Vanderbilt University Medical Center

NIH Research Projects · FY 2025 · 2024-09

Dr. Cathy Eng is an exemplary Clinician Scientist who, throughout her career, has held numerous roles within the National Clinical Trials Network (NCTN) and is viewed, by her peers, to be one of the leading senior female NCTN members in the field of gastrointestinal (GI) oncology. Dr. Eng has participated in NCI-funded clinical research since her fellowship and continues to provide support for the National Clinical Trials Network (NCTN) through development of clinical trials, service engagement and leadership, and mentorship. Dr. Eng has led the development of multiple trials within NCTN and Experimental Therapeutic Clinical Trials Network (ETCTN), of which two have changed the treatment landscape for anal cancer: EA2133, identified a new chemotherapy standard in treatment-naïve metastatic patients; NCI9673 Part A resulted in a change in national guidelines for the role of immune checkpoint inhibition in refractory metastatic patients. Dr. Eng is the national PI of EA2176, which is the first NCI-sponsored phase III trial in metastatic treatment-naïve patients exploring chemotherapy plus immune checkpoint inhibition. Dr. Eng has been a contributing member to ECOG-ACRIN and SWOG since 2006, serving in multiple leadership roles for the NCTN including lead PI of the NCTN Lead Academic Participating Site (LAPS) grant while at MD Anderson Cancer Center. Following her transition to Vanderbilt, she continued to serve as the institutional SWOG PI and Vice-Chair of the SWOG GI Committee. In 2021, she was nominated by her peers to serve as the co-Chair of the NCI Gastrointestinal Steering Committee. In this role, she provides insight and oversight of all NCTN phase II/III GI concepts in development. She is also co-leading a new working group that is focused on incorporating circulating tumor DNA biomarker studies in future NCTN trials. For continuity of high- quality clinical research, it is imperative that successful Clinician Scientists mentor early career faculty. Dr. Eng has served as a mentor for several NCTN mentees include Drs. Van Morris, Jennifer Dorth, Anwaar Saeed, Rajiv Agarwal, and Kristen Ciombor all impactful contributors to NCI-sponsored clinical research. In her new role for the cancer center, Dr. Eng is now the Director for Strategic Relations which allows her to interact regularly with multidisciplinary leadership institution-wide with an overarching shared objective of increasing clinical trial engagement and enrolment with a critical component being NCI-sponsored clinical efforts given the association with her current role as NCI GI Steering Committee Co-Chair, institutional SWOG PI, and the impact on the UM1, LAPS UG1 and the CCSG. The R50 grant affords the ability of Dr. Eng to continue to participate and expand on NCI-sponsored clinical trials research efforts through development of novel trials with early and mid-career faculty, executive administration, and leadership roles both internally at Vanderbilt, within the NCTN Network and the NCI to help guide the next generation of Clinician Scientists so that they may also develop into successful contributors to their own institutions and at the national level for all NCI-sponsored clinical cancer research.

NIH Research Projects · FY 2024 · 2024-09

Language ability is a strong and consistent predictor of outcomes for individuals on the autism spectrum (ASD). ConsequenUy, understanding key predictors and mechanisms underlying positive early language development, and alterations thereof across the variability in language development in autism, is paramount for optimizing the design, targets, and timing of interventions. In typically developing (TD) and autistic infants, beginning in the second half of the first year of life and continuing into the second year, infants shift their preferential attention from a speaker's eyes to their mouth. Increased visual attention to the mouth during infant-directed speech during this stage is associated with language development in TD infants, likely because shifting attention to a speaker's mouth enables infants to take advantage of visual cues that complement the auditory speech signal. Multi modal signals, such as the integrated face and voice of an engaging caregiver, draw attention to and facilitate processing of features that occur across modalities. This is especially beneficial when processing is difficult, suggesting that attention to the mouth should be particularly relevant during initial stages of language acquisition in TD, as well as for children with communication challenges, including autism. We recenUy demonstrated that the naturally increased multi modality of infant-directed singing relative to speech potentiated TD infants' attention to the mouth of an engaging caregiver, with differential cues (e.g., rhythmic predictability, tempo, audiovisual synchrony, affect) driving mouth-looking at different developmental stages; we extended these findings to ASD in pilot data for the current project. As well, our team demonstrated that the adaptive value of mouth-looking for expressive language in autism is moderated by children's expressive language level. Building on these findings, the current project leverages the continuum of multimodal cues across infant-directed speech and song to investigate links across visual attention (especially mouth-looking), differential multimodal cue sensitivity, and expressive language in TD and autism. We harness a large existing dataset of well-characterized TD and autistic infants (Aim 1a), as well as infants at increased family likelihood for autism with varied outcomes (Aim 1b}, followed prospectively over the first two years of life, to quantify differential trajectories of mouth-looking during speech and song in relationship with expressive language outcomes. We combine this with new cross-sectional data collection in well-characterized cohorts of TD, autistic, and non-autistic expressive language delay (ELD) children to determine how communicative contexts (song, speech; Aim 2) and sensitivity to specific multi modal cues (Aim 3) drive mouth-looking and are adaptive for expressive language skills across different diagnoses and expressive language levels. This research will identify basic mechanisms by which multimodal cues support language development in specific populations, actionable targets for language intervention using diverse forms of ecologically-valid infant-directed communication, and developmental windows of opportunity for intervention development and delivery for autistic children.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY The use of antibiotics in the first year of life has been recognized as a strong, consistent, and modifiable risk factor for the development of asthma in childhood in numerous individual studies. However, a critical window during which infant antibiotic exposure could have a greater effect on childhood asthma risk has yet to be identified. Furthermore, whereas the results of some studies indicate that this association is likely due to changes in the human microbiome, these studies have used techniques that are unable to accurately identify relevant bacterial species or their function, which is critical to design interventions to prevent the long-term detrimental effects of infant antibiotic exposure. To address these multiple knowledge gaps, the goals of this proposal are 1) to determine the age when infants are most susceptible to the harmful consequences of antibiotics on childhood asthma risk, 2) to examine microbial pathways through which infant antibiotic exposure could lead to childhood asthma, and 3) to identify early-life upper respiratory tract (URT) and gut bacterial species, patterns, and/or products that could increase the resilience of these 2 microbial communities and be protective for childhood asthma onset after infant antibiotic exposure. To achieve these goals, we propose the following specific aims: 1) to test the hypothesis that the age of infant antibiotic exposure is inversely associated with childhood asthma risk (aim 1), 2) to test the hypothesis that infant antibiotic exposure is associated with changes in the taxonomic and functional profiles of the URT and gut microbiome throughout the first year of life (aim 2A), and that these changes mediate the association of infant antibiotic exposure with childhood asthma risk (aim 2B), and 3) to test the hypothesis that, among infants exposed to antibiotics, specific taxonomic and functional profiles of the early-life URT and gut microbiome are associated with childhood asthma risk. To accomplish our goals in an effective and cost-efficient manner, we will 1) capitalize on the strengths of our prospective birth cohorts with distinct longitudinal study designs, comprehensive information on infant antibiotic exposure, and serial sampling of the URT and gut, 2) leverage the cutting-edge laboratory and bioinformatic pipelines that we have assembled for our numerous prior studies of the human microbiome, and 3) build upon an ongoing and successful collaboration between experts in the field. Our proposal is a stepping stone to address a critical and unmet need: how to protect children from the long-term detrimental effects of infant antibiotic exposure. By identifying a critical window of opportunity to intervene, the microbial pathways to target, and candidate probiotics and/or bacterial products, the ultimate goal of the planned studies is to inform the design of microbiome-based therapeutics that can help deliver antibiotics safely during early life and reduce the burden of childhood asthma.

