Vanderbilt University Medical Center

NIH Research Projects · FY 2026 · 2023-04

PROJECT SUMMARY Genetic factors play a significant role in the etiology of colorectal cancer (CRC). To date, approximately 180 genetic susceptibility loci have been identified for CRC through genome-wide association studies (GWAS). However, causal genes for the large majority of these loci remain unknown, hindering the translation of GWAS findings into disease prevention and treatment. Recently, we and others have identified many putative CRC susceptibility genes using transcriptome-wide association studies (TWAS) that focus exclusively on mRNAs. However, it is the proteins not mRNAs that primarily perform cellular functions. Furthermore, cellular proteins are only moderately correlated with their corresponding mRNAs, and for many proteins, correlation is poor as many factors affect protein synthesis and post-translation stability. Herein, we propose a well-powered proteome-wide association study (PWAS) to systematically search the proteome to identify proteins associated with CRC risk and further characterize their roles in colorectal tumor progression and cellular functions. Specifically, we propose the following aims. Aim 1: To conduct a well-powered PWAS to identify proteins for CRC risk. We will generate proteomics (~10,000 proteins) and genomics data in normal colon tissues from 300 subjects to build genetic models to predict protein expression across the proteome. These models will be applied to the GWAS data of 125,487 individuals (58,131 cases) of European descent to evaluate associations of genetically predicted proteins with CRC risk. We will integrate PWAS findings, along with results from GWAS/TWAS to assess inter-relationships of genes, mRNAs and proteins in the pathogenesis of CRC. Aim 2: To investigate potential roles of PWAS-identified proteins in the adenoma-carcinoma sequence. We will analyze spatial expression of 30 selected PWAS-identified proteins in FFPE samples from 150 early-, late- stage adenoma, and invasive carcinoma from white patients (N= 50 for each group) to investigate if these proteins affect the adenoma-carcinoma sequence. Aim 3: To conduct a nested case-control study to evaluate associations of CRC risk with promising blood proteins uncovered in Aims 1/2: We will analyze circulating levels of 21 proteins selected from Aims 1 and 2 in pre-diagnostic blood samples collected from 1,000 and their matched 1,200 controls of Asian, African and European ancestry. Aim 4: To investigate effects of up to 10 selected PWAS-identified proteins on cellular functions using CRISPRi/a perturbation experiments in multiple normal colon epithelial, and CRC cell lines. We will also assess their potential roles in regulating known CRC signaling, and newly identified CRC pathways uncovered from our study by performing RNA-sequencing and further in vitro verification in both treated and vehicle cells. Given the rigorous study design, the unique resources, and the methodological strengths, we expect that this proposed study will greatly advance our understanding of CRC biology to accelerate the translation of genetic findings in CRC prevention and the development of therapeutic targets.

NIH Research Projects · FY 2026 · 2023-04

PROJECT SUMMARY The human gut microbiota provides essential functions in human health. However, the microbiota is constantly subjected to challenges such as intestinal inflammation, which drives the microbiota into a perturbed state that can cause or exacerbate diseases. Therefore, microbial resilience, which maintains the structural and functional stability of the gut microbiome in the face of perturbations, is crucial to host health. Despite a central role in host health, the mechanisms underlying microbiota resilience remain poorly defined. During intestinal inflammation, host processes known as nutritional immunity starve gut microbes from essential micronutrients such as iron, constituting stress that both commensal and pathogenic bacteria must cope with to survive. Enteric pathogens overcome nutritional immunity using a series of exquisite mechanisms, including encoding receptors for host iron-binding proteins and producing iron-chelating molecules termed siderophores. In contrast to these well-studied strategies, how gut commensals survive iron starvation in the inflamed gut remains largely unknown. We propose that maintaining iron homeostasis is an essential strategy for commensals to remain resilient during gut inflammation. In preliminary studies, we demonstrated that the model gut commensal Bacteroides thetaiotaomicron (B. theta) acquires iron by pirating siderophores from an enteric pathogen that induces intestinal iron limitation. Our new preliminary data suggest that B. theta captures siderophores using an extracellular lipoprotein. We further show that enteric pathogens such as Salmonella can exploit this capture mechanism to “re-pirate” siderophores from gut commensals to evade nutritional immunity. In addition to increasing iron uptake, our unpublished data demonstrate that B. theta employs small, non-coding RNAs to orchestrate iron conservation to maintain intracellular iron homeostasis and combat nutritional immunity in the inflamed intestine. As such, our central hypothesis is that B. theta couples siderophore acquisition with small RNA-mediated intracellular iron conservation to maintain resilience in the inflamed gut. We will test our hypothesis by pursuing the following specific aims: 1) Elucidate how siderophore acquisition mediates B. theta resilience and modifies host nutritional immunity in the inflamed gut; and 2) Determine how B. theta maintains intracellular iron homeostasis in the inflamed gut. The completion of this work will reveal the mechanisms by which gut commensals adapt to iron limitation and how such adaptation shapes the structural and functional stability of the microbiota during gut inflammation. This research is innovative because it adds commensal iron metabolism as a previously unrecognized dimension to the intricate interactions between pathogen and nutritional immunity. This proposed work is impactful because establishing a model for iron regulation in B. theta will provide insights into how interphylum iron metabolism may broadly contribute to gut microbiota resilience in the inflamed gut.

NIH Research Projects · FY 2026 · 2023-04

Project Summary Sickle cell disease (SCD) is associated with chronic hemolysis, systemic endothelial dysfunction, inflammation and vascular occlusion. This complex pathophysiology leads to severe pain, progressive multi-organ damage and premature death with a median lifespan of 48 years in high- income countries. We and others have determined that young adults with progressive heart, lung, and kidney damage, either individually or in combination, are at particularly high risk for premature death. Many individuals with SCD are candidates for high-risk treatments that can potentially eliminate symptoms and arrest organ damage, including allogeneic hematopoietic stem cell (HSC) transplantation and various forms of autologous HSC gene therapy. However, several individuals who received these treatments have developed acute myeloid leukemia or other myeloid neoplasms. In many cases, the blood cancer arose from an autologous, premalignant HSC harboring a somatic “clonal hematopoiesis” (CH) mutation that was present before therapy. We and others have shown in individuals without SCD that CH mutations confer a growth advantage to aging HSCs, predisposing to not only myeloid leukemia, but also endovascular disease affecting the heart, lung and kidney. Additional preliminary data derived from deidentified genomic or exonic sequences indicate that individuals with SCD develop CH at earlier ages than that of the general population. Based on these data, we hypothesize that individuals with SCD have an increased prevalence of CH, which accelerates the development of heart, lung, and kidney disease. We will test this hypothesis by first determining the prevalence and incidence of CH in three well-characterized multi-center cohorts of older children and adults with SCD (n= 2645) and matched controls (n= 7935, Aim 1). We will use a novel, scalable, cost- effective, error-corrected sequencing assay that can detect low-level (0.1%) somatic CH mutations. Next, we will determine whether CH mutations are associated with heart, lung or kidney disease in these cohorts (Aim 2). Our team has already completed whole-genome sequencing of the cohorts through the NIH NHLBI Trans-Omics for Precision Medicine (TOPMed) program, which will allow us to study genetic interactions between CH mutations and germline variants that are known to influence SCD outcomes. Our project will provide novel insights into the importance of CH as a risk factor for heart, lung, and kidney disease in SCD, identify individuals who could benefit from individualized strategies for organ protection administered prospectively, and fuel future studies to determine whether CH predisposes to the development of myeloid leukemia after allogeneic HSC transplantation or gene therapy for SCD.

