Vanderbilt University Medical Center

NIH Research Projects · FY 2025 · 2023-07

Project Summary/Abstract While there is abundant evidence that certain musical behaviors (e.g., regularly listening to loud music) are risk factors for age-related hearing loss (ARHL), human musicality also has the potential to support hearing health across the lifespan. For example, studies in small samples of younger adults show that individual differences in musical aptitude are positively associated with hearing outcomes such as speech recognition in noisy conditions, and that musicians show enhanced hearing outcomes and auditory processing compared to non- musicians. Further, advances in the genetics of musicality show that genes involved in cochlear development are associated with phenotypic variation in musical aptitude. Preliminary studies also show a positive association between music engagement frequency and hearing sensitivity. Given this evidence, could higher degrees of musicality – both aptitude for and engagement with music – be a protective factor against hearing loss as we age? This project systematically tests this novel hypothesis using experimental, epidemiological, and genomic approaches. Aim 1 uses robust experimental approaches to characterize associations between musical aptitude and hearing outcomes in older adults, over and above music engagement (e.g. practice, formal training, listening) and neurocognitive skills (e.g. executive function). Aim 2 uses epidemiological approaches to characterize associations between music engagement frequency and hearing outcomes in large cohorts of middle-aged and older adults. Aim 3 uses computational genomics approaches to investigate shared genetic architecture between human musicality and ARHL, in large cohorts of middle-aged and older adults for whom available health, phenotypic, and genotypic information is known. Evidence for and against our hypotheses will allow us to disentangle three competing theories about the links between human musicality and hearing health, namely that links are either driven by (a) shared genetic and neural architecture underlying both traits, (b) auditory neurocognitive affordances and preferences shaping musicality, (c) or “wear and tear” of sensorineural auditory biology due to cumulative loud music exposure. Taken together, findings from this project will help evaluate musicality as a protective factor against hearing loss as we age, and lay the groundwork for understanding longitudinal and causal relationships between music engagement and hearing health. Further, findings will lay the groundwork for examining specific biological functions (e.g., expression and regulation) of genes linking musicality, sensorineural auditory mechanisms, and hearing outcomes. This work addresses a critical health need: one in three adults aged 70 or older in the United States suffers from hearing loss, with cascading consequences on social isolation, depression, and cognitive decline and dementia. Innovations in personalized prevention and care are sorely needed. Further the work is timely and leverages recent advances in computational genomics and health biobank approaches, and in the genetics of human musicality traits.

NIH Research Projects · FY 2024 · 2023-07

In this Research Opportunity Announcement for Area of Interest 4, we describe the seminal work of establishing an infrastructure that operationalizes engagement of diverse research participants, distinct from recruitment/enrollment, and building on the foundational work of integrating research participants within the governance of research programs. Our approach and best practices are embedded into the Engagement Core’s five aims 1)Serve as the central hub for participant engagement – providing resources, expertise, and tools – to the All of Us Consortium for engaging participants as partners in the governance, priority setting, implementation, and evaluation of All of Us; 2) Effectively integrate participants, who reflect the broad diversity of All of Us, as partners in the governance, oversight, and evaluation of All of Us; 3) Capture and integrate the voices of diverse participants to enhance the design, implementation, and use of All of Us data, resources, and results; 4) Continuously assess the impact of participant engagement on all aspects and phases of All of Us including governance, design, implementation, and evaluation; and 5) Advance the science of engagement with an emphasis on engaging historically marginalized and minoritized groups. To date, our Engagement Core has established the infrastructure for participant engagement, by successfully integrating 81 participants (including 58 [72%] from minoritized and historically excluded communities into various All of Us governance roles including 12 members on the steering committee and 6 on the executive committee. Our Engagement Core has responded to 55 requests for engagement reflecting a range of activities including review of a mental health and well-being PPI survey and generating potential solutions to safely extend data access to non-traditional researchers in the All of Us Researcher Workbench. In the next phase, we will continue the multi-faceted strategies above and will expand our approaches to include voices currently missing from existing engagement such as young adults, and parents of children aged 18 and younger (critical given upcoming pediatric enrollment). We will also create new mechanisms such as a rapid feedback panels - a diverse group of participants who will provide time-sensitive feedback in critical areas. Ultimately, we will document successful strategies to contribute evidence-based recommendations for future large-scale studies with a substantial participant engagement component.

NIH Research Projects · FY 2026 · 2023-06

Clinical research comes in many different shapes and sizes, and a robust network must accommodate all trial types. No single organization can do this work alone. We have a deep commitment to both trial innovation and collective network capacity within and beyond the CTSA Consortium and have a lengthy history of supporting this approach. We have demonstrated an exceptional ability to collaboratively innovate and share tools supporting clinical research coordination, including: global data management, mobile data collection, recruitment, Electronic Health Record (EHR) research, single IRB coordination, contracting, community engagement, returning value to participants, eConsent, virtual/remote participation in studies, and EHR integration with REDCap. We will leverage and expand upon these programs as we are Engaging Cooperative Sites for Trial Acceleration, Trust, Innovation, and Capability (ECSTATIC). We will establish a distributed alliance of 6 CTSA-aligned coordinating centers to add elastic capacity and broaden expertise to the TIN’s CCC/DCC infrastructure. Our alliance has 14 expert trialists that can inform the use of integrated approaches for more efficient clinical research. Additionally, we will partner with the well-established Biostatistics, Epidemiology, and Research Design (BERD) group to ensure every study has access to needed expertise starting from study design through analysis. We will broaden the types of organizations that can readily participate in clinical research across the U.S. Based on our novel structure, merging teams from six different coordinating center groups, our TIC’s capacity is both scalable and matched by expertise to intentionally accommodate all study design types. Led by Gordon Bernard, MD, Jonathan Casey, MD, and Christopher Lindsell, PhD, each seasoned in leading and collaborating with multisite clinical trial networks, ECSTATIC will embrace and draw on expertise to build, test, and share new resources that will enhance and accelerate rigorous, reproducible research for all CTSAs, to more rapidly improve human health. Our Specific Aims are to: 1) demonstrate and disseminate novel integrated approaches for more efficient clinical research including EHR-embedded, remote no-touch, and platform trials, aligning with study needs; 2) expand and enrich clinical trial capability by increasing potential participating site Expression of Interest (EOI) reach and readiness support (rural Practice-Based Research Networks), better process integration with CTSAs, preparing study teams, and broader expert engagement; 3) innovate clinical trial methodology by creating, evaluating, and disseminating new methods for risk monitoring, AE reporting, direct EHR to REDCap data capture, and data standards to all CTSAs; and 4) provide a distributed alliance of clinical and data coordinating centers with extensive and multi-disciplinary expertise to offer support tailored for trial design, population, and condition.