NIH Research Projects · FY 2024 · 2024-09

PROJECT SUMMARY Telomere length is considered a good biomarker of organismal and cellular aging. Telomeres get progressively shorter with each cell division and rates of cellular turnover vary from cell type to cell type and tissue to tissue. When telomeres become critically short, cells arrest their proliferation and go into senescence resulting in tissue dysfunction. Telomere length and the rate of telomere shortening shows a great deal of interindividual variability and is dependent on many factors including genetics, age, environment, and lifestyle. Several age- related diseases have been associated with telomere shortening including pulmonary fibrosis, COPD, liver fibrosis, aplastic anemia, myelodysplastic syndrome, Alzheimer’s disease, Parkinson’s disease, myocardial hypertrophy, dilated cardiomyopathy, ischemia-reperfusion injury, chronic kidney disease, kidney fibrosis, osteoporosis, and osteoarthritis. The effect of genetics on telomere length has been estimated to be 35-85% and at least 17 genes have been reported to regulate telomere length and cause telomere biology disorders (TBD) when disrupted (DKC1, TERC, TERT, NOP10, NHP2, TINF2, WRAP53, CTC1, RTEL1, PARN, ACD, POT1, NAF1, STN1, ZCCHC8, RPA1, and DCLRE1B). These genes do not explain all cases of TBD and more telomere length regulators have yet to be characterized. Our proposal is in response to NOT-AG-23-020, which is meant “to encourage the use of existing cohorts and datasets for well-focused secondary analyses” to address critical questions in aging research. We have designed our proposal to harness the unique large data resources at Vanderbilt University Medical Center (VUMC), including idiopathic pulmonary fibrosis (IPF) and BioVU, and the large public data resources (GTEx consortium, All of Us, and the UK Biobank). We will reanalyze these datasets, combining multi-omics modeling and phenome-scale interrogation, to identify new genes and variants responsible for telomere shortening, telomere disease risk, premature aging, and their phenome-wide consequences. By re-analyzing large data sets already at our disposal, we will be able to identify novel genes and variants responsible for the telomere shortening and provide a more complete picture of the role of aberrant telomere length and dysfunctional telomere maintenance in pathophysiological processes. A better understanding of the genetic and biological drivers of telomere shortening may provide insights into disease risk, earlier diagnosis, and new kinds of therapies. Our Aims are to: 1) Determine the genetic basis of telomere shortening in diverse tissues, 2) Determine the phenome-wide consequences of telomere length using large-scale biobanks, 3) Identify disease causing variants (DVs) in novel genes associated with Telomere Biology Disorders (TBD)

NIH Research Projects · FY 2025 · 2024-09

The etiology and effects of musicality, broadly defined as the set of fundamental human capacities to interact with music, have mainly been studied via brain and behavioral methods and primarily at small scale, until very recently. We formally established the Musicality Genomics Consortium (MusicGens) in 2022 as an international network of researchers dedicated to the advancement of research on the genomics of human musicality traits via multisite, cross-disciplinary collaboration. The purpose of MusicGens is to enable scientific discoveries related to the genetics, genomics and phenomics of musicality, by fostering research directions of a large magnitude that would not be possible for any single research group to pursue alone. The overarching objective of this grant is to provide a stable forum to nurture a robust and rigorous science of musicality genetics via conference support for the annual meeting of MusicGens. The conference funding will support the educational and research missions of the annual meeting, with specific resources dedicated to interdisciplinary workforce development and to developing strategies for augmenting musicality genomics research in global populations that reflect the broadest range of genetic variation and musicality phenotypes in humans. The conference support has the potential for impact in the arena of multiple basic science and translational manifestations of how and why musicality unfolds over the lifespan, with particularly innovative potential for precision health.