NIH Research Projects · FY 2026 · 2023-04

PROJECT SUMMARY/ABSTRACT Despite more than 5 million people living in the U.S. with the long-term effects of traumatic brain injury (TBI), it remains unknown at what point the TBI functional recovery trajectory is fixed. Existing TBI prognostic models are imperfect and static, relying on data from admission and the first 6 hours only. Current models explain only one-third of the variability in outcomes. Despite the multiple CT and MRI scans obtained in TBI clinical care, neuroimaging remains underutilized for TBI prognostics. Image-based biomarkers and radiomics can extract predictive signals from neuroimaging already being obtained. Prognostication matters: better prognostics translate to better patient-centered clinical decision making and better prognostic stratification for clinical trials. Multiple TBI therapies have failed in clinical translation due to basic challenges in patient selection and predicting TBI recovery. At many hospitals across the U.S., trauma surgeons are the primary providers responsible for patients with hospitalized TBI. We can and should do better by developing a mature quantitative approach to prognostication that incorporates time-varying clinical data, advanced statistical modeling, TBI-specific biomarkers, and image-based biomarkers from clinical imaging already being obtained. This career development plan (PI: Amelia W. Maiga, Trauma Surgeon) helps sustain a minimum of 75% protected effort to hone her research expertise and eventual independence in advanced statistical modeling, clinical trials, and neuroimaging analysis for TBI prognostication. The research specific aims are to: AIM 1) build and validate a TBI prognostic model for 12-month functional outcomes with rich time-varying clinical data, radiomics imaging analysis, and biomarkers using two NIH cohorts (R01GM120484 and U01NS086090); and AIM 2) conduct a trajectory analysis of long-term functional and neurocognitive outcomes after TBI. This career development plan for Dr. Maiga integrates a) advanced didactics in clinical trials and neurocognitive follow-up in the critically injured, sophisticated statistical modeling, imaging analysis, and scientific communication and leadership; b) participation in local, regional, and national conferences to advance expertise in the above areas; c) a multidisciplinary mentored research experience; and d) an outstanding environment to propel towards independence. Her mentorship team consists of Drs. Mayur B. Patel (Primary Mentor, trauma, critical illness and TBI); Pratik P. Pandharipande (cognitive impairment); Rameela Raman (prognostic modeling, trajectory analysis); James C. Jackson (long-term outcomes); and Bennett A. Landman (neuroimaging, radiomics), supported by a Research Advisory Council of Drs. E. Wesley Ely (Director of Critical Illness and Brain Dysfunction Center); Robert S. Dittus (Director of Vanderbilt’s Institute of Medicine and Public Health); Geoff T. Manley (PI TRACK-TBI; Transforming Research and Clinical Knowledge in TBI). This research award will position Dr. Maiga to become a leader in TBI prognostics.

NIH Research Projects · FY 2026 · 2023-04

PROJECT SUMMARY Lower respiratory tract infections (LRTI), including pneumonia, bronchiolitis, and infection-related exacerbations of asthma, are responsible for nearly one-third of all emergency department (ED) visits and 40% of all infection-related hospitalizations in children each year in the United States. While viruses are responsible for the vast majority of LRTIs, antibiotics are very frequently prescribed. In fact, more days of antibiotic use are attributable to LRTI than any other condition in children’s hospitals. Starting antibiotics unnecessarily, using less effective or overly broad-spectrum antibiotics, and treating for longer durations than necessary all contribute to inappropriate antibiotic use in pediatric LRTI in both ED and inpatient settings. Use of unnecessary antibiotics has profound consequences, including common and uncommon but severe adverse side effects, increased health care utilization and costs, and fueling the development of antimicrobial resistance, an ongoing global public health threat. To curtail inappropriate antibiotic use, Antimicrobial Stewardship Programs (ASPs) have become commonplace in United States hospitals and have proven to be effective. Unfortunately, the benefits of ASPs have largely failed to translate to the unique and fast-paced ED environment. This represents a key missed opportunity since many more children are cared for in the ED as compared to inpatient settings, and because ED care often critically influences subsequent hospital care. Our prior research suggests that high quality electronic health record-based clinical decision support (CDS) is a strategy that could bridge the ED antibiotic stewardship gap and reduce inappropriate prescribing in the ED and hospital. Our proposed research builds upon this foundational work and leverages an accomplished and diverse study team with expertise across the continuum of clinical care and in biomedical informatics, clinical and health services research, implementation science, and biostatistics, all housed within supportive and well- resourced research environments. Within three children’s hospitals, we will: define critical facilitators and barriers governing use and acceptance of antibiotic CDS at the point of care in the ED and inpatient settings (Aim 1); create two CDS interventions seamlessly integrated into clinician workflows in the ED and inpatient settings, including a) an antibiotic advisor (Abx CDS), and b) a real-time ASP tool (ASP CDS) (Aim 2); measure the effectiveness of Abx CDS and ASP CDS, alone and in combination, against usual care for increasing appropriate antibiotic use in pediatric LRTI in the ED and inpatient settings within the framework of a pragmatic randomized controlled trial (Aim 3); and evaluate Reach, Adoption, and Implementation domains within the trial among encounters receiving Abx CDS and ASP CDS (Aim 4). We hypothesize that we will create stewardship-focused CDS tools that meaningfully improve antibiotic use for children with LRTI and that are scalable in order to optimize care delivery and outcomes across a wide variety of settings.

NIH Research Projects · FY 2026 · 2023-04

Chronic Kidney Disease (CKD) affects 15% of the US adult population 30 and vasopressin is associated with progression of non-diabetic, diabetic, and polycystic kidney disease (PKD). 1-18 However, the specific mechanism(s) through which vasopressin worsens progression of kidney disease are unclear. Vasopressin is the biologically active end-product of a 164 amino acid pre- pro-peptide and physiologic production is currently thought to be limited to the brain. We recently found that vasopressin is also made in the kidney under physiologic conditions and expression is increased in PKD in both humans and mice. Therefore, the aim of this project is to understand the function, regulation, and impact of kidney-derived vasopressin in health and disease. We have preliminary data that show that mice that lack kidney-derived vasopressin in the distal nephron have altered water balance. We propose to (1) determine the mechanism through which kidney-derived vasopressin influences water balance and (2) determine if kidney- derived vasopressin is involved cyst growth and progression of PKD. Successful completion of this project will help clarify the mechanism(s) through which the interplay between local and systemic vasopressin signaling impacts kidney disease, potentially identifying new therapeutic targets and approaches for CKD and PKD. Work will occur in one of the largest and most scientifically diverse nephrology divisions in the world, within the Vanderbilt University Medical Center Department of Medicine. This project has already received extensive external (Harold Amos Medical Faculty Development Award – 2020) and institutional support in the form of financial support and a comprehensive career development plan involving internal and external mentorship, workshops, and coursework.

