Univ Of North Carolina Chapel Hill

NIH Research Projects · FY 2026 · 2024-04

PROJECT ABSTRACT Malaria is the leading cause of morbidity and mortality in the Democratic Republic of the Congo (DRC), which bears the second largest burden of malaria and accounted for 13% of global malaria deaths in 2021. Effective treatment is an essential component of malaria case management. Artemisinin-based combination therapies (ACTs) are the current first-line and most effective antimalarial treatment. Reports of resistance to ACTs in neighboring Rwanda, Tanzania, and Uganda raise concerns about the future of malaria control in the DRC and across sub-Saharan Africa. Moreover, few studies have investigated the role of overtreatment of individuals with false-positive rapid diagnostic test results and how it modifies the selective pressure of artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL), two first-line ACTs in the DRC. Improved understanding of the extent and drivers of drug resistance and of the influence of malaria misdiagnosis on selective drug pressure is imperative to inform ongoing malaria control efforts in the DRC and similar high-burden countries. This proposal uses data and samples collected during a 2015-2022 malaria longitudinal cohort study of children and adults in areas of varying endemicities in Kinshasa Province, DRC. Leveraging this well-characterized cohort as well as the two-decade of strong research collaboration between the University of North Carolina at Chapel Hill and partner institutions in Kinshasa, this proposal will focus on the following specific aims: 1) determine genetic markers and factors associated with antimalarial drug resistance, and 2) Identify predictors of overtreatment and explore the effect of recent treatment on ASAQ and AL resistance. Through this research proposal and tailored training plan, the trainee will achieve the following fellowship goals: 1) acquire advanced skills in epidemiological and statistical methods, molecular and spatial epidemiology applied to infectious diseases; 2) pursue clinical training at the intersection of infectious diseases and other areas of medicine to inform my choice of residency; and 3) hone the professional skills needed to succeed as a physician- scientist and navigate international collaborations.

NIH Research Projects · FY 2025 · 2024-04

Knee osteoarthritis (OA) is a leading cause of pain and disability. Exercise is a first-line component of care for knee OA. However, the majority of individuals with knee OA are inactive, and exercise-based physical therapy (PT) is underutilized across health care systems. There are no established processes or pathways for systematically integrating exercise-based therapies into clinical care for knee OA; this is a major contributor to underutilization. We recently developed and tested a STepped Exercise Program for Knee OA (STEP-KOA) as a systematic approach to delivering exercise-based therapies. STEP-KOA begins with a home-based exercise program, supported by evidence-based and behaviorally informed tools (Step 1). After 3 months, patients are evaluated for clinically meaningful improvement in pain and function; patients not meeting criteria for improvement “step up” to telephone-based coaching (Step 2). After an additional 3 months, patients still not meeting criteria for clinically relevant improvement progress to PT visits (Step 3). Patient-centeredness and efficiency are hallmarks of STEP-KOA, as the interventions are based on patient needs and improvement, and the more resource-intensive interventions (particularly PT) are reserved for later stages. In our randomized controlled trial conducted within the Department of Veterans Affairs Healthcare System, STEP-KOA resulted in significant improvements in self-reported pain and function compared with an Arthritis Education control group. We are preparing to conduct a multi-site hybrid type 1 effectiveness-implementation randomized controlled trial (RCT) that will take important steps toward enhancing and implementing STEP-KOA in different health systems. We will add physical activity monitoring, behavioral messaging and tailored exercise prescriptions (that emphasize progression to ensure a sufficient training response) to STEP-KOA. We specifically plan for a 2-site RCT in which individuals with symptomatic knee OA are randomized to STEP-KOA or a usual care / wait list control group., with outcomes collected at baseline, 9 months (end of intervention period) and 15 months (6-month maintenance period). In this planning period, we will: 1) Finalize the scientific details and intervention tools for the multi-site STEP-KOA RCT; this will include enhancing the STEP-KOA patient tools to incorporate the new components, refining tools for STEP-KOA coaches and physical therapists, finalizing training materials and fidelity assessment plans, establishing procedures for telehealth delivery of PT visits, finalizing assessment plans, and establishing the randomization scheme and statistical analysis plan. 2) Finalize the logistical and practical aspects of the multi-site STEP-KOA RCT; this will include identifying referring clinics and PT clinics, addressing regulatory and logistical details, building the study database and developing data management plans, finalizing recruitment and enrollment processes, finalizing the trial budget and preparing the protocol, manual of operating procedures and study timeline. The proposed planning period will ensure our team is prepared to conduct a rigorous and efficient multi-site RCT of STEP-KOA.