NIH Research Projects · FY 2025 · 2024-09

Project Summary Genome-wide association studies (GWAS) have identified over 200 genetic loci for breast cancer. To translate these findings into an improved understanding of cancer biology, and thus, disease prevention and treatment, it is essential to identify the target genes of these loci. However, causal genes (and the underlying biological mechanisms) remain unknown for most of the GWAS-identified breast cancer risk loci despite recent publications of transcriptome-wide association studies that have discovered a few putative causal genes. Proteins, the final gene products, are key working molecules for cellular functions. Thus, proteins have a more direct impact on disease risk than mRNAs. In addition, protein levels and mRNA levels are only moderately correlated, with the median correlation being only 0.46, and for many genes, the correlation is close to zero. Therefore, compared with investigating RNAs, directly investigating proteins may be more likely to reveal causal genes and underlying biological mechanisms. We propose a novel proteogenomics study to identify putative target proteins for breast cancer by capitalizing on multiple existing unique resources, 1) normal fresh- frozen breast tissue samples from over 5,000 cancer-free women in the Susan G. Komen Tissue Bank (KTB); 2) proteomics and genomics data in 125 breast cancer tissue samples in the Clinical Proteomic Tumor Analysis Consortium (CPTAC); and 3) GWAS data of ~ 427,000 breast cancer cases and controls from three large consortia. We will conduct a well-powered proteome-wide association study (PWAS) by integrating genomics and proteomics data in breast tissues in three racial groups (Aim 1). We will prospectively validate the promising breast cancer risk proteins in pre-diagnostic normal breast tissues in a nested case-control study including 120 incidence breast cancer cases and 480 individually matched controls (Aim 2). We will evaluate the biological functions of the top breast cancer risk proteins by conducting a series of bioinformatics analyses and in vitro functional assays (Aim 3). The proposed study will be conducted by an interdisciplinary collaborative team of experts in breast cancer, epidemiology, genomics, proteomics, bioinformatics, and biostatistics, with almost 20 years of collaboration. This proposed project is extremely cost-efficient because breast tissue samples and the genomics data for Aim 1 will be available at no cost to this proposed study. The proposed study is highly innovative as it is the first prospective breast tissue-based proteomics study and also the first proteogenomics study by integrating genomics and proteomics data. Our study will be highly significant and impactful by 1) unveiling the target proteins for future mechanistic research; 2) improving our understanding of the genetic and biological basis for breast cancer; and 3) having important implications for disease prevention and treatment for this common malignancy.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY One of the areas of emphasis on the NEI strategic plan is to bridge the gap between genomics and mechanisms of disease. Diabetic retinopathy (DR) is a leading cause of blindness and disproportionately affects Hispanics/ Latinos (HL). DR-specific blood biomarkers and systemic treatments are not used clinically. Although research into biomarkers and genetic variants has informed our understanding of DR, whether these signatures cause or are caused by DR, and how genetic variants contribute to DR etiology is still not clear. Further, few of these studies have meaningful representations of HL despite their high DR burden. Because transcript and metabolite levels provide a window into gene function, they can help us interpret genome-wide association study (GWAS) results to better understand complex diseases like DR. Given the growing HL population in the US and their disproportionate cardiometabolic disease burden, HL representation in functional genomic studies of diabetic sequelae is imperative. The Cameron County Hispanic Cohort (CCHC) is a cohort of HL with poor cardiometabolic health and high risk for DR. Participants range between metabolically healthy and metabolically disordered individuals without or with diabetes, some with various levels of DR. We will quantify differential transcript (Aim 1) and metabolite (Aim 2) abundance between participants with Type 2 diabetes (T2D) with or without clinical diagnosis of DR in CCHC and replicate our findings in the Hispanic Community Heath Study/Study of Latinos (HCHS/ SOL), an independent, extant, diverse, larger HL dataset with T2D and self- reported DR status. Using gene regulatory and metabolite network and pathway analyses we will clarify DR pathophysiology, inform novel blood biomarkers and drug targets for DR, and validate their temporal precedence with DR using both cohorts. In Aim 3, we will apply two-sample Mendelian randomization and colocalization methods to interpret known and novel transcriptomic and metabolomic biomarkers (eQTLs and mQTLs) using results from a novel HL-specific GWAS meta-analysis and the literature. Finally, using diverse electronic health record (EHR)-linked databases, we will perform eQTL-, mQTL-, variant-, and polygenic risk score-based phenome wide association and enrichment studies to expand our understanding of the broader clinical comorbid profile of, and pathogenic mechanisms shared with, DR. Our study will clarify mechanistic causes/consequences of DR-associated expression patterns in the blood. The aims will independently inform novel diagnostic and therapeutic systemic DR-targets and our understanding of the causality and broader clinical implications of blood signatures dysregulated in DR. This project meets several NIH/NEI strategic goals including: 1) enhancing our understanding of ocular epidemiology in groups under-represented in vision science; 2) enriching data capturing molecular signatures of disease; 3) using data science to integrate cross-modality data to understand disease; 4) understanding how genomic variants affect disease; 5) identifying risk factors for ocular disease in underserved populations to decrease visual impairment; and 6) promoting a diverse vision research workforce.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY In this K99/R00 Pathway to Independence application, the candidate proposes a structured, rigorous and detailed training plan to build expertise in ex vivo gestational tissue modeling and preterm birth physiology along with continued education in the latest approaches for drug discovery. This training plan will be supported through hands-on-training, coursework, workshops, training in the responsible conduct of research, seminars and conferences. The candidate also proposes to gain experience in operating an independent research lab through grant writing workshops, networking and mentorship from a multidisciplinary advisory committee with expertise in obstetrics, reproductive sciences, neonatology, infectious disease and chemical biology/pharmacology, whom have long track records in training future independent researchers. The work in K99 phase will be completed at Vanderbilt University Medical Center, which has a plethora of resources and expertise available that perfectly aligned with the PI’s needs. The candidate`s primary goal is to establish a successful, independent research program that tests translational interventions aimed at management of infection-induced preterm labor (III-PTL). Preterm birth, defined as delivery before 37 weeks of gestation, is the leading worldwide cause of infant morbidity and mortality. Intrauterine infection and/or inflammation is a major trigger of early labor leading to preterm birth and fetal inflammation causing adverse neonatal outcomes. Unfortunately, there is a critical lack of therapeutics for the management of early labor that occurs as the result of infection/inflammation during pregnancy. Studies involved in the K99 and R00 phases of this proposal encompass novel approaches to identify effective therapeutic agents to manage III-PTL without adverse effects. Recent transcriptomic studies on gestational membranes have identified gene targets implicated in III-PTL and we have determined which of these genes are part of the druggable genome and could be explored for therapeutic regulation of III-PTL. In Aim 1 (K99) we will optimize a high-throughput screening (HTS) assay to measure changes in proinflammatory cytokines released from pathogen-associated molecular patterns (PAMP)-induced gestational membrane (GM) explants in 96-well format. We will utilize this HTS assay to screen a customized library of small-molecules that target the druggable transcriptome associated with III-PTL. We will perform a series of secondary screens to prioritize hit-molecules into leads. In Aim 2 (R00 phase), we will utilize a high-throughput combination screen to identify combination therapeutics with synergistic effects. In Aim 3 (R00 phase), mouse models of III-PTL will be used to confirm the in vivo ability of our lead-single or synergistic combinations to manage PTL and protect against fetal inflammation. The training plan and outstanding mentoring committee will ensure the success of the project and support the candidate’s career development towards the establishment of an independent research lab in the R00 phase.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY: Single-cell genomic studies have transformed our understanding of the cellular organization and plasticity of the human lung, providing substantial insights into molecular pathways active in end-stage lung diseases including pulmonary fibrosis (PF), bronchopulmonary dysplasia (BPD) and others. A common theme emerging across these studies is that there is a profound loss of highly specialized cells and cellular phenotypes in advanced lung diseases. The critical signals responsible for tissue organization and cellular specialization during lung development occur in three-dimensional space, and spatial context is critical to understand the intercellular communication mechanisms, and relationships among different cell types and states that establish and maintain distal lung “niche specialization”. These observations lead us to hypothesize that perturbations of cell-cell signaling in the alveolar niche lead to loss of cellular specialization, and disease-specific programs of progressive pathologic remodeling in PF, BPD and other chronic lung diseases. The goal of this LungMAP3.0 Research Center is to identify key molecular targets at the early stage of disease most amenable to stabilization or reversal. Our specific aims are to: 1) Develop a spatially-resolved molecular atlas of chronic parenchymal lung diseases, 2) Define mechanisms of niche dysregulation that result in the progressive histopathologic patterns of chronic lung diseases across the lifespan and 3) Investigate the transcriptional regulatory mechanisms through which niche-perturbations promote and prevent disease progression. We have assembled a team of investigators with a strong history of productive collaboration who offer expertise in chronic lung diseases that manifest across the lifetime and share a deep commitment to rapid and transparent data sharing in support of the lung biology community. We are excited to partner with other LungMAP Research Centers, the Data Coordinating Center and Human Tissue Core as we leverage state-of- the-art single-cell and spatial transcriptomic approaches that enable interrogation of archival samples from highly unique cohorts of early-stage lung disease as we investigate the molecular origins of alveolar niche dysregulation in IPF, other forms of interstitial lung disease, and BPD.