NIH Research Projects · FY 2026 · 2023-04

Project Summary Kaposi’s sarcoma-associated herpesvirus (KSHV) is a member of the subfamily gammaherpesvirinae and is causally associated with the development of several malignancies including Kaposi’s sarcoma and primary effusion lymphoma (PEL). The virus’ ability to establish latency as well as reactivate are essential for the development of KSHV-associated disease. Despite these requirements for disease progression there are significant gaps in knowledge regarding cell-intrinsic mechanisms that restrict the KSHV lifecycle. While innate restriction is typically thought of in the context of antiviral immune responses, growing evidence suggests that cellular RNA quality control pathways have an antiviral role. Nonsense-mediated RNA decay (NMD) is an evolutionarily conserved RNA decay pathway that facilitates degradation of RNAs on which ribosomes are deemed to terminate translation aberrantly. Emerging evidence has pointed to a role for NMD in antiviral restriction with a prominent role limiting replication of positive-stranded RNA viruses, however, a role for NMD in DNA virus restriction, such as KSHV, was unknown. We recently reported the discovery that NMD is a cell- intrinsic restriction mechanism for DNA viruses and demonstrated that it imposes a significant restriction on the KSHV lifecycle in PEL cells. Our data demonstrate that NMD-dependent restriction is linked both to the regulation of the unfolded protein response (UPR) as well as targeted degradation of the main KSHV transcription factor, RTA. Building upon these observations our central hypothesis is that NMD restricts KSHV reactivation by targeting key viral mRNAs as well as cellular transcripts in pathways important for viral gene expression and that the virus antagonizes NMD through viral-encoded mechanisms. To test this hypothesis, we propose an integrated series of experiments aimed at determining the interactions between NMD and KSHV. In Aim 1, we will investigate how NMD-dependent regulation of the UPR pathway regulates the KSHV lifecycle. In Aim 2, we will investigate a class of KSHV mRNAs that escape NMD despite harboring sequence features that should render them NMD-susceptible. In Aim 3, we will determine the mechanism by which KSHV-encoded proteins inhibit NMD. Completion of these studies is expected to determine how NMD restricts the KSHV lifecycle as well as the mechanisms the virus employs to antagonize it. These will represent fundamental new insights into how DNA virus infection is regulated by cell-intrinsic mechanisms and can be harnessed for the development of new therapeutic strategies.

NIH Research Projects · FY 2026 · 2023-04

Project Summary Persons with HIV (PWH) on antiretroviral therapy (ART) suffer from higher rates of cardiometabolic diseases compared with the general population, which contributes to poor health outcomes. Adipose tissue is a critical regulator of systemic metabolic processes, and changes in adipose tissue immune cell populations that modulate adipose tissue function, may in part, contribute to the risk of metabolic disease in PWH. Prior studies have shown striking changes in adipose tissue CD4+ and CD8+ T cell profile in PWH. Yet the current understanding of the role of adipose tissue immune cells in metabolic disease is limited by few studies to date evaluating PWH on contemporary ART, limited studies using single cell technologies to characterize specific cell populations, and finally limited understanding of the relationship of adipose tissue T cell populations with adipose tissue viral reservoir. Defining the mechanisms through which adipose tissue innate and adaptive immune cells contribute to metabolic diseases is critical for identifying preventative and therapeutic strategies that reduce morbidity and mortality in PWH. I leveraged single-cell RNA sequencing (scRNA-seq) to define adipose tissue compositional and transcriptional changes that occur with glucose intolerance in PWH using cross-sectional data, and compared these changes to diabetic HIV-negative adipose tissue. I found that higher proportion of CD4+ and CD8+ T effector memory (TEM) cells and lipid-associated macrophages (LAMs) was associated with glucose intolerance in PWH and higher CD4+ and CD8+ TEM proportion were associated with greater fibroblastic cells in PWH only. Our overall hypothesis is that proinflammatory TEM cells expressing interferon-g and tumor necrosis factor a are increased in PWH on ART, infiltrate adipose tissue and promote macrophage polarization, are associated with the adipose tissue viral reservoir, and contribute to the development of metabolic disease. Building upon my computational analysis skills, my career development plan will enhance my skills and knowledge in: 1) T cell immunology and analyses; 2) conducting clinical and translational research; and 3) application of multi-omic analysis to address critical research gaps. In Aim 1, I will define the cell-type specific transcriptional pattern and adipose tissue composition that are associated with progressive insulin resistance in PWH on long-term ART. In Aim 2, I will investigate the adipose tissue T cell transcriptional and compositional pattern pre-treatment and at one year of integrase strand transferase inhibitor-based regimen in those who develop progressive insulin resistance compared with those who do not. In Aim 3, I will determine the relationship between anti-viral T cells, the adipose tissue viral reservoir, and adipose tissue inflammation. Completion of these aims will greatly increase the understanding of specific immune cells contributing to inflammation and the potential factors that drive inflammation. Additionally, the training and data from the K23 award will allow me to transition to research independence in the HIV co- morbidities field with a concentration on immune cell response.

NIH Research Projects · FY 2026 · 2023-04

Over 40% of adults are obese in the US. Although reducing caloric intake and/or increasing physical activity can lead to weight loss in the short to medium term in some people, they lose efficacy in the long term. Bariatric surgeries are currently the most durable and effective treatment for obesity but substantial complications have been reported. Pharmaceutical options for treating obesity have been very limited and not efficacious. Anti- obesity medications generally target either central nervous system (CNS) pathways that regulate sensations of satiety and fullness, or peripheral modulators of digestion, metabolism and lipogenesis that result in only modest effects. One of the major challenges in developing anti-obesity medications is that our CNS (i.e., hypothalamus, brainstem, and limbic system), which regulates appetite and food intake, substantially overlaps with those that modulate mood, anxiety and behavior. Several CNS-acting drugs that have been developed to suppress appetite for weight loss have adverse behavioral effects. For example, Rimonabant (endocannabinoid receptor antagonist) and Ecopipam (dopamine receptor antagonist) precipitate severe depression and suicide ideations; and the recent FDA-approved MC4R agonist (Setmelanotide) for individuals carrying pathogenic mutations in POMC, PCSK1 or LEPR genes along the leptin-melanocortin pathway also incurs similar psychiatric effects in 26% patients. All of these highlight safety issues in targeting the CNS for appetite suppression. However, the recent success of glucagon-like peptide-1 receptor (GLP1R) agonists (Liraglutide, Semagglutide, Tirzepatide, etc.) and amylin analogs (Cagrilintide) in treating obesity without apparent CNS-related adverse effects demonstrates the proof of principle that targeting certain parts of our CNS for weight loss can be safe, i.e., targeting specific neural circuits primarily in the brainstem for GLP1R agonists and amylin analogs. It also indicates that a subset of obesity genes can be safely targeted pharmaceutically in the CNS. There has been tremendous progress in genetic studies of obesity and adiposity traits in the past 20 years, especially led by our Genetic Investigation of ANThropometric traits [GIANT] consortium, which has identified >1,700 adiposity loci. These efforts offer an unprecedented opportunity to identify novel drug targets to treat obesity, a field that urgently needs a paradigm shift. By leveraging comprehensive GWAS resources for adiposity, psychiatric traits and addictive risk behaviors, and rich phenome information across large-scale biobanks, we propose to integrate multi-layers of omics to identify obesity genes using whole-exome sequencing, transcriptome-wide and proteome-wide association analyses (Aim 1), predict pharmacological effects upon targeting obesity genes using drug-target Mendelian randomization analyses and gene-based phenome-wide association analyses (Aim 2), and screen neuronal effects of obesity drug target genes in iPSC-derived neurons with CRISPR-based functional genomics (Aim 3). Our work will identify novel obesity drug targets that are both efficacious and safe to fill in the critical unmet need of pharmaceutical therapy of obesity.