NIH Research Projects · FY 2025 · 2023-06

PROJECT SUMMARY Evidence-based obesity treatment is inaccessible to most children in the United States. This lack of access is a source of health inequity, whereby children from rural and minority communities, who have the highest rates of childhood obesity, are also the least likely to receive an evidence-based intervention. Developing strategies to improve access to evidence-based obesity interventions could reduce health disparities by improving reach to these underserved communities. The premise of this study is that using a systematic framework to adapt a community-based behavioral intervention for childhood obesity that accounts for individual, family, and community factors will increase reach and effectiveness among low-income, minority, and rural populations. COACH is a multi-level obesity intervention that supports 1) the individual child through developmentally appropriate health behavior curriculum, 2) the family by directly addressing parent weight loss and engaging parents as agents of change for their children, and 3) the community by building the capacity of local community centers to offer parent-child programming. COACH has been tested in a prior RCT and demonstrated effectiveness at reducing child BMI at 1-year follow-up. We propose testing the process of adapting COACH in a cluster-randomized trial. In Aim 1, we will conduct a community readiness assessment for COACH in 50 community centers serving rural, minority, and low-income families in middle TN. This assessment was developed and pilot-tested by our team and assesses barriers to study implementation in multiple domains. In 25 randomly selected community centers, we will use a systematic process to adapt the intervention protocol based on the assessment results, while maintaining fidelity to COACH’s core components. In Aim 2, in a cluster-randomized trial, we will test the comparative effectiveness of each implementation strategy (adaptation vs. original program) on the implementation outcomes of reach, adoption, implementation, and maintenance. In Aim 3, we will test the comparative effectiveness of the adapted and original intervention on child BMI-Z at 6-month follow-up. Children with obesity (BMI percentile ≥95th) ages 6-11 and their families (N=750; 15 index children/center) will be recruited from communities served by each center. This research is innovative because it uses adaptation science as a potential solution to reduce health disparities in childhood obesity. By testing this intervention in a community resource available to 230 million Americans (community centers), we will create a scalable obesity intervention that could be implemented in traditionally underserved populations across the country. This study will also develop and test a theory-based process for adapting behavioral interventions for both obesity and other health outcomes among diverse rural and urban communities. This research aligns with the NHLBI’s mission to identify the best strategies for ensuring successful integration of evidence-based interventions within public health settings.

NIH Research Projects · FY 2026 · 2023-06

ABSTRACT Carrie E. Fry PhD, MEd is an Assistant Professor in the Department of Health Policy in the Vanderbilt School of Medicine. She is a health services and policy researcher whose portfolio is focused on improving health and social outcomes for Americans with a substance use disorder (SUD) or mental illness through rigorous observational and quasi-experimental methods. This training grant will support Dr. Fry’s career goal of becoming an independent researcher with expertise in evaluation strategies to inform policy affecting marginalized Americans. This type of expertise is in high demand: the incidence and prevalence of opioid use disorder (OUD) has significantly increased since the mid-2010s with related harms, including emergency room visits and fatal overdoses, increasing at a similar pace. Access to evidence-based OUD treatments, especially among Medicaid enrollees, has not increased at the same rate. For these reasons, understanding the Medicaid policy levers to increase access to treatment is crucial to combatting the broader SUD crises in the US. One way state Medicaid programs have responded is by expanding the continuum of care to include residential treatment. Historically, Medicaid programs not been allowed to provide residential SUD treatment for most adults. Following guidance issued in 2015, states could apply for time-limited, demonstration waivers to expand coverage for residential treatment to adults between 21-64 years old. Since then, 32 states have received approval for and implemented a Section 1115 waiver to provide residential SUD treatment. States have flexibility regarding the specific provisions of these waivers potentially leading to mixed outcomes, and the impact of expanded residential treatment coverage in Medicaid is largely unknown. The research proposed in this K01 will address these gaps to inform future policy. Aim 1 will survey Medicaid officials in the 13 states participating in the Medicaid Distributed Research Network (MODRN) to identify variation in Medicaid residential treatment coverage. Then, I will conduct semi-structured interviews with Medicaid and other state officials from six MODRN states to further explore these differences. Aim 2 will use Medicaid claims data from three states to produce reliable and generalizable evidence on the effect of expanded coverage for residential treatment on beneficiary-level health and utilization outcomes. Details gleaned from these survey and interviews will be used to appropriately contextualize Aim 2’s results; the evaluation proposed in Aim 2 can be completed regardless of these findings. Finally, Aim 3 will produce the first generalizable estimates of co-morbid SUD among Medicaid enrollees with OUD, a subpopulation more likely to access residential treatment. Results from these aims will provide extensive preliminary data for an R01 evaluating these coverage expansions among sub-populations identified in Aim 3 and inform future Medicaid policy around residential treatment. With the assistance of her mentors, Dr. Fry has identified training objectives in addiction medicine, state health policy, and measurement issues in administrative claims data that will further her progress toward becoming a leading, independent researcher in the field of SUD and Medicaid policy.

NIH Research Projects · FY 2026 · 2023-06

SUMMARY The complement system comprises over 30 proteins, mostly plasmatic, forming the oldest branch of the human immune system. When activated by a pathogen, the complement system amplifies a loop that leads to the destruction of the invading organism. Plasma and surface inhibitors tightly regulate complement activation to prevent or limit self-damage. Unfortunately, gain-of-function (GOF) mutations in the complement activator factor B (FB) found in some rare patients cause permanent complement activation that can lead to autoinflammation. GOF-FB is more efficient at activating complement and is resistant to natural complement inhibitors. Given the enhanced activity of these mutants, we hypothesize that we can redirect GOF-FB to target specific malignant cells or tissues for therapeutic purposes and with minimal side effects. In this application, we propose generating and testing in vitro molecules to direct GOF complement activating proteins specifically to cancer cells and solid tumors. In Aim 1, we will fuse GOF-FB to single-chain variable antibody fragments (scFV) to direct complement activation to specific cells or antigenic targets. This engineered biologic approach to target immunotherapy will lead to less expensive and off-the-shelf alternatives to chimeric antigen receptor T cells (CAR-T) and be immediately relevant for hematologic malignancies. These molecules could also overcome some of the current issues with antibody therapies, including complement consumption and inhibition by the tumor cells. In Aim 2, we will couple GOF-FB to proteins that bind components of the solid tumor or its microenvironment. This approach will promote inflammation in regions in and around solid tumors and enhance local immune responses that can ultimately eliminate tumors or resolve tissue damage. Due to the nature of GOF-FB, these molecules will be resistant to tumor microenvironmental immune suppression mechanisms. In aim 3, we will generate murine GOF-FB that will pave the way to translate our findings to animal models allowing for in vivo proof of concept experiments, preclinical studies, and assessments of safety and efficacy. Our proposed work is highly innovative and yet supported by solid literature evidence. We propose to prove in vitro that GOF-FB can have potential as an anti-cancer therapy. These newly engineered molecules based on human complement immune disorders could pinpoint a new class of immune modulators with greater specificity, reach, and activity than current treatments. It represents a different direction from previous research performed in our lab, but the expertise required to carry out the proposed work and the collaborators are already in place. Furthermore, the proven efficacy of some FDA-approved complement inhibitors used to treat diseases caused by GOF mutations in complement activation assures that our approach will have minimal side effects that can be readily addressed. The work proposed here to leverage GOF mutations to identify new therapies could improve the treatment of a myriad of severe diseases, including cancer, autoimmunity, and even infectious diseases.