NIH Research Projects · FY 2024 · 2024-09

PROJECT SUMMARY Phospholipids, the fundamental components of cell membranes, play a crucial role in brain function. Research indicates that changes in membrane lipid composition and fluidity may be contributing to the development of Alzheimer’s disease (AD). By studying the distribution and alteration of membrane lipids in response to Aβ exposure, new insights into the biology of AD and potential biomarkers for the disease may be uncovered. Despite numerous studies on the role of membrane lipids in AD, research has been restricted to ex-vivo tissues, and has not been utilized for diagnosis due to the absence of non-invasive imaging techniques. This project aims to bridge this gap by developing an innovative MRI imaging technique to assess membrane lipid properties in AD. The technique uses a nuclear Overhauser enhancement (NOE) saturation transfer method. Our preliminary studies strongly suggest that the NOE signal primarily originates from phospholipids and changes significantly in AD on animal models. The NOE signal relies on both the underlying pool concentration and the NOE coupling rate. Moreover, according to NOE theory, the NOE coupling rate depends on the molecular motional properties, which may serve as an indicator of lipid fluidity as they likely share similar physical properties. Based on these preliminary findings and analysis, we hypothesize that the NOE pool concentration could reflect membrane lipid content, and the NOE coupling rate could represent lipid fluidity regulated by membrane composition. The project is divided into three aims: 1) verifying the dependency of the NOE signal on lipid properties on reconstituted phospholipid samples and cultured cells with varied lipid composition; 2) confirming the origin of the NOE imaging in AD by correlating it with phospholipid species maps determined by imaging mass spectrometry on animal AD models; and 3) evaluating the potential of NOE for early detection of AD by comparing it with other traditional imaging methods in a longitudinal study. The ultimate goal of this project is to provide a groundbreaking tool for AD research and diagnosis, enabling the non-invasive study of membrane lipids in live brains. This could significantly improve our understanding of AD pathology, potentially leading to new treatment strategies and early diagnosis.

NIH Research Projects · FY 2025 · 2024-09

Project Summary/Abstract Despite an equal hypertension treatment rate between Blacks and Whites (79.7% vs. 79.1%), racial/ethnic disparities in blood pressure (BP) control persist with lower rates in Blacks (39.2%), Hispanics (40.0%), Asians (37.8%), compared to Whites (49.1%). Blacks in the Southeastern US were 27% less likely to achieve BP control while they were 69% more likely to receive treatment. Existing studies point towards individual risk factors and lack of healthcare access and insurance as potential causes for these disparities; however, even after accounting for these factors, racial disparities in BP control persist. The reasons for this inequality are yet to be fully understood. Additionally, BP control rates remain low (44%–57%) among treated hypertensives while clinical trials have demonstrated that a high rate of BP control (ranging from 80-90%) can be achieved with currently available therapies by strictly following recommended treatment protocols. This suggests that a higher proportion of uncontrolled BP could be explained by less aggressive treatment, poorer follow-up, and use of fewer or less effective drugs. Despite this, in a national survey, antihypertensive therapy was intensified in only 22-40% of patients with uncontrolled hypertension, and 43% of physicians did not initiate drug therapy unless systolic BP reached ≥160 mmHg. The 2017 Hypertension Treatment Guidelines advocate evidence- based medication selection and titration, however, the role of provider concordance to these guidelines and its impact on racial/ethnic disparity in BP control remains unexplored. Furthermore, conclusions from studies regarding compliance with older hypertension treatment guidelines were compromised due to failure to evaluate multiple aspects of hypertension care, such as comorbidities, follow-up, laboratory assessments, drug side effects, and contraindications. We propose to address these limitations and use an objective and validated measurement of concordance to treatment guidelines. We will utilize data from the Stakeholders, Technology, and Research Clinical Research Network (STAR CRN) – a database of ~14 million racially diverse patients from the Southeastern US, to evaluate: 1) the extent of racial disparity in hypertension treatment based on the AHA/ACC 2017 guidelines in the southeastern US; 2) investigate the patient, physician, clinic, and geo-social factors that predict racial/ethnic disparity in the treatment of hypertension according to recommended guidelines; and 3) ascertain if racial disparity in BP control can be attributed to providers' lack of adherence to treatment guidelines. Moreover, we aim to conduct qualitative interviews with clinicians and patients to gather information on the reasons for providers' deviation from the guidelines and recommendations on improving compliance with the guidelines. Our findings will offer valuable insights into the factors contributing to racial disparities in the treatment of hypertension according to recommended guidelines, and the role of providers' hypertension treatment practices on racial disparity in BP control in the Southeastern US, thereby informing future interventions for promoting BP control and health equity.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY One of the areas of emphasis on the National Eye Institute's (NEI) strategic plan is to bridge the gap between genomics and mechanisms of disease. Vast clinically relevant information on diseases, demographics, exposures, and traits is captured in electronic health records (EHRs). This phenome data can be overlayed on biospecimen-derived data (such as genetic variants) and interrogated to uncover and clarify disease associations. These associations can in turn help us infer mechanisms of disease, contextualize clinical observations, develop risk prediction models for clinical management, and identify new research directions. Phecodes quickly capture a coded representation of the entire phenome in EHRs without accessing identifiable information, thus allowing an unrestricted exploration of any disease or phenotype as a potential cause or consequence of all others. Phecodes were last revised in 2013, when we published a replication study of known genetic associations from published GWAS. The current version of our phecodes (v1.2) has proven useful for numerous research applications and, as such, has been incorporated into novel phenome-based research pipelines to accelerate the study of both rare and complex diseases. However, our preliminary work shows that phecode v1.2's hierarchical structure lacks the resolution required to accurately identify many sigh-threatening conditions. This limits the scope of eye-related knowledge that can be gleaned from phenome-dependent association studies using biobanks. Our goal is to support new and evolving use-cases for phecodes to study eye-related diseases and health disparities in diverse biobanks. To fill this gap, we recently created a new version of phecodes (PheX) with enhanced granularity to resolve and capture many more clinical diagnoses than v1.2. We propose to: (1) Compare the resolution and reliability of PheX (vs. v1.2) to capture common and rare eye phenotypes; (2) Develop linkages between eye related-PheXs and numerous controlled vocabularies and ontologies for research; (3) Test the scalability of PheX in external biobanks through replication of eye disease GWAS results to enhance generalizability of association studies to diverse populations; (4) Incorporate PheX into novel phecode-based research pipelines; (5) Use PheX for PheWAS to study comorbid associations and to develop a catalog of morbidity and comorbidity maps with a focus on population disparities; (6) Incorporate post- coordination methods for phecode terms to enhance phenome capture; and (7) Share the new eye-specific PheX (iPheX) along with quality assessment methods in easily accessible and deployable packages to facilitate ophthalmic research in diverse biobanks. This project meets several strategic goals of the NIH and NEI, including: (1) enriching our awareness of ocular epidemiology in groups under-represented in vision science and identifying risk factors for ocular disease in underserved populations (we will use All of Us, a biobank with intentional population diversity); (2) using science to integrate cross-modality data to understand diseases (genomics, phenomics); and (3) understanding how genomic variants affect disease.