NIH Research Projects · FY 2026 · 2023-04

ABSTRACT: Approximately 5-10% of older adults have aortic stenosis (AS) with anticipated doubling by 2050; with no available medical therapy to slow progression, treatment is limited to aortic valve replacement (AVR). While AVR has historically been reserved for symptomatic severe AS, cardiac remodeling and irreversible injury occur before the onset of symptoms and before AS is "severe" and contribute to death and persistent heart failure (HF) symptoms/rehospitalization in up to 40% of patients 1 year after AVR, suggesting that AVR before onset of irreversible changes to the heart is likely to improve post-AVR outcomes. Fortunately, randomized strategy trials are underway to test the benefit of earlier less invasive transcatheter AVR (TAVR) before symptoms and severe AS. However, earlier TAVR isn't a panacea; beyond inherent procedural risks, this will also lead to more repeat procedures (with risks/costs) when prosthetic valves degenerate. Echocardiography and standard biomarkers (e.g., left ventricular hypertrophy [LVH], BNP) have limited sensitivity/specificity for detecting maladaptive remodeling and lack relevant biological insight. In preparation for this application, we identified circulating proteomic signatures of tissue/global cardiac phenotypes in the heart (e.g. LVH, fibrosis, systolic/diastolic function with cardiac magnetic resonance [CMR]/echo) in a group of 115 individuals across a spectrum of AS (mild to severe), defining subsets of biologically plausible and novel proteins associated with an increased risk of HF/mortality, with validation in a broader at-risk population without AS. Our central hypothesis is that myocardial remodeling/dysfunction early in the course of AS (mild-moderate; asymptomatic severe) will be accompanied by alterations in the circulating proteome pointing to known/novel pathways contributing to HF and providing an early molecular barometer for clinical surveillance and pharmacologic targeting. We will utilize state-of-the-art cardiac imaging alongside high-throughput proteomics on longitudinal samples from four cohorts of AS, including mild to severe asymptomatic AS, controls, pre- and post-TAVR sampling, and two randomized trials to: (1) develop/validate circulating proteomic signatures that reflect adverse myocardial remodeling/dysfunction relevant to AS surveillance and personalized timing of AVR; and (2) identify known/novel pathways underlying cardiac remodeling (before AVR) and cardiac recovery (after AVR) for downstream pharmacological targeting to reduce residual risk from HF. Our specific aims are: (1) identify whether proteomic signatures of myocardial remodeling/dysfunction are present early in AS before traditional clinical thresholds for intervention; (2) identify proteomic signatures of LVH regression after AVR in severe AS; and (3) determine whether proteomic signatures of cardiac health are associated with post-AVR outcomes and able to identify asymptomatic patients who benefit from prompt AVR. If successful, the current application will identify a set of circulating proteins (known/novel) linked to early cardiac remodeling phenotypes in AS for clinical surveillance, precision therapy, mechanistic study, and pharmacologic targeting.

NIH Research Projects · FY 2026 · 2023-03

PROJECT SUMMARY With no universal cure, development of an effective vaccine to prevent HIV-1 infection remains a primary goal. A major hurdle for the development of successful vaccination strategies has been the lack of affordable, accessible, tractable, and relevant preclinical model systems. Investigations on HIV infection, pathogenesis, and prevention using small animal models have been limiting due to the species-specific tropism of HIV. The advent of immunodeficient mice harboring a human immune system (HIS) in many ways has broadened accessibility and interest in HIV-related translational studies including viral replication, T cell depletion, methods of transmission, and evaluation of antiretroviral therapies. Nevertheless, efforts to develop vaccination strategies against HIV in current HIS mice have been thwarted due to poor adaptive immune responses and antigen- specific antibody development following immunization. Thus, there is a great need for advances in HIS mice that promote vaccine-mediated antibody development to specific epitopes that would easily translate to humans. We hypothesize that enhanced human T cell function and priming via human antigen presenting cells in HIS mice will facilitate efficient T/B cell interactions and enable evaluation of vaccination strategies against HIV-1. To this end, we have developed a novel HIS mouse strain expressing human leukocyte antigens (HLA)-DQ and HLA-A in the absence of murine major histocompatibility complex (MHC) I/II (to ensure human T cell selection on a more appropriate molecules in the mouse thymus) in combination with human CSF1 knocked into the murine Csf1 locus. Based on published data from our group and others, this novel strain, we anticipate, will support improved T cell development/function as well as the development of human myeloid cells with increased capacity to prime human T cells following immunization and facilitate HIV-1-specific antibody production. We will leverage this new translational HIS platform to: i) Determine the scope of the human adaptive immune response to infection with HIV-1 R5 virus, ii) Determine the neutralization ability of, define the Env epitopes targeted by, and delineate the sequence features for the human adaptive immune response to HIV-1 immunization, and iii) assess a novel vaccination strategy using optimized multivalent immunogens for broad neutralizing antibodies (bNAb) elicitation. Together, these results will provide critical insights into the utility of this advanced HIS model system to assess HIV-1 vaccination strategies capable of generating bNAbs to accelerate prioritization to validate in human clinical trials.

NIH Research Projects · FY 2026 · 2023-03

ABSTRACT About 25% of the 69,710 U.S. opioid overdose deaths in 2020 involved prescription opioids directly, and many of the remaining overdose victims started opioid use with prescribed medication. Post-surgical opioid prescribing comprises an increasing share of opioid prescribing, with considerable risks for misuse, new persistent opioid use (NPOU), and opioid use disorder (OUD). There is a need to decrease these iatrogenic risks without compromising postoperative analgesia. Buccal buprenorphine represents a potential alternative to traditional post-surgical opioid prescribing with known lower respiratory depression risk. However, minimal data exists regarding whether its administration yields: (1) decreased abuse potential or (2) acceptable analgesia for acute pain. The Research Training Plan addresses these key gaps in understanding regarding the risk/benefit ratio of postoperative buccal buprenorphine. Aim 1 involves pharmacodynamic and psychophysical assessment of abuse potential and analgesia following buccal buprenorphine administration in a controlled experimental setting. Aim 2 entails a preliminary study assessing the feasibility and acceptability of a randomized clinical trial of prescribing buccal buprenorphine for postoperative pain management. In each aim, buccal buprenorphine will be compared with oxycodone, a commonly prescribed postoperative opioid. The candidate has prior experience with small observational studies and large clinical database studies related to post-surgical opioids and pain, with several first- and co-first-author publications in major journals. The Career Development Plan will allow him to gain new proficiencies in the assessment of abuse potential and pain as well as clinical trial design and execution, biostatistics, grantsmanship, and professional development. Mentor Dr. Stephen Bruehl specializes in the experimental assessment of the subjective and analgesic response to opioid administration. Co-mentor Dr. Sharon Walsh performed the seminal studies on buprenorphine pharmacodynamics and is an expert on OUD. Co-mentors Dr. Chad Brummett and Dr. David Edwards are authorities on postoperative opioid prescribing, and co-mentor Dr. Benjamin French is a specialist in clinical trial design and biostatistics. Vanderbilt’s setting is highly conducive to research training and implementation. This project will set the candidate on course for a career as an independent translational and clinical investigator. The proposed studies promise to offer insights into whether buccal buprenorphine can serve as an alternative postoperative analgesic with lower abuse potential. The subsequent planned definitive trial could reshape post-surgical opioid prescribing patterns.

