Vanderbilt University Medical Center

NIH Research Projects · FY 2025 · 2023-09

SUMMARY Primary central nervous system (CNS) tumors are the most common solid tumors in children and the leading cause of childhood-cancer-related deaths. Thus, there is an urgent need to identify novel therapeutic treatments. One such advancement is carbon-ion radiation therapy (CIRT). Yet, despite treating 20,000 patients over 2 decades, there is a significant reluctance to use this modality to treat pediatric brain tumors because of a fear that normal tissue would be irreparably harmed. This fear is a consequence of the many questions that are unanswered regarding the ability to quantify the relative biologic effectiveness (RBE) of CIRT. An important attribute of the physical dose delivered by charged particles is ionization density, which varies with particle charge and velocity. Ionization density is frequently described in terms of linear energy transfer (LET), defined as the mean energy lost 𝑑𝐸∆/𝑑𝑙 by a charged particle per unit distance 𝑑𝑙 traversed due to interactions with electrons in matter. For charged particles, the dose and LET increase dramatically over the terminal few millimeters of the pristine Bragg peak as the particle halts. A major uncertainty is the scaling from dose and LET to biological effect, which varies within tumors and normal tissues in a complex manner. The computational dose and RBE models simulate on a millimeter-scale the variation of dose, energy and LET spectra, and particle fragment spectra within the patient anatomy and link these physical properties to biologic data, often determined from in vitro clonogenic survival assays. A critical gap in knowledge is the true in vivo tissue response to high-LET radiation in clinically relevant biological assays. The uncertainty is enormous and the impact of incorrect assignment of an RBE value to a given voxel can be catastrophic in clinical practice. Therefore, RBE values need to be determined with the greatest possible accuracy. Our central hypothesis is that optimization of carbon-ion radiation therapy will allow for improved curative outcomes for pediatric brain tumors, with equivalent or lower neurologic toxicity compared to x-ray therapy. Two specific aims will be used to test the hypothesis. Aim 1 will systematically quantify the RBE of CIRT normal-tissue toxicity in a rodent model of pediatric brain, for various functional and pathologic endpoints, at variable dose and LET, compared to x-ray therapy. Aim 2 will test the working hypothesis that high-LET carbon ions are more effective in controlling pediatric high-grade glioma than conventional radiation. Thus, the overall objective of this work is to investigate the normal brain toxicity, cognitive side effects, second cancer risks, and anti-tumor efficacy in preclinical models relevant for pediatric patients, providing a sound foundation for advancing this modality into clinical practice. We will answer the question as to whether carbon-ion therapy, which shows immense potential for historically radioresistant cancers, can be expected to improve the therapeutic window for pediatric high-grade glioma patients. Furthermore, we will contribute fundamental new knowledge regarding treatment risks and neurotoxic side effects relevant for all pediatric CNS tumors treated with radiation.

NIH Research Projects · FY 2025 · 2023-09

Attentional Mechanisms of Cognitive Compensation in Subjective Cognitive Decline and AD Risk Candidate: Dr. Kimberly Albert, PhD is an assistant professor in the Department of Psychiatry and Behavioral Sciences at the Vanderbilt University Medical Center with a strong background in cognitive and systems neuroscience. Her long-term career goals include gaining the necessary training to become an independent investigator with research focused on identifying brain mechanisms that maintain cognitive function in the early stages of pathological brain aging and may underlie subjective cognitive decline (SCD). Career Development: Dr. Albert seeks to translate her mechanistic work to clinical research that mitigates the cognitive effects of early AD pathology. Dr. Albert requires advanced training in 1) clinical trials development, implementation, and management.; 2) the clinical presentation, course, and assessment of SCD and Alzheimer’s Disease; 3) neuroimaging using EEG/ERP to provide the temporal resolution to assess brain activity related to component cognitive processes. This training will build on Dr. Albert’s prior experience in human cognitive neuroscience using functional neuroimaging to examine the neurobiology of cognitive aging. Research Project: These career goals will be facilitated through a research study focused on the role of cholinergic support of attention as a cognitive compensatory mechanism in SCD. As early AD-related neuropathology affects medial temporal areas important for memory, there may be a compensatory enhancement of attention network activity via increased cholinergic function. Although memory performance is maintained through this compensatory process, subtle cognitive changes may be obscured. Additionally, the individual may experience this change as increased required effort or occasional memory failures which result in subjective cognitive decline despite normal cognitive testing. Cholinergic activity may be an integral component of maintaining memory function in early AD, through enhanced attention. The proposed study focuses on attention as a compensatory cognitive process and the relationships between AD-related pathology and cholinergic neurotransmitter mechanisms that may underlie this compensation in SCD. The ultimate aim of the study is to identify the role of attention network changes in supporting cognitive performance in SCD using EEG and fMRI as complimentary neuroimaging approaches. Anticholinergic challenge will be employed to model AD progression and examine the relationships between cognitive concerns, attention, and AD pathology. The results of this study will improve our understanding of brain changes that maintain cognitive performance in the early stages of AD pathology and may underlie SCD. Environment: Mentoring, collaborations, and resources available through the Department of Psychiatry and Behavioral Sciences, the Center for Cognitive Medicine, and the Vanderbilt Alzheimer’s Disease Research Center provide an ideal environment to support Dr. Albert’s transition to independent funding and leadership in the field of attentional changes in cognitive aging.

NIH Research Projects · FY 2024 · 2023-09

PROJECT SUMMARY Cardiovascular disease and its risk factors are major contributors to health burden and early death. Physical activity and sleep patterns are important behaviors that are causally tied to cardiovascular morbidity and mortality. Additionally, an individual’s genetic predisposition contributes to either increased or decreased risk of these conditions. The extent to which modifiable activity and sleep behaviors combine with genetic background to influence cardiovascular risk is not known. This is an important knowledge gap because contemporary physical activity recommendations do not account for genetic variability. The All of Us Research Program offers a unique combination of long-term activity and sleep data from wearable devices, whole-genome sequencing, and clinical outcomes from patients seeking care. These data sources provide an opportunity to understand how behaviors interact with genetic factors to contribute to incident disease risk. We hypothesize that increased physical activity and improved sleep will be necessary to mitigate excess genetic risk. Physical activity and sleep duration and quality can be quantified and tracked by wearables that are now widely used by the public. These devices enable high quality, longitudinal collection of these measures to integrate to inform impact on disease. Genetic risk is a significant contributor to cardiovascular disease and an important factor to consider when quantifying the role of modifiable behaviors. Genetic background represents a risk floor upon which behavior and environment interact to determine disease onset and severity. It is currently unclear to what degree behaviors such as physical activity and sleep might need to be adjusted to the specific genetic background of the individual. In preliminary work using All of Us data, we performed a phenome-wide association study of the association between step counts and incident chronic disease. Over 5.9 million person-days of monitoring, cardiovascular risk factors (obesity, diabetes, hypertension, and major depression) emerged among 1,700 phenotypes as most strongly associated with lower step counts. We now propose to extend our work to measure the impact of underlying genetic risk and activity and sleep patterns on cardiovascular risk. Aim 1 will quantify the interaction of genetic risk and physical activity on modifying incident cardiovascular risk factors using polygenic risk scores for obesity, hypertension, dyslipidemia, diabetes, and depression. Secondary analyses will examine the impact of genetic risk on cardiovascular outcomes. Aim 2 will assess the impact of sleep duration on incident cardiovascular risk factors with and without integration of genetic risk. Our investigative team is uniquely qualified to maximally leverage the available sources of data in All of Us to quantify the combined impact of sleep, activity, and genetics on cardiovascular risk. We have collective expertise in cardiovascular disease, genomic analysis, electronic health record cohorts, sleep research, and use of Fitbit data. The results of this work will provide an initial step toward personalization of activity and sleep guidance that incorporates genetic background.

