Vanderbilt University Medical Center

NIH Research Projects · FY 2026 · 2022-01

Project Summary Obstructive sleep apnea (OSA) is a major source of cardiovascular morbidity and mortality where the first-line treatment, positive airway pressure, is often poorly tolerated. The development of effective alternative surgical therapies has been hindered by a fundamental lack of insight into the anatomic and neurophysiologic mechanisms responsible for airway patency. A substantial body of physiology literature documents that caudal pharyngeal stretch via tracheal traction is an important stabilizing mechanism of the upper airway, but forty years of surgical interventions for OSA have focused solely on destructive techniques or ventral displacement of pharyngeal soft tissue structures. Our proposal will address this knowledge and therapy gap by elucidating the distinct effects of caudal traction on upper airway patency in OSA patients. Our central hypothesis is the therapeutic stabilizing power of caudal tracheal traction can be harnessed via ansa cervicalis stimulation (ACS) of the sternothyroid muscle, which generates caudal traction on the pharynx by contracting the sternothyroid muscle, replicating many of the well-documented effects of caudal traction on pharyngeal patency. This hypothesis challenges the long-held concept that the genioglossus is the major pharyngeal dilator muscle responsible for the maintenance of pharyngeal patency during sleep. It rests instead on strong evidence that caudal pharyngeal traction, normally mediated by tracheal pull, increases pharyngeal patency during sleep through several distinct mechanisms. In SA1, we will elucidate the physiologic effects of unilateral and bilateral ACS on pharyngeal patency during drug-induced sleep endoscopy (DISE) with and without hypoglossal nerve stimulation (HNS), the current state-of-the-art neurostimulation therapy for the management of OSA (DISE, SA1). In SA2, we will determine the impact of ACS on the maintenance of airway patency in NREM and REM sleep. In both SAs, we will test the impact of anatomic constraints on stimulation responses. We hypothesize that ACS stretches the pharynx caudally, stiffening the soft palate and lateral pharyngeal walls. We additionally hypothesize that the combination of HNS and ACS creates synergistic effects through opposing forces that further stabilize the pharynx against collapse. Our aims challenge the primacy of the genioglossus in the maintenance of airway patency during sleep. This project outlines rigorous approaches for establishing synergistic mechanisms between the genioglossus and sternothyroid muscles based on our proven ability to activate these muscles independently. State-of-the-art physiologic methods will be deployed to probe the effects of muscle stimulation, sleep state, and anatomy on pharyngeal patency. Our findings will (1) transform our understanding of upper airway neuromuscular control during sleep, (2) establish relevant neuromotor targets for neurostimulation, and will (3) identify potential physiologic and anatomic predictors of therapeutic success.

NIH Research Projects · FY 2026 · 2022-01

PROJECT SUMMARY An obesogenic Western-style (HF) diet causes low-grade intestinal inflammation, intestinal microbiota imbalance, and an increased risk of cardiovascular disease. However, our knowledge about the pathways producing each of these different disease manifestations is incomplete, making it difficult to see connections. Experiments proposed in this application are aimed at addressing this critical gap in knowledge. Our long-range goal is to elucidate molecular mechanisms that make the gut microbiota a liability during non-communicable diseases. This application aims to study the mechanisms through which HF diet drives gut dysbiosis and determine whether the resulting imbalance escalates the production of microbial metabolites that increase the risk for cardiovascular disease. Our central hypothesis is that mitochondrial dysfunction induced by an obesogenic HF diet activates epithelial repair responses (e.g., crypt hyperplasia), which in turn drives an expansion of facultative anaerobic Enterobacteriaceae, a taxon known to produce metabolites that accelerate atherosclerosis. To test our hypothesis, we will determine whether mitochondrial dysfunction-induced monocyte recruitment promotes colonic epithelium repair responses (specific aim 1). We will identify the role of colonic epithelium repair responses in driving HF diet-induced Enterobacteriaceae expansion (specific aim 2). We will also elucidate the mechanism by which HF diet-induced Enterobacteriaceae expansion increases circulating trimethylamine N-oxide (TMAO) levels and promotes cardiovascular disease (specific aim 3). By defining the complex order of events that links these disease manifestations, we expect the completion of the proposed experiments to usher in a decisive conceptual advance to understand how HF diet increases cardiovascular disease risk.

NIH Research Projects · FY 2025 · 2022-01

PROJECT SUMMARY/ABSTRACT Preeclampsia occurs in 3% – 6% of women in the US and is a leading source of maternal and fetal morbidity during pregnancy, immediately after pregnancy and has long term cardiovascular health implications for both mother and child. Cost of healthcare management of preeclamptic mothers and infants within one year of delivery averages over $2.8 billion dollars annually. Prevalence of preeclampsia is increasing overtime in the US. African American women have higher prevalence of preeclampsia, are more likely to have severe preeclampsia and are three times as likely to die as white Americans due to pregnancy related complications. No effective preventative strategy for preeclampsia exists to-date in part due to a lack of understanding of causality – be it clinical risk factors, genetic predisposition or socially mediated factors. Epidemiological studies identify multiple clinical risk factors anad predictors for preeclampsia such as obesity, diabetes, preexisting hypertension, chronic kidney disease, and thrombophilia. Studies also show that in women without these preexisting conditions, those with preeclampsia are at higher risk of developing hypertension, chronic kidney disease, venous thromboembolism, stroke and diabetes 5 to 10 years later. Inferring causality for these associations is difficult with epidemiologic data alone due to potential for confounding and reverse causation. Preeclampsia, many of its risk factors and its consequences are heritable with hundreds of genetic variants identified for some traits like blood pressure, diabetes and kidney function. Since genetic variants do not change during a lifetime and cannot be influenced by reverse causation, and are less prone to confounding due to Mendel's laws of inheritance which dictate random assortment and segregation of genes, we can design Mendelian randomization (MR) experiments to use genetic variants as instrumental variables for exposures to robustly evaluate causality between exposure and outcome under certain assumptions. Coalescing genetic data on preeclampsia from multiple sources and leveraging existing EHR-linked biobank (BioVU) at Vanderbilt, we form the PreEclampsia Genetics Network (PEGNet) to study the genetic architecture of preeclampsia in over 28,000 preeclampsia cases and over 290,000 controls. Using preeclampsia data from PEGNet and recent developments in MR methods, we propose to evaluate causal relationships between clinical risk factors and predictors of preeclampsia including blood pressure, kidney function, liver function, obesity and metabolic traits. We will evaluate whether preeclampsia is causally associated with future cardiovascular complications or if this is due to reverse causality. With emerging MR methods such as drug target MR, we propose to screen gene and protein targets associated with preeclampsia and also druggable. We propose MR experiments to validate gene targets for existing drugs in the pipeline for preeclampsia prevention including aspirin, metformin, statins, and PDE5 blockers. We propose a novel MR framework to elucidate the role colorism, a social construct of discrimination based on skin color, on preeclampsia risk by using genetic variants of skin pigmentation as instrumental variables for skin tone. We propose admixture mapping to understand how genetic ancestry influences preeclampsia in women of African ancestry. Using MR methods in innovative ways, our research informs causal mechanisms in preeclampsia, the first step necessary to design effective intervention strategies.