NIH Research Projects · FY 2025 · 2023-03

OVERALL PROJECT SUMMARY Vanderbilt Antibody and Antigen Discovery for Clostridioides difficile Vaccines VANDy-CdV Clostridioides difficile is a spore-forming anaerobic bacterium that is the leading cause of hospital- acquired gastrointestinal infection in the United States. The rising incidence of community- acquired C. difficile infection (CDI) in otherwise healthy adults is linked to increased antibiotic use and the emergence of new strains. CDI symptoms and pathology are mediated by two large homologous toxins, TcdA and TcdB, and therefore the toxins represent attractive targets for prevention and therapeutic strategies. While efforts centered around the use of toxoids for immunization have shown promise in reducing the severity of symptoms, the toxoid approach has not resulted in a decreased incidence of CDI in clinical trials. There are several opportunities to improve upon existing vaccine strategies. First, large scale genomic studies show that TcdB is undergoing rapid evolutionary change; the identification of conserved toxin epitopes can be used to direct the immune response toward the production of broadly neutralizing responses. Second, the identification of conserved antigens on the surface of the vegetative bacteria or spores that can serve as immunogens will allow the host to elicit mucosal immune responses that prevent bacterial colonization. The inclusion of mucosal immunization routes is expected to further enhance vaccine efficacy and durability. The overarching goal of the VANDy-CdV program is to identify toxin subunits and novel cell surface antigens that, when combined, promote durable protection against C. difficile infection and symptoms. Among many innovative strengths, the approach includes the use of human CDI patient samples as a resource for understanding what antigens promote IgG, IgA, and sIgA responses in natural infection. The approach also includes the use of powerful single B cell sorting and sequencing methods. The ability to identify paired heavy and light chain sequences from individual memory B cells binding toxins and/or bacteria allows for the production of unique antibodies that can then be used as tools for epitope mapping and novel antigen discovery. A third highlight of the approach involves the use of a newly created C. difficile transposon library which will be used to identify novel antigens in an in vivo vaccination/challenge experiment. Other innovations include a structure-guided approach to identifying potent, neutralizing epitopes and a systematic evaluation of how intestinal lymphocyte responses vary with routes of immunization. Vaccine efficacy and the mucosal correlates of protection will be evaluated in pre-clinical models of colonization, infection, and recurrence. At the end of five years, we expect to have the pre-clinical data needed to advance a novel antigen cocktail and immunization strategy forward into human safety and efficacy trials.

NIH Research Projects · FY 2026 · 2023-03

Project Summary / Abstract Candidate: David Isaacs, MD, MPH is Assistant Professor in the Department of Neurology at Vanderbilt University Medical Center. During his faculty tenure, he has demonstrated enthusiasm and aptitude for patient- centered research, with emphasis on non-motor aspects of movement disorders. Notable early career highlights include founding Vanderbilt’s Adult Tourette Syndrome (TS) Clinic and co-directing Vanderbilt’s Tourette Association of America (TAA) Center of Excellence; securing multiple extra- and intra-mural grants, including the TAA Young Investigator Award to support research into sensory phenomena in TS; and serving as site principal investigator for industry-sponsored clinical trials in TS. He seeks to become a leading researcher in neurophysiologic mechanisms of non-motor symptoms in TS and other movement disorders. Research Project: TS affects 0.5-0.8% of school-aged children, one-third of whom suffer bothersome tics into adulthood. Tics are the defining feature of TS, but sensory symptoms are widespread. In particular, over 50% of children and 80% of adults with TS report sensory over-responsivity (SOR), defined as heightened awareness of and behavioral reactivity to sensory stimuli. SOR is an integral facet of the TS phenotype, but significant knowledge gaps surround its clinical significance and neurobiological underpinnings. This proposal seeks to clarify the mechanistic bases of SOR in TS (Aims 1 and 2) and to determine whether SOR is a risk marker for more severe clinical course in TS (Aim 3). To achieve Aims 1 and 2, Dr. Isaacs will use quantitative electroencephalography (EEG) and multi-modal autonomic measurement to assess neurophysiologic response to auditory and tactile stimuli in adults with TS. To achieve Aim 3, he will use validated rating scales to assess motor, sensory, and psychiatric symptoms in adolescents with TS at two time points: baseline and 2 years. Study results will deepen insight into TS pathophysiology and identify risk markers for more severe TS course. Career Development Plan and Goals: With guidance from his Scientific Steering Committee, Dr. Isaacs has created a curriculum incorporating formal coursework, workshops, conferences, and individualized training with mentors and collaborators to adequately prepare himself for independent research in the neurophysiologic basis of non-motor aspects of movement disorders. His short-term career goals are to develop proficiency in 1) measurement of sensory and neuropsychiatric symptoms; 2) event-related potentials and quantitative EEG methodology; and 3) psychophysiological techniques complementary to EEG. Environment: Vanderbilt University Medical Center is an optimal academic environment for nurturing Dr. Isaacs’ maturation into a fully-fledged independent researcher. The institution has an exceptional track record for fostering productive, independently funded, and internationally renowned clinician-scientists. The primary mission of Vanderbilt’s Clinical and Translational Science Award is provision of infrastructure for clinical research excellence, with an entire arm devoted to training and career development.

NIH Research Projects · FY 2026 · 2023-02

Project Summary This proposal responds to PAR-22-039 and aims to develop focused ultrasound (FUS) as a next generation high precision device-based pharmacological neuromodulation tool and evaluate its use in non- human primates as a translational step to humans. Current device-based neuromodulation technologies rely on interaction with cells’ endogenous sensitivities to different forms of energy. Although FUS alone overcomes spatial and depth limitations of other non-invasive neuromodulation modalities, the diverse response of cells to FUS presents a limitation and can make predictable neuromodulation difficult. We seek to move beyond the paradigm of modulating via endogenous sensitivity by developing FUS in combination with phase shift nanoemulsions (PSNEs)—200 nm liquid particles that can carry a drug payload and become microbubbles when exposed to brief (<1 msec) FUS pulses above a threshold. By developing FUS combined with PSNEs, we will be able to predictably modulate millimeter-scale regions throughout the brain by either locally enhancing blood brain barrier (BBB) permeability and injecting a drug or by releasing drugs from PSNEs loaded with a drug. We propose a research plan that will move these technologies forward in the non-human primate as an important translational step to humans. We first propose to develop an ultrasound transducer that will decrease the focal spot size including receive elements that will allow us to map particle activation through the skull. We will integrate the transducer into a FUS neuromodulation system built by our team under the BRAIN Initiative and develop open-source software that will improve treatment planning for FUS neuromodulation. We will apply this system to open the BBB in the sensorimotor region by activating PSNEs, driving the resultant microbubble and injecting the inhibitory drug GABA, which does not cross the unopened BBB in concentrations high enough to inhibit neurons. Because opening the BBB is not desirable in many scenarios, we will also develop activatable drug-loaded PSNEs to locally deliver the anesthetic sodium pentobarbital without opening the BBB. We will characterize the inhibitory effect of both neuromodulation methods using BOLD fMRI and assess safety using neuroimaging and behavioral analysis. Our multidisciplinary team has all expertise for MR-guided FUS with fMRI feedback and will collaborate with co- investigator Dayton whose laboratory developed a condensation-based PSNE formulation that uses the same excipients as commercially approved contrast agents. The acoustic technologies we propose to develop would improve the spatial capabilities of FUS neuromodulation and explore two approaches for focal pharmacological neuromodulation in the monkey including safety assessments that pave the way for translation.