NIH Research Projects · FY 2025 · 2023-09

Sudden unexpected death in epilepsy (SUDEP) is the most common cause of death in patients with refractory epilepsy. Currently, it is impossible to predict or prevent SUDEP. However, SUDEPs that have occurred in monitored settings were characterized by hypoventilation and apnea prior to cardiac dysfunction, implicating seizure-related respiratory dysfunction as a critical factor. Human intracranial data suggests the amygdala as a forebrain structure that may be important for respiratory control and involved in seizure-related respiratory dysfunction. Understanding the neural circuit mechanisms involving amygdalar structures that underlies seizure-related respiratory dysfunction that leads to hypoventilation and death is critical to advancing SUDEP prevention options, which currently do not exist. Our long-term goal is to identify the neural circuits underlying seizure-related respiratory dysfunction to predict and prevent sudden death. The main objective of the proposed project is to delineate brainstem projecting extended amygdalar neurons involved in seizure-related respiratory dysfunction and arrest. Preliminary data in a mouse model of SUDEP show that the extended amygdalar structure the bed nucleus of the stria terminalis (BNST) represents a potential mediator underlying seizure-related respiratory dysfunction. Our hypothesis is that BNST activation during seizures contributes to seizure-related respiratory dysfunction, respiratory arrest, and death via downstream activation in the parabrachial nucleus (PBN) of the pons. This hypothesis will be tested via the following specific aims in a model of SUDEP: (1) Characterize the role of BNST and BNSTPBN activation in respiratory dysfunction in a model of SUDEP. (2) Determine the effect of acute BNST inhibition on seizure-induced respiratory dysfunction in a model of SUDEP. In Aim 1, we will use a viral approach to selectively identify and dissect BNST neurons activated by seizures as well as determine the relationship between BNST activation and respiratory dysfunction during seizures. In Aim 2, we will use in vivo optogenetic inactivation of the BNST to determine the critical period of activity for respiratory depression and potential intervention. At the successful completion of the proposed research, the expected outcomes are characterization of seizure-activated BNST-brainstem circuitry and the temporal relationship of BNST activation to seizure-related respiratory dysfunction to determine sufficiency and the timepoint necessary for acute BNST activation in this effect. The proposed research is conceptually innovative through its focus on BNST circuitry in terms of SUDEP pathophysiology and technically innovative through the use of cutting-edge systems neuroscience techniques applied to SUDEP including fiber photometry, virally-mediated Targeted Recombination in Active Populations (TRAP) and in vivo optogenetics. These results are expected to have a significant impact on our current understanding of alterations of forebrain respiratory circuits that lead to SUDEP and will provide a strong basis for future development of novel therapeutics and clinical targets for neuromodulation to prevent SUDEP.

NIH Research Projects · FY 2024 · 2023-09

Project Summary Speech-language impairments have been clinically and genetically linked with risks for mental health disorders, poor physical health, and poor educational outcomes. However, large-scale studies of speech-language deficits primarily remain the purview of research on learning disabilities and developmental disorders (e.g., articulation and fluency disorders; developmental language disorder; autism), underestimating the health impact of speech and language traits for all individuals. This project aims to investigate the overall health impact of speech and language difficulties, disorders, and risk. Specifically, we use unbiased, data-driven, computational approaches to examine the medical "phenome", or entire collection of health and disease outcomes (phenotypes) found in the All of Us Electronic Health Records (EH Rs). These phenome-wide association studies (PheWAS) have great potential to discover comorbidities, shared genetic risk for multiple health conditions, and identify targets for early intervention and therapies. In Aim 1 studies, we characterize associations between speech-language difficulties or disorders, and the entirety of the medical phenome. In Aim 2A and 28 studies, we investigate how genetic predispositions for speech-language abilities that have not been measured in All of Us participants (e.g., spelling; phonemic awareness), are associated with the entire medical phenome. In Aim 2A, we focus on genetic risk markers that are derived directly from common genetic variants associated with speech-language phenotypes; and in Aim 28 we build on this by additionally incorporating aspects of the transcriptome (e.g., gene expression), which improves portability of genetic risk predictions across multiple ancestry, and particularly in African Americans - a community who are highly underrepresented in biomedical research, and both historically and presently subject to systemic health inequity. Our approach, which is agnostic to specific clinical phenotypes, symptoms, diagnoses, or disorders, will reveal population-level health and disease outcomes associated with speech-language traits in populations that are usually underrepresented in biomedical research. This project directly responds to the call to make discoveries using high-quality All of Us data; advances the NIDCD mission to improve the lives of people with communication disorders; and enhances diversity in genomics research through the use of diverse data, and through opportunities for diversifying the workforce. By combining precision medicine techniques with a health equity and community-engaged focus, findings from this project will address critical health needs for subsets of individuals with certain clinical and/or genetic risk factors related to speech and language, as well as entire communities in whom communication traits/disorders have been understudied.

NIH Research Projects · FY 2025 · 2023-09

Abstract: Bariatric surgery, currently the most effective treatment for morbid obesity, has become increasingly common in the US. Besides substantial and sustained weight loss, bariatric surgery leads to dramatic changes in many aspects of human physiology, including glycemic control, bile acid metabolism, immunosurveillance, and gut microbiota. These changes, if sustained after surgery, may affect the risk of colorectal cancer (CRC). On one hand, reduced obesity, insulin resistance, and systemic inflammation may lower CRC risk; meanwhile, increased exposures to some bile acids (e.g., ursodeoxycholic acid) and beneficial bacteria (e.g., Akkermansia muciniphila & Faecalibacterium prausnitzii) may also lower CRC risk. On the other hand, increased exposures to other bile acids (e.g., deoxycholic acid) and bacteria (e.g., aerotolerant species) may increase CRC risk after bariatric surgery. While the interplays of gut microbiota with host metabolism & immunity have been implicated in CRC etiology, it is unclear what sustained changes in gut microbiota are induced by bariatric surgery and how post-surgery “gut microbiota-host interactions” may impact CRC risk. Longitudinal studies with repeated collections of biospecimens (e.g., blood & stool) and patient data (e.g., diet & medication) are needed to tackle these questions but currently lacking. ●Building on a longitudinal cohort of bariatric surgery patients, we propose to investigate, in Aim 1 (targeted evaluation): pre- to 1-year and 3-years post-surgery changes in potential CRC-related bacteria (e.g., Fusobacterium nucleatum, enterotoxigenic B. fragilis, & pks+ E. coli), major microbial metabolites (e.g., bile acids & short-chain fatty acids), and established markers of systemic and microbial inflammation (e.g., C-reactive protein & LPS-binding protein); in Aim 2 (omics-wide discovery): the most significantly and consistently altered bacteria, microbial metabolites, and inflammatory & immune response proteins at 1- and 3-years post- vs. pre-surgery, using shotgun metagenomics, global metabolomics, and proteomics; in Aim 3 (in vivo experiments): the causality and molecular mechanisms of post- vs. pre- surgery gut microbiota in CRC carcinogenesis. We will perform fecal microbiota transplant (FMT) on antibiotic- treated, genetic mouse models of CRC using preserved pre- and 3-years post-surgery stools and compare adenoma/tumor burden, colonocyte biology, and systemic & intestinal inflammation between those groups and with mice receiving a group of bacteria with the largest and consistent post-surgery increases as identified in Aim 2 and with control. ●Leveraging a longitudinal cohort of bariatric surgery patients and applying state-of- the-art multi-omics and FMT in pre-clinical models, our study will fill research gaps regarding sustained post- bariatric surgery changes in gut microbiota and microbial molecules and how they contribute to patients' metabolic, inflammatory, and immunological profiles, and eventually CRC risk. Our results may translate into better patient advice on post-surgery gut health and CRC risk and novel therapies targeting gut microbiota, microbial molecules, and/or immunosurveillance to reduce CRC risk among individuals with morbid obesity.