NIH Research Projects · FY 2024 · 2024-09

Project Summary This application requests funding to support the purchase of a new PET radiochemistry synthesis system for the production of investigational carbon-11 radiotracers. The system will be installed at the Vanderbilt University Institute of Imaging Science’s Radiochemistry Core (RCC) facility; a core that allows access to research radiotracers for use on three human PET/CT imaging systems, two pre-clinical PET imaging systems and a variety of other end uses. The core also offers expertise in allowing investigators to develop novel radiotracers for routine production. Currently, the RCC operates a GE TRACERlab FXc Pro as the sole automated system capable of manufacture of carbon-11 radiotracers, which are extensively utilized by Vanderbilt researchers. Specifically, [11C]PIB, a radiotracer targeting beta-amyloid, is currently produced at maximum capacity with this single-system and additional capacity for manufacture of carbon-11 radiotracers is in high demand. Additional carbon-11 capacity would allow for higher throughput for pre-clinical and clinical research at Vanderbilt and support further projects that would not only benefit Vanderbilt researchers, but also maximize the use of the PET scanners at VUIIS. Furthermore, breakage or extended down-time of the FXc Pro would cause major disruptions to the core’s ability to support all ongoing and future NIH-funded studies that use carbon-11 radiotracers. Thus, the proposed carbon-11 production system was chosen to augment the current carbon-11 capacity. The selected system, composed of a FX2 MeI, FX2 M, and FASTlab 2, would substantially advance our radiotracer production capabilities to support ongoing and future NIH-funded research. The addition of the FASTlab 2 portion of the combined system allows for dual-productions of [11C]PIB in a single setup, which would enable multiple dual- tracer studies (amyloid/tau) to be conducted in a single day. This upgraded capability would provide more reliable production of some of the most requested radiotracers and allow for smooth integration of newly developed radiotracers to support ongoing and future NIH-funded research, ranging from studying the molecular basis of cancer, cardiovascular, and neurological diseases to developing novel therapeutic approaches.

NIH Research Projects · FY 2025 · 2024-09

Dr. Yan received his Ph.D. in computer science with a focus on developing privacy-preserving technologies to defend information systems against data breaches. His growing enthusiasm for maximizing the potential of AI/ML to deepen the understanding of patient data has oriented him toward a career in biomedical informatics. Throughout this transition, Dr. Yan has been dedicated to devising new methodologies to optimize the utility of patient data and encourage its ethical use. Specifically, Dr. Yan has developed and evaluated multiple generative AI algorithms to produce high-fidelity and privacy-respecting synthetic health data for critical downstream tasks. Over the past several years, synthetic electronic health record (EHR) data generation powered by generative AI technologies has gained substantial attention in the health domain due to its ability to protect privacy, promote data sharing, and improve the performance of medical AI by providing datasets that are larger and more comprehensive. Despite its great potential, there are significant gaps between the current state of this technology and its maximal worth: the evaluation of synthetic EHR data is subpar, its development cannot leverage data sources privately owned by multiple institutions and integrate established medical knowledge (which largely limits the quality of synthetically generated EHR data), and it is unknown how to use synthetic data to produce fair and reliable medical AI. This proposal aims to innovate computational methods, realized in open-source software, to enable the assessment, development, and utilization of synthetic health data. Aim 1 focuses on the development of a multi-dimensional, customizable evaluation framework that appraises synthetic health data in terms of its utility, privacy, and fairness. This framework will further inform synthetic data creators of the appropriateness of a data generation model for a particular use case. Aim 2 will develop an ML architecture that allows multiple institutions to collaboratively train knowledge-integrated synthetic health data generation models using privately held datasets without data sharing. Aim 3 focuses on the development of a fairness-aware pipeline that 1) utilizes synthetic data to balance data distributions, 2) embeds fairness constraints into the model training process, and 3) is agnostic of the AI/ML models relied upon. With the assistance of a multidisciplinary mentoring team from VUMC, Penn Medicine, and Weill Cornell Medicine, Dr. Yan will leverage EHR data from these institutions, as well as the All of Us and MIMIC EHR data, to develop and evaluate the proposed computational methods. Dr. Yan will expand his expertise through training in fairness design, federated learning algorithms, biomedical informatics and statistical methods. This training will help Dr. Yan become an independent investigator in biomedical informatics to develop computational methods to maximize the potential of biomedical data in supporting reliable health research and applications that benefit all patients.

NIH Research Projects · FY 2025 · 2024-09

ABSTRACT Diabetes is broadly classified as type 1 diabetes (T1D), with primary defect in insulin production due to autoimmune destruction of beta cells, and type 2 diabetes (T2D), with primary defect in insulin sensitivity in organs that regulate energy metabolism. There is an emerging conceptual change that diabetes is not composed of discrete sets of syndromes but a spectrum of heterogenous phenotypes with complex pathophysiology across different ethnic and racial populations. More than 90% of adult patients with diabetes are classified as T2D with variable clinical risk factors, prognosis, and treatment response. There is an unmet need to assess individual risk for developing diabetes, its complications, and drug response based on underlying pathophysiology, which change over time. This proposal will embark on studies of large-scale electronic health records (EHRs) with comprehensive phenome assessed during the course of diabetes, and multi-omics integration, to address the following Specific Aims. AIM 1: Classification of diabetes subtypes using clinical features in EHRs of diverse ancestries. AIM 2: Classification of diabetes subtypes in response to treatments for diabetes and cardiometabolic diseases in EHRs of diverse ancestries. AIM 3: Multi-omics characterization of diabetes subtypes in African Americans. Successful implementation of the proposal will build a framework to identify subtypes of diabetes and their underlying physiological drivers to impact clinical practice towards more precise diagnosis, prognosis, and effective intervention.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY For head and neck cancer patients, a positive surgical margin results in treatment intensification, increased cost, and an increased risk of recurrence and death. Positive surgical margin rates in oral cavity cancer are the highest among solid malignancies and have not improved over the past two decades. If a positive margin is identified intraoperatively, the surgeon relies on verbal descriptions during a phone call with the pathologist to relocate the margin and resect additional tissue. Relocating the positive margin site using current protocols with no visual aid is difficult in the head and neck due to complex 3D anatomy. Therefore, it is not surprising that re-resection fails to improve oncologic outcomes. To address this unmet need, I have developed a protocol to create a virtual 3D model of the resected cancer specimen that shows the sites of margin sampling. In a prior cadaveric study, I established the feasibility of placing the 3D specimen model into an augmented reality (AR) environment to guide re-resection. AR superimposes a computer-generated image on a user's view of the real world, thus providing a composite view. The goal of this project is to determine the accuracy of placing a 3D specimen hologram into the surgical defect in actual head and neck cancer patients and develop custom AR software to improve time and accuracy of alignment. In Aim 1, I will determine the accuracy of alignment of the projected 3D specimen model into the surgical defect. The tumor will be resected per standard of care, 3D scanned, and uploaded into the AR environment. The surgeon will wear the Microsoft HoloLens 2, a portable, handsfree, AR headset. The surgeon will align the 3D specimen hologram into the resection bed and accuracy will be measured. In Aim 2, I will develop a custom AR surgery platform to improve time and accuracy of alignment. The existing AR software has significant limitations for surgical use, including limited voice commands, inability to adjust transparency, and lack of a lock-in-place feature. To address this, I am creating custom AR software in collaboration with the Vanderbilt Institute for Surgery and Engineering. In a cadaveric study, surgeons will align the 3D specimen hologram into the resection bed using both the custom and existing AR software. Time and accuracy of alignment will be measured. During this project I will benefit from the guidance of my primary mentor, who is an established surgeon-scientist with substantial experience in bringing new technologies into the operating room, as well as three co-mentors with expertise in specific areas. Additionally, I will undertake advanced training in AR systems, surgical pathology processing, and clinical trial design, which will provide a strong foundation for pursuing my career goal of becoming a surgeon-scientist focused on implementation of AR systems to improve the effectiveness of oncologic surgery. This project will lay the groundwork for a future R01 application to include expansion of AR technology to other solid malignancies and a prospective clinical trial to determine whether use of 3D scanning and AR-guided oncologic surgery improves positive margin rates and ultimately patient outcomes.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY/ABSTRACT Cardiovascular disease (CVD) is a major cause of death in individuals with type 1 diabetes (T1DM), but the underlying mechanisms are not well understood. Despite efforts to control blood glucose levels, patients with T1DM who meet glycemic targets (i.e., HbA1c ≤ 6.9%) are still at a 3-fold increased risk of CVD death. By contrast, studies of a different type of diabetes called glucokinase maturity onset diabetes of the young (GCK- MODY) have found that these individuals do not have an increased risk of CVD, despite having a similar level of long-term high blood glucose. Our previous research suggested that one important difference in CVD risk is that people with T1DM have insulin resistance and those with GCK-MODY do not. Our data suggested that the presence of iatrogenic hyperinsulinemia in T1DM—not hyperglycemia—was the principal factor contributing to the decreased insulin sensitivity. This iatrogenic hyperinsulinemia occurs because patients with T1DM must deliver insulin into the peripheral circulation rather than more physiologically into the hepatic portal circulation. Because this delivery route bypasses first-pass hepatic clearance, people with T1DM have 2½-fold higher peripheral insulin levels than people who have normal insulin secretion. These studies imply that reducing iatrogenic hyperinsulinemia can improve insulin sensitivity and possibly other aspects of cardiometabolic risk. Insulin adjunctive therapies may facilitate the needed reduction in hyperinsulinemia. We will conduct paired experiments to investigate the effects of modifying iatrogenic hyperinsulinemia on three markers of cardiometabolic risk: nitric oxide bioavailability (Aim 1), insulin sensitivity (Aim 2), and thrombotic potential (Aim 3). We will compare the effect of lowering iatrogenic hyperinsulinemia in T1DM to the effect of raising insulinemia by the same amount in individuals at low risk for cardiometabolic disease: those with GCK- MODY and those without diabetes (control). We will compare the three cardiometabolic risk markers in T1DM patients (n=13), GCK-MODY patients (n=7), and those without diabetes (n=7) under conditions of high insulin levels (Hi-Ins, 20-25 μU/mL as seen in T1DM) and normal insulin levels (Eu-Ins, 5-10 μU/mL, as seen in CGK-MODY and control). To allow T1DM participants to acutely lower peripheral insulinemia to normal levels without consequent hyperglycemia, we will use a sodium-glucose cotransporter-2 inhibitor (SGLT2i) as a research tool. Overall, our goal is to determine how much reducing iatrogenic hyperinsulinemia using insulin adjunctive therapy can improve CVD outcomes, and to understand the underlying mechanisms behind this effect. This small, mechanistic pilot study will provide needed data to inform the development of larger trials of insulin adjunctive insulin therapy in T1DM.