NIH Research Projects · FY 2026 · 2023-06

PROJECT SUMMARY Influenza virus is a significant pathogen in pediatric solid organ transplant (SOT) recipients. However, these individuals respond poorly to standard-dose (SD) inactivated influenza vaccine (IIV). Recent studies have investigated two strategies to overcome poor immune responses in SOT recipients: (1) administration of high- dose (HD)-IIV compared to SD-IIV and (2) two doses of SD-IIV compared to one dose of SD-IIV in the same influenza season. One study compared HD-IIV vs. SD-IIV in adult SOT recipients and noted that HD-IIV was safe and more immunogenic; however, the median post-transplant period was 38 months. A phase I pediatric study comparing a single dose of HD-IIV vs. SD-IIV was safe with higher immunogenicity, but the study was limited by small sample size and median post-transplant vaccine administration was 26 months. In another phase II trial of adult SOT recipients, two doses of SD-IIV one month apart compared to one-dose of SD-IIV revealed modestly increased immunogenicity when given at a median of 18 months post-transplant. Therefore, these studies lack both evaluation in the early post-transplant period and substantive pediatric populations. Additionally, the administration of two-doses of HD-IIV in the same influenza season has not been evaluated in pediatric SOT recipients. Thus, the optimal immunization strategy for pediatric SOT recipients less than 24 months post-transplant is unknown. In addition, immunologic predictors and correlates of influenza vaccine immunogenicity in pediatric SOT recipients have not been well-defined. The central hypothesis of our proposal is that pediatric SOT recipients 1-23 months post-transplant who receive two doses of HD- quadrivalent inactivated influenza vaccine (QIV) will have similar safety but higher HAI geometric mean titers (GMTs) to influenza antigens compared to pediatric SOT recipients receiving two doses of SD- QIV. To test this hypothesis and address the critical knowledge gaps outlined above, we propose to conduct a phase II, multi-center, randomized-controlled immunogenicity and safety trial comparing two doses of HD-QIV to two doses of SD-QIV in pediatric kidney, heart, and/or liver SOT recipients 1-23 months post-transplant. The results of this study will address significant knowledge gaps regarding influenza vaccine strategies and immune responses in pediatric SOT recipients and will guide vaccine recommendations in the early post- transplant period.

NIH Research Projects · FY 2026 · 2023-06

SUMMARY Lymphatic vessels are essential to maintaining interstitial fluid homeostasis, immune cell trafficking and antigen clearance. Ineffectual clearance due to inadequate lymphatic transport is a key promoter of many diseases that reflects insufficient number, reabsorptive capacity and contractility of the lymphatic vascular network. In contrast to blood vessels, lymphatic vessels are exquisitely sensitive to interstitial elements, including Na+ which is a powerful regulator of lymphatic growth in hypertensive settings. Our studies in hypertensive settings, have found Na+ activates the highly reactive lipid oxidation product, isolevuglandin (IsoLG) in antigen presenting immune cells (APCs) via the epithelial Na+ channel (ENaC). Our new data reveal proteinuric kidney disease increases intrarenal Na+ and thus establish a high Na+ environment within the kidney parenchyma. Like ENaC in immune cells, Na+, not osmolality, modulates expression of the sodium potassium chloride co-transporter (NKCC1) in lymphatic endothelial cells (LECs). Proteinuric animals as well as humans have elevated levels of urinary IsoLG adducted to apolipoprotein AI (apoAI) best known for its role in inflammation, oxidative stress, and cholesterol handling in atherosclerotic heart disease. Although kidney disease manifests all co-morbidities linked to modified apoAI, little is understood about these effects on kidneys. We show for the first time that kidney injury promotes intrarenal IsoLG and that IsoLG-apoAI upregulates NKCC1 in LECs. Together, our published and preliminary data support the hypothesis that kidney injury leads to renal Na+ accumulation which stimulates lymphangiogenesis, activates LECs, weakens lymphatic dynamics that encourages immune cell trafficking into the renal interstitium through mechanisms that involve Na+ sensing via NKCC1 and IsoLG uptake by LECs. Our studies will define how intrarenal Na+ accumulation modulates the lymphatic network and crosstalk between renal lymphatics and activated immune cells which we postulate promote interstitial stagnation of potentially harmful molecules and cells and subsequent tubulointerstitial fibrosis. To test this hypothesis, we propose three mechanistic aims. Aim 1 will test the hypothesis that that injury-driven accumulation of Na+ in renal interstitium directly disrupts the structure and function of the renal lymphatic network via a IsoLG-NKCC1 pathway. Aim 2 will define how Na+ activated immune cells involve IsoLG and vasoconstricting endothelins to impair renal lymphatics thereby increasing renal interstitial stagnation. In Aim 3 we will determine that activated monocytes with high IsoLG from humans with CKD blunt lymphangiogenesis and weaken lymphatic pumping that promotes progressive kidney fibrosis in humanized mice.

NIH Research Projects · FY 2026 · 2023-06

Project Summary / Abstract The HIV, HCV, and opioid epidemics disparately impact populations in different regions of the US, with higher burden (51% of new HIV diagnoses in the US) and poorer outcomes (highest HIV mortality in the US, at 6-10 per 1,000 persons with HIV) in the South, particularly largely rural states. Southern states also rank among those with the highest rates of acute and chronic Hepatitis C virus (HCV), with massive increases in HCV infections due to injected opioid use in Tennessee, Kentucky, Virginia, and West Virginia between 2006 and 2012 (from 1 to nearly 4 per 100,000). The region has also seen a dramatic increase in overdose mortality during the COVID-19 pandemic (West Virginia and Tennessee ranked 1st and 3rd in the US, respectively, with ≥50 deaths per 100,000), with opioid abuse a continued driver of the regional HIV/HCV syndemic. With the relatively recent HIV/HCV outbreak in Scott County, Indiana in mind, the CDC assessed county-level vulnerabilities to an HIV outbreak based on acute HCV infection. Acute HCV infection was used as a proxy of high HIV risk due to the proximal cause of shared injection drug use, an increasingly common practice in areas afflicted with high rates of opioid use and overdose. The research directly informed the initiation of the Tennessee Prescription Drug Overdose Program, a CDC-funded surveillance system to monitor both fatal and non-fatal drug overdoses. Reporting requirements have also been revamped and a new informatics infrastructure has been created to accommodate automated laboratory uploads of viral hepatide antibody, antigen, and nucleic acid testing to ascertain acute HCV infection, alongside the state’s already robust HIV surveillance program. Similar programs now exist in 32 states. In addition, over the past several years, syringe service programs and expanded access to non-prescription naloxone were made legal under Public Chapters 413 and 596 in Tennessee, while the state’s “fetal assault” law, along with similar ones in Alabama and South Carolina, penalized expectant mothers with opioid addictions until recently. The proposed research will therefore harmonize, link, and analyze readily available “big data” sources to enhance the epidemiology of HIV, HIV/HCV co-infection, and opioid overdose mortality outcomes which will inform HIV/HCV and overdose prevention and treatment activities by improving the targeting of highest- risk/highest-reward populations for their receipt (Aims 1 and 2). Assessing the impact of individual behavior and environmental context (neighborhood characteristics such as structural poverty and disorder, lack of transportation, etc.) as well as policy changes on these outcomes will be an essential addition to the literature, and as importantly, to data dissemination platforms (e.g., dashboards) which will improve deployment of prevention and treatment activities in southern states (Aims 1, 2, and 3). Using epidemiologic research to inform policy, while creating dissemination platforms which may be updated and re-deployed in future for regional pandemic preparedness, means this work will remain a valuable resource for years to come.