NIH Research Projects · FY 2025 · 2023-09

Project Summary: . Obesity is at epidemic proportions in the US. Over 60% of the population is either overweight (Body Mass Index [BMI] ≥25 to <30 kg/m2) or obese (BMI ≥30 kg/m2), placing them at risk for a large number of chronic diseases, including insulin resistance, metabolic syndrome, and type 2 diabetes. The annual costs of obesity exceed $100 billion, making it one of the most significant public health and economic issues facing the country. Unfortunately, the treatment of obesity is unsatisfactory. Lifestyle and behavioral approaches have a modest, and often transient, effect while FDA-approved therapeutic options targeting appetite or fat absorption have poor tolerability and, in some cases, safety concerns. Thus, there is a critical need for novel approaches to treat obesity. Agents acting via peripheral mechanisms to increase energy expenditure would be valuable. The sympathetic nervous system (SNS) is well-known as an activator of brown adipose tissue (BAT) and the “browning” of cells in white adipose tissue (WAT) depots to increase uncoupled mitochondrial respiration and energy expenditure. Our earlier work established signaling cascades from β-adrenergic receptors (βARs)  cAMP  protein kinase A (PKA)  p38 MAP kinase (MAPK), and also from PKA to mTORC1. These downstream signaling modules are key to drive the transcription of brown adipocyte genes such as uncoupling protein-1 (UCP1), PPAR-gamma coativator-1α (PGC-1α), and the broader program of mitochondrial biogenesis. The Scientific Premise of this project is based upon our identification of substrates of PKA- activated mTORC1 that convey the brown-adipose promoting machinery, and we will determine their molecular mechanisms. Our long-term goal is to define signaling pathways that are critical to metabolic and cardiovascular disease and, using this knowledge, to target pivotal components of these signaling pathways to prevent or reverse the diseases.

NIH Research Projects · FY 2025 · 2023-09

Due to the organ shortage, more than 15,000 patients with end-stage liver disease (ESLD) are waiting for a life-saving liver transplant (LT) in the US, but fewer than 50% of waitlisted patients will go on to receive a LT.1 As a result, more than 2,000 LT waitlisted patients die each year. Racial disparities compound the organ shortage: ESLD rates are increasing in the Black population, but Black patients receive disproportionately fewer LTs than White patients.2 Living donor liver transplantation (LDLT) is a safe and effective treatment that increases organ availability for LT.3 Yet Black ESLD patients receive fewer than 10% of LDLTs. Efforts to redress these disparities are urgently needed. Assessing multilevel factors that affect Black potential LT recipients (LTR) along with potential living liver donors (LLDs) is essential for developing interventions that foster access to LDLT. In particular, it is important to understand how social determinants of health (SDOH) mediate racial disparities in access to LDLT because SDOH-related barriers are concentrated in racial minorities. Few retrospective studies have identified patient-level factors associated with disparities in access to LDLT (e.g., distance to transplant center, insurance, and neighborhood income). Understanding the mechanisms of the interaction between potential LLD and LTR experiences during the transplant and donor selection process is critical to effectively targeting interventions designed to improve access to LDLT to both the donor and recipient experiences. The objective of the proposed study is to assess multilevel factors contributing to disparities in access to the LT waitlist and LDLT for Black patients with ESLD and potential LLDs. In this descriptive study, we will compare access to LT and LDLT among Black and White patients at two transplant centers with large Black ESLD patient populations (Nashville, TN, and Durham, North Carolina). We will engage LDLT stakeholders (i.e., potential LTRs, potential LLDs, and transplant clinicians) to identify multilevel barriers, facilitators, and strategies for overcoming barriers to LT and LDLT using mixed methods. We will leverage findings to develop an intervention designed to foster access to LT and LDLT for all, and assess its feasibility using implementation science. The specific aims are to: 1. Assess center documented multi-level factors contributing to racial disparities in LT and LDLT 2. Characterize patient perceived multi-level factors that influence access to LT and LDLT 3. Assess the interaction between multilevel factors contributing to racial disparities in LT and LDLT over time Study results will inform the development of a culturally sensitive, multilevel, transplant center-based intervention to increase Black patients’ access to LDLT, and to save lives.

NIH Research Projects · FY 2025 · 2023-09

Project Summary In this MOSAIC K99/R00 Pathway to Independence application, Dr. Brian O’Grady proposes training in models of subarachnoid hemorrhage (SAH) and development of therapeutics that will strategically compliment his expertise in the development of arteriole-specific growth of ex vivo brain tissue in a biomimetic hydrogel and 3D printed microfluidic fabrication. The training plan is paired with scientific studies that will develop and apply a novel microfluidic device for modeling subarachnoid hemorrhage stroke events and for use as a screening platform for a dual-targeted nanoparticle as a potential therapeutic for the damage caused by SAH and delayed cerebral ischemia. Dr. O’Grady’s primary goal is to become an independent researcher focused on creating biomimetic in vitro models of the brain vasculature and developing novel therapeutics for neurological diseases. The rigorous training described and the outstanding team of mentors in vascular biology (Dr. Lippmann), neurological disease pathology (Dr. Jefferson), and nanoparticle development and therapeutics (Dr. Duvall) will ensure his success in transitioning to independence. Through his training plan, Dr. O’Grady will gain 1) deeper knowledge of blood-brain barrier physiology and the neurovascular unit; 2) experience synthesizing and characterizing nanoparticles; 3) knowledge of modeling SAH and neurological disorders in vitro; and 4) strategies for running a successful interdisciplinary and collaborative research lab. SAH is defined as a cerebrovascular disease with the initial event of a ruptured brain aneurysm and accounts for 5% of all types of strokes. Despite this small percentage, SAH accounts for one third of all stroke-related years of potential life lost before the age of 65. While a new era of neurocritical care management has contributed to improved outcomes for SAH, the secondary consequences result in delayed cerebral ischemia (DCI). DCI has varying degrees of patient functional outcome and has no known interventions to improve quality of life. This lack of effective treatments is largely attributed to the high failure rate of translating brain-targeting drugs from animals to humans. Recently, there has been a global effort to produce a tissue engineered, in vitro model system that can represent the complex vascular anatomy and microenvironment of the neurovascular unit. Dr. O’Grady’s preliminary work demonstrates that a novel biomimetic hydrogel supports induced pluripotent stem cell-derived neural, mural, and glial cells and induces arteriole-specific growth of ex vivo human brain vasculature. This new vasculature consists of anatomically correct, concentric layered structures that were previously unobtainable. When supported by a microfluidic device, the arterioles anastomose and can be lumen- perfused and photoablated. Based on his preliminary data, Dr. O’Grady hypothesizes that the dynamic neurovascular microenvironment of a stroke-like event can be accurately modeled by this new in vitro system. In addition to developing a new in vitro model of SAH, this project will test and validate the neural protective efficacy of a dual-targeted therapeutic for SAH and DCI in the human in vitro model.

