transport in vivo. We will use genetic approaches to generate mild disturbances in the DAergic system from birth that cause only modestly altered phenotypes (behavioral and cellular). We will then test whether Mn exposure is sufficient to drive these mild presentations towards full expression of abnormal phenotypes mimicking a classic gene x environmental exposure model of development of Intellectual and Developmental Disabilities. We will further test the potential for Mn to impact efficacy of common treatments for ADHD. Finally, in Specific Aim 3 we will determine whether Mn has an ADHD-related differential impact on DA functional characteristics of human induced pluripotent stem cell (hiPSC)-derived DAergic neurons. We will use cell lines derived from males and females under baseline conditions, and following genetic mutation of the DA transporter, or exposure to chemical ADHD risk factors. We will assess changes in neurochemistry and post- translational modifications to test the potential translational relevance of Aims 1 and 2. We will use single-cell genetic pathway analysis to test hypotheses about which pathways are disrupted by Mn.

NIH Research Projects · FY 2024 · 2024-09

The Network of Genomics-Enabled Learning Healthcare Systems (gLHS) Coordinating Center will support a national, highly functional, integrated genomic medicine implementation infrastructure that will enhance the quality, efficiency, and scientific rigor required to deploy and refine interventions chosen by the Network. We are a team composed of leading content and methods experts at Vanderbilt University Medical Center. We propose that a Demonstrating Real-world Advancement in Genomics Operations Network (‘DRAGON’) will allow us to “we learn from what we do and do what we learn.” We will support the clinical sites (CSs) in appropriately embedding genomic medicine into routine workflows to promote more ready access to testing for patients who would benefit. This requires assurance that clinicians understand and are willing to act upon a strong evidence base utilizing vetted, established best practices. It necessitates a landscape survey to identify the barriers and facilitators that the selected CSs may encounter. It also demands engagement with patients and communities to help the Network communicate genetic risk and how testing will improve their care. Functionally, 1) we will coordinate all Network activities via our Operations Unit to ensure the collective is able to set, monitor and reach programmatic goals. This will include supporting site communications, establishing oversight committees, defining channels for NHGRI interaction, and facilitating network evolution. 2) We will work with the CSs to select and optimize Network projects through our Design and Outcomes Unit. This group will offer statistical, methodologic, and operations expertise to promote both master protocol development and tailored local context modifications. We will cooperatively determine how best to refine and redeploy interventions after evaluation to foster cycles of true learning. 3) We will institute and co-produce a shared technical gLHS architecture with our Data and Informatics Unit and CSs. This standardized approach will be essential to enabling effective collaboration, monitoring, and evaluation across sites. 4) We will implement the Engagement Unit. This group will promote bidirectional, longitudinal engagement from multiple health systems serving a variety of communities; help CSs build and sustain trust; ensure strengths of each CS are nurtured and shared; facilitate dissemination of findings; and encourage engagement with payors, providers, and health systems. DRAGON efforts will broaden the clinical availability, appropriateness, and actionability of genomic medicine interventions by creating a community of practice dedicated to continual accountability, improvement, and enhancement in genomic testing utilization. Modified Narrative Section Translating genomic discoveries into clinical practice is vital but riddled with challenges - slow adoption of guidelines, studies focused on only specific health systems, inadequate reimbursement policies, and more. By integrating world-class scientific expertise in genomics with success in learning healthcare system implementation and internationally recognized high quality coordination capability, Vanderbilt University Medical Center (VUMC) will create a unified, genomics-enabled, learning healthcare system (gLHS) Network. We will facilitate project selection and optimization, establish a shared technical gLHS architecture, adapt and tailor to meet various local contexts, and build trust through authentic partner engagement enabling the next frontier in precision medicine by making genomics a more readily accessible component of routine care.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY Advances in population-scale genetic data linked to the electronic health record (EHR), along with the rise of learning health systems (LHS) to enable the rapid translation of new knowledge to clinical care, have brought us to the threshold of revolutionizing healthcare by using genomic medicine to predict and prevent diseases. To cross this threshold, there is a need for a robust infrastructure to support the integration of existing genome science advances into clinical care, and to evaluate outcomes of that integration. We propose here the Vanderbilt Genomic Learning Health System as a Clinical Site in the genomic LHS (gLHS) Network. Work in our clinical site will be implemented in diverse settings and in underserved populations with stakeholder partners at Vanderbilt and the University of Miami Hospital and Clinics. Our team brings expertise in delivery of care, basic and clinical genome science, and implementation science, and is part of an institutional environment with recognized capabilities in integrating genomic data into the EHR, in genomic medicine, and in clinical informatics, and includes a robust and productive LHS. The Network’s initial activity will be to select specific projects and implementation strategies for the group. We outline three potential high-value projects each of which builds on our team and institutional accomplishment: (1) using advanced EHR-based phenotyping to increase identification of monogenic disorders, (2) using family health history to identify patients at high disease risk due to actionable hereditary disease-causing mutations, and (3) personalizing genomic- based laboratory reference ranges to avoid needless testing and increase equity in clinical medicine. We are well-positioned to contribute to other Network-chosen projects, given our comprehensive clinical environment and expertise in multiple domains of genomic medicine that are in advanced stages of institutional implementation; these include pharmacogenomics, cancer genomics, and sequencing in the setting of critical illness and in disease-specific genetics clinics. In our Aim 1, we will share our resources and expertise with the Network to develop a data-driven framework for selecting proposed gLHS interventions and strategies. Aim 2 will incorporate the selected interventions into clinical practice, using a multi-component implementation strategy with stakeholder engagement. Aim 3 will evaluate the effectiveness and implementation of each gLHS intervention within our health system and across the Network, followed by refinement and re-implementation. By identifying, implementing, and critically evaluating high value interventions across multiple and diverse practice settings, the gLHS network represents a crucial next step in the maturation of the discipline of Genomic Medicine.