NIH Research Projects · FY 2026 · 2023-06

Despite progress in the treatment of primary tumors, metastatic disease remains incurable. While all metastatic sites are important clinically, skeletal metastases are common in patients with breast, prostate, lung cancer, and other, with approximately 70% of women that die from metastatic breast cancer experiencing serious complications from bone metastases. Once established in the bone, tumors disrupt normal bone homeostasis leading to increased pain, fracture, and general morbidity. Our previous work has established the transcription factor Gli2 as a promising target for reducing tumor induced bone disease. After identifying the small molecule inhibitor, Gli Antagonist 58 (GANT58), as a promising inhibitor of Gli2 activity in bone metastatic tumors, we discovered the poor bioavailability of GANT58 limited its use in systemic delivery models. Thus, we developed polymeric NPs to solubilize, improve the pharmacokinetics (PK), and promote bioavailability of GANT58 (GANT58-NPs). The NPs comprised reactive oxygen species (ROS)-responsive poly(propylene sulfide-block- oligoethylene glycol acrylate) (PPS-b-POEGA). Intravenous injection of the 1st generation GANT58-NPs (Dh=93 nm) reduced TIBD in models of intratibial and intracardiac breast tumor cell inoculation and in a lung cancer model (3 unique models). GANT58-NPs were safe (did not elevate serum markers of liver/kidney toxicity or cause detectable histopathology. Our 2nd generation NPs were bone targeted (BT-GANT58-NPs), and the chemistry utilized enabled tuning of the density of the bone binding ligand, alendronate (ALN), a bioactive bisphosphonate (osteoclast inhibitor). While both formulations reduced tumor invasion into bone and reduced tumor proliferation by ki67 staining, they did not eliminate tumor and did not significantly reduce tumor bulk in models of established bone metastatic disease. Here, we propose to screen a broader polymer chemistry space focusing on: (1) Developing an alternative bone targeting strategy without inherent bioactivity; (2) Studying how NP core chemistry affects GANT58 loading, GANT58 triggerable release, and consequent in vivo PK; (3) Defining the maximum tolerated dose (MTD), dose-limiting toxicities, and dose dependent PK / PD. In addition, we will evaluate the efficacy of a co-loaded GANT58 and paclitaxel BT-NP formulation. Each of these formulations will be evaluated for detailed PK/PD and biodistribution properties to identify promising formulations to reduce tumor induced bone disease without inducing systemic toxicity. Our preliminary data show promising results that include low toxicity and efficacy in reducing tumor burden in bone and bone destruction. This proposal will explore the efficacy and PK/PD properties in more detail to develop a promising therapy for eventual translation. The results of these studies will help identify a novel and promising strategy to reduce tumor burden and bone destruction in patients with bone metastatic disease. Due to the current lack of effective therapies for these patients, the results of these studies could impact patient outcomes and lead to exciting new therapies for patients with bone metastatic tumors.

NIH Research Projects · FY 2024 · 2023-06

Project Summary/Abstract This proposal is to develop a miniature balun to meet the emerging meet in flexible RF coils in MRI. Flexible coils improve patient comfort and can be formed into desired shapes to match the human anatomy of interest. Therefore, compared to conventional rigid coils, they exhibit improved filling factor and signal-to-noise ratio, especially when imaging curved anatomies such as cervical spinal cord, pelvis, and hands. Although the challenges in building flexible coils have been solved with the numerous methods mentioned above, in practice, it is still an open question to make fully flexible coils since the balun or cable trap circuits associated with coils are still rigid and bulky. The first goal of this project is to theoretically analyze, build and test a miniature LC balun with a novel topology, namely LCCC balun. The second goal of this project is to integrate the LCCC balun with flexible receive-only coils and transmit/receive coils at 3T and 7T. The theoretical analysis, script for component value calculation, circuit simulation models, and PCB designs, will be distributed for open access. This miniature LCCC balun can be easily transferred to other RF coil designs, with benefits for the entire community.

NIH Research Projects · FY 2025 · 2023-06

Summary This multi-Pl R01 is submitted in response to NCI FOA PAR-20-062 Co-infection and Cancer and includes 2 seasoned, collaborative Pis with complementary expertise in microbial carcinogenesis (Richard Peek and James Fox). H. pylori confers the highest known risk for gastric adenocarcinoma. However, studies by the CoPis and others have demonstrated that gastric microbiota populations affect cancer risk in synergy with H. pylori. We have full access to a unique longitudinal, prospective human cohort in Colombia where gastric adenocarcinoma and H. pylori infections are endemic. Full clinical, endoscopic, and histologic data are available at baseline and at each interval follow-up out to 26 years, including frozen gastric tissue for microbiota analysis and culture from the 20- and 26-year timepoints from persons who either progressed histologically or remained stable, providing a unique opportunity to define disease mechanisms. We also have access to prospectively obtained gastric tissue from patients at Stanford with or without premalignant lesions, allowing us to extend these studies into a US population. Our laboratories have developed models that closely recapitulate the gastric niche to define mechanisms of carcinogenesis within the context of H. pylori and the microbiota. Dr. Fox has utilized germ-free (GF) INS-GAS mice to demonstrate 1) H. pylori accelerates carcinogenesis in mice harboring a gastric microbiota compared to GF mice, and 2) colonization with bacteria differentially represented in high vs. low cancer risk populations modifies the ability of H. pylori to induce gastric injury. Dr. Peek has developed complex primary gastroid:macrophage:T cell systems to demonstrate that H. pylori drives oncogenic signaling in a cell- and strain-specific manner and that non-H. pylori gastric species successfully colonize these models. Collectively, our scientific scope, available resources including cutting-edge metabolomics, and innovative model systems will allow us to fully address the hypothesis that progression to gastric cancer is influenced not only by H. pylori virulence constituents, but also by prolonged interactions with members of the gastric microbiota. which can modulate immune responses. We will address this hypothesis via these Aims. Aim 1: Identify and define components of the gastric microbiota in persons who did or did not progress towards gastric cancer using Whole Metagenome Shotgun (WMS} sequencing Aim 2: Utilize innovative ex vivo systems to define the carcinogenic potential of gastric microbiota species and prioritize candidates for more definitive in vivo studies of gastric cancer Aim 3: Utilize novel germ-free rodent models and metabolomics to define causality of high priority gastric microbiota species and corresponding immune responses linked to disease progression within the gastric niche

NIH Research Projects · FY 2025 · 2023-05

RNA editing, a fundamental cellular process, involves the deamination of some adenosines in RNA to inosines, by the adenosine deaminases Adar1 (ADAR) and Adar2 (ADARB1). Recent studies have shown that a critical role of RNA editing is to disrupt double-stranded RNA (dsRNA) structures that are generated by retroelements inserted in the genome in an inverted orientation within expressed genes. The dsRNA formed by such sequence configurations is a powerful and dangerous activator of the ancient antiviral interferon response, which may lead to pathogenic inflammation. While RNA editing has been studied in the context of some organs and in cancer, very little is known about the role of ADAR enzymes in islet cell function and health. Our goal is to elucidate the role of RNA editing in islets, and particularly in alpha and beta cells. Strikingly, GWAS studies of type 1 diabetes (T1D) have revealed protective variants of IFIH1/MDA5, a cytosolic receptor that recognizes double-stranded RNA (dsRNA) from either viral or endogenous origins, and elicits an inflammatory response. Thus, defective RNA editing can in principle contribute to the islet anti-viral response which precedes autoimmunity. We hypothesize that impaired RNA editing and accumulation of endogenous dsRNA in beta cells trigger an IFIH1-dependent interferon response causing islet inflammation, which leads to beta cell dysfunction and potentially to autoimmunity. In our preliminary findings, we found that disruption of A-to-I RNA editing in adult mouse beta-cells in vivo or in human islets triggers an interferon response. In mice with Adar1-deficient beta cells, this leads to massive immune response localized to islets, including both innate immune cells and T cells. Alpha cells appear to resist Adar1 disruption or islet inflammation brought about by Adar1 deficiency in beta cells. We propose to 1) characterize mouse and human islet cells following genetic disruption of RNA editing, via knockout or knockdown of the key RNA editing enzyme Adar1; 2) examine the effects of Adar1 deficiency on beta and alpha cell function and viability, as well as islet inflammation and autoimmunity; and 3) investigate the molecular basis for the differential dependence of alpha and other islet cell types on Adart1. The proposed research is a close collaboration between 3 teams with complementary expertise: Al Powers (human islet biology and function), Yuval Dor (mouse models, molecular biology) and Erez Levanon (computational analysis of RNA editing). This work will shed light on the role of RNA editing, a key epitranscriptomic modification, in islet cells. It will also refute or provide pre-clinical support for the provocative hypothesis that defective RNA editing may contribute to aspects of T1D pathogenesis, particularly the early, anti-viral inflammatory response. 1