NIH Research Projects · FY 2025 · 2023-09

SUMMARY Early-life environmental exposures (e.g., social-environmental, parental risk factors, nicotine, diet, infection) are increasingly implicated in the early pathogenesis of childhood diseases that have life-long consequences. Mechanisms linking these exposures to longer-term outcomes remain limited. In 2016, the NIH established the Environmental influences on Child Health Outcomes (ECHO) Program, a collaborative multi-dimensional research initiative to characterize the impact of early-life environmental factors on childhood health (>70 cohorts, >50K participants). While targeted assays within ECHO are likely to lead to disease-specific insight, broad, comprehensive, unbiased assessment of the molecular space for novel discovery—a key mission of ECHO— will necessitate centralization of biobanking efforts/laboratory management with capability for high-throughput “OMICs”/non-“OMICs” assay as well as novel assay development, bioinformatics, and cloud architecture/data sharing for collaborative science. In response to RFA-OD-22-016, Vanderbilt will address this need by establishing the ECHO Laboratory Core at Vanderbilt for Integrated Sample Biobanking and Processing (ELVIS). ELVIS facilitates the collection and processing of biospecimens; manages the biorepository; performs a wide range of biospecimen assays (including novel development), and coordinates metadata and assay data transfer to the Coordinating Center. ELVIS is organized in core “resources” to provide leadership/integration to manage ECHO biobanking, assay performance, and data delivery: (1) administrative/LIMS/biobanking; (2) metabolomics; (3) proteomics; (4) nucleic acid assessment; (5) metagenomics; (6) bioinformatics/study design. We are uniquely positioned for this initiative, leveraging Vanderbilt’s unique long-term strategic investment in functional biobanking and assay: (1) large-scale, reliable biorepository receipt and laboratory management (“LIMS”) capability (>350K patients currently with biospecimens; many other NIH funded biobanks); (2) nationally recognized systems for clinical metadata capture (REDCap, REDBrics; used in NIH initiatives, like All of Us); (3) cutting-edge laboratory cores with capability for novel assay development/validation. We will establish harmonized protocols and workflow for ECHO cohort biospecimen collection and tracking infrastructure from the point of sample collection to long-term storage (Aim 1); perform high-quality, well-powered multi-OMICs and targeted assays to identify molecular correlates of disease trajectories in early life (Aim 2), and provide comprehensive data management platform to facilitate integrated data analysis (Aim 3). ELVIS is an ideal mechanism for ECHO given (1) deep, funded experience in handling the requisite sample sizes in banking and high-throughput assay, including quality assurance measures; (2) prior track record in ECHO to ensure ECHO- specific metadata collection, curation, and harmonization; (3) secure methods for cloud infrastructure for data analysis pipelines and data flow to clinical sites and data analysis center. Successful completion will enable the success of ECHO’s mission to discover molecular underpinnings of early childhood determinants of disease.

NIH Research Projects · FY 2025 · 2023-09

Genetic counselors have rigorous training in genetics and extensive skills in communicating the impact of genetic disease while facilitating coping. There are ~ 6,000 Certified genetics counselors who work in broad areas of medicine and science. The Fellowship in Genomics Outcomes Research (FIGOR) pairs genetic counselors seeking additional training and mentorship in research with leading scientists in genomic research. Facilitating genetic counselors' involvement in research will enhance the quality of the science of genomic and personalized medicine through interdisciplinary collaborations. We request funding for 7 genetic counselor scholars who would each commit to 0.5 FTE of research over 24 months. The long-term goal is for these genetic counselors to contribute as investigators to genomic research by seeking funding, conducting and collaborating in research, and presenting and publishing translational research beyond the clinical spaces where genetic counselors have typically contributed. The training begins with exploration of research opportunities and development of an individualized research plan. Included in the research plan is an educational plan which outlines their timeline and tasks to gain the skills necessary for their research. Students will interact with leaders in genomic and personalized medicine through their collaborations, research seminars, and attendance at national meetings. This measured and focused timeline will allow scholars to craft an immersive experience while benefiting from the unique and plentiful resources at Vanderbilt including BioVU, the Data and Research Center for NIH’s “All of Us”, the Undiagnosed Disease Program, eMERGE, and the ICARE registry. With the establishment in 2015 of the Vanderbilt Genetics Institute, Vanderbilt has committed substantial resources for recruitment of collaborative faculty at Assistant, Associate and Professor levels in genetics and genomics. The Vanderbilt Master of Genetic counseling degree program has demonstrated how GCs are successfully engaged in research at Vanderbilt. Of the 11 recent graduates 9 have presented at national or international meetings. Graduates have published 5 articles in 3 different journals. Skills-focused classroom instruction will complement experienced-based learning through research and active collaboration with experienced mentors. Through these collaborations both the mentee and the mentors will contribute to the growth of genomic research outcomes for personalized medicine.

NIH Research Projects · FY 2025 · 2023-09

ABSTRACT Older adults with Alzheimer’s disease and related dementias (ADRD) require care from numerous specialists and clinical teams to manage ADRD-related symptoms and other comorbidities. The majority of patients with ADRD have their healthcare managed by non-specialists who often lack the time, confidence, and expertise to manage ongoing ADRD needs, which leads to significant referral-based care that often suffers from a lack of coordination. Supporting primary care providers in their ongoing management of care for patients with ADRD by promoting deliberate organization of care activities and information sharing among clinical teams is a critical opportunity to limit unintended gaps and ensure that patients with ADRD receive the high-quality multidisciplinary care necessary for long-term wellbeing. Few solutions exist to measure and identify gaps in care coordination. Current approaches primarily rely on single payor claims data to evaluate patient sharing relationships between providers, which neglects to provide granular insight necessary to improve local healthcare delivery. Applying advanced statistical modeling to EHR usage and communication data will provide critical insight into healthcare delivery patterns necessary to accurately model and optimize referral-based care coordination. In the proposed project, I will apply innovative knowledge representation and machine learning to improve referral-based care coordination by developing intelligent approaches that monitor coordination activities and recommend actionable opportunities for improvement. Under the guidance of a multidisciplinary team of mentors, I will receive training to expand my knowledge in healthcare delivery to promote healthy aging, further my knowledge of state-of-the-art machine learning techniques, and will develop a deeper understanding of quantitative approaches to investigate complex sociotechnical systems. I will apply this training to address knowledge gaps related to the formation of referral-based clinical teams in the first two aims: (1) model and identify patterns of collaboration among healthcare providers teams treating patients with ADRD that contribute to improved healthcare delivery; and (2) apply natural language processing to messages sent via patient portal understand how patient and caregiver interactions influence care patterns. In aim 3, I will combine insights and collaboration networks from the first two aims to develop explainable machine learning models to identify optimal patterns of care coordination. I will use these optimal care coordination patterns to highlight features that cause deviation in a patient’s treatment pathway and identify actionable steps for improvement. This career development award will provide the rigorous training and mentorship necessary to become a fully independent principal investigator. The research will benefit from a PI who has a strong background in information science, knowledge representation, and collaboration analytics. I have assembled an outstanding multidisciplinary team of mentors with extensive expertise across all areas of the proposed project and will receive exceptional support from an outstanding environment at Vanderbilt University Medical Center.