NIH Research Projects · FY 2025 · 2024-04

PROJECT SUMMARY A key priority for the NIH is to limit disability caused by osteoarthritis (OA) and other chronic diseases that emerge with age. Our long-term goal is to catalyze effective strategies for early intervention by establishing the mechanisms that lead to OA. Through genome-wide association studies (GWAS), it is clear that the genetic risk for OA is driven primarily by a large number of non-coding single nucleotide variants (SNVs) that alter the regulation of gene expression in chondrocytes and other cell types of the joint. Our overall hypothesis is that testing the effect of OA GWAS SNVs on enhancer strength will identify the most likely causal variants, and that analyzing transcription factor binding at these variants will provide insight into the mechanisms of genetic risk in OA. We work with cadaveric chondrocytes from donors with no history of joint disease to provide a regulatory environment that represents cartilage homeostasis. In addition to this baseline state, we also stimulate cells with bioactive matrix fragments to initiate gene expression and chromatin accessibility changes that mimic the cellular state during OA. The first aim is to identify expression modulating variants (emVars) in primary human chondrocytes at baseline and in response to an OA-relevant stimulus. We will use massively parallel reporter assays (MPRAs) to assess allele-specific activity of the 1259 variants that reside within 104 known OA GWAS loci. The results from MPRAs and expression quantitative trait loci (eQTL) studies in other cell types and diseases give us the expectation that we will identify 1-3 emVars for each of 10-30 loci and that some of these will be specific to either baseline or stimulus conditions. The second aim is to computationally determine the transcription factors that differentially bind to emVars. We expect to find that emVars preferentially reside in regions that have accessible chromatin (as determined by ATAC-seq) and contain histone marks present in enhancers (as determined by Cut & Run for H3K27ac). Further, we expect that emVars will alter transcription factor binding strength and that stimulus-specific emVars will disrupt the binding sites of transcription factors that we have shown coordinate gene expression changes in response to this stimulus. This proposal is innovative, as it represents the first MPRA in primary human chondrocytes and one of the first “response MPRAs” to test the effect of cell state on allele-specific enhancer function for any disease. These results will have a substantial effect on the field by providing some of the first examples of how specific non-coding variants alter transcription factor binding to mediate the genetic risk of OA.

NIH Research Projects · FY 2026 · 2024-03

ABSTRACT Wildfires are a threat to public health worldwide, growing in both intensity and prevalence year-by-year, particularly in regions at the Wildland Urban Interface (WUI). The health impacts associated with exposures to wildfire smoke include those relevant to the pulmonary system, including asthma, bronchitis, dyspnea, chronic obstructive pulmonary disease, and respiratory infections; however, the impacts and quantified health risks at the WUI remain understudied. This research gap likely exists due to the inherent difficulties surrounding the evaluation of these complex and variable atmospheric exposures. The team brought together by the PI has established methods and recent data measuring harmful chemicals in simulated wildfire scenarios, including conditions that incorporate anthropogenic materials indicative of the WUI environment. We have also demonstrated through vigorous pilot experimentation that different wildfire smoke conditions converge upon biological changes in the lung relevant to lung cell stress and hypoxia. Recent molecular-based experimentation has also uncovered novel mediation of pulmonary toxicity through extracellular vesicle mechanisms coinciding with incidences of cell stress and hypoxia. This study set out to test the innovative hypothesis that forest and WUI burn scenarios will initiate MOAs with shared components across in vitro, in vivo animal, and human systems, facilitating health risk predictions in humans for exposure conditions that need health guidances. We will address this hypothesis through aims designed to carry out the following: First, we will use in vitro lung models derived from human donors to evaluate biological responses across multiple forest and WUI-relevant exposures, including conditions that are difficult to evaluate in vivo, particularly in humans due to feasibility limitations and ethical considerations. Second, we will evaluate in vivo responses to select burn scenarios in mice and humans, with analyses focusing on the prototypical burn scenario of smoldering red oak, without WUI- relevant materials in humans and +/- WUI-relevant materials in mice. Biological responses that will be characterized across systems include lung cell transcriptional and protein-level responses relevant to cell stress and hypoxia, emphasizing hypoxia inducible factor 1 subunit alpha (HIF1A) and connected pathways. Functional responses will include changes in lung function in vivo and markers of tissue injury/stress/inflammation. Pulmonary secreted signals that are known to coincide with cell stress and hypoxia include extracellular vesicles, which will also be evaluated for changes in physical characteristics, count, and molecular cargo. All aims incorporate advanced computational toxicology approaches, paralleling strengths of the PI, and pave the way for health risk estimates across a wide domain of wildfire exposures. This cross-cutting approach aligns with many NIEHS goals and will serve as a solid foundation for the PI’s laboratory, to support future research efforts aimed at improving environmental and public health.