NIH Research Projects · FY 2025 · 2024-08

ABSTRACT: Breast cancer in Uganda presents a pressing public health challenge, characterized by late-stage diagnoses and high mortality rates, particularly among women residing in rural and semi-urban areas. This proposal addresses this critical issue by optimizing, validating, and deploying a point-of-care diagnostic kit, tailored for primary care clinics in Uganda, where most women access care. The proposed diagnostic kit combines (1) an FDA-cleared automated AI-enabled whole breast ultrasound and (2) a smartphone- enabled AI-powered device that performs brightfield imaging of basic cytology preparations and incorporates a self-contained immunodiagnostic chip to quantify breast tumor biomarkers. Our approach involves a two-fold validation strategy. First, we will validate the diagnostic performance of the proposed diagnostic kit in a U.S. clinical setting, comparing it to standard-of-care methods such as ultrasound, mammography, tissue sampling, and pathology (aim 1). Utilizing quality improvement cycles and feedback from end-users, we will refine the kit's performance and usability. Next, we will validate the kit at the Uganda Cancer Institute, tailoring it to Uganda's healthcare landscape, considering factors like infrastructure, health workers’ expertise, and accessibility (aim 2). Following validation, and guided by a Ugandan Community Advisory Board, we will implement a cluster randomized controlled trial involving eight community health centers (CHCs) across two health districts in Uganda (aim 3). A mobile breast cancer detection clinic will deliver the diagnostic kit to CHCs during bi-monthly Breast Health Days for N=1000 patients referred for diagnostic evaluation, at 4 CHCs. We will compare the effectiveness of the diagnostic kit with women receiving care at control CHCs, who will be referred for standard-of-care ultrasound at Regional Hospitals (N=1000). Our collaboration draws upon expertise in engineering and biomedical device development, breast cancer research, and global health, positioning us to significantly impact breast cancer outcomes in Uganda. This initiative aligns with the RFA-CA-24-005 mission to develop cancer-relevant technologies suitable for use in low- and middle-income countries. By validating and deploying a practical, cost-effective, and user-friendly detection and diagnostic technology, we aim to empower healthcare providers in Uganda and, ultimately, improve patient outcomes. If successful, this innovation stands to enhance access to timely breast cancer detection and diagnosis in resource- constrained settings.

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY Uterine fibroids, benign tumors of the uterus, affect 77% of women by menopause in the U.S. and account for up to $34 billion in annual healthcare costs. Black women have at least a two-fold higher risk of fibroids than White women, develop fibroids at younger ages, are more likely to have a clinical diagnosis, and are more likely to have a hysterectomy. Black women are also more likely than White women to have larger and more numerous fibroids. Fibroids are also highly heritable. We have shown associations between increasing African ancestry and fibroid risk that risk varies by African geographic region. We will leverage VUMC’s extensive research infrastructure in Nigeria, our state-of-the-art tissue collection, -omics expertise, and the high level of genetic diversity within Africa-origin populations to test the hypothesis that Nigerian women have stronger risk for fibroids than US Black women. Nigeria is an ideal locale to study these issues as ancestry from Nigerian populations represents a large proportion of the African American genome. Several large-scale genome- wide association studies (GWAS) of fibroid risk have identified multiple fibroid risk loci. However, the mechanisms by which these genes function in the uterus or in fibroid tumors remain poorly defined. Within this grant we will use bulk RNA (RNAseq) and single cell RNAseq (scRNAseq) to better understand the mechanisms by which GWAS identified loci function in fibroid risk in African ancestry women. We will conduct the following specific aims: 1. Test for the association of known and novel fibroid GWAS loci among Nigerian women and identify loci associated with gene expression in myometrium. We hypothesize that effect sizes are larger for fibroid risk loci among Nigerian women and these loci associate with gene expression. We will run bulk RNAseq on 1,000 myometrium samples (500 discovery and 500 validation) and conduct germline low pass sequencing from whole blood from the 3,000 with 1,000 overlapping individuals. 2. Detect cell-specific gene expression unique to normal or fibroid tissue in African ancestry women. We hypothesize that there are differences in cell-type specific gene expression across normal and fibroid uteri. Using overlapping samples from Aim 1, we will run scRNAseq on fibroid tumors and normal myometrial tissue (75 non-fibroid, and 75 fibroid tissues from US Blacks, age-matched). 3. Build a myometrial tissue eQTL atlas and gene expression prediction models. We hypothesize that eQLTs identified from Aim 1 and 2 can be used to develop predicted gene expression models. Combining genotypes and bulk RNAseq data generated in Aim 1 and scRNAseq data from Aim 2, we construct bulk and cell-specific predicted gene expression models. We will then conduct a multi-stage predicted gene expression association analyses using GWAS summary statistics and data. We propose an efficient and cost-effective approach to identify functional loci associated with fibroid determinants by developing a uterine tissue gene expression reference in Black women.