NIH Research Projects · FY 2025 · 2022-01

Sepsis is a major cause of organ failure and death in both children and adults around the world for which there are no specific therapies other than antibiotics and supportive care. A major reason for the lack of targeted therapies is our incomplete understanding of the genetic, environmental, microbial, socioeconomic and biologic factors that underly risk of and outcomes from human sepsis and that drive heterogeneity within this clinical syndrome. We propose to create a unique resource, the Sepsis ClinicAl Resource And Biorepository (SCARAB), a two center prospective study in adults and children with sepsis and critically ill controls that is designed to be both comprehensive and scalable to large multicenter implementation. To create this resource, we will leverage our experience with large scale prospective observational studies in the ICU, our novel method of non-invasively sampling the distal airspace in mechanically ventilated patients, our world class bioinformatics expertise, state-of-the-art phenotyping methodologies, and unique institutional resources. SCARAB will prospectively enroll subjects from pediatric and adult ICUs at VUMC and Meharry Medical College, an institution that cares for a primarily minority population. Subjects will be enrolled early in their illness and serial biologic specimens of blood, DNA, respiratory micro-droplets (from Heat Moisture Exchange (HME) filters), tracheal aspirates and urine will be collected. To study the end organ most commonly injured in sepsis, we will establish best practices for collection, processing and storage of lung fluid collected from HME filters, a novel method for sampling the distal airspace in ventilated patients. Working with our collaborators in Biomedical Informatics, we will develop automated phenotyping algorithms to identify patients with sepsis and organ failures including ARDS, AKI and delirium. We will use cutting edge natural language processing methods such as concept mapping to conduct detailed sub-phenotyping for clinically important variables that are challenging to phenotype on a large scale, such as hyper- and hypoactive forms of delirium. SCARAB will also be linked to unique VUMC resources such as MicroVU which retains clinical isolates of all microbial specimens at VUMC allowing large studies of host-pathogen interactions using contemporary multi-omics approaches. SCARAB clinical data and biospecimens will be accessible to the broader research community through an application on our web based study portal. Proposals will be reviewed by a Resource Utilization Committee comprising study investigators and national experts in sepsis and organ dysfunction. Data will be de-identified using the most rigorous security standards. SCARAB is also designed to be readily accessible to early career investigators by providing statistical support, customized phenotyping and access to Studios for expert engagement for study design. Bringing together all of these innovative elements will allow for mechanistic studies, development of predictive biomarkers, understanding of pre-hospital factors and clinical outcome studies in patients with sepsis and appropriate controls at a scale not previously possible.

NIH Research Projects · FY 2026 · 2022-01

Pulmonary arterial hypertension (PAH) is a rare lung disease characterized by progressive pulmonary vascular obliteration resulting in right ventricular failure and ultimately death. Throughout the last three decades there has been tremendous progress in understanding disease mechanisms that have led to new therapies, however survival remains poor at approximately 8 years after diagnosis for most patients. There have been several recent NIH/NHLBI sponsored workshops on phenotyping patients with PAH and moving accumulating “Omic” data into the clinic to advance precision medicine in PAH, yet there are few centers in where this work is ongoing and training the next generation of researchers in these techniques will be critically important to advancing the field of PAH therapy and pulmonary vascular disease more broadly. Dr. Hemnes is a well- recognized expert in this field and her objective is to use the support of the K24 Midcareer Investigator Award in Patient-Oriented Research to focus on training the next generation of scientists to bring precision medicine approaches to PAH patient therapy. The candidate’s immediate and long-term career objectives are directly in line with the goals of the NIH K24 award, to provide support for protected time for awardees to devote to patient-oriented research and culturally-sensitive mentoring for students, residents, fellows and junior faculty. Specifically, this award will allow her to focus on the development of (1) a patient-oriented research program in pulmonary vascular disease research and (2) a mentoring program to facilitate the career development of new investigators. This award will provide protected time for the candidate to devote specifically to developing mentoring skills in patient-oriented research. Her objective is to recruit and mentor students, residents, fellows and junior faculty for successful clinical research careers in pulmonary vascular disease and to support the career advancement of her current trainees who are fellows and junior faculty members. To expand her patient-oriented research program in PAH, she will combine two lines of study in her research portfolio (1) understanding how insulin resistance in the lipid axis may predispose to PAH or affect outcomes and (2) using Omic techniques to deep phenotype patients with pulmonary vascular disease. The proposal here will build on her funded work to test the hypothesis that Omic signatures in PAH can identify features of resilience to PAH progression and metabolic intervention susceptibility. The specific aims are (1) To compare PAH patients with and without Omic signatures of metabolic dysfunction, define differences in clinical and molecular features and measure relevant outcomes between the two groups, (2) To test and validate Omic predictors of metformin responses in completed and ongoing clinical trials in PAH patients. Completion of these aims will enhance understanding of the pathogenesis of PAH and uncover potentially improved treatment strategies of metabolic disease in PAH specifically. The proposed new research, along with the candidate’s other funded research projects, will provide invaluable training opportunities in patient-oriented pulmonary vascular disease research.

NIH Research Projects · FY 2026 · 2021-12

Orthostatic hypotension (OH) is a common disabling condition in the elderly, particularly in those with impaired autonomic reflexes. Supine hypertension is the most common comorbidity; it not only increases the risk for target organ damage but also induces pressure natriuresis during nighttime causing nocturia and volume depletion that contributes to OH. Thus, nocturnal hypertension worsens daytime OH. Unfortunately, there is reluctance to treat supine hypertension for fear of worsening OH. Sleeping in a head-up tilt (HUT) position can improve nocturnal hypertension by reducing venous return, stroke volume and cardiac output, but tilt levels needed to produce these effects are difficult to achieve clinically. In this application, we propose that increasing intrathoracic pressure with continuous positive airway pressure (CPAP), at levels used clinically, will produce similar hemodynamic effects as HUT, by inducing venous pooling into the splanchnic circulation. Indeed, our preliminary studies show that CPAP, at levels used clinically, induces an acute and reversible decrease in blood pressure in autonomic failure patients without obstructive sleep apnea (OSA) by a direct hemodynamic mechanism, and this effect is sustained during the night and associated with decreased nocturia. In normal subjects this effect is masked by compensatory sympathetic activation. The overall goal of this application is to test the hypothesis that increasing intrathoracic pressure with CPAP is an effective treatment for nocturnal hypertension in patients with autonomic failure and that, by reducing pressure diuresis, it will improve daytime OH. In Specific Aim 1, we will characterize the hemodynamic mechanisms of CPAP in autonomic failure patients, determine its effects on volume shifts from the thoracic to abdominal segments, on hormones that regulate natriuresis, and on central blood pressure and indices of arterial stiffness. These indices are better predictors of negative cardiovascular outcomes than brachial blood pressure, and this unique patient population will allow us to determine the effects of CPAP unencumbered by sympathetic modulation. We also propose overnight proof-of-concept studies to test the hypotheses that CPAP is effective in controlling nocturnal supine hypertension (Specific Aim 2) and reduces nighttime diuresis, resulting in improvement of daytime orthostatic tolerance (Specific Aim 3). For these initial proof-of-concept mechanistic studies we exclude patients with OSA because our focus is on the novel hemodynamic effects of CPAP rather than suppression of apneic episodes. We believe the proposed studies will lead to a clinically significant and innovative approach for the management of nocturnal hypertension in patients with autonomic failure, changing the way we manage patients, and eliminating the controversy of whether to treat, or not to treat, supine hypertension. If successful, lowering nighttime blood pressure will reduce nocturia, which not only impairs sleep but also exposes patients to falls. More importantly, it will improve daytime orthostatic tolerance and improve the quality of life of our patients. Our studies will also improve our basic knowledge about the effects of CPAP on cardiovascular regulation, that can then be applied to other conditions.