NIH Research Projects · FY 2026 · 2024-03

PROJECT SUMMARY Ischemic heart disease and its complications are the primary cause of death in industrialized nations. Following myocardial infarction (MI), ~20-30% of patients develop heart failure, primarily due to loss of contractility through cardiomyocyte death, inflammation, and formation of scar tissue. Despite intensive research efforts, outcomes from new regenerative therapies for MI - such as those utilizing stem cells - have been disappointing to date. However, there is now compelling evidence that mesenchymal stem cells (MSCs) exert their cardio-reparative effects through the secretion of extracellular vesicles (EVs), whose intrinsic biological properties make them ide- al candidates for off-the-shelf therapies for ischemic heart disease. Despite a large body of research demon- strating the tissue-regenerative effects of EVs, their efficient delivery to injured myocardium has been hampered by three significant challenges: 1) injected EVs tend to diffuse quickly; 2) EVs and other carriers are not retained long-term in the heart; and 3) local intramyocardial injection is highly invasive. Systemic injection is safer but fails to deliver a sufficient dosage to the heart. Despite significant efforts to develop targeted delivery methods, there have been no substantive breakthroughs in addressing these challenges. The main objective of the proposal is to develop a novel delivery strategy that significantly improves EV accumulation and substantially prolongs cardiac retention in the injured heart. The specific aims of the study are as follows: (1) Synthesize and optimize EV formulations and dosing regimens and evaluate their biodistribution, biocompatibility, toxicity, and immunogenicity using a mouse model of MI. Furthermore, we will assess EV interactions with cells. (2) Investigate the capability of the optimized EV formulations to facilitate cardiac repair and explore the underlying mechanisms of action in a mouse model of MI. (3) Assess the effectiveness of EVs in mediating cardiac repair in a swine model of MI. These studies will pave the way for developing off-the-shelf EV therapies that can be administered non- invasively, offering effective treatment options for post-MI care without requiring invasive, open-chest surgery. This study will establish the critical design parameters of a first-in-class, non-invasive delivery and treatment strategy achieved through controlled in situ crosslinking. Importantly, our approach can be applied to different ligands and carrier systems (i.e., micro- and nanoparticles) for enhanced accumulation and retention, not only at infarct sites, but also other diseases.