NIH Research Projects · FY 2024 · 2024-08

PROJECT SUMMARY Staphylococcus aureus is a leading cause of a wide range of bacterial infections globally and the most common bacterial cause of mortality in the United States. These poor outcomes are driven by the high rates of antibiotic treatment failure (15-40%) seen with many types of S. aureus infections including osteomyelitis, prosthetic joint infections, and endocarditis. Antibiotic tolerance, which is defined as the ability of bacteria to survive in the face of antibiotics through phenotypic changes without the acquisition of antibiotic resistance, is the major driver of antibiotic treatment failure in S. aureus infections. Even with appropriate antibiotic therapy, mortality rates can exceed 20% for some of these infections. Given the high incidence and the frequent treatment failure, new and improved treatment options are needed to combat S. aureus infections. Despite the clinical significance of antibiotic tolerance, the mechanisms by which it occurs are poorly understood. To gain new understanding of treatment failure in S. aureus infections, my fellowship research focused on understanding antibiotic tolerance by conducting comprehensive, unbiased genetic and proteomic screens of S. aureus during antibiotic exposure. With this approach, I identified a previously unknown relationship between antibiotic tolerance and arginine metabolism where antibiotic tolerance in mature S. aureus communities increases when arginine is depleted. In addition to being an essential amino acid for S. aureus growth, arginine is also required for the production of nitric oxide by host immune cells such as neutrophils and macrophages. Nitric oxide production is important for the host response to S. aureus infections, which establishes arginine as an important contributor to the ability of the immune system to combat S. aureus. Collectively, these results support the hypothesis that S. aureus influences arginine levels during infection by carefully regulating arginine metabolism as a means to survive both in the face of antibiotics and the innate immune response. Through this proposal, I plan to test this hypothesis by (1) elucidating the mechanism(s) by which arginine metabolism influences antibiotic tolerance in S. aureus, (2) determining the role of S. aureus arginine metabolism in persistence in the presence of innate immune effector cells, and (3) identifying the contribution of S. aureus arginine metabolism to persistence and antibiotic treatment failure during infection. Together, these experiments will better define the role of an essential amino acid at the host-pathogen interface. The work in this proposal has the potential to uncover new therapeutics targets for the treatment of recalcitrant infections that fail conventional therapies. In addition, through this award, I will receive important mentorship while gaining specific research skills in animal models, eukaryotic cell culture, and imaging mass spectrometry. This NIH K08 Mentored Clinical Scientist Research Career Development Award will help me establish my own independent research program as part of my long-term goal of becoming a physician-scientist leader in the field of infectious diseases with an expertise in bacterial pathogenesis and antibiotic treatment failure.

NIH Research Projects · FY 2024 · 2024-08

Project Summary Pathogenic picornaviruses and bunyaviruses have an enormous impact on public health worldwide, and our understanding of mechanistic correlates of immunity for members of these virus families is limited. Because of the diversity of viruses in these families, it is unlikely medical countermeasures (such as vaccines and antibodies) can be developed ahead of time for each one of these viruses, therefore a prototype pathogens approach is warranted. We have assembled a highly interdisciplinary consortium of leading investigators in the field of picornavirus and bunyavirus virology, immunology, vaccine biology and antibody sciences to study the mechanistic correlates of immunity to prototype pathogens for these families, and then apply the principles we learn with the prototype pathogens to different pathogenic viruses in those families that are antigenically distinct. All five Research Projects (RP) in the Center focus on developing strategies effective against all pathogenic members of a group of viruses, picornaviruses, hantaviruses, and diverse arenaviruses. RP1 focuses on innovative vaccine strategies for picornaviruses (enterovirus D68, enterovirus A71, echovirus 11 and rhinovirus C types), RP2 focuses on human anti-picornavirus monoclonal antibodies, RP3 focuses on novel vaccine candidates for hantaviruses, RP4 focuses on human mAbs for Sin Nombre, Andes and Hantaan hantaviruses, and RP5 proposes studies on arenavirus vaccines and antibodies, with LCMV as an initial prototype for study. A unique aspect of this Center is that it includes full complementary research projects for both vaccine and mAbs, which are the two most well-studied countermeasures that provide complete pre- or post-exposure protection against virus infections. The advanced level of certain preliminary findings in the work described in the RPs is a major strength and advantage of our Center. There has relatively little significant progress over the last decade in the development of vaccines or postexposure therapies for picornaviruses or bunyaviruses. Preventive vaccines would have utility for the public during local or large-scale outbreaks, for laboratory workers, for first responders or individuals at high-risk exposure, and for certain travelers or military personnel. In the case of a biological attack or natural outbreak, however, a preventative or postexposure antibody treatment would be the most practical approach for rapid deployment and has the advantage that antibodies can be used in any age or health condition, including the immunocompromised. perform pivotal studies that will facilitate the development of products used for the prevention and treatment of Nipah and Hendra infections. The cooperation among the paired vaccine + mAb RPs, the Administrative Core, the sample acquisition, structural biology, and vaccine technology cores is built into the Center by design, as all components work together to provide broadly effective candidate countermeasures. Quality system data management will be employed in both the preparation of advanced stage test articles and in the conduct of animal studies.

NIH Research Projects · FY 2025 · 2024-08

ABSTRACT Pregnancy is a unique, early moment of cardiovascular stress in young women that may “unmask” cardiovascular disease (CVD) propensity. Preeclampsia (PreE)—characterized by new-onset hypertension and proteinuria—has been linked to left ventricular diastolic dysfunction that may persist for years post-partum, and an increased risk of developing heart failure with preserved ejection fraction (HFpEF) over the decade following pregnancy. It is unclear if PreE simply represents a failed stress test or directly contributes to the pathophysiology of future CVD. Women and minorities are traditionally understudied in HFpEF, despite their disproportionate risk. This is the first large prospective study to investigate the hypothesis that PreE leads to persistent functional, hemodynamic, structural and biochemical cardiovascular changes that mirror early HFpEF. By defining the echo, proteomic and hemodynamic risk profile for early HFpEF, this will afford the opportunity for future studies to mitigate disease through pharmacologic/lifestyle interventions in a targeted population. We hypothesize that persistent structural-functional myocardial alterations in women with PreE are linked to pre- and post-gravid cardiometabolic risk factors and functional capacity and select pathways of vascular and inflammatory stress central to HF risk. We will use perturbational hemodynamic studies to elaborate myocardial phentoypes defining of HFpEF in women with PreE. We address our central hypothesis in 3 Specific Aims (SA): SA1: To measure relation between post-partum subclinical LVDD and pregnancy-specific risk factors in 250 women with PreE and 250 normotensive women (25% Black) through rest and provocation echocardiographic imaging, SA2: To quantify the hemodynamic consequences of early persistent LVDD in women with PreE, SA3: To identify differences in cardiovascular pathways of vascular remodeling and inflammation and their association with subclinical myocardial dysfunction in women with PreE. For this study, we will leverage the infrastructure of our NIH funded multidisciplinary cardio-obstetrics clinical research team for recruitment, retention, and risk factor modification (U01HG013189, R21NR020857). A fundamental strength of this proposal is the ESI PI’s experience in recruiting and retaining women at this critical stage in CV development. Our targeted enrollment of Black women addresses clinical and investigative gaps in this population at high short and long-term CV risk following a preeclamptic pregnancy. Successful completion of these studies in a large group of women across race will define high-risk PreE-linked structural/functional changes to support risk stratification and future interventional studies at this critical moment in CVD development in women.