NIH Research Projects · FY 2025 · 2023-09

SUMMARY: We propose a multicenter open-label, single-arm type I hybrid trial to assess the effectiveness of hydroxyurea therapy for primary stroke prevention in children with sickle cell anemia (SCA) living in Nigeria. Our team just completed a double-blind, parallel-group phase III randomized controlled trial (SPRING), where we compared low-dose to moderate-dose hydroxyurea for primary stroke prevention in children with SCA and abnormal transcranial Doppler (TCD) velocities (>200 cm/sec). Children with abnormal TCD velocities have a high stroke risk of approximately 10.7 events per 100 person-years (observation arm in the STOP trial). In the low- (n=109) and moderate-dose (n=111) hydroxyurea groups, the stroke incidence rates were 1.2 and 1.9 per 100 person- years, respectively, p=0.77 (combined incidence rate 1.5 per 100 person-year). Despite equal efficacy for stroke prevention in both treatment groups, moderate- when compared to low-dose hydroxyurea, was more effective in preventing severe acute pain and all-cause hospitalizations. Our findings supported the American Society of Hematology's evidence-based guidelines for hydroxyurea therapy for primary stroke prevention in low-income settings. Our hypothesis to be tested: in a multicenter single-arm type I hybrid trial, for children with abnormal TCD velocities treated with hydroxyurea, the stroke incidence rate will be non-inferior to the SPRING trial results, with an upper non-inferiority margin of 4 strokes per 100-person-years. The point estimate method was used to determine the non-inferiority margin based on the Nigerian pediatrician's judgment of what maximum stroke rate would be clinically meaningful to demonstrate the effectiveness and justify treatment for the high-risk stroke group. A non-inferiority test with an overall sample size of 220 participants will achieve 91% power at a 0.050 significance level to detect non-inferiority when the expected proportion of strokes is 0.035, a minimum follow-up period of 2.5 years and a loss to follow-up of 10% per year. Participants will be followed as per standard care, including clinic visits every 3 months and complete blood cell counts every 6 months. We will conduct the following aims:1) Determine the incidence of the first stroke and TIA in children with abnormal TCD velocities treated with hydroxyurea for 2.5 years in the type 1 hybrid trial; 2) Evaluate the implementation and sustainability of the intervention within the extended RE-AIM framework; 3) Evaluate the cost-effectiveness of low- compared to a higher dose of hydroxyurea for primary stroke prevention in children with abnormal TCD velocities. Capacity building for the three Nigerian Multiple Principal Investigators, the statisticians, and nurses will be focused on three areas- a) developing a Nigerian data coordinating center and the required skills to support a clinical trial; b) developing a regional TCD course for nurses, enhancing task shifting and reach, and c) performing cost-effective analysis for the type I hybrid trial comparing low-and moderate dose hydroxyurea.

NIH Research Projects · FY 2026 · 2023-09

Project Summary/Abstract Liver disease is a leading cause of mortality in persons with HIV (PWH), and PWH suffer a disproportionate burden of non-alcoholic fatty liver disease (NAFLD). While the mechanisms underlying this disparity are not well understood, intestinal dysbiosis and intestinal barrier dysfunction are implicated in the pathogenesis of NAFLD in HIV-negative persons. HIV infection has been shown to alter the intestinal microbiome, change the plasma metabolome and impair intestinal barrier function; however, there are few data on the microbiome and metabolome among PWH with NAFLD. My pilot preliminary data show that hepatic steatosis is associated with differences in the intestinal bacterial community (reduction in butyrate-producing bacteria), bacteria-related metabolites (including phosphatidylcholine), and markers of intestinal barrier dysfunction among PWH on long- term ART. I hypothesize that intestinal dysbiosis in PWH promotes NAFLD through 1) impairment of intestinal barrier function and 2) alteration of the plasma metabolome to promote hepatic lipid deposition. In Aim 1 I will determine whether differences in plasma levels of NAFLD- and bacteria-related metabolites, including phosphatidylcholine and trimethylamine N-oxide, are associated with hepatic steatosis in PWH. In Aim 2 I will determine whether decreased abundance of butyrate-producing gut bacteria and markers of impaired intestinal barrier function are associated with hepatic steatosis in PWH. In Aim 3 I will test the feasibility and limited efficacy of a multi-strain probiotic and prebiotic fiber on NAFLD biomarkers in a prospective trial in PWH. Aims 1 and 2 will leverage existing data and specimens from 134 PWH in the NIH-supported HIV, Adipose Tissue Immunology and Metabolism (HATIM) cohort, which includes metabolomic, microbiome, and imaging studies from participants with a spectrum of metabolic fitness and in the absence of viral hepatitis or excessive alcohol use. Secondary analyses will compare the findings from the HATIM cohort with both HIV-negative controls and PWH with viral hepatitis and heavy alcohol use. The Aim 3 pilot trial will leverage the well-developed infrastructure and large recruitment pool of the Tennessee Center for AIDS Research. Collectively, these Aims address the call for research related to HIV-associated comorbidities, coinfections and complications described in NIH Strategic Plan for HIV and HIV-related Research, and have the potential to inform new microbiome- based diagnostics and treatments that will reduce the burden of NAFLD in PWH. My research and training plan will be supported a multi-disciplinary team of scientists who have a strong record of mentoring young investigators and the world-class training environment and resources available at Vanderbilt University Medical Center. In addition to the benefits to the health of PWH, the proposed K23 studies and training plan will allow me to further my expertise in patient-facing research and generate the data and publication track record necessary to develop a self-sustaining research career in the field of HIV-related liver disease.

NIH Research Projects · FY 2024 · 2023-09

ABSTRACT The overarching goals of this application are to: 1) maintain retention of children in the Vanderbilt CANOE birth cohort with emphasis on diversity and implementation of the ECHO Cohort Protocol with high fidelity and conduct new enrollment, and 2) address key questions in the field about one of the most common and modifiable early life environmental exposures consistently associated with significantly increased asthma risk, respiratory syncytial virus (RSV) infection, delineating the severity-dependent and age-dependent effects of RSV infection on asthma risk. This innovative project has significant public health impact, as establishing the age- and severity-dependent relationship between RSV and asthma is the first and most important step in disease primary prevention. We propose to address key unanswered questions in the field: the severity- and age-dependent association of RSV and asthma, and the impact of infection on lung function. In addition, we will explore the broad impact of the SARS-CoV-2 pandemic on asthma incidence and control in an exploratory aim, which may provide support for multi-faceted environmental modifications in asthma prevention and control, and data to inform the potential impact of broad public health interventions. The birth cohort that this application supports is the Vanderbilt CANOE (Childhood Allergy and the NeOnatal Environment) study. CANOE is a birth cohort designed to identify and understand how environmental factors modify the development of the airway epithelium. The study includes the unique longitudinal sampling of the child airway throughout the first year of life, and annually. The Vanderbilt CANOE study has unique early life exposure and outcomes ascertainment, including surveillance for RSV and a novel biospecimen repository of nasal airway epithelial cells. The CANOE cohort also has important information for longitudinal development of the airway microbiome and the airway epithelium. The proposed research is innovative and timely given the anticipated licensure of multiple RSV prevention products in the coming year (maternal vaccines and long- acting monoclonal antibodies for infants). The proposed work represents a novel, multi-faceted approach to identifying and understanding the influence of severity of RSV infection and age of RSV infection on asthma risk and lung function. The answers to these questions will be critical to developing prevention strategies and informing public health expectations for RSV non-pharmaceutical preventive strategies and evaluating potential long-term value-added benefits of vaccines in preventing lifelong chronic respiratory disease. These data may not only bolster RSV vaccine acceptability and uptake in the US, but will almost certainly be useful in evaluating the cost-effectiveness of RSV prevention strategies in low and middle income countries.