NIH Research Projects · FY 2025 · 2023-05

PROJECT SUMMARY Neonates born during the saccular stage of lung development (23-32 wks gestation) are at highest risk for bronchopulmonary dysplasia (BPD), a leading preterm birth complication. The mechanisms underlying this vulnerability are poorly defined, a knowledge gap we consider foundational to the lack of curative BPD therapies. To understand the irreversibility of arrested alveologenesis in BPD, we require a refined, mechanistic understanding of the normal saccular to alveolar transition. Our preliminary data from 4- dimensional live imaging and single-cell transcriptomics support a new model of alveologenesis in which myofibroblast ring structures support the extrusion of AT2s (alveolar type 2 cells) followed by their differentiation into AT1s (alveolar type 1 cells). According to our model, mature AT1s produce ECM proteins and other factors that recruit specialized endothelial cells to become the alveolar capillary bed. Sequential, spatiotemporally restricted signaling pathways, including Wnt and BMP, coordinate cell movement, proliferation, and architecture. We have developed a neonatal injury model with a phenotype of impaired alveologenesis that is relevant to human BPD by exposing neonatal mice to hyperoxia and inflammation during the saccular stage. Our preliminary data from this model associate overexpression of Wnt5A/Wnt11 with impaired alveologenesis. Post-injury deficits include decreased BMP production and activity in alveolar epithelial cells and impaired AT2 to AT1 cell differentiation and decreased expression of extracellular matrix (ECM) components by AT1 cells. Based on preliminary and published data, we hypothesize that alveologenesis involves formation of a ring of myofibroblasts that express Wnt5a and Wnt 11 to drive AT2 proliferation and promote extrusion through the ring. Subsequent epithelial BMP production down-regulates Wnt, promoting AT2 to AT1 differentiation and generation of an extracellular scaffold for capillary assembly. Injury dysregulates Wnt and Bmp signaling, perturbing the precise spatiotemporal patterning during this critical timeframe and resulting in arrested alveologenesis and long-term functional deficits. We will test this hypothesis in the following specific aims: 1) Define the role of myofibroblast Wnt expression in regulating AT2 proliferation and alveolar development; 2) Characterize mechanisms by which BMP signaling regulates AT2-to-AT1 cell differentiation; 3) Determine the mechanisms whereby nascent AT1 cells generate a scaffold for the developing alveolus. Successful completion of this proposal is anticipated to transform our understanding of alveologenesis, identifying new molecular targets to promote post-injury alveolar restoration and the optimal time windows for deployment of such newly directed therapies.

NIH Research Projects · FY 2026 · 2023-05

Project Summary. The human immune system participates in complex interactions with virtually all other systems in the body. In particular, the B cell component of the adaptive immune response plays a role in various disease settings, including infectious disease, cancer, autoimmunity, cardiovascular, hematologic, neurologic diseases, and others. In addition, antibodies (a product of B cells) are effectively used in diagnostics, therapy, and prevention. Yet, despite decades of antibody discovery efforts, there is still very limited data linking human antibody sequence to antigen specificity (the preferential recognition of target antigens by a given antibody). One of the major reasons for such limited data is the fact that even high- throughput antibody sequence identification methods such as next-generation sequencing (NGS) of B cell receptor (BCR) sequences are generally decoupled from the process of antibody functional characterization. As a result, even though there are typically thousands to millions of antibody sequences within a single NGS dataset, functional information is obtained only for a handful of antibodies against not more than 2-3 target antigens at a time. To address these significant challenges for current technologies for B cell characterization and antibody discovery, our group has been focusing on the development of a single-cell technology that, for a given sample, enables the mapping of antibody sequence to antigen specificity from a single high-throughput experiment for a large number of antigens and B cells at a time. The technology, LIBRA-seq (LInking B-cell Receptor to Antigen specificity through sequencing), involves physically mixing a B cell sample with a (theoretically unlimited) pool of DNA-barcoded antigens, thus transforming B cell-antigen binding into a “sequenceable event”. In essence, LIBRA-seq offers all of the following features: (a) Characterization of thousands to tens of thousands of B cells at a time, at the single-cell level; (b) Screening against a large number of antigens at a time; (c) For each B cell, determination of the paired heavy-light chain BCR sequence; (d) For each B cell, generation of a high-resolution antigen specificity map. We initially validated LIBRA-seq in proof-of-concept studies in the context of HIV-1, and subsequently coronavirus, infection. These initial studies lay the foundation for generalizing the LIBRA-seq technology for application toward diverse antigen targets, and highlight areas for technology optimization, which will be the focus of this technology development proposal. In particular, here we propose to optimize LIBRA-seq for generalized application toward a broad diversity of antigen targets. Ultimately, the LIBRA-seq technology will have a long-lasting impact on both basic and applied immunology, helping revolutionize our understanding of antibody-antigen interactions and leading to the discovery of novel antibody therapeutics targeting a large variety of disease areas of biomedical significance.

NIH Research Projects · FY 2026 · 2023-05

SUMMARY Dilated cardiomyopathy (DCM) affects up to 1:250 individuals and is responsible for ~40% of cardiac transplants. Guidelines recommend genetic testing in DCM probands to help establish diagnosis, guide medical care, inform risk stratification, and identify at-risk relatives. However, causal variants are identified in fewer than half of patients, ~30-40% of tests return variants of uncertain significance (VUS), and a modest number of genes have adequate genotype-phenotype data to inform medical management. In this proposal we address 4 gaps in DCM research: 1) Most data are from individuals of European ancestry referred for genetic testing, creating bias in estimates of the contribution, penetrance, and phenotype in the broader clinical and community population. 2) Most established DCM genes have insufficient genotype-phenotype data to inform gene-specific clinical management. 3) The evidence for most candidate genes is equivocal due to lack of study in cohorts sufficiently large to evaluate pathogenicity. 4) Some disease loci likely remain undiscovered because GWAS and linkage approaches used in prior studies are not well-powered for diseases, such as DCM, with variable age of onset, both high genetic and allelic heterogeneity, and incomplete penetrance. We will address these fundamental knowledge gaps using innovative genetic methods and a novel, large-scale DCM research platform that includes harmonized phenotypic, genotyping, sequencing, and identity-by-descent (IBD) data from 5 large biobanks comprising ~1M participants and >10,000 DCM cases. Specifically, we propose to use rare variant and IBD- based methods to: Aim 1) Define the contribution and phenotypic manifestations of established disease genes in multiple diverse, non-referral DCM populations; Aim 2) Assess the pathogenicity of candidate DCM genes with equivocal evidence and establish a novel platform to evaluate VUS in established genes; and Aim 3: Discover novel DCM genes via IBD mapping and rare variant association within and across biobanks at scale. To balance the innovation of these aims, we present compelling preliminary data demonstrating the feasibility of our approaches which identified a cluster of distantly related individuals harboring a common pathogenic variant in RBM20. We anticipate these analyses will substantially expand our understanding of the genetic factors underlying DCM risk and their clinical manifestations. Once established, our platform will support future clinical and genetic research and advance the long-term goal of implementing targeted interventions at the clinic and population level to reduce the burden of DCM for all patients.