NIH Research Projects · FY 2025 · 2024-08

The 548,000 Americans who rely on dialysis to stave off death from kidney failure suffer from malnutrition, inflammation, immune defects, and vastly increased incidence of coronary thromboses and pulmonary embolisms. Conventional hemodialysis cartridges are designed to remove urea, because urea removal is fundamental to dialysis quality metrics. However, urea is a largely non-toxic stand-in for other waste products, and urea-focused efforts fail to capture the complexity of dialysis in renal failure. One class of uremic wastes that are thought to contribute to the illness of dialysis patients is called "protein-bound uremic toxins" (PBUTs), such as indoxyl sulfate, kynurenic acid, and p- cresyl. Because dialyzers do not allow albumin to pass from blood to dialysate, the toxins bound to albumin do not pass in appreciable quantities either. Dialyzer design has focused on urea removal. We hypothesize that increasing the residence time of blood in the dialyzer will allow for increased PBUT removal and eventually, better health for patients who depend on dialysis. Hemodialysis treatment is associated with an increased risk of clotting despite anemia, uremia, and chronic heparin use. The superphysiological shear stresses that platelets experience in hemodialysis appear to prime them to form clots inappropriately. We designed a parallel-plate dialyzer with tightly controlled shear forces. We will test whether platelet activation with this novel design reduces platelet activation, compared to conventional dialyzers.

NIH Research Projects · FY 2025 · 2024-08

Project Summary Multiple preclinical and clinical studies show that glucagon-like peptide-1 receptor (GLP-1R) agonists, FDA approved agents used in type 2 diabetes, obesity, and cardiovascular risk reduction, are a promising novel treatment strategy for asthma. However, the key cellular targets and mechanisms by which GLP-1R agonists reduce airway inflammation in asthma remain poorly understood. The rationale for the proposed research is that a better understanding of the cellular targets and anti-inflammatory mechanisms of GLP-1 signaling is required in order to maximize the clinical use of GLP-1R agonists for the treatment of both lean and obese patients with asthma. The overall objective in this proposal is to identify the direct immunologic mechanisms by which GLP-1 signaling reduces inflammation to inform the clinical repurposing of GLP-1R agonists in asthma. The central hypothesis, based on preliminary data generated in the investigators’ laboratories, is that GLP-1R agonists directly attenuate both type (T)2 and non-T2 cells and mediators in asthma. Guided by robust preliminary data which supports that GLP-1R signaling regulates the function of specific human immune cells, we will test our central hypothesis in two distinct, but highly integrated specific aims. We will determine the anti- inflammatory role of GLP-1 signaling in 1) platelet-derived T2 and non-T2 inflammation and 2) CD4+ T cell function in asthma. In aim 1, we will evaluate platelets from lean and obese asthma patients to determine the role of GLP-1 signaling on platelet inflammatory mediator release (aim 1a). We will assess platelet aggregation as a biomarker of the inflammatory and clinical response to GLP-1R agonist therapy (aim 1b), and the effect of GLP-1R agonist therapy on platelet activation and platelet-leukocyte formation in patients with asthma (aim 1c). In aim 2, we will evaluate CD4+ T cells and platelet-adherent CD4+ T cells from lean and obese asthma patients to determine the role of GLP-1 signaling on CD4+ T cell subset differentiation (aim 2a). We will assess the effect of GLP-1R agonist therapy on CD4+ T cell activation in patients with asthma (aim 2b). This proposal capitalizes on sample collection and mechanistic and clinical data from the investigator’s ongoing randomized controlled trial of a GLP-1R agonist in asthma with comorbid obesity. This fully human approach is innovative because it defines how GLP-1R agonists regulate multiple key immune cell populations, independent of GLP- 1R agonist effects on comorbid metabolic disease. This proposal is significant because it defines a precision medicine approach for repurposing GLP-1R agonists in both lean and obese patients with asthma. This study will inform the use of GLP-1R agonists in asthma and other inflammatory diseases in the absence of metabolic comorbidity.

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY Substance use and associated HIV, hepatitis C (HCV), and mental health comorbidities continue to drive morbidity and mortality. Interdisciplinary, interinstitutional collaborations can challenge paradigms to achieve advances in substance use treatment that limit the spread of HIV/HCV and decrease morbidity and death. Vanderbilt University Medical Center (VUMC) and Oregon Health and Science University (OHSU) are national leaders in substance use research and are located in states with high rates of substance use and new HIV infections. For these reasons, this application seeks to establish the Vanderbilt Oregon COllaborative Scholar Training in Addiction Research (COSTAR) K12 program to train and mentor the next generation of substance use researchers. We propose to support a minimum of three faculty Scholars who have completed an MD or PhD in the health sciences at a level of 75% effort for up to five years. VUMC and OHSU have a rich research environment and highly successful history of developing the careers of research scientists . Additional strengths of VUMC/OHSU include four addiction fellowship programs, the Tennessee Center for AIDS Research, the Vanderbilt Center for Tobacco Addiction and Lifestyle at VUMC and the Western States Node of the National Drug Abuse Treatment Clinical Trials Network, the Portland Alcohol Research Center, and the Rural Opioids Initiative at OHSU. In this application, Drs. Tindle (nicotine dependence), Freiberg (unhealthy alcohol use), and Korthuis (drug use) will partner with interdisciplinary faculty mentors from both VUMC and OHSU to develop and implement COSTAR. The COSTAR training curriculum includes (1) mentored research projects, (2) didactic education, (3) completion of a structured institutional career development program, and (4) optional multisite research training. COSTAR objectives and Specific Aims: 1. To create a sustainable K12 program that fosters interdisciplinary, intensive mentored research training and career development for early career MD, PhD, MD/PhD investigators that focuses on substance use/disorders with an emphasis on vulnerable populations (e.g., people with HIV); 2. To produce a diverse group of well-trained Scholars with the expertise to study: the risk factors for, and mechanisms underlying, substance use/disorders, and the behavioral and health disparity aspects of substance use/disorders and its associated morbidity; 3. To provide Scholars with a research environment that offers mentors and topic experts with expertise in key research domains and protected time to innovate and build an individualized research program; 4. To leverage VUMC and OHSU existing infrastructure and location to provide Scholars with hands-on instruction in a mentor’s laboratory, didactic education, access to existing cohort/trial data and statistical support and facilitate participation in a mentored research project that leads to an R01 or external career development award submission; and 5. To build the administrative structure that creates program cohesion, guides selection of mentors, oversees steady progress in career development, and continuously improves program components.