NIH Research Projects · FY 2026 · 2023-01

PROJECT SUMMARY Brazil has the highest tuberculosis (TB) burden in the Western Hemisphere, and among the highest in the world. Advances in TB diagnosis, treatment, and prevention are necessary to improve the incidence, morbidity, and mortality of TB in Brazil, and globally. Regional Prospective Observational Research in TB (RePORT)- Brazil was initiated by our group in 2013, and enrolled 1,188 pulmonary TB patients and 1,930 of their close contacts in Phase 1. Clinical data and stored biorepository specimens have facilitated studies of predictors of TB and TB/HIV treatment outcomes, predictors of M. tuberculosis (Mtb) infection and progression to TB disease and incipient TB, TB-diabetes, drug-resistant TB, TB diagnostics, and Mtb transmission. Strong collaborations have been established with investigators in Brazil and the United States, as well as other RePORT networks (e.g., South Africa and India), the Caribbean Central America South America network for HIV epidemiology (CCASAnet) and its TB Sentinel Research Network (TB-SRN), which is part of the International epidemiologic Databases to Evaluate AIDS (IeDEA) network. In Phase 2 of RePORT-Brazil we will utilize the rich, high-quality clinical, genomic, and transcriptomic data generated in Phase 1, together with new participant enrollment, to extend our understanding of TB epidemiology and pathogenesis, and improve the diagnosis, treatment, and prevention of TB. This will be accomplished through three Specific Aims: 1) Gain insights that improve TB diagnosis, treatment, and outcomes. This will include external validation utilizing the TB case registry in Brazil (SINAN; the Brazilian National System of Diseases Notification), and other Brazilian registries as appropriate; 2) Improve our understanding of Mtb transmission and infection, including latent, incipient, and sub-clinical disease; predictors of progression to TB, and protection against TB; and 3) Support and develop the next generation of TB scientists, and enhance the scope and collaboration of RePORT-Brazil. For Aim 3, we will fund Fellowships in TB Science, focusing on Brazilian investigators. This will include two Early Career Development Fellowships per year, for pilot projects that support Brazil-US partnerships, and generate preliminary data for subsequent grant funding; and two Post-Doctoral Fellowships per year. Both categories of support will be for studies that utilize RePORT-Brazil data and/or specimens; proposals that also include data and specimens from other TB cohorts will be encouraged. The three Aims will facilitate further growth and strengthening of RePORT-Brazil, and generate insights that improve the diagnosis, treatment, and prevention of TB in Brazil.

NIH Research Projects · FY 2026 · 2023-01

Project Summary Physician-scientists are crucial for translating new discoveries in basic science into improvements in patient care. As advances in biomedical research continue to expand our understanding of human biology, it is critical to maintain a strong cadre of physician scientists who will be able to apply this new knowledge to improve health outcomes. Concern has been growing for years that physician-scientists are decreasing in numbers, and current trends indicate that this decrease is likely to get worse. Thus, new approaches are needed to recruit more physicians into research careers and provide them with the skills and mentorship necessary for success. The Vanderbilt Training of Otolaryngology Physician-Scientists (V-TOPS) program addresses this challenge by providing mentored research experiences for otolaryngology residents and medical students. We hypothesize that two characteristics of our research education program will make it more likely that trainees will continue to pursue research careers: (a) research experiences aligned with a trainee’s clinical interests and (b) mentor-mentee relationships with successful physician-scientists. After matriculation, trainees are paired with a physician-scientist mentor who continues as an important adviser throughout their training. Residents in the program will spend two years doing research, between the second and third year of clinical otolaryngology training, thus providing adequate time for them to decide on a clinical focus area and pursue relevant research projects. We have assembled an experienced cohort of 15 faculty mentors representing a variety of research areas, including laryngeal physiology, rhinology/olfaction, airway immunology and inflammation, head and neck oncology, cochlear implants, and language disorders. We will accept one resident per year into the research program out of a total cohort of 5 residents. In addition, the V-TOPS program will accept two medical students each year for a one-year research experience, supplemented with a didactic program and individual mentoring by successful physician-scientists. Our expansive research portfolio, experienced faculty of basic and translational scientists, and the rich history for research education at Vanderbilt, make this an ideal environment to develop the next generation of physician scientists in otolaryngology

NIH Research Projects · FY 2026 · 2023-01

The goal of this application is to continue the highly successful Vanderbilt - Stimulating Access to Research in Residency; V-StARR) mentored training program for residents in Medicine or Pediatrics who possess both the aptitude and passion for becoming a new generation of clinician-scientists. We will continue to focus on “late bloomers”; typically, those residents who decide to pursue a career as a clinician-scientist after acceptance to a standard clinical residency pathway. The primary goal is to provide a nurturing mentored environment for Resident Investigators to perform highly rigorous research training to facilitate a successful transition to a research-focused fellowship and subsequent appointment as tenure track faculty. The overarching goal is to expand the pipeline of those achieving independence as clinician-scientists. Each Resident Investigator will develop and complete a mentored research project in an area of focus consistent with the missions of NHLBI and will also participate in selected workshops and courses and in our clinician-scientist development communities. Investigation may be basic, translational, clinical, or population health. All of our R38 graduates have gone on to pursue research-based careers and based on their success, and our deep applicant pool, we are expanding our program to six training slots to support Resident Investigators for 1-2 years with a minimum of 80% protected research time. Four of these slots will be funded by the R38 award and one slot each by the Departments of Medicine and Pediatrics. There is a formal program selection process to identify the most competitive applicants. Our proven success in recruitment to the program demonstrates our ability to attract a strong group of applicants. The program will provide intense scientific mentorship and personalized career development. The Resident Investigators will have access to a cadre of more than fifty carefully selected NIH-funded preceptors who have successful track records of mentoring early career scholars. Each Resident Investigator will have a personalized Scholarly Oversight Committee to assist them in achieving program goals, to evaluate resident progress, and to develop, advise on, and track their career development plan. Evaluation of Resident Investigators includes competency-based milestone assessments. There will be equally rigorous program assessments. Key outcomes for the program include: Academic productivity (presentations, peer-review publications, grants); entry of residents into research intensive fellowships; and success in obtaining T32 positions and K38 grants. Long-term follow-up of all Resident Investigators will be performed using Flight Tracker and through personal contact.

NIH Research Projects · FY 2026 · 2022-12

ABSTRACT Noise-induced hearing loss (NIHL, including clinically measurable audiometric threshold shifts) affects over 25 million adults, with the primary cause being exposure to occupational or other loud environmental sound. However, many noise-exposed individuals report difficulty hearing in noisy environments without clinically significant threshold increases. Animal model studies have revealed potential mechanisms of noise induced hearing difficulties (NIHD) and their accompanying psychophysical and physiological changes, including a candidate mechanism (with evidence from rodent models and emerging support from the macaque model) for clinically normal hearing with difficulty in noisy environments: cochlear synapse loss. However, animal models typically use single exposure protocols to create cochlear pathology, which are unlike the chronic noise exposures leading to NIHL in humans, who experience smaller, repeated daily noise doses that result in NIHL. Data from our macaque model of NIHL (having noise susceptibility similar to humans) suggests that the single exposure noise levels needed to induce NIHL and cochlear synapse loss are much higher than sound levels typically experienced by humans occupationally or recreationally. Nonetheless, preliminary data in macaques show that single noise exposures that cause temporary threshold shifts (TTS) result in cochlear synapse loss 2- months post exposure but not at 10-months post-exposure, and auditory processing deficits. This project will expand these early observations to more realistic chronic noise exposures similar to those experienced by workers. We propose psychophysical, physiological, and histological studies 1) to establish a timeline for the development of sustained auditory processing deficits and cochlear pathology in macaques chronically exposed to noise, and 2) to define behavioral and electrophysiological assays that detect changes in hearing that develop prior to permanent threshold shifts (PTS). Our hypothesis is that chronic noise exposures (8 hours a day, 5 days a week) cause a sequence of non-transient NIHD that progress to PTS. Specifically, we predict that chronic noise exposures will cause psychophysical changes (Aim 1): the earliest deficits will be in spatial and temporal processing, followed by deficits in processing signals in noise, followed by audiometric deficits (PTS). Physiological changes (Aim 2) will parallel psychophysical changes: earliest deficits will be in middle ear muscle reflex (MEMR) and measures of binaural and temporal processing, followed by deficits in distortion product otoacoustic emission (DPOAE) amplitudes and masked auditory brainstem responses (ABR), followed by deficits in DPOAEs and ABR thresholds. These deficits will be paralleled by cochlear pathology: early, non-transient cochlear synapse loss, followed by outer hair cell loss, followed by a combination of outer and inner hair cell loss (Aim 3). The results of these studies will reveal sensitive markers of early auditory damage with realistic noise exposures, and the sequence of cochlear pathology. Study results will be used to develop reliable, clinically viable early indicators of NIHL and enhance hearing loss prevention program outcomes.