NIH Research Projects · FY 2025 · 2024-09

Project Summary Adverse pregnancy outcomes are a global issue that affects more than 50 million people per year. Infections during gestation contribute significantly to adverse pregnancy outcomes, such as preterm birth and neonatal sepsis. Streptococcus agalactiae or Group B Streptococcus (GBS) is a major cause of ascending vaginal and intrauterine infection during pregnancy. To initiate infection, GBS must colonize the vagina and initiate a robust biofilm to turn the vaginal mucosa into a replicative niche. Subsequently, GBS ascends the reproductive tract in an undefined process to invade the gestational membranes, cross the placenta, and infect the amniotic cavity and the fetus. Currently, there is no commercially available vaccine against GBS to prevent its cognate disease outcomes. However, epidemiological data has indicated that exposure to maternal breast milk is associated with protection against GBS infection of the neonate. We have new and exciting data to suggest that components of human breast milk, such as human milk oligosaccharides (HMOs), have antibiofilm activity against GBS. Given this, we hypothesize that treatment with HMOs could lead to decreased GBS biofilm formation, colonization, invasive infection cognate inflammation, microbiome disruption, and disease progression. We will test this by determining the contribution of HMOs on bacterial and immunological responses in primary human placental macrophages, an organ-on-a-chip infection model, ex vivo gestational membrane model, vaginal tissue models and a mouse model of infection during pregnancy. This work will help us establish the efficacy of deployment of prebiotic HMOs as a cost-effective dietary or chemotherapeutic strategy against GBS which may improve pregnancy outcomes in vulnerable groups.