NIH Research Projects · FY 2026 · 2021-12

PROJECT SUMMARY B lymphocytes orchestrate autoimmune beta cell attack in type 1 diabetes (T1D) by presenting autoantigen to T cells which kill beta cells. Circulating insulin autoantibodies (IAAs) are not directly pathogenic but help predict T1D by signaling this dangerous B/T lymphocyte crosstalk. Immune targeting of insulin-producing beta cells occurs for months or even decades before symptomatic diabetes onset. Heterogeneity in diabetes progression and clinical trial responses slow the search for a T1D cure. Better biomarkers to identify and mechanistically explain responders are needed to overcome this bottleneck. Protective immune responses typically arise by T cell selection and affinity maturation of B lymphocytes in germinal centers, resulting in memory B lymphocyte and antibody-secreting cell differentiation. However, autoimmune responses do not always follow this pathway. For example, we find anti-insulin B cells (AIBCs) accelerate diabetes in T1D-prone mice, yet few AIBCs differentiate into IAA-secreting cells, despite entering germinal centers. To fill gaps in knowledge AIBC expansion early in T1D, we built a unique, carefully-curated biobank of pre-symptomatic T1D TrialNet participants. We find AIBCs in the peripheral blood of IAA-negative pre-symptomatic T1D donors, demonstrating B lymphocyte autoimmunity for insulin evades conventional detection via circulating IAAs in a subset of at-risk individuals. Longitudinal sampling and clinical testing at each T1D TrialNet visit provide opportunities to identify donor-specific changes as T1D progresses from stage 1 (normal glucose tolerance) to stage 2 (impaired glucose tolerance) and stage 3 (diabetes). We find AIBCs are skewed towards a memory B cell phenotype. Clonally-expanded, memory B lymphocytes express germline and minimally-mutated B cell receptors in stage 1 T1D donors. These data support our hypothesis that AIBCs expand and enter the memory compartment prior to glucose tolerance impairment, sometimes without IAA production. We will integrate AIBC phenotype, B cell receptor (immunoglobulin) sequence identity, clonal relatedness, B cell receptor affinity/avidity for insulin, and insulin epitope mapping to identify features that govern insulin recognition. High- throughput single cell analysis of B cell receptor repertoire paired with cell phenotype will identify changes in the same donor over time and with T1D stage progression to determine B lymphocyte repertoire and subset shifts that occur as glucose tolerance is lost. In addition to memory skewing, AIBCs show biased V and J immunoglobulin gene use. We will track this combination of features and use LIBRAseq to identify candidate autoreactive BCRs to recombinantly express and test for islet autoantigen recognition, including other known islet autoantigens (GAD65, IA-2, ICA512, and ZNT8). The human monoclonal antibodies, anti-insulin BCR sequence database, and analysis pipeline/code we will develop will be made publicly available. These studies are a necessary step towards using AIBCs as biomarkers in clinical trials to identify favorable changes in cellular autoimmunity and zero in on specific changes AIBCs undergo to deconvolute response heterogeneity.

NIH Research Projects · FY 2025 · 2021-09

Abstract In response to PAR-20-099 “Harmonization of Alzheimer’s Disease and Related Dementias (AD/RD) Genetic, Epidemiologic, and Clinical Data to Enhance Therapeutic Target Discovery”, we have assembled a multidisciplinary team that includes experts in neuroimaging, neuropsychology, fluid biomarkers, neuropathology, and vascular contributions to ADRD to work in close partnership with the NIH and the Alzheimer’s Disease Sequencing Project (ADSP). Our ADSP Phenotype Harmonization Consortium, or “ADSP-PHC”, seeks to work in coordination with existing ADSP workgroups and initiatives to (1) streamline access to endophenotype data, (2) provide high quality endophenotype harmonization across multiple research domains, and (3) provide comprehensive documentation of both data availability and harmonization procedures. This project includes two coordinating centers, three cores, and eight domain- specific harmonization teams led by world-renowned experts in their fields. While our efforts will focus on data access, documentation, and harmonization, we will work closely with other ADSP workgroups and other large-scale harmonization efforts to maximize the impact and align with NIH priorities. In particular, we will focus harmonization on ADRD-related endophenotypes, including cognitive scores derived from detailed neuropsychological assessments, measures of neuropathology measured both ex vivo (neuropathological assessment at autopsy) and in vivo (fluid biomarkers and positron emission tomography biomarkers), concomitant pathways of injury (vascular risk factors and vascular brain injury), and measures of neurodegeneration focusing on both white (diffusion-weighted MRI) and grey matter (T1-weighted MRI). The proposed harmonization effort will provide an unprecedented opportunity to disentangle the genetic architecture of individual biological contributors to ADRD risk and progression. The harmonized data, protocols, and educational tools developed by the ADSP-PHC will transform the ADRD landscape, accelerate discovery, and facilitate the application of emerging big data analytic approaches leveraging machine learning and artificial intelligence.

NIH Research Projects · FY 2025 · 2021-09

Abstract Myosin Vb (MYO5B) is a motor protein that is critical for cell polarization and protein trafficking towards the apical membrane in epithelial cells. Inactivating MYO5B mutations cause the congenital diarrheal disease, microvillus inclusion disease (MVID), which leads to life-threatening diarrhea and malabsorption. In MYO5B knockout mice, as well as in MVID patient intestines, apical proteins that mediate nutrient and water absorption are mis-localized away from the brush border of intestinal epithelial cells. We recently found that a bioactive phospholipid, lysophosphatidic acid (LPA), can promote microvillus maturation and normalize localization of sodium-dependent glucose cotransporter 1 and sodium/proton exchanger (NHE)3, important apical sodium transporters that promote water absorption, both in MYO5B knockout tissues and organoids. However, LPA injection did not significantly improve body weight loss induced by conditional MYO5B knockout in mice. We hypothesize that the low solubility and fast degradation of natural LPA limit delivery of a sufficient dosage to ameliorate intestinal deficits in vivo, and that potent LPA receptor (LPAR) agonists are more efficient. We synthesized selective agonists for LPAR1 and LPAR5. Our preliminary data indicate that the LPAR5 agonist, Compound-1, significantly improved villus/crypt ratios and apical NHE3 localization in MYO5B knockout mice. We anticipate that LPAR5 activation can stimulate enterocyte differentiation and apical membrane trafficking that bypass the blockades induced by loss of MYO5B function, leading to improved microvillus and villus structure, nutrient transporter localization, and nutrient absorption. First, we will evaluate the therapeutic potential of LPAR5 agonist treatment on epithelial cell function in mice with inactivating MYO5B mutations. In addition to MYO5B deletion models, we will evaluate the effects of Compound-1 on mice with a G519R point mutation in MYO5B (identified in a severe MVID patient). In addition to the mis-trafficking of nutrient transporters, we have found that functional MYO5B loss induces cell lineage differentiation deficits. MYO5B knockout mice show increased numbers of Paneth cells along with hyperproliferation, while sensory tuft cells are reduced by 80%. LPA treatment reversed the tuft cell reductions in MYO5B knockout mice, suggesting that LPA signaling enhances proper cell differentiation. Second, to specify MYO5B function in progenitor cells, Myo5bflox/flox mice will be crossed with Lrig1-CreERT2 mice and the effects on epithelial proliferation and differentiation will be characterized with or without Compound-1 treatment. Third, to understand the mechanisms that underlie the hyperproliferation and differentiation deficits, we will determine the alterations in cellular metabolic pathways in MYO5B-deficient mouse intestine before and after LPAR5 activation. We will utilize imaging mass spectrometry techniques to provide spatial and quantitative metabolomics data in situ. The use of potent and soluble LPAR5 agonist as a treatment for malabsorption may provide a safer alternative to transplantation or life-long TPN in children with MVID as well as general diarrheal symptom.