NIH Research Projects · FY 2026 · 2022-12

PROJECT SUMMARY/ABSTRACT Magnetic resonance imaging (MRI) is a powerful non-invasive tool for imaging brain activity that allows for investigating the dynamically changing activity patterns and structure that give rise to human brain function and dysfunction. Functional MRI (fMRI) signal variations linked with vigilance states, and the subcortical-cortical networks that underlie these fluctuations in vigilance, are being increasingly recognized as fMRI signals of interest both for neuroscience and in studying disease. However, vigilance has been largely ignored in routine fMRI studies, despite the fact that subjects tend to fall asleep in the scanner and certain patient populations may be susceptible to fatigue or daytime sleepiness. More precisely characterizing the role of vigilance in disease, and its effects in fMRI data, could be key for developing imaging biomarkers as well as improving treatment. My doctoral work thus far, (Aim 1.1) developed a method for extracting a vigilance metric, based on fMRI data alone, using a vigilance-related activity pattern built from correlations between simultaneous fMRI-EEG in healthy young adults. For my F99 phase, I will (Aim 1.2) investigate whether a state-of-the-art image acquisition/processing method, multi-echo independent component analysis (ME-ICA), improves the correspondence between fMRI signal and EEG signal, and whether using the ME-ICA approach improves sensitivity in detecting subcortical arousal networks. Finally, I will (in Aim 1.3) attempt to distinguish between mild cognitive impaired (MCI) patients and healthy aging controls by leveraging fMRI-based vigilance as a biomarker. By comparing vigilance fluctuations and functional connectivity differences in vigilance network regions of interest, we seek to understand the role of vigilance in early-stage Alzheimer’s disease. The proposed project will help the candidate, Sarah Goodale; achieve her career goal of becoming an independent investigator at the forefront of aging neuroimaging at a research-focused institution. This project provides cutting-edge research training in EEG and fMRI analysis and advanced statistical methods. Further, the proposed studies will provide professional and technical training to prepare the candidate to successfully transition the postdoctoral (K00) phase. The postdoctoral laboratory will extend Sarah’s training to incorporate structural imaging to characterize the impact of structural degeneration on functional networks with respect to age-related cognitive decline. Vanderbilt University is an ideal environment to achieve these goals as it (1) encourages collaboration, (2) has state-of-the-art technical resources to perform cutting-edge research, and (3) contains renowned faculty that encourage training, mentorship, and the development of aspiring researchers. The complete plan proposed for both the F99 and K00 phases is designed to develop an independent neuroimaging scientist prepared for a successful postdoctoral position and transition to an aging focused career, with an ultimate goal of becoming an independent tenured investigator.

NIH Research Projects · FY 2025 · 2022-12

ABSTRACT Noise-induced hearing loss (NIHL, including clinically measurable audiometric threshold shifts) affects over 25 million adults, with the primary cause being exposure to occupational or other loud environmental sound. However, many noise-exposed individuals report difficulty hearing in noisy environments without clinically significant threshold increases. Animal model studies have revealed potential mechanisms of noise induced hearing difficulties (NIHD) and their accompanying psychophysical and physiological changes, including a candidate mechanism (with evidence from rodent models and emerging support from the macaque model) for clinically normal hearing with difficulty in noisy environments: cochlear synapse loss. However, animal models typically use single exposure protocols to create cochlear pathology, which are unlike the chronic noise exposures leading to NIHL in humans, who experience smaller, repeated daily noise doses that result in NIHL. Data from our macaque model of NIHL (having noise susceptibility similar to humans) suggests that the single exposure noise levels needed to induce NIHL and cochlear synapse loss are much higher than sound levels typically experienced by humans occupationally or recreationally. Nonetheless, preliminary data in macaques show that single noise exposures that cause temporary threshold shifts (TTS) result in cochlear synapse loss 2- months post exposure but not at 10-months post-exposure, and auditory processing deficits. This project will expand these early observations to more realistic chronic noise exposures similar to those experienced by workers. We propose psychophysical, physiological, and histological studies 1) to establish a timeline for the development of sustained auditory processing deficits and cochlear pathology in macaques chronically exposed to noise, and 2) to define behavioral and electrophysiological assays that detect changes in hearing that develop prior to permanent threshold shifts (PTS). Our hypothesis is that chronic noise exposures (8 hours a day, 5 days a week) cause a sequence of non-transient NIHD that progress to PTS. Specifically, we predict that chronic noise exposures will cause psychophysical changes (Aim 1): the earliest deficits will be in spatial and temporal processing, followed by deficits in processing signals in noise, followed by audiometric deficits (PTS). Physiological changes (Aim 2) will parallel psychophysical changes: earliest deficits will be in middle ear muscle reflex (MEMR) and measures of binaural and temporal processing, followed by deficits in distortion product otoacoustic emission (DPOAE) amplitudes and masked auditory brainstem responses (ABR), followed by deficits in DPOAEs and ABR thresholds. These deficits will be paralleled by cochlear pathology: early, non-transient cochlear synapse loss, followed by outer hair cell loss, followed by a combination of outer and inner hair cell loss (Aim 3). The results of these studies will reveal sensitive markers of early auditory damage with realistic noise exposures, and the sequence of cochlear pathology. Study results will be used to develop reliable, clinically viable early indicators of NIHL and enhance hearing loss prevention program outcomes.

NIH Research Projects · FY 2025 · 2022-09

PROJECT SUMMARY The proposed research addresses an urgent need to support personalized breast cancer treatment decision making based on the unique needs, values, and preferences of each patient. Breast cancer is the most common cancer in women, with approximately 280,000 new cases diagnosed each year. Breast cancer treatment decisions are complex as there are often several clinically viable treatment options available, each with differing risks, benefits, and implications on the patient’s life. It is important to involve patients in this preference-sensitive decision, yet, approximately 50% of breast cancer patients do not make informed decisions regarding treatment, and patients report only knowing half of the information relevant to the decision. Poor understanding or insufficient participation in the treatment decision making process can lead to poor patient outcomes, reduced patient satisfaction, and higher healthcare costs. We propose that a COMputerized PAtient-centered Collaborative Technology (COMPACT), designed with Human Factors Engineering (HFE) approaches, can improve personalized breast cancer decision making and patient outcomes. During this 4- year project, we will design and test the COMPACT system using human centered design (HCD). This research will support the PIs transition to research independence and propel her towards achieving her long-term goal of becoming a leader in the field of HFE design and implementation of augmented intelligence technologies to support teamwork in cancer care. The research will take place in the strong institutional environment at Vanderbilt University Medical Center. Building on her expertise in HFE design of health information technology (HIT), she will develop essential knowledge and skills in (1) breast cancer care, (2) design of patient HIT, and (3) implementation science. The PI will grow these skills with the following Aims: Research Aim 1 is a thorough HFE work system analysis to understand the sociotechnical work system in which breast cancer care occurs. Interviews with and observations of patients, their family caregivers, and clinicians will generate detailed care process maps and patient journey maps to support the design of COMPACT. The PI will gain knowledge on cancer care processes and the needs of breast cancer patients. Research Aim 2 is the HCD of COMPACT. Using Aim 1 findings, we will conduct a series of collaborative design sessions with patients, their caregivers, and clinicians to develop the COMPACT user interfaces. Formative usability testing and a heuristic evaluation will identify design improvements to the prototypes. The PI will develop skills in patient-facing HIT and implementation science. Research Aim 3 is the evaluation of COMPACT in a scenario-based simulation. Scenario-based simulations with potential breast cancer patients and clinicians (individually and in groups) using COMPACT under realistic conditions will evaluate COMPACT’s potential usefulness, usability, and acceptance. Future work will study COMPACT in a randomized controlled trial to understand its impact on patient care.