NIH Research Projects · FY 2025 · 2023-05

SUMMARY Despite the number of adults within their child-bearing years diagnosed with, treated for, and surviving colorectal cancer (CRC), reproductive health concerns stand as an unmet care need among adults ages 18 to 49 years with CRC (early-onset CRC) and their families. This is because there is a paucity of prospective data to objectively measure the deleterious effects of CRC and its therapies on fertility and sexual health over time within this patient population. Given the unexplained, rising incidence of early-onset CRC over the last decades, the time is now for us to address these unmet fertility and sexual health care needs in order to improve outcomes within this growing population of reproductive age CRC survivors. Thus, this study is specifically designed to address a long-standing unmet need and achieve its overarching goal: to identify changes in gonadal function caused by CRC treatments and investigate psychosocial dimensions of sexual health and fertility-after a diagnosis of early-onset CRC. We will use validated PROM IS sexual function and satisfaction (SexFS), PROMIS-29 core health, lifestyle-related and reproductive health questionnaires, and qualitative interviews (Aim 1) to prospectively define the psychological dimensions of reproductive health at diagnosis, treatment and surveillance timepoints; as well as changes in these measures over time. This will inform the highest reproductive health concerns and needs specifically for early-onset CRC patients at uniform timepoints across the cancer care continuum. We will then use fasting blood samples (Aim 2) and detailed clinical and treatment data that are collected in parallel to prospectively quantify the impact of CRC therapies on gonadal function at three uniform study timepoints. Both specific aims utilize the same study population--the PREserving Fertility After Colorectal CancEr (PREFACE) Study cohort that is enrolling a total of 220 newly-diagnosed CRC patients between ages 18 and 49 years at Vanderbilt-Ingram Cancer Center. All laboratory assays in Aim 2 will be conducted using FDA-approved clinical immunoassays for AMH, estradiol, FSH, SHBG, LH, DHEAS, inhibin B, testosterone, DHT, and androstenedione in a CUA-accredited and CDC-certified laboratory. Overall, this study is conceptually innovative in that our cohort pairs standardized, fasting blood collection with robust sexual health, fertility, reproductive history, menstrual patterns, sociodemographic, exposures, and quality of life data, and is 11-fold larger than previous fertility-related studies in early-onset CRC. This project will generate crucial new data from a unique cohort and is statistically powered to drive significant advances toward concordant reproductive health care assessment and physical/psychosocial support strategies specific to CRC patients of reproductive age. Our findings will lead to incorporating reproductive health care in the clinical management of early-onset CRC, and ultimately improve clinical outcomes specifically for this patient population.

NIH Research Projects · FY 2025 · 2023-05

Project Summary Prior studies have identified several risk factors related to cardiometabolic diseases. However, the rates of risk factor elevation are highly variable among patients. For example, despite obesity being identified as a primary risk factor for cardiometabolic diseases, a subgroup of obese patients does not develop downstream cardiometabolic complications. This suggests that there are other mediating mechanisms, independent of known risk factors, underlying cardiometabolic diseases. This project will leverage multi-omics data in conjunction with clustering approaches capitalizing on genome-wide association study (GWAS) data in BioVU, GWAS and other omics data generated by the NHLBI Trans-Omics for Precision Medicine (TOPMed) program and metabolomics data collected at 3 time points in a prospective cohort of bariatric surgery to identify: 1) clusters of individuals that represent cardiometabolic diseases (defined as novel/endotypic determinants of diseases), 2) endotypes of each cardiometabolic disease by clustering individuals within each disease (determined as pathobiological mechanisms related to disease) and 3) endotypes of responsiveness to bariatric surgery. To explore these overall study goals, the similarity network fusion method will be used along with the consensus clustering approach. Specifically, this project aims to 1) create genetically predicted levels of transcriptome, proteome and metabolome in 54,000 individuals in BioVU, use these predicted levels to construct clusters of individuals and examine whether these clusters represent diseases using the BioVU phenotype data, 2) construct clusters of individuals using direct measurements of multi-omics data (transcriptome, proteome and metabolome) in over 5,000 individuals in TOPMed, construct genetically predicted levels of the obtained clusters and impute them in BioVU using the BioVU GWAS data and explore whether these predicted levels represent cardiometabolic diseases using phenotype data in BioVU and 3) create metabolomic driven clusters using the plasma metabolomics data at baseline, 3 months and 12 months post bariatric surgery in 104 patients, explore the association of the identified clusters with cardiometabolic responsiveness and identify novel baseline metabolomic predictors of responsiveness to weight loss surgery . The proposed study will leverage multilayered –omics data using a novel and innovative network modeling analysis, providing Dr. Bagheri with critical skills, tools and experience to complete the research aims. This will be achieved by the accomplishment of the following two training goals which will help her to become an independent ‘big data’ cardiometabolic scientist: 1) gaining more in-depth knowledge of small molecule metabolism in biologically-informed cardiometabolic disease subtypes and 2) gaining expertise and expand her existing experience in bioinformatics and statistical multi-omics integration methods.

NIH Research Projects · FY 2026 · 2023-05

ABSTRACT: Interstitial cystitis/bladder pain syndrome (IC/BPS) is a debilitating chronic condition characterized by pain, pressure, and discomfort in the pelvic region coupled with urinary symptoms. The pain involved in IC/BPS can be debilitating and is incurable. As it stands, many of the available treatments for IC/BPS lack strong evidence for their use and are costly to patients. Further, patients report significant dissatisfaction with medical care, describing treatments as “trial-and-error," expensive, and having “fragmented” treatment plans to follow. Treatment advances in IC/BPS have stalled due to a lack of clear understanding of the condition, as symptoms and presentations vary widely. For these reasons, national organizations have prioritized the need to improve both treatment options and understanding of IC/BPS. Leading multi-institutional research networks have now identified that individuals with IC/BPS have distinct subgroups, or “phenotypes,” largely characterized by the distribution of pain throughout the body. These presentations of IC/BPS have distinct clinical and neurobiological features. Specifically, while a proportion of individuals with IC/BPS have symptoms primarily in the pelvic region (“peripheral” phenotype), others experience additional pain outside of the pelvis coupled with unrefreshing sleep, cognitive dysfunction, emotional distress, and energy depletion (“centralized” phenotype). In terms of neurobiological features, individuals with “centralized” presentations also exhibit exaggerated inflammatory responses to ex vivo stimulation and heightened responses to evoked pain. Supported by our preliminary evidence, the overall goal of this project is to assess how IC/BPS phenotype may affect response to two different therapies often given without regard to patient phenotype, pelvic floor physical therapy (PT) and cognitive-behavioral therapy (CBT) for IC/BPS. We hypothesize that we can predict those who will respond preferentially to either form of treatment based on reported bodily pain distribution (pelvic pain primarily, pain outside of the pelvis). We are proposing a randomized mechanistic trial to evaluate which participants may benefit from each treatment (Aim 1) and evaluate whether neurobiological mechanisms may moderate outcomes and change with treatment (Aim 2). Per an individual’s reported level of baseline widespread pain, we will randomize 220 participants to receive either 8-weeks of CBT or 10-weeks of PT. Participants will receive three assessments throughout, [before, after, and at 6- months]. Assessments include patient-reported outcomes, biological markers of inflammation, and psychophysical testing [taken at each timepoint]. This project has great potential to tailor treatment and improve future IC/BPS precision-medicine care efforts.