NIH Research Projects · FY 2024 · 2023-09

ABSTRACT The overarching goals of this proposal are 1) to maintain retention of children in the INSPIRE birth cohort with emphasis on diversity, and implementation of the ECHO Cohort Protocol with high fidelity, and 2) tackle the major limitation in diagnosis and management of childhood asthma - addressing the need to identify asthma phenotypes and endotypes to develop targeted treatment and prevention strategies. The term asthma is an umbrella diagnosis for several disease states with distinct variable clinical presentations (phenotypes) and mechanistic pathways (endotypes). Central to understanding the causal role of environmental exposures in asthma development and to disease management is identifying distinct asthma phenotypes. The scientific aims of this proposal are: 1) Aim 1: to determine the incidence and prevalence of two highly relevant asthma phenotypes, atopic and non-atopic asthma, by age, sex, cohort decade and geographic location, using widely available and harmonized variables and those collected through the ECHO Cohort Protocol. We will also determine the contribution of established environmental risk and protective factors with these specific clinically relevant asthma phenotypes. Lastly, we will calculate comparative estimates of childhood asthma morbidity by asthma phenotypes; 2) Aim 2: to further characterize asthma phenotypes and endotypes into clinically useful entities within the ECHO consortium and expand the findings to clinical practice by utilizing available or to be collected samples to add biomarkers of asthma routinely available in clinical practice, and nasal samples to perform transcriptomic analyses to define asthma endotypes; 3) Aim 3: to facilitate and oversee longitudinal follow-up of the established INSPIRE cohort, and biosample collection to maximize retention of existing participants with emphasis on diversity, and implement the ECHO Cohort Protocol with high fidelity. The INSPIRE birth cohort is a population-based birth cohort study that originally enrolled over 1950 term healthy infants. INSPIRE is unique in including surveillance for infant respiratory viral infection through biweekly active and passive surveillance using PCR for viral detection and respiratory syncytial virus (RSV) serology at age one. The children will be ages 8-10 years when the current ECHO funding period ends, entering adolescence, and will be followed to age 15-17 years during this next funding period. The proposed research is an innovative, novel, multi-faceted and practical approach to move away from viewing “asthma” as a single umbrella disease, and identifying and understanding asthma phenotypes, endotypes, and the influence of risk and protective factors on specific asthma phenotypes. The approach we propose is also practical in moving toward solutions that utilize currently available technologies and laboratory testing to aide in development of diagnostic criteria for childhood asthma sub-types.

NIH Research Projects · FY 2025 · 2023-09

In the last 30 years, there has been no significant improvement in rates of venous thromboembolism (VTE). These blood clots develop in the limbs and can travel to the lungs and form pulmonary emboli, which are the most common cause of preventable deaths in the hospital. Currently available tools for predicting and preventing hospital-acquired VTE (HA-VTE) were developed without sufficient input from frontline clinicians, add to clinician workload, are too cumbersome to implement in daily clinical practice, exhibit poor-to-fair prediction accuracy, and do not consider the risk of bleeding complications. Importantly, use of these tools has not been shown to improve patient outcomes. A significant gap therefore exists between the current system of variable practice patterns in VTE risk assessment and the goal of driving down rates of HA-VTE and reducing preventable deaths. Our objective is to refine, implement, and test a real-time prognostic model for HA-VTE among hospitalized adults to facilitate appropriate and timely initiation of thromboprophylaxis by busy clinicians. Our multidisciplinary team has developed a model that predicts the probability of HA-VTE among all adult inpatients based on clinical factors and medical history. The model updates as the clinical scenario evolves, discriminates well between high- and low-risk patients, and exhibits superior prediction performance compared with extant risk-stratification tools. It is unknown whether use of a prognostic model for HA-VTE in clinical practice improves patient outcomes. To achieve this important objective, we will: conduct observations and interviews with clinicians to elucidate their challenges with the current risk-assessment workflow and preferences for timing, content, and visualization of a prognostic model (Aim 1); create user-friendly clinical decision support (CDS) tools—based on an accurate and validated prognostic model for HA-VTE—that can be seamlessly integrated into existing clinical workflows, simultaneously consider the risk of bleeding complications, and maximize use of electronic health record data in real time (Aim 2); and conduct a pragmatic randomized trial and implementation evaluation of the prognostic model plus CDS for prophylaxis compared with usual care for the prevention of HA-VTE. In an adaptive platform trial, we will evaluate on a prospective basis the effectiveness of model-guided CDS to reduce HA-VTE, both overall and among key patient subgroups, and study through randomization the implementation strategies that work best for clinicians and improve patient outcomes (Aim 3). We will broadly disseminate the generalizable knowledge and implementation tools that are urgently needed to prevent HA-VTE and avoid deaths in the hospital, including an implementation manual, CDS knowledge artifacts, and open-source statistical software. Relevance: Our proposal closely aligns with NHLBI objectives, namely: developing and optimizing a real-time prognostic model to prevent HA-VTE, a HLBS disease; creating sustainable, adaptive implementation strategies to reduce rates of HA-VTE; and leveraging emerging opportunities in data science through integration of multiple types of data, innovative statistical methods, and informatics methodology to facilitate broad dissemination.

NIH Research Projects · FY 2025 · 2023-09

Project Summary With age, dividing cells acquire DNA mutations. A small number of these somatic mutations confer a selective advantage leading to a clonal proliferation of cells harboring the somatic mutation. In blood, this process is termed ‘clonal hematopoiesis’. These mutations include both point mutations in cancer driver genes (eg. clonal hematopoiesis of indeterminate potential ‘CHIP’) and megabase-scale deletions, duplications and copy-neutral loss-of-heterozygosity (eg, mosaic chromosomal alterations, ‘mCAs’). CHIP and mCAs have each been detected in ~5% of individuals over 60. While both predict shorter lifespans, CHIP leads to a myeloid biased stem cell differentiation while mCAs lead to a lymphoid biased stem cell differentiation. As a result, CHIP and mCAs have distinct disease associations with infection, cardiovascular disease, cancer and other diseases of aging. Although CHIP has been an area of significant research activity, multiple gaps persist in our knowledge of mCAs and their impacts on aging and population health. mCA clones that expand to make up a larger proportion of the blood predict worse health consequences. However, we do not know why some mCA clones but not others expand, what factors predict the rate of clonal expansion and how rate of expansion associates with disease outcomes. Overall, we hypothesize that mCAs with higher rates of clonal expansion confer a greater impact on health and that the propensity to expand has genetic and environmental underpinnings that are mediated through gene expression. A barrier to addressing this gap is a paucity of large well-annotated collections of longitudinally-sampled blood. Fortuitously, our team has two recent accomplishments that enable us to address this gap: 1) a survey of mCAs in 67,000 whole genomes and 2) development of a novel computational method to estimate the rate of mCA expansion from single timepoints. In Aim 1, we will measure the rate of mCA expansion by leveraging unique serial blood samples (collected up to 19 years apart) from 729 individuals with mCAs from three deeply phenotyped cohorts. In Aim 2, we will refine our method for clonal expansion rate estimation and apply this method at population scale to estimate mCA clonal expansion rates in 1.3 million individuals from several diverse cohorts. We will identify genetic and environmental factors predisposing to clonal expansion and establish the relationship between mCA clonal expansion and disease. In Aim 3, we will analyze bulk and single-cell RNA-sequencing to ascertain the cell type specific biological impact of mCAs and identify pathways leading to clonal expansion. Our multidisciplinary team with deep expertise in computational genomics, statistics, hematology and human epidemiology is uniquely poised for success in this effort. Successful execution of our aims will inform risk models to stratify individuals with mCAs for personalized prevention, such as interventions or enhanced screening, and identify new biological pathways to target for therapeutic development. Finally, our study serves as a model for insights on somatic mosaicism in other tissues and disease sites beyond the blood to support healthy aging and improve population health.