NIH Research Projects · FY 2025 · 2022-09

Vanderbilt University Medical Center is responding to RFA-TR-22-012 to be the Recruitment Resource Center (RRC). We will work collaboratively with each ERN study team and the other HEAL ERN Resource Centers and continue to develop and monitor comprehensive strategies to address barriers to recruitment and retention in the five funded HEAL pain studies and two additional studies, demonstrate their effectiveness in recruiting participants and broadly disseminate evidence on the most effective approaches to recruitment and retention of people experiencing pain. Our Recruitment Resource Center application has the following Specific Aims: Specific Aim 1. Develop comprehensive recruitment and retention strategies for HEAL Pain ERN clinical trials to ensure studies efficiently enroll and retain a sufficient number of participants who represent the affected pain population. Specific Aim 2. Provide centralized participant-centered recruitment and retention services to support HEAL Pain ERN sites in identifying, approaching, screening, consenting, enrolling, and retaining participants. Specific Aim 3. Implement, study, and refine novel recruitment and retention strategies (such as EHR-based participant screening, e-consent, embedding patients on study teams, and behavioral, informational and/or social incentives) and disseminate evidence on the most effective approaches to recruitment and retention of people who have pain. Our collaboration with ERN investigators and integration with the other TIN Resource Centers will maximize the likelihood of successful and timely completion of the HEAL Effectiveness Research Network clinical trials, leading to translation of research findings to the effective interventions and management strategies for pain while, improving functional outcomes, and reducing pain across the continuum of acute to chronic pain.

NIH Research Projects · FY 2025 · 2022-09

Abstract Studies of human pancreas development have begun to elucidate influences in the establishment of β cell mass and formation of islets, but genetic and environmental influences that manifest during postnatal pancreas development remain unknown. The first decade of life (termed the pediatric period for this proposal) is a dynamic time in pancreas development when two critcal processes occur: (1) β cell mass is established and (2) β cells and islets functionally mature. In addition, it is the time β cell-directed autoimmunity of type 1 diabetes (T1D) often begins. Thus, understanding the molecular and cellular processes that govern pediatric pancreas development and function is key to improving the diagnosis of children and adolescents with T1D and T2D and developing strategies to prevent, or treat the β cell dysfunction. While several ongoing initiatives including the Human Islet Research Network (HIRN) have been generating datasets from adult nondiabetic, T1D, and T2D donors, there is a major gap in deep molecular and tissue-level phenotyping of pancreata from the pediatric period. Furthermore, the contributions of vascular, immune, and other stromal cell populations and their β cell interactions, to human pediatric pancreas development are largely uncharacterized, despite their known influence on adult β cell function. Our proposal is based on our exciting single-cell multi-omic spatially-resolved pilot data that will allow us to map the context specificity of T1D and related trait GWAS signals in pancreas across cell type, age, sex, and developmental stage. Moreover, using living slice technology, we will be able to investigate cellular physiology and cell-cell communication in situ with high temporal resolution to provide an insight into processes that govern β cell maturation and establishment of healthy pancreatic architecture. The overlay of spatial, physiological, transcriptional, and chromatin data from the same organs will provide unprecedented access to define changes in molecular signatures, tissue architecture, and β cell maturation. This will not only complement phenotypic data collected from mostly adult donors in the Human Pancreas Analysis Program (HPAP), but will also generate data useful to several HIRN consortia and the broader research community. Our multidisciplinary research team with complementary expertise in pancreas and islet biology, in situ physiology, single cell genomics and epigenomics, image data analysis, statistical genetics, and machine learning devised tools and analyses to discover cell state dynamic changes across the first decade of life and define how these changes influence downstream biology from transcriptional regulation, to cellular spatial organization within the pancreas, and cellular function. If successful, these studies will provide new mechanistic insights about the functional maturation of human β cells during the critical pediatric life stages. This will likely influence the way we perceive T1D pathogenesis and lead to new therapies for diabetes and other pancreas diseases.

NIH Research Projects · FY 2025 · 2022-09

PROJECT SUMMARY Infection with non-typhoidal Salmonella is 1 of 4 most prevalent global causes of diarrheal disease. In the United States, Salmonella enterica serovar Typhimurium (S. Tm) infection results in 1.35 million illnesses annually. To infect the gastrointestinal tract, S. Tm contends with the resident commensal bacteria (gut microbiota). The gut microbiota benefits the host by limiting enteric pathogen expansion (colonization resistance), partially via the production of inhibitory metabolites such as short-chain fatty acids (SCFA) (e.g., propionate) and nutrient sequestration (e.g., amino acids). Thus, successful bacterial pathogens must possess mechanisms to survive in the competitive ecosystem of the gut. S. Tm uses a Type III secretion system (T3SS- I) to invade intestinal epithelial cells (EICs) and induce intestinal inflammation. As a result, S. Tm disrupts the host-microbiota ecosystem and overcomes microbiota-mediated colonization resistance by using inflammation- derived electron acceptors such as fumarate and nitrate for anaerobic respiration. However, the mechanisms that drive Salmonella-induced disruption of the microbial ecosystem in the gut and how this disruption affects host physiology and promotes pathogen expansion remain largely unknown. In this application, we will elucidate the mechanisms by which S. Tm-induced intestinal inflammation enables the pathogen to (i) overpower SCFA- mediated colonization resistance and (ii) gain access to microbiota-derived aspartate for anaerobic fumarate respiration. Our robust preliminary data obtained from in vitro studies and murine models demonstrate that the pathogen may use propionate metabolism to fine-tune virulence through modulation of T3SS-I expression. Our studies further reveal that S. Tm-induced inflammation causes an increase in Bacteroides-derived aspartate in the intestinal lumen and that aspartate conversion into fumarate fuels S. Tm fumarate respiration in vitro and in vivo. Our preliminary data support our central hypothesis that pathogen-induced intestinal inflammation allows S. Tm to overcome mechanisms of colonization resistance established by the microbiota by (i) downregulating invasion of EICs via catabolism of Bacteroides-derived propionate and (ii) promoting the release of aspartate by commensal Bacteroides, which S. Tm uses to outcompete commensal Enterobacteriaceae. To test this hypothesis, we will define the impact of propionate catabolism on S. Tm pathogenesis in the inflamed gut (Aim 1). Aim 2 will identify the mechanism by which intestinal inflammation promotes increased aspartate availability in the inflamed gut. In Aim 3, we will determine how aspartate enables S. Tm to overcome colonization resistance by Enterobacteriaceae, a bacterium taxon that plays a critical role in protecting the host against S. Tm infection. If successful, this research will establish critical conceptual advances in understanding how enteric pathogens exploit the gut microbiota for expansion during gastroenteritis. Expected findings will provide a deeper understanding of a novel mechanism used by this bacterial pathogen to evade the intestinal microbiota and establish infection.