NIH Research Projects · FY 2025 · 2023-05

ABSTRACT Diseases of the ear, particularly acute otitis media (AOM) and middle ear effusions, are the most commonly treated childhood pathologies. The financial burden of ear disease is estimated at more than $3.2 billion per year. Because ear diseases are common, a significant problem is over-diagnosis and over-treatment, due to two factors. First, the subjective nature of diagnosing ear disease - based on a brief glimpse of the eardrum with an otoscope - makes an accurate diagnosis difficult, even for experienced primary care, emergency medicine, or ear, nose, and throat (ENT) physicians. Second, with a growing shortage of primary care physicians in the US, more Advanced Practice Providers (Nurse Practitioners and Physician Assistants) serve as first-line clinicians in primary care and emergency settings but lack extensive training in otoscopy (i.e., clinical examination of the eardrum). Consequently, clinicians often err on the side of making a diagnosis of ear infection and prescribing oral antibiotics. Over 8 million unnecessary antibiotics are prescribed annually, contributing to the rise of antibiotic-resistant bacteria and creating the largest number of pediatric medication-related adverse events. Children with inaccurate ear diagnoses are often referred to ENTs for surgical placement of ear tubes for recurrent infections, and up to 70% of these cases are not indicated. Diagnosing ear pathologies still depends on clinician subjectivity, based on a brief glimpse of the eardrum. This diagnostic subjectivity creates a critical barrier to decreasing healthcare costs and reducing over-diagnosis and over-treatment of ear disease. Devices are needed to assist in a more accurate, consistent, and objective diagnosis of ear pathology. Our previous work laid the foundation to develop machine-learning approaches to provide an objective approach to ear diagnosis using digital otoscopy computer-assisted image analysis. This project will dramatically expand on our previous work with the overarching goal of developing new machine learning applications to analyze eardrum videos collected with a digital otoscope, which will be combined with tympanometry, demographic, and clinical data, to achieve diagnostic objectivity. The long-term goal is to improve clinicians’ diagnostic accuracy for ear diseases, using novel computer-assisted approaches. To accomplish these goals, we propose three Specific Aims: Specific Aim 1 will refine an objective computer-assisted image analysis (CAIA) software to differentiate multiple eardrum abnormalities. Specific Aim 2 will develop an otoscopy clinical decision support system by combining CAIA with additional data sources, including tympanometry, demographic, and clinical information. Specific Aim 3 will determine how the otoscopy clinical decision support system improves clinicians’ diagnostic performance.

NIH Research Projects · FY 2026 · 2023-05

PROJECT SUMMARY/ABSTRACT Progress in HIV prevention in the United States (US) has stalled, according to reports from the Centers for Disease Control and Prevention. Most recently, the Department of Health and Human Services has made Ending the HIV Epidemic (EHE) a national priority, with intermediate goals of a 75% reduction within five years and a 90% reduction in 10 years. Getting to Zero (GTZ) programs rely on the concept of combination HIV prevention, using evidence-based methods that have been tailored to suit local needs. Among each of these programs is an emphasis on pre-exposure prophylaxis (PrEP), which is a versatile tool able to prevent acquisition of HIV infection within diverse HIV-risk communities. Despite the success of PrEP in efficacy trial settings, uptake has been slow in the US and highly variable: coverage among those with indications for PrEP is estimated to range from 5-41% (median 18%), among US states. Agent-based stochastic modeling is highly equipped to investigate complex epidemiologic questions, such as the effects of the PrEP continuum in diverse settings, populations, and as part of combination HIV prevention. The HIV Calibrated Dynamic Model (HIV-CDM), simulates HIV testing, transmission, treatment, and prevention among a wide range of epidemic settings and is able to address the crucial questions facing PrEP implementation in the US. Using the HIV-CDM, we propose to address the following aims: Specific Aim 1: To expand and calibrate the current HIV-CDM to capture the epidemic dynamics, HIV risk behavior, network mixing, and access to HIV prevention modalities within the most prominent GTZ programs and priority settings throughout the US, using empirical data from ongoing and completed studies among MSM, men who have sex with men and women, people who inject drugs, and high-risk heterosexuals. Specific Aim 2: To simulate the PrEP continuum in eight key US cities, including PrEP eligibility within specific populations, access, retention, and adherence. To inform these simulations, and generate estimates for PrEP utilization up to 10 years into the future, we will integrate empirical data for each step of the continuum. This will include a focus on both the development and testing of diverse PrEP eligibility measures, including electronic health record-based algorithms, clinical checklists, and CDC guidelines. Specific Aim 3: To evaluate the potential to reduce HIV incidence by 75% in five years, and 90% in 10 years, through targeted PrEP expansion, within the context of existing combination prevention packages in settings with a history of HIV prevention successes (e.g., Boston and San Francisco), settings that have struggled in their GTZ efforts (Miami, Atlanta), and largely-rural settings (Birmingham) that are priority areas for the EHE initiative. This approach will include network-based analyses that will investigate the most efficient methods of PrEP delivery within heterogenous epidemics.

NIH Research Projects · FY 2026 · 2023-05

The ARDS, Pneumonia, and Sepsis (APS) Coordinating Center will support a highly functional and integrated clinical and translational research infrastructure that will enhance the quality and scientific rigor of the research conducted by the APS Phenotyping Consortium. We are a team composed of leading content and methods experts at Vanderbilt, Johns Hopkins, and University of California San Francisco. We will provide Coordination for ARDS, Pneumonia, and Sepsis supporting Training, Organization and Network Efficiency: ‘CAPSTONE’. We will support the clinical centers (CCs) in enrolling and sustaining a diverse cohort; enable the efficient and standardized capture of multi-modal cohort data with repeated measurements; model the data to understand mechanistic underpinnings of APS, including the interplay of underlying and static risk factors; and segment the population into similar prognostic and predictive phenotypes. This will enable scientific progress towards a deeper mechanistic understanding of critical illness syndromes and recovery. Functionally, we will 1) Implement the study design, data capture, and statistical analysis unit. Coordinate protocol development; establish a REDCap-based data collection, management, and security framework; conduct and support analyses; generate reports; make curated data widely available for research through a facilitated storefront; 2) Implement the clinical research management unit. Maintain cohort integrity and adherence to the protocol and manual of operations, perform routine monitoring of data quality and site performance; training of study staff; image and biospecimen management. Support site communications; facilitate recruitment and retention; and 3) Implement the stakeholder engagement and development unit. Establish bidirectional, longitudinal engagement from diverse communities; help CCs build and sustain trust; ensure strengths of each CC are nurtured and shared; facilitate dissemination of findings; support skills and career development among research teams. Our efforts will expand foundational work on APS phenotyping, identify gaps, and help create methods for redefining critical illness syndromes with the ultimate goal of improving and personalizing management strategies that will curtail the devastating morbidity and mortality caused by APS.