NIH Research Projects · FY 2025 · 2021-09

ABSTRACT The burden of health disparities is most evident in the southeastern United States, where populations suffer the highest rates of cardiovascular disease, diabetes, obesity, hypertension, cancer, and asthma. These chronic conditions are a primary cause of poor health, reduced quality of life, and premature death, and account for more than 50% of health care expenditures. Despite substantial reduction of some chronic diseases and risk factors over the last few decades, the Southeast continues to have the highest number of potentially preventable deaths for each of the five leading causes of death. People living in the Southeast fare worse on many health indicators compared to other regions, in large part due to poor socioeconomic status, with more than 22% of Southeastern residents living in poverty. Effectively addressing pervasive chronic diseases will require interventions that consider the needs, priorities, and lived experiences of those impacted. Research teams with expertise in social, environmental, behavioral, and biological disciplines must collaborate to develop and test multicomponent strategies aimed at the multilevel determinants that drive chronic diseases. Via a new center - the Southeast Collaborative for Innovative Solutions to Chronic Diseases, we will bring together Vanderbilt University Medical Center, University of Miami, and Meharry Medical College to reduce risk factors for diabetes, cardiovascular disease, obesity, and related conditions among populations in the Southeast. We aim to: 1) Establish the human and technical infrastructure to foster highly collaborative, transdisciplinary research collaborations focused on using technology and data science to reduce chronic diseases among populations in the southeastern United States. 2) Facilitate a regional, cross-institutional pilot awards program focused on chronic diseases that nurtures and supports career development, advances use of data science, technology, and bioinformatics to address the complex drivers of chronic diseases. 3) Propel novel research leveraging technology, individual-level and community-level health data, and genomic and phenotypic data to prevent, treat, and manage diabetes, cardiovascular disease, obesity and related conditions. 4) Partner with communities in the Southeast to integrate their priorities into the Center’s infrastructure, and collaboratively develop, adapt, and test interventions to secure the earliest impact on eliminating chronic diseases.

NIH Research Projects · FY 2024 · 2021-09

PROJECT SUMMARY Non-neurogenic overactive bladder (OAB) (i.e. urinary urgency, with or without urgency urinary incontinence, frequency, and nocturia) affects 1 in 7 U.S. men and women. It can be difficult to treat effectively, and the present approach is one-size-fits-all, trial-and-error, in large part because the etiology of OAB remains unclear. A substantive body of animal and ex vivo research implicates increased afferent activity and altered CNS processing of excitatory signals in OAB pathophysiology, contributing to bladder hypersensitivity. However, clinical characteristics that may reflect a bladder hypersensitivity state are poorly recognized and thus phenotyping OAB based on afferent pathophysiologic mechanisms, which would be crucial for individualized OAB care, has remained elusive. In response, we hypothesize that central sensitization (CS) is a pathophysiologic mechanism underlying OAB in certain individuals, which might explain the bladder hypersensitivity proposed in OAB. Findings from our preliminary work demonstrating elevated temporal summation to pain (i.e. primary marker for CS indexed with quantitative sensory testing, TSP) in female OAB patients appear to support this. Yet, we still know very little about how CS manifests in OAB, including how relevant it may be for men with OAB. Therefore, we now propose that CS not only contributes to bladder sensitivity, but also to psychosocial burdens, specifically increased negative affect (which is a frequent finding both individuals with CS-mediated conditions and OAB), which then impacts bladder symptoms. We will test this hypothesis with a sample of 200 men and women with OAB and 60 non-OAB controls, using a highly innovative, interdisciplinary approach. Aim 1 identifies phenotypic features characteristic of CS in OAB, including greater central sensory sensitivity, elevated psychosocial factors, co-morbidity with chronic pain conditions, and greater urinary symptoms. Because CS links to OAB have not previously been examined in men, we will test for sex differences in CS-related phenotypes. Aim 2 will directly test, for the first time, the effects of CS on bladder sensitivity in OAB. Aim 3 will examine whether CS moderates the day-to-day negative affective influences on OAB symptoms using a state-of-the-art ecological momentary assessment approach. When completed, we expect to be able to identify OAB individuals with a mechanism-based phenotype (CS-associated OAB) defined by signature mechanistic and phenotypic features for the first time. We anticipate that individuals with this CS- OAB association, likely because of the high psychosocial impact and CS-mediated hypersensitivity, will be more difficult to treat using standard OAB interventions (i.e. OAB medications) and may require multimodal or advanced therapy. This will be assessed with future intervention studies to measure individualized OAB treatment outcomes based on underlying CS mechanisms and determine causality of this OAB-CS association, which will help usher in an era of precision medicine to optimize care of men and women with OAB.

NIH Research Projects · FY 2024 · 2021-09

The overarching goal of this project is to reveal the microstructural features that underlie the diffusion-time dependent changes in the apparent diffusion coefficient measured diffusion weighted magnetic resonance imaging (DWI) in neural tissue. While time dependent changes in the diffusion coefficient have been measured in numerous previous studies of neural tissue, the exact microstructural characteristics of that underly these changes remain unclear. Uncovering the microstructure that underly these measurements could improve the diagnosis, staging and differentiation of numerous neurological diseases that otherwise show nonspecific changes with DWI. We propose that time dependent changes in diffusion originate primarily from three sources: mean axon diameter, heterogeneity of extra-axonal space, and orientation dispersion. Within this project, we propose to (1) develop and use numerical simulations to test the sensitivity of time dependent diffusion to tissue microstructure, (2) validate time dependent changes in the diffusion coefficient in specific animal models that vary axon diameter, heterogeneity of extra-axonal space, and complexity of white matter, and (3) provide baseline estimates of the time dependent diffusion coefficient and the variability in these measurements in a population of healthy human controls.