NIH Research Projects · FY 2025 · 2023-09

Approximately 80% of human cancers are caused by adverse environmental exposures, unhealthy lifestyles and/or their interactions with host susceptibility factors. Previous studies have mostly focused on evaluating behavioral risk factors, such as tobacco smoking, physical inactivity, unhealthy diets and obesity. While more than 80,000 chemicals have been registered by the EPA, very few of them have been adequately investigated in relation to human cancers in epidemiologic studies. There are considerable challenges in studying environmental exposures in epidemiologic studies. Humans are exposed to large numbers of chemical and physical substances and their mixtures, typically at low levels over extended periods of time. Previous environmental epidemiologic studies have mostly evaluated exposures one at a time. However, because of a typically weak association of a given exposure with disease risk, coupled with limited tools and biomarkers for environmental assessments, most studies have failed to provide convincing evidence to link environmental exposures to cancer risk. To overcome these challenges, we propose to establish a large cohort study including ~35,000 participants with an extensive collection of survey and geospatial exposure data, as well as biological and environmental samples, to address critical issues in the environmental etiology of cancer. We propose to include 800 of the study participants in a deep-exposome study to comprehensively assess the exposome, identify key biomarkers of external exposures, examine associations of external and internal metrics with cancer-related biological responses, and develop cumulative exposome risk scores. The proposed study will enable direct evaluation of associations of environmental exposures with cancer outcomes in the long term, and associations with cancer intermediate biomarkers in the short term. By integrating environmental exposure data from multiple sources, including personal exposure assessments and biologic markers of environmental exposure and responses, this proposed study will allow us to systematically and rigorously investigate environmental exposures in relation to cancer risk and provide substantial novel data to improve the understanding of both external and internal exposomes, which will pave the way for future remediation of environmentally induced cancer.

NIH Research Projects · FY 2025 · 2023-09

The overarching goals of this proposal are (1) to maintain retention of children in the INSPIRE birth cohort with emphasis on high enrollment into Cycle 2, and implementation of the ECHO Cohort Protocol with high fidelity, and (2) tackle the major limitation in diagnosis and management of childhood asthma - the need to identify asthma phenotypes and endotypes to develop targeted treatment and prevention strategies. The term asthma is an umbrella diagnosis for several disease states with distinct variable clinical presentations (phenotypes) and mechanistic pathways (endotypes). Central to understanding the causal role of environmental exposures in asthma development and to personalizing disease management is identifying distinct asthma phenotypes. The scientific aims of this proposal are: (1) Aim 1: to determine the incidence and prevalence of two highly relevant asthma phenotypes, atopic and non-atopic asthma, by age, sex, cohort decade and geographic location, using widely available and harmonized variables and those collected through the ECHO Cohort Protocol. We will also determine the contribution of established environmental risk and protective factors with these specific clinically relevant asthma phenotypes. Lastly, we will calculate comparative estimates of childhood asthma morbidity by asthma phenotypes; (2) Aim 2: to further characterize asthma phenotypes and endotypes into clinically useful entities within the ECHO consortium and expand the findings to clinical practice by utilizing available or to be collected samples to add biomarkers of asthma routinely available in clinical practice, and nasal samples to perform transcriptomic analyses to define asthma endotypes; (3) Aim 3: to facilitate and oversee longitudinal follow-up of the established INSPIRE cohort, and biosample collection to maximize retention of existing participants with emphasis on the implementation of the ECHO Cohort Protocol with high fidelity. The INSPIRE birth cohort is a population-based birth cohort study that originally enrolled over 1950 term healthy infants. INSPIRE is unique in including surveillance for infant respiratory viral infection through biweekly active and passive surveillance using PCR for viral detection and respiratory syncytial virus (RSV) serology at age one. The children will be ages 8-10 years when the current ECHO funding period ends, entering adolescence, and will be followed to age 15-17 years during this next ECHO funding period. The proposed research is an innovative, novel, multi-faceted and practical approach to move from viewing “asthma” as a single umbrella disease, and identifying and understanding asthma phenotypes, endotypes, and the influence of risk and protective factors on specific asthma phenotypes. The approach we propose is also practical in moving toward solutions that utilize currently available technologies and laboratory testing to aide in development of diagnostic criteria for childhood asthma sub-types.

NIH Research Projects · FY 2025 · 2023-08

Project Summary: Radiation induced lung injury is a crucial dose-limiting factor in patients receiving thoracic radiotherapy, affecting a significant proportion of patients even with use of newer radiotherapy techniques. This proposal investigates a novel pathway regulating fibroblast activation that can be directly targeted to limit progressive radiation-induced lung fibrosis. We found that the thromboxane-prostanoid receptor (TPr) was constitutively expressed in human and murine fibrotic pulmonary fibroblasts and that pharmacological inhibition or conditional genetic ablation of the TPr markedly attenuated pulmonary fibrosis in mice resulting from ionizing radiation, bleomycin-induced oxidative stress or Hermansky-Pudlak syndrome. Although thromboxane A2 is a major ligand for TPr, we found that TPr signaling was being driven by F2-isoprostanes (F2-IsoPs), resulting from non-enzymatic, free-radical oxidation of arachidonic acid. We have demonstrated that ionizing radiation induces F2-IsoP generation in cell culture and in murine pulmonary tissue in vivo, as does bleomycin. F2-IsoPs are increased in idiopathic pulmonary fibrosis due to oxidative stress in this disease, but whether they are increased in patients who develop radiation-induced pulmonary fibrosis (RIPF) is unknown, although preclinical and clinical studies provide key support for the overall hypothesis that non-enzymatic free radical-induced oxidation of arachidonic acid signaling significantly contributes to RIPF. We hypothesize that a contributing factor is via calcium-induced calpain- mediated release of TGFβ from the latent complex in lung fibroblasts. The small molecule ifetroban is a TPr antagonist that has undergone extensive human testing and has an excellent safety profile. Thus, research validating TPr antagonism in inhibiting RIPF could result in rapid translation via repurposing of existing and safe drugs. However, there are key gaps in our knowledge that need to be filled before a clinical trial would be appropriate. First, the therapy would need to work in the context of existing standard of care, including immune checkpoint therapy. Second, although it is likely that there is an increase in either thromboxane or F2-IsoPs in RIPF, we need to verify that patients receiving thoracic radiation actually show an increase in one or more of these molecules. Finally, we need a better understanding of the mechanism by which TPr regulates pulmonary myofibroblast differentiation and activation in the context of radiation. The goal of this proposal is to fill these gaps.

NIH Research Projects · FY 2026 · 2023-08

The Analysis, Visualization, and Informatics Lab-space (AnVIL) platform is a scalable cloud-based computing resource that aims to accelerate genomics research by providing broad access to genomics datasets and the infrastructure necessary to improve analysis workflows and enhance collaboration. The AnVIL Clinical Environment for Innovation and Translation (ACE-IT) project will bring together a network of expertise to address a major gap in clinical genomics research and operationalize a key mission of the AnVIL project by expanding its existing ecosystem to include a comprehensive suite of clinical genomics research tools and services. The newly developed AnVIL Clinical Resource will bring together data, tools, and support resources meant to amplify the benefits of the existing platform and provide a critical foundation for the clinical genomics research community to better leverage this innovative resource. Development of the ACE-IT will be guided by three key aims: 1. Engagement with clinical community and research partners to characterize barriers and facilitators to adopting federally-supported, cloud-connected clinical genomics research services; 2. Develop and deploy approaches to ingest, index, and search data to support clinical genomics research; and 3. Integration of tools, APIs, and workflows that enable clinical genomics research methods on the AnVIL, including rare disease diagnosis and genomic risk scores as use cases. The ACE-IT team consists of expertise across multiple health care centers, including Vanderbilt University Medical Center, Brigham and Women’s Hospital, and Massachusetts General Hospital. This team will develop infrastructure on AnVIL’s cloud environment to meet clinical genomics researchers' needs over time and integrate with existing AnVIL working groups and meetings as team members and stakeholders where appropriate. The tools and resources we develop will support clinical genomics research by focusing on both rare and common diseases and integration into translational research.