NIH Research Projects · FY 2026 · 2023-05

While vaccination is the most efficient tool for the prevention of infectious diseases both in developed and developing countries, the global implementation of effective immunization programs is challenging. Many important infectious pathogens of epidemic or pandemic potential originate or circulate outside of the United States. The development, introduction and implementation of effective vaccination or other immunization strategies against infectious diseases relevant to the United States, Peru and other countries depends on availability of locally generated evidence, especially data required by local regulatory authorities. An essential requirement to make this happen is to have well-trained local researchers who have a clear understanding of the process behind vaccine development, vaccine introduction and program implementation and evaluation. Training of researchers on the achieved impact of vaccination on antimicrobial resistant infections, the relevance of indirect protection and the biological pressure induced by vaccination programs are examples of well-established vaccination topics that are highly relevant to the United States and Peru but are commonly overlooked. Similarly, a proper understanding of the effects of vaccination on unvaccinated groups through indirect or herd immunity is crucial, but this is frequently misinterpreted. Moreover, there is a growing conversation about the safety and effectiveness of vaccines and vaccination programs that needs to be addressed by researchers with appropriate technical skills. Thus, there is a growing global need for training in vaccinology and the study of vaccine-preventable diseases relevant to the United States and Peru encompassing the entire process from vaccine development to field implementation and program evaluation. To address these needs, Vanderbilt University Medical Center (VUMC), the Instituto de Investigacion Nutricional (IIN) and the Universidad Peruana Cayetano Heredia (UPCH) are joining forces to build the Peru-Vanderbilt Prevention through Vaccination Training Program (PREVENT). The overall goal of PREVENT is to develop a cadre of researchers and educators equipped with modern knowledge and expertise to lead research and training on vaccine preventable diseases relevant to the United States and Peru and to support United States-based research efforts in low- and middle-income countries (LMICs), where many global infectious threats originate. PREVENT builds on the very successful 14-year Research Partnership with the IIN and UPCH and on the Vanderbilt Vaccine Training and Evaluation Unit and the Division of Pharmacoepidemiology’s expertise in the study of vaccine preventable diseases, training and mentoring. PREVENT will support 10 medium-long term trainees (Master’s, PhD and faculty fellowships). Specifically, PREVENT aims to 1) Train a cadre of researchers and educators (trainers) to conduct multidisciplinary vaccine preventable diseases research and build training capacity in Peru; 2) Train scientists and future leaders in vaccine-preventable diseases research in Peru; and, 3) Ensure and document PREVENT’s long-term impact. The ongoing IIN/UPCH-Vanderbilt Research Partnership has proven highly productive and successful. A new training program focusing on the study of vaccine preventable diseases relevant for both the United States and Peru, and the growth of structures and efforts to increase grant success will address the need for a world-class workforce trained in global vaccine-preventable diseases.

NIH Research Projects · FY 2026 · 2023-05

PROJECT SUMMARY Current approaches to classifying critical illness focus on broad clinical syndromes including sepsis and the acute respiratory distress syndrome (ARDS). However, application of consensus definitions of these syndromes has not translated to syndrome-specific, targeted therapies. Recent transformative studies of ARDS have revealed underlying (latent) biological phenotypes, termed hyper- and hypo-inflammatory, that are remarkably consistent across multiple ARDS cohorts. Further, in post hoc analysis, these phenotypes respond differentially to both process of care (fluids, PEEP) and pharmacologic (simvastatin) treatments. These findings suggest that biological phenotyping in ARDS, pneumonia and sepsis may pave the way towards a deeper understanding of the biology of critical illness that will translate, for the first time, into targeted, personalized therapies. Our multidisciplinary team of investigators and clinical enrollment sites brings together deep scientific expertise in pathophysiologic mechanisms and phenotyping of ARDS, sepsis and pneumonia, world- class infrastructure for collecting long-term outcomes after critical illness, strong experience in designing and implementing observational clinical cohort studies that include long-term follow-up, and proven ability to enroll large numbers of critically ill patients in observational and clinical studies. Our team proposes two studies: (1) a Consortium-wide 5,000 patient observational cohort study, the MUltidimenSional phenotyping In Critical care (MUSIC) Study. The primary Aim of this study is to test the hypothesis that latent phenotypes are generalizable across critical illness syndromes and associate with both short- and long-term outcomes. Determining whether inflammatory phenotypes are identifiable across common critical illness syndromes can fundamentally alter our approach to classifying critical illness in a way that captures a more uniform biological phenotype agnostic to syndromic diagnosis. (2) a Clinical Center Study that addresses the critical need to better understand airspace biology in patients with ARDS and other etiologies of acute respiratory failure (ARF). It has long been recognized that airspace biology differs significantly from that of the circulation, but the field has lacked a non- invasive, inexpensive, simple, and safe method of sampling the distal airspace in ARF. Our group has pioneered a new method for sampling the airspace in intubated, mechanically ventilated patients with ARF using fluid extracted from heat moisture exchanger (HME) filter. The HARMONY study (HME for Acute Respiratory failure MultidimensiONal phenotYping) has a primary goal of identifying lung-specific phenotypes in ARF that will be tested for associations with long term functional and structural respiratory outcomes. Our Center will leverage our expertise in critical illness phenotyping, robust ED/ICU patient enrollment (37,756 patients in 5 years), pioneering work in long term outcomes in ICU survivors, decades of experience studying biomarkers of critical illness and novel approaches to study airspace biology, to play a key role in the APS Consortium and have a major and sustained impact in the field of ARDS, pneumonia, and sepsis.

NIH Research Projects · FY 2025 · 2023-04

PROJECT SUMMARY/ABSTRACT This K24 proposal will provide protected time for Dr. Cyndya Shibao to deliver high-quality mentoring to post-doctoral and junior faculty investigators at Vanderbilt University Medical Center. In this regard, she proposes a comprehensive and dedicated mentoring plan that will facilitate the effective transition of her mentees into independent academic careers. Her application includes an across-the-board strategy to augment her training through acquisition of advanced skills in mentoring, training in diversity, leadership, and strategic planning. In addition, her research plan includes a cross-collaboration with members of the Feinstein Institute of Bioelectronic Medicine to acquire additional expertise in vagus nerve stimulation, which is thematically link to her current studies on parasympathetic cholinergic regulation of vascular oxidation. Endothelial dysfunction, a pro-thrombotic, inflammatory condition that causes impaired vascular reactivity is an early reversible step in the development of atherosclerosis and cardiovascular disease (CVD). Multiple studies consistently shown that African Americans (AAs) have impaired endothelial function compared to whites. African Americans also experience disproportionately higher CV morbidity and 20% higher mortality than whites or Hispanics. Endothelial dysfunction is caused by the overproduction of reactive oxygen species (ROS), particularly superoxide which interferes with endothelial-derived nitric oxide signaling pathways. One of the major sources of superoxide is NADPH oxidase; our previous work found that activation of NADPH oxidase contributes to vascular oxidation through immune cell activation. It is well-known that inflammation and oxidative stress are modulated by the parasympathetic nervous system (PNS). Dr. Shibao and others found that AAs have reduced PNS activity compared with whites. Currently, her funded studies are focused on the effect of central acetylcholinesterase inhibition, which increases cholinergic activity, on vascular oxidative stress in this population. For this K24 application, she will expand these studies to determine if trans- auricular vagus nerve stimulation (TaVNS), another intervention that stimulates PNS, prevents immune cell activation, reduces markers of vascular oxidation in harvested endothelial cells and improve endothelial function as measured by flow-mediated dilation. The planned studies will provide a comprehensive assessment of the mechanism underlying the effect of increased PNS transmission on vascular oxidation and inflammation, which precedes endothelial dysfunction in African Americans. Furthermore, these studies will provide ample training opportunities for Dr. Shibao’s mentees in the area of cholinergic regulation of vascular oxidation.