NIH Research Projects · FY 2025 · 2021-09

PROJECT SUMMARY Sarcomas represent a rare and highly heterogeneous subtype of tumors that may develop across the lifespan. In the United States (US), there are approximately 14,000 new cases annually, with approximately 65% survival. Aside from those included in pediatric cancer survivor cohort studies, there are no sarcoma survivor cohorts in which to systematically study recurrence, organ toxicity, function, quality of life, and survival as well as their predictors. We propose to address these critical gaps in knowledge by establishing a cohort of approximately 2100 sarcoma survivors through the Vanderbilt University Medical Center (VUMC) Sarcoma Treatment Center, which is amongst the largest sarcoma programs in the US, in existence since 1987. In this cohort, we will systematically collect repeated information on disease, treatment, response, relapse, treatment-related toxicity, sociodemographics, lifestyle, functional status, quality of life, physical health outcomes, and survival, together with biospecimens (tumor tissue and peripheral blood samples). We hypothesize that: 1) extrinsic factors, tumor biology, and germline genomics contribute to oncologic outcomes and long-term organ toxicity; 2) healthy lifestyle, e.g., high quality of diet, exercise, abstinence from cigarette smoking and alcohol drinking mitigate the adverse health consequences, improve survival and quality of life among sarcoma survivors; and 3) liquid biopsy tools, developed through identifying genomic drivers of sarcoma, will be of predictive and prognostic utility. Our aims for current grant period are to evaluate1) the impact of disease, treatment, sociodemographic and lifestyle contributors on adverse oncologic and non-oncologic outcomes and mortality in the cohort; 2) the role of drug metabolism and DNA repair gene functional polymorphisms, genetically predicted gene expression levels, and polygenic risk scores, on treatment efficacy and therapy-induced normal tissue toxicity; and 3) genomic drivers of sarcoma to develop personalized liquid biopsy assays for monitoring treatment response, recurrence, and minimal residual disease. Establishment of a prospective cohort of sarcoma survivors across the lifespan, with extensive and well characterized clinical and epidemiologic data, patient reported outcomes, tumor tissue and serial blood samples builds a foundation for a long-term prospective investigation on life after sarcoma. This effort is critically important to improve the understanding of a rare tumor affecting the lifespan but seriously underrepresented in research. Identification of health outcomes and their predictive and prognostic factors can lead to precision treatment and survivorship care, which are currently clinically unmet needs.

NIH Research Projects · FY 2024 · 2021-09

PROJECT SUMMARY The goal of this proposal is to characterize and quantify the impact of (a) sex, (b) gender-related exposures, and (c) their interactions on heritable disease across the entire medical phenome. The growing availability of large-scale biobanks with electronic health records (EHRs) linked to biospecimens has created a powerful, but still relatively untapped, opportunity for research aimed at understanding the impact of sex and gender-related exposures on human health. The National Human Genome Research Institute (NHGRI) organized the Electronic Medical Records and Genomics (eMERGE) network which brought together investigators around the U.S. to facilitate EHR-based genomic research and the implementation of genomic medicine. We have created a new collaborative between two of the original eMERGE centers that leverages the resources and existing infrastructure at each site including a combined total of over 9 million patient records and over 100,000 genotyped samples linked to EHRs. Large patient cohorts like the Vanderbilt and Northwestern populations are critical resources that enable research on sex and gender-related exposures and their interaction at scale across the clinical phenome. Our preliminary data demonstrates that sex and gender-related exposures including socioeconomic position and sexual assualt trauma can be mined from the medical record. Moreover, we show that these factors are significantly associated with ~30% of the medical phenome. Finally, we provide evidence that sex and gender-related exposures also moderate genetic risk for complex disease. These findings lead to our central hypothesis that sex and gender-associated exposures interact to modify risk for heritable complex diseases. Building on this preliminary data, our first Aim is to identify and validate the effects of sex and gender-related exposures across the clinical phenome. In Aim 2 we employ a genetic epidemiology approach to identify sex-differences in the genetic architecture of 1,051 clinically utilized laboratory tests. Finally, in Aim 3 we bring these two lines of inquiry together to test whether the clinical manifestations of polygenic risk scores (PRS) are modified by sex and gender-related exposures. The proposed research includes both quantitative and qualitative analyses aimed at investigating the genetic, clinical, and psychosocial risk factors that contribute to the development of complex disease in extremely large samples with phenome-wide data and linked genotypes. These sex-aware analyses can be thought of as essential, but currently missing, pieces of the precision approach to medicine.

NIH Research Projects · FY 2024 · 2021-09

Project Summary/Abstract There is an urgent need for effective diabetes self-management interventions that are convenient, scalable, sustainable, and able to meet the needs of diverse patients and those with limited health literacy that may be disproportionately affected by the disease. Based on our preliminary studies, My Diabetes Care (MDC) may fill this critical gap by bringing together some of the best aspects of diabetes mHealth apps and incorporating them into a patient portal intervention that was developed to be interoperable with a variety of electronic health records (EHRs) and that offers direct integration into routine care without creating additional work for healthcare teams or the need for additional staff. MDC is a multi-faceted patient portal intervention designed to help patients better understand their diabetes health data as well as promote and support self-management. Developed at Vanderbilt University Medical Center (VUMC), MDC uses infographics to facilitate users' understanding of their diabetes health data, incorporates motivational strategies and access to an online patient support community, and provides literacy level-appropriate and tailored diabetes self-care information. To ensure interoperability and optimize scalability, we built MDC using Substitutable Medical Applications, Reusable Technologies on Fast Healthcare Interoperability Resource (SMART on FHIR) that allows MDC to be installed into a wide variety of EHR platforms across the U.S. Our preliminary studies suggest MDC is acceptable, feasible, improves understanding of diabetes health measures, and increases patient activation. The objective of the proposed research is to: (1) expand MDC's display of user's diabetes health data beyond hemoglobin A1C, blood pressure, cholesterol, and flu vaccination status to include microalbumin and BMI and enhance access by creating a Spanish-language version; (2) evaluate the effects of the expanded & enhanced version of MDC on diabetes-related outcomes while demonstrating its scalability by integrating it into another health system and conducting a pragmatic randomized controlled trial in an ethnically and racially diverse patient population, and (3) examine how the effects of MDC arise by studying causal mediators. The proposed work is important because racial/ethnic minorities and those with limited health literacy are more likely to experience barriers to diabetes self-care and technology use. By designing, testing, and evaluating, MDC in diverse groups of patients including those with limited health literacy and developing a Spanish language version, we will advance the understanding of how to create patient-facing health technologies to achieve broad uptake and address health inequities. By leveraging SMART on FHIR, our project will also demonstrate the current state of the art by implementing and testing MDC without needing to rebuild it and will serve as a model for future patient portal-based interventions.