NIH Research Projects · FY 2025 · 2023-08

Project Summary Obesity is a risk factor for the development of insulin resistance (IR), a hallmark of type 2 diabetes (T2D). Weight loss improves obesity-evoked IR; however, the majority of individuals who lose weight, regain the weight within 1-5 years. This ‘weight cycling’ further increases risk of metabolic disease compared to weight maintenance. Our group developed a mouse model of weight cycling to uncover mechanisms by which weight regain poses additional risk of metabolic disease. We show that weight cycled diet-induced obese (WC-DIO) animals have worsened glucose tolerance than equally obese mice that have not weight cycled. A unique finding is that glucose intolerance in WC-DIO mice is linked to impaired insulin secretion (in vivo during a hyperglycemic clamp and ex vivo in perifused islets). This key finding indicates that β-cell compensation fails to completely adapt to the physiological IR evoked by weight regain in the same way it does during the first bout of weight gain. At the cellular level, WC-DIO mice manifest with atypical β-cell mitochondrial morphology and decreases in gene signatures linked with mitophagy, redox metabolism, and TCA cycle regulation. Mitochondrial metabolism is fundamental for normal nutrient stimulated insulin secretion. Thus, the mitochondrial alterations evoked by weight cycling support a mechanism for impaired insulin secretion. Poor functioning mitochondria are also linked with disruptions to redox control, which can increase oxidative stress and impair β-cell function. We find that a major regulator of pro-oxidant status in β-cells, thioredoxin interacting protein (TXNIP), is increased in WC-DIO islets and inversely associates with insulin secretion. Together, these preliminary studies support that in response to repeated nutrient overload, β-cells are less efficient at coupling metabolic processes to insulin secretion. The central hypothesis is that repeated nutrient overload decreases mitochondrial function and evokes oxidative impairment in β-cells. This loss of β-cell adaptation to nutrient overload impairs insulin secretion and in vivo glucose regulation. This proposal will: i) determine whether impaired mitochondrial function evoked by repeated nutrient excess is central to loss of pancreatic function and ii) examine whether TXNIP is responsible for driving oxidative stress and loss of pancreatic function with weight cycling. Stable isotopes will be used to measure metabolic flux rates in isolated islets. 13C-labeled metabolites will be administered in vivo and incorporation in β-cells quantified using imaging mass spectrometry. Pharmacological inhibition and β-cell specific deletion of TXNIP will be used to determine whether attenuation of oxidative stress restores insulin production and secretion. In vivo insulin secretion and insulin sensitivity will be determined using the frequently- sampled intravenous glucose tolerance test coupled with glucose tracers to quantify glucose fluxes. Ex vivo islet function will be determined in static culture and in perifusion assays. The experiments proposed herein will define the means by which weight cycling uncouples peripheral IR from pancreatic insulin demand, which will lead to a better understanding of the underlying mechanisms of pancreatic adaptability to excess nutrients.

NIH Research Projects · FY 2025 · 2023-08

PROJECT SUMMARY Neural crest progenitors are essential for development of peripheral ganglia in the autonomic nervous system. Much is known about processes that control differentiation of neural crest progenitors for many autonomic ganglia. However, very little is known about formation of cell lineages within pelvic ganglia. Regulatory processes that control neurogenesis, differentiation, diversification, and maturation of pelvic autonomic neurons are undefined. Pelvic ganglia play essential roles in initiating bladder contraction and mediating efficient emptying. Thus, studies of pelvic neurons will inform understanding of urinary tract conditions that affect a large portion of the population. In humans, pelvic autonomic neurons are scattered primarily in the inferior hypogastric plexus, while in rodents pelvic neurons are aggregated into major pelvic ganglion situated alongside the lower urinary tract (LUT). Our prior LUT studies in mice identified expression of the transcription factor Pax3 in fetal and postnatal pelvic ganglia when pelvic autonomic neurons are differentiating and maturing. Because Pax3 is widely expressed during development, mutations in this gene are typically lethal due to neural tube defects. We generated novel lines of mice that have loss of Pax3 in neural crest lineages. These animals are postnatal viable and exhibit deficits of bladder wall innervation with altered voiding patterns. Neural-crest restricted Pax3 mutants offer an exciting opportunity to identify key regulatory aspects of pelvic ganglia formation and determine how deficits of pelvic autonomic neurons relate to LUT dysfunction. In this study we focus on postnatal stages of pelvic ganglia maturation to test the following hypotheses: 1 – Pax3 is essential for producing the normal allocation of neuron types as the mouse major pelvic ganglion matures postnatally. 2 – neural crest-specific loss of Pax3 reduces total numbers of pelvic autonomic neurons at maturity. Use of single-cell sequencing and high-resolution large-scale microscopy will be applied to assess the final composition of pelvic ganglia in postnatal Pax3 mutants compared to normal littermates. Research outcomes will provide greater understanding of how alterations in pelvic innervation contribute to LUT dysfunction.

NIH Research Projects · FY 2025 · 2023-08

PROJECT SUMMARY High provider workload is a threat to care quality, patient safety, and providers’ well-being and job satisfaction. Workload – which lacks a universally accepted definition - is a complex multi-dimensional construct that is affected by external task demands and environmental, organizational, and psychological factors. The importance of managing high workload is nowhere more evident than in neonatal intensive care units (NICUs). Critically ill neonates are highly vulnerable to iatrogenic events due to their immaturity and fragility, and high clinician workload has been directly associated with increased incidence of adverse neonatal safety outcomes. Despite the evidence and need, patient safety researchers have been slow to develop multi-level models, scalable workload measurement systems, or other health information technology interventions to improve workload management and patient safety. Conventional workload management tools predominantly measure and predict workload using unit-level (e.g., staffing ratios) or patient-level (e.g., acuity) data rather than data collected across the four levels of workload recommended by human factors engineers (HFEs) - unit, job, patient, and situation. As a result, current tools under-measure the workload experienced by providers and are not designed to identify mutable microsystem factors that contribute most to provider workload. A promising development in workload research is the increasing emphasis on measuring situational workload which best explains the workload experienced by clinicians due to healthcare microsystem design. Situational workload is most affected by performance obstacles (i.e., delays, interruptions, etc.) in the local work environment and can be applied at the unit, job, or patient-levels. Most importantly, it is diagnostic of underlying contributory factors and therefore actionable for improvement. To date, situational workload has been measured using subjective surveys which are work-interrupting, thus difficult to integrate into practice. Vanderbilt University Medical Center (VUMC), in collaboration Johns Hopkins University (JHU), will employ a systems engineering human-centered design process to design, develop, and validate new multi-level model of NICU nurse practitioner workload derived from readily accessible electronic health record (EHR) data. The validated model will be the foundation for a future EHR-based clinical decision support (CDS) tool that will track the real-time workload of NICU providers, predict near- term future unit workload, and guide workload reduction and balancing interventions. The project’s three Specific Aims are: Aim 1. To conduct a comprehensive HFE-based analysis of NICU provider (i.e., neonatal nurse practitioner) workload; Aim 2. To design and develop real-time multivariable workload models and Aim 3. To validate the real-time workload models at VUMC (A) and to determine the generalizability of the models at an external hospital (B).