NIH Research Projects · FY 2025 · 2024-09

R21: Human Craniosynostosis Atlas (HuCA) : Standardizing & Establishing a Public Repository for Genomic and Imaging data. Project Abstract: Craniosynostosis is a premature fusion of the cranial sutures which affects approximately 1 in 2000 babies each year. Left untreated, significant skeletal, respiratory, ocular, and neurocognitive abnormalities can result. Surgical treatment is usually offered in the first year of life to mitigate these consequences. There is a wide genotypic and phenotypic presentation and to date there is insufficient characterization of the disease in children, and its effects on the brain. The Human Craniosynostosis Atlas (HuCA) as put forth in this proposal seeks to remedy this gap in knowledge by creating community resource with standards for data acquisition, which will allow for a diverse array of sites to gather CT, multi-contrast MRI, and genomic data in individual patients, which can be analyzed in concert. We ultimately seek to improve the characterization & understanding of all types of craniosynostosis through systematic neuroimaging and genotyping shared with the scientific community through the existing NIH-NIDCR biorepository, FaceBase 3. We propose to create the first publicly accessible repository of comprehensive human data for the purpose of broadly, yet deeply characterizing all types of craniosynostosis. Specific Aim 1 will focus on neuroimaging and establish low dose head CT protocols to verify diagnosis and allow head shape analysis. Brain structure and function will be assayed with MRI based on the Healthy Brain and Child Development (HBCD) protocol for developing brains and will be extended to the craniosynostosis population. Sequences will include anatomical imaging (T1, T2), functional (resting state fMRI), and microstructural (multi-shell HARDI) imaging. Specific Aim 2 will focus on a genomic characterization of the affected child and biological parents ( a trio) using a standard protocol of acquisition from subjects’ cheek swab to whole genome sequencing (WGS) with standard coverage, (99%) & depth (30x). Output will be standardized file formats to include VCF, FASTQ and BAM files and transferred to FaceBase for preliminary variant analysis. Aim 3 will focus on HIPPA compliant data transfer to Facebase of neuroimaging and genomic information data of babies with all types of infants with craniosynostosis. It will also codify and publicize the data acquisition protocols and quality standards as a pre-requisite for contribution to HuCA. A new web landing page for HuCA will be built allowing permitted researchers to access the data in an intuitive and interactive way, filterable by metadata. The synergy of CT, MRI and genomic data will enable Facebase to house and share an unprecedented complement of multi-dimensional information about craniosynostosis that can improve fundamental knowledge and classification of disease. A clear pathway and protocol for data contribution and sharing will enable the large- sample size study needed for both conventional and AI/ML/DL analysis. When a clinician is newly faced with a baby with craniosynostosis, they will benefit from a vastly improved understanding of the condition at baseline and thus may be able to better predict and optimize outcomes given a particular treatment.

NIH Research Projects · FY 2026 · 2024-09

This K01 award will launch Dr. Kerry Kinney’s independent research career focused on reducing disparities in the diagnosis and treatment of generalized anxiety disorder (GAD). GAD is the most common anxiety disorder in primary care settings, where the rate of GAD misdiagnosis is estimated at 67-71%. Misdiagnosis can delay treatment, exacerbate chronicity, and increase personal and societal costs. The proposed K01 research leverages large-scale, epidemiologic and electronic health record (EHR) datasets to evaluate two potential contributors to GAD misdiagnosis: 1) longitudinal measurement non-invariance, or indications that GAD’s diagnostic criteria fail to capture the same construct across over time or across various levels of economic hardship, and 2) lack of patient-centered care, which is characterized by collaborative decision-making and respecting patients’ values and context. To accomplish Aim 1, Dr. Kinney will assess for the presence of measurement non-invariance and differential item functioning in GAD symptom criteria over time and whether longitudinal measurement invariance is moderated by economic hardship in epidemiologic datasets. To accomplish Aim 2, Dr. Kinney will employ natural language processing in EHR data to identify language indicative of non-patient-centered care in primary care notes. She will assess how non-patient-centered care relates to individual patient characteristics and GAD diagnosis. Dr. Kinney proposes to build upon her strong foundational training by targeting career development in: 1) advanced quantitative modeling to enhance theoretical models of GAD; 2) the technical biomedical informatics and textual analysis skills necessary to harness EHR data for health disparities research; and 3) grant-writing skills to obtain independent extramural funding. Dr. Kinney has assembled a highly qualified, interdisciplinary team of mentors, collaborators, and consultants to support her in achieving these training aims. Collectively, the proposed mentor (Dr. Matthew Morris), collaborators (Drs. Glenn Gobbel, Mohammed Al-Garadi, David Cole, and Jacquelyn Pennings), and consultants (Drs. Matthew Diemer and Siddharth Pratap) provide the optimal combination of expertise to facilitate the successful completion of the proposed research and training plan and launch Dr. Kinney’s independent research career. The research and training aims will occur in the exceptional, multidisciplinary, resource-rich environment at Vanderbilt University Medical Center. This K01 award will support Dr. Kinney in establishing an independent research program that aims to advance the field’s understanding of GAD and elucidate the mechanisms underlying missed or delayed opportunities to diagnose and treat GAD.