NIH Research Projects · FY 2025 · 2021-09

Project Summary End-stage renal disease (ESRD), the final stage of chronic kidney disease (CKD), requires renal replacement therapy such as hemodialysis. Every year more than 100,000 individuals start hemodialysis. Patients undergoing hemodialysis are at increased risk of frailty and sarcopenia. Frailty is a multisystem impairment associated with vulnerability to stressors, and it is characterized by the presence of unintentional weight loss, self-reported exhaustion or fatigue, measured muscle weakness, slow walking speed, and low physical activity. Sarcopenia, defined as a reduction of muscle mass and/or muscle strength, is one of the components of the frailty phenotype. In the general population, physical exercise prevents the loss of muscle mass and improves frailty status. In patients with ESRD, however, exercise is not as effective as in the general population. Mitochondria are essential for proper muscle function, and recent studies suggest that mitochondrial dysfunction contributes to the reduction in muscle mass. We and others have found that mitochondrial abnormalities and decreased mitochondrial content are present in patients with ESRD. The number of mitochondria depends on the balance between biogenesis (generation of new mitochondria) and mitophagy (degradation of mitochondria). Physical exercise improves mitochondrial function and increases the mitochondrial number in skeletal muscle in the general population. But the benefits of exercise on mitochondrial function in patients with ESRD have not been studied. In this study, we will evaluate the overarching hypothesis that mitochondrial dysfunction hinders the beneficial effects of exercise in patients with ESRD. Thus, in Specific Aim 1, we will test the hypothesis that Coenzyme Q10, a mitochondrial-targeted therapy, improves muscle adaptation to exercise training in patients with ESRD. For this aim, patients with ESRD will be enrolled in a 12-week exercise program or in an observational group. Patients will also receive either Coenzyme Q10 supplementation or placebo. As a result, patients will be assigned to four different groups, exercise plus placebo, exercise plus Coenzyme Q10, observational plus placebo, observational plus Coenzyme Q10. This study design will allow us to evaluate the individual effect of the interventions and the additive effect of the interventions. We anticipate that the combination of exercise and Coenzyme Q10 will have an additive effect in improving and mitochondrial function and physical performance in patients with ESRD. In Specific Aim 2 we will test the hypothesis that the combination of exercise training and Coenzyme Q10 improves mitochondrial function in patients with ESRD by increasing mitochondrial respiration and content, and improving mitochondrial dynamics (i.e., remodeling through fission and fusion). Therefore, we will measure mitochondrial respiration and markers of mitochondrial biogenesis and dynamics in muscle biopsies within a sub-group of patients from Specific Aim 1. Results from these studies could affect millions of people with ESRD by improving physical function and their quality of life.

NIH Research Projects · FY 2024 · 2021-09

The need for mechanical ventilation (MV) following acute respiratory and myocardial failure is the leading cause of admission to the pediatric intensive care unit (PICU). Over 90% of MV pediatric patients receive continuous sedation, most commonly with gamma-aminobutyric acid (GABA) agonist benzodiazepines. Recently, we demonstrated that exposure to the benzodiazepine midazolam contributed to iatrogenic harm in pediatric patients—prolonging PICU length of stay and increasing the prevalence and duration of delirium. Delirium, itself a manifestation of acute brain dysfunction, is prevalent in the PICU with rates of up to 30% in older children, over 50% in infants and toddlers, and over 60% in pediatric patients requiring MV. Delirium in children is a significant contributor to longer duration on MV, prolonged PICU length of stay, and death, with significant consequential costs. Adult studies have shown that an alternative sedation paradigm using dexmedetomidine, an alpha-2 agonist, decreases the duration of delirium and coma, length of MV, ICU length of stay, cost, and infection rates compared to benzodiazepine-based sedation. Dexmedetomidine has unique anti-inflammatory and anti-oxidant characteristics, making it an appealing sedative agent as inflammation, endothelial and blood-brain barrier (BBB) injury are mechanistically associated with prolonged delirium and worse cognitive impairment in adults. Though sedation may be unavoidable in PICUs, a dexmedetomidine- based regimen may complement goal-directed sedation, as over-sedation (30%) rather than under-sedation (10%) is common in the PICU setting, and thus far, sedation protocolization alone have not demonstrated significant impact on improving outcomes in pediatric patients. The FDA recently published warnings regarding the possible role of anesthetics, including benzodiazepines, on cognitive development in children. We therefore propose mini-MENDS (Maximizing the Efficacy of Goal-Directed Sedation to Reduce Neurological Dysfunction in Mechanically Ventilated Infants and Children Study), in which we will test the hypotheses that sedation of MV pediatric patients with an alpha-2 agonist (dexmedetomidine) versus a GABA- ergic agent (midazolam) will (Aim 1A) decrease daily delirium prevalence, (Aim 1B) decrease length of MV, (Aim 2A) improve functional and behavioral recovery, (Aim 2B) be associated with fewer symptoms of post- traumatic stress, (Aim 2C) decrease the incidence of cognitive impairment, and (Aim 3) reduce levels of pro- inflammatory cytokines and biomarkers of endothelial and blood brain barrier injury. We will randomize 372 pediatric patients on MV, aged 6 months to 11 years, to receive goal-directed continuous sedation with either dexmedetomidine or midazolam for up to 10 days. The study will have 80% power to detect at least a 10% absolute reduction in daily delirium prevalence between groups, this a clinically meaningful outcome; extrapolation of current pediatric data would estimate a 10% decrease in delirium prevalence to be associated with a 1.2-day (20%) decrease in PICU LOS and 15% lower odds of dying.

NIH Research Projects · FY 2024 · 2021-09

PROJECT SUMMARY/ABSTRACT Over 80% of emergency department (ED) patients with acute heart failure (AHF) are admitted to the hospital, with only 10% at high-risk for in-hospital events. We developed and validated a prediction rule (STRATIFY) that identifies ED patients with AHF that may be safe to discharge. If successfully implemented, it will save substantial resources without sacrificing patient outcomes and help institutions achieve goals for accountable care. Real-world adoption of prediction rules for AHF and other conditions treated in the ED is challenged by barriers such as time-pressured workflow, real-time data availability and quality. A solution would have considerable implications for implementing any clinical decision algorithm. The central objective of this grant is to develop a multilevel approach and the necessary statistical methods to close the gap in implementation of our AHF risk prediction tool, as a model for other automated risk prediction approaches within an electronic health records system. Through inter-disciplinary collaboration among ED physicians, biostatisticians, qualitative research experts, implementation scientists and bioinformaticians, we propose to rigorously develop and test a clinical decision support-based approach including 1) robust stakeholder engagement to participate in user-centered design and identify approaches to overcome barriers to implementation, 2) overcoming real-time data integration challenges through statistical methods, and 3) a detailed evaluation of effectiveness and implementation in multiple centers. Our proposal will have a broad impact on both acute care practice and risk model implementation by closing the gap between scientific discovery and health care delivery using risk prediction tools. Importantly, the methods developed here will generalize to other risk prediction tools and be readily translatable to other complex ED-based diseases such as pulmonary embolism, stroke, and COPD, thereby maximizing opportunity for impact both scientifically and on patient care.

NIH Research Projects · FY 2025 · 2021-09

ABSTRACT A K24 Mid-Career Investigator Award in Patient-Oriented Research (POR) is requested to: 1) augment my capabilities in POR to include new expertise in network science, and the cognitive neuroscience and neuroimaging of the human thalamus; 2) apply these new expertise to perform novel studies of thalamic connectivity, function, and structure in psychotic disorders; and 3) enhance my mentorship skills and provide protected time to mentor trainees. My research program investigating the neural basis of psychotic disorders serves as a platform for training POR trainees. This includes mentoring junior faculty, postdoctoral fellows, graduate students, and MD/PhD medical students in psychotic disorders, neuroimaging, and neuropsychology. For the past several years my lab has focused on investigating thalamocortical circuit abnormalities in psychotic disorders. We were among the first to show that functional connectivity of the thalamus in schizophrenia is characterized by a combination of lower connectivity with the prefrontal cortex (PFC) and hyper-connectivity with sensorimotor cortical areas. Our findings coincided with groundbreaking discoveries in the cognitive neuroscience of the thalamus. However, many recent advances in the fundamental neuroscience of the thalamus have yet to translate to improved understanding of the mechanisms of psychosis phenotypes. This translational gap is impeding progress in identifying potential treatment targets for cognitive impairment. Progress is further hindered by limitations of conventional neuroimaging methods which are unable to directly visualize individual thalamic nuclei in humans. This proposal provides the foundation for addressing these challenges. Specifically, I will develop new research skills in network science (Aim 1) and the cognitive neuroscience of the thalamus (Aim 2A), extend existing expertise in neuroimaging to include state-of-the-art methods for imaging the human thalamus in vivo (Aim 2B), and apply these new expertise to characterize thalamic nuclei structure and function abnormalities in early stage schizophrenia (Aim 3). This proposal will: 1) enhance ongoing work in my lab characterizing brain connectivity in psychopathology and normal cognitive development; and 2) provide me with critical expertise required for future studies focused on informing thalamocortical mechanisms of psychosis phenotypes.

NIH Research Projects · FY 2025 · 2021-09

PROJECT SUMMARY Overactive bladder (OAB) (i.e. urinary urgency, with or without urgency urinary incontinence, frequency, and nocturia) affects 1 in 7 U.S. men and women and results in substantial impairment to quality of life (QOL). To help self-manage and cope with OAB, many people adopt compensatory bladder behaviors, such as restricting fluids, using containment products, strategic planning and mapping restroom access, and even curtailing activities or travel altogether, which further adversely impact QOL. These behaviors may be driven by anxiety and stress related to urinary urgency and incontinence episodes as well as ensuing distress and embarrassment. Prior research has linked anxiety and OAB: up to 40% of women and 30% of men with OAB also have generalized anxiety disorder. The link between stress and OAB is less studied. In animals, experimental stress can cause OAB-like symptoms and behaviors as well as bladder and somatic hypersensitivity. In limited human studies, women with OAB may have greater physiologic and psychologic stress reactivity, and acute stress may exacerbate urinary urgency. However, how stress impacts on the bladder in the context of OAB or what psychological factors drive compensatory behaviors that impair QOL in OAB remain unknown, as there are no highly-controlled studies of anxiety-OAB links. Understanding these relationships would be a critical advance to individualizing care of patients with OAB. The proposed project will comprehensively investigate for the first time how stress, anxiety and OAB interact, including the impacts on bladder sensitivity, urinary symptoms, and compensatory bladder behaviors. We propose a feedforward loop, whereby increased OAB symptoms increase anxiety (via response to coping with stressful situations), which in turn increases OAB symptoms (via increased bladder sensitivity). We further propose that compensatory behaviors are driven by anxiety-related learning processes that help perpetuate this relationship. We will test our hypotheses in a sample of men and women with OAB and healthy controls. Aim 1 will test the hypothesis that acute, experimentally induced psychological stress will be more strongly associated with increased bladder sensitivity in OAB patients than in controls, using a novel bladder sensation meter with oral hydration and stress induction procedures. Aim will test the hypothesis that psychological stress and anxiety will have concurrent and lagged effects on day-to-day urinary symptoms that are stronger in individuals with OAB than in controls, using an ecological momentary assessment approach (7-day electronic diary) to examine prospective associations between everyday perceived stress, anxiety and urinary symptoms. Aim 3 will test the hypothesis that compensatory behaviors (i.e. coping) used at the time of voiding will be associated with subsequent reductions in anxiety levels, using a 3-day sensation-related bladder diary that captures concurrent bladder behaviors and anxiety symptoms as well as lagged symptoms 30 minutes post-void. Delineating these relationships and patterns will allow for identification of potentially modifiable factors or areas for intervention, which we envision as a future R01 clinical trial submission.

NIH Research Projects · FY 2025 · 2021-09

Abstract As the population ages, late-onset Alzheimer’s disease (AD) is becoming an increasingly important public health issue. AD disproportionately affects women. Of the more than 5 million people in the United States afflicted with this disease, two-thirds are women. Women with AD have more neuropathology than men with AD, have more severe cognitive symptoms, and more severe neurodegeneration, suggesting that the disease affects male and female brains in different ways. Thus, a focus on sex differences in AD is essential to move the field towards effective interventions. The identification of sex-specific genetic drivers of AD and AD-related endophenotypes could transform the way treatments are administered and be a critical step towards personalized interventions for AD. Research from both our group and others has begun to uncover genetic factors that explain some of the observed differences between males and females, specifically in terms of AD neuropathology and cognitive decline. To advance the field, additional genetic effects must be discovered and the underlying mechanisms of sex-specific pathways of injury must be examined. The objective of this project is to identify and replicate genetic effects that act in a sex-specific manner to drive the neuropathological presentation and clinical progression of AD. The present proposal will advance our understanding of sex- specific genetic contributors to AD endophenotypes by leveraging data from 30 studies of aging and AD (n=33,740) to assess genetic associations with AD neuropathology and cognitive decline. The outcome of this project will highlight new candidate pathways and begin the process of characterizing the mechanisms by which genetic variation among males and females affects the risk and clinical symptoms of AD. The sex- specific pathways identified will offer therapeutic targets and help move the field towards personalized interventions that consider an individual’s sex and neuropathological presentation.

NIH Research Projects · FY 2026 · 2021-09

Project Summary The 5-year overall survival from acute myeloid leukemia (AML) is less than 30%. While some patients are cured with initial induction therapy, most patients relapse, and the expected outcomes in patients with relapsed and refractory (R/R) AML are dismal. For this reason, developing methods to identify therapies likely to benefit R/R AML patients is a top priority. This proposal aims to address critical unmet needs with a unique Academic- Industry Partnership (AIP) between investigators at Vanderbilt University Medical Center, Karyopharm Therapeutics, and Notable Labs. The BCL2 inhibitor, venetoclax (VEN), is transforming clinical practice for AML, but activity in R/R AML is less pronounced, and resistance occurs in most patients. AIP investigators currenty lead a multi-site investigator-sponsored study, testing VEN in combination with the selective inhibitor of nuclear export (SINE) selinexor (SEL) in a Phase I trial for R/R AML (NCT03955783). This SEL/VEN trial grew from the discovery that SEL synergizes with VEN and overcomes resistance mechanisms in some VEN-insensitive patient samples. Given this, our AIP team has worked together to develop a precision medicine functional platform for this novel combination in R/R AML. Notable Labs utilizes an automated high-throughput, immunophenotype-based flow cytometry method to provide real time drug sensitivity data on multiple, specific cell populations simultaneously within a given patient sample. Building from the only annotated cohort of patient samples treated with SEL/VEN in the world, we propose to develop a precision medicine functional assay to identify R/R AML patients most likely to benefit from SINE/VEN combination therapy. We will build, refine and optimize the functional platform for SEL/VEN with samples from our current Phase I study and train the platform on samples from the Phase 2 SEL/VEN clinical trial proposed by the AIP. Aim 1 will focus on determining assay parameters specifically for SEL/VEN in R/R AML. Aim 2 will train the model with the phase II clinical trial of SEL/VEN in R/R AML, and Aim 3 will contextualize the predictive analytic model on heterogenous genotypes found in R/R AML. At the conclusion of this study, the functional medicine platform will be a companion diagnostic ready for external validation which we will lead in a phase III efficacy trial of SEL/VEN in R/ R AML, and serve as proof-of-principle for development of similar therapy-specifc precision medicine tools.

NIH Research Projects · FY 2025 · 2021-09

There is a rapidly expanding knowledge base enabling precision therapeutics for a number of human diseases, but there are significant unmet needs in evidence generation to support translation to the treatment of children and pregnant/post-partum women. The recent widespread adoption of electronic health records (EHRs) and the linkage of these data to other large datasets represents an unprecedented opportunity for clinical research and discovery. The goals of this Center of Excellence in Maternal and Pediatric Precision Therapeutics are: to address key knowledge gaps and perform clinical research in pharmacogenomics and neonatal opioid withdrawal syndrome; to leverage data science methodologies and develop novel tools that support maternal and pediatric precision therapeutics research; and to enhance training for maternal and pediatric precision therapeutics at the local, regional, and national levels. We bring to this effort a unique collection of investigators, institutional support, tools, and resources that enable a paradigm-shift from current norms of slow, incremental progress. Project 1 will: use a community engaged approach to illuminate knowledge of, attitudes about, and priorities for pharmacogenomics; and validate pharmacogenomic associations for maternal and pediatric populations using the innovative and generalizable strategy of EHR phenotyping. Project 2 will: develop and validate EHR-based algorithms to identify a cohort of opioid-exposed infants and their mothers (dyads) and create a novel linkage of these data to state-wide data; test the hypothesis that use of medications for opioid use disorder is associated with improved early outcomes; and test the hypothesis that opioid use disorder treatment is associated with improvements in the novel longitudinal outcome of dyadic stability. These projects are led by multidisciplinary teams that include Investigators in Pediatrics and Obstetrics, and who are nationally recognized leaders in their respective fields. Both Projects will be supported by a Scientific Core – the Phenotyping Support Core - which enhances each project with expert phenotyping, machine learning/artificial intelligence, and experience in generalizing and disseminating phenotyping approaches. An Administrative Core will provide logistical support for the Center, supervise training opportunities, and ensure scientific interchange within the CET and with the MPRINT Hub. This work will contribute to innovative approaches to precision therapeutics for mothers and children and will develop the educational infrastructure to support the training of physician-scientists to support further advances well into the future.

NIH Research Projects · FY 2025 · 2021-09

The overarching theme for this program project grant (PPG) is that alcohol associated gut dysbiosis and gut dysbiotic metabolites are cardiovascular disease (CVD) risk factors among people living with HIV infection (PLWH) who are heavy drinkers. The goals of this research are (1) to determine if a tailored probiotic (i.e., contains bacteria supporting butyrate synthesis) can mitigate alcohol associated gut dysbiosis and lower levels of microbial translocation, inflammation, and improve harmful dysbiotic metabolite profiles (e.g. trimethylamine N oxide, TMAO) and (2) to determine if these metabolites are associated with incident CVD and death among PLWH. We hypothesize that, among PLWH, a probiotic vs. placebo can mitigate alcohol associated gut dysbiosis and lower levels of microbial translocation, inflammation, and improve metabolite profiles (Project 1 RCT, n=250); and that harmful alterations of these metabolites will be associated with higher risk of incident CVD and death (Project 2 Cohort, n=2,900). Project 1 will be conducted at Vanderbilt University Medical Center in Nashville, TN. Project 2 will leverage the Veterans Aging Cohort Study, an observational cohort of veterans living with and without HIV. The Projects will be supported by our Administrative Core at Vanderbilt University Medical Center and the Integrated Metagenomics and Metabolomics Core at the University of Louisville’s Alcohol Research Center (ULARC). The latter is the core for ACME HIV and will generate the metagenomics and metabolomics for this PPG. The former will coordinate all study projects/cores and integrate the Vanderbilt SCHolars in HIV and Heart, Lung, Blood, and Sleep ReSearch NIH K12 training program into the PPG. Our preliminary data: (1) HIV infection is a CVD risk factor; (2) inflammation is associated with increased risk of CVD among PLWH; (3) among PLWH, heavy drinking is associated with increased CVD risk and correlated with measures of gut dysbiosis, characterized by loss of butyrate producing bacteria; (4) gut dysbiosis among PLWH who are heavy drinkers is correlated with higher levels of inflammation, TMAO, and adverse bile acid metabolite profiles; and (5) ULARC data in murine models show heavy drinking causes dysbiosis, that dysbiosis leads to increased biomarker levels of inflammation, and that probiotic administration targeting alcohol-associated gut dysbiosis attenuates the rise in these inflammatory biomarkers even in the presence of alcohol consumption. Cross project validation: Biospecimens from Project 1 will be used to validate significant findings in Project 2. Metabolites significantly associated with alcohol and CVD in Project 2, will be explored in Project 1 to see if probiotics favorably impact the levels of those metabolites. The Microbiome, METabolites, and Alcohol in HIV to reduce CVD (META HIV CVD) PPG will inform probiotics’ role as standard adjunctive therapy complementing alcohol interventions among PLWH who are heavy drinkers and advance the understanding of how alcohol associated gut dysbiosis and its metabolites contribute to CVD and death.

NIH Research Projects · FY 2025 · 2021-09

PROJECT SUMMARY - Mandatory Component A Acute respiratory illness (ARI) and acute gastroenteritis (AGE) are the leading causes of death worldwide in young children. Established leading viral etiologies of AGE are rotavirus and norovirus and respiratory syncytial virus (RSV) and influenza virus for ARI. Our understanding of ARI and AGE epidemiology is constantly changing due to spatiotemporal fluctuations, discovery of new or re-emerging pathogens [e.g. enterovirus D68 (EV-D68) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)], and use of rotavirus and influenza vaccines. Hence, surveillance efforts are imperative to define ARI and AGE disease burden, causative pathogens, outcomes, and vaccine impact. The primary influenza prevention strategy in the United States is vaccination for all individuals six months or older. There is a paucity of data regarding vaccine effectiveness (VE) against laboratory-confirmed influenza in children, and influenza viruses and vaccine antigenic components change annually. Therefore, perpetual assessments of VE are needed to monitor the impact of influenza vaccination on disease and inform strategies to improve magnitude, durability, and breadth of protection. Pediatric SARS-CoV-2 vaccines are an urgent public-health priority and likely will become available on an accelerated timeline in an effort to curb the COVID-19 pandemic. Rigorous, prospective surveillance of SARS-CoV-2 VE is crucial to support reliance on vaccines as primary prevention. Thus, the first main objective of this project is to conduct population-based active surveillance for respiratory and enteric viral pathogens in pediatric inpatient and emergency department settings and asymptomatic controls. Our team of Vanderbilt investigators is highly experienced in conducting prospective, population- based ARI and AGE surveillance. We propose to conduct ARI and AGE surveillance with the following specific aims: 1) To perform prospective, active surveillance to determine the etiology and burden of inpatient and emergency department (ED) acute viral respiratory and enteric diseases among the pediatric population. 2) To characterize the clinical and epidemiologic factors of pediatric infections (including in asymptomatic children) through active surveillance. 3) To evaluate vaccine effectiveness and impact of vaccines and other interventions (e.g., immunoprophylaxis with antiviral agents or other therapeutics) available or projected to become available during the period of performance. The second main objective of this project is to conduct surveillance and epidemiologic characterization of acute flaccid myelitis syndrome in children. Given the epidemiologic connection between EV-D68 infection and acute flaccid myelitis (AFM), it will be important to conduct rigorous, active, longitudinal surveillance for AFM across multiple consecutive seasons; carefully define AFM clinical spectrum, risk factors, incidence rates, and laboratory parameters; and document local circulation of EV-D68 and other ARI and AGE pathogens coincident with increased AFM occurrence. This work underpins development of preventive, diagnostic, and therapeutic strategies for AFM.