NIH Research Projects · FY 2026 · 2024-03

Summary Interstitial Telomere Sequences (ITS tracts) are degenerate telomere repeat tracts found on metazoan chromosome arms whose functional significance is not known. We propose to develop a new paradigm in the field of telomere biology, by demonstrating a telomere binding protein in somatic cells regulates a suite of stress response and longevity genes that possess introns with ITS tracts. We discovered that ITS tracts are enriched in the introns of C. elegans genes, and this is also true in humans. We identified hundreds of C. elegans genes with ITS tracts that are bound by a telomere binding protein. The vast majority of these genes are upregulated in response to environmental stresses and in mutants that are long-lived and stress resistant. We discovered environmental stresses that alter localization of telomere binding proteins to telomeres of embryos and as well as nuclear localization in somatic cells of L4 larvae. We propose to characterize how environmental stresses and longevity pathways epigenetically reprogram the expression of genes whose introns possess ITS tracts, in part by remodeling the structures of ITS tracts of genes with roles in stress resistance and longevity. Preliminary data indicate that mutating the single-stranded telomere binding protein pot-1 impedes binding of all single-stranded telomere binding proteins to telomeres. Moreover, pot-1 mutation also induces moderate longevity, and both longevity and disrupted telomere capping phenotypes can be transmitted by pot- 1 mutant gametes to multiple generations of progeny that possess wild type POT-1 protein. We propose to study the heritable consequences of telomere uncapping in pot-1 mutant germ cells on expression of genes with ITS tracts. We will ask if longevity of long-lived mutants, including pot-1 mutants, grown with or without arsenic is modified by RNAi silencing of ITS tracts or by re-wiring the expression of dsDNA telomere binding proteins. We will assess the consequences of telomere uncapping defects of pot-1 mutants as well as arsenic or copper on telomere stability in the absence of telomerase, on telomere mutations and on T-loop formation. This work will help to develop a model created by Charles Darwin and Jean-Baptiste Lamark, who hypothesized that environmental stresses perceived by parents might modify germ cells in a manner that would improve fitness of their children. This project may reveal that telomere capping as a malleable epigenetic factor that can be transmitted from parent to child and is coupled to regulation of genes with ITS tracts in their introns, in a manner that modulates longevity and resistance to environmental stress in future generations. However, because somatic telomere length shortens as humans age, and because irreparable DNA damages accumulate at telomeres in the context of human aging, insight into roles of telomere uncapping, arsenic or copper in modulating expression of stress response and longevity genes with ITS tracts may be relevant to understanding how normal human aging occurs and can be modulated.

NIH Research Projects · FY 2026 · 2024-03

PROJECT SUMMARY/ABSTRACT Food allergy affects an estimated 26 million American adults and 5.6 million children. The Consortium for Food Allergy Research (CoFAR) is a network of clinical research centers who work together to conduct clinical research to advance understanding of food allergy and the care of food-allergic patients. The University of North Carolina Food Allergy Initiative (UNCFAI) Clinical Research Center (CRC) is a leader in food allergy research, clinical care, and education. Under the leadership of Drs. Edwin Kim and Corinne Keet, the UNCFAI CRC will leverage the well-established infrastructure and resources available at the UNCFAI to conduct high quality clinical research in food allergy. The specific aims are to: (1) Develop a flexible and collaborative CoFAR Clinical Research Center to efficiently initiate, enroll, and implement multi-center trials in conjunction with the consortium, (2) Establish sustainable CRC operations through mentorship, leadership training, and research opportunities for junior investigators, (3) Propose a network-wide trial building on the strengths of the UNCFAI and the broader CoFAR network to advance treatment of food-allergic patients and (4) Perform high-yield CRC-specific research projects that expand UNCFAI research capabilities, provide opportunities for junior investigators, and inform future CoFAR research. As part of the application, the UNCFAI proposes a multi-center, randomized, placebo- controlled trial to evaluate the safety and efficacy of peanut and cashew multi-food sublingual immunotherapy in young children. Biosamples from this study will illuminate the local and systemic mechanisms of sublingual immunotherapy (SLIT). In addition, the UNCFAI will conduct two site specific research projects. Project 1 will take and analyze biosamples from a recently completed randomized, placebo-controlled trial of peanut SLIT in young children in order to identify predictors of response to SLIT and explore the mechanisms of desensitization and remission. Project 2 will create a prospective longitudinal registry of food-allergic patients in order to define phenotypes of food allergy, attitudes and preferences about food allergy management, and predictors of food- allergic reactions. These projects will inform future larger studies of food allergy while serving as training opportunities for junior investigators to ensure that UNCFAI remains a highly productive and sustainable CoFAR CRC.

NIH Research Projects · FY 2026 · 2024-03

ABSTRACT Renal cell carcinoma (RCC) is one of the most lethal urologic malignancies with approximately 81,800 new cases and 15,000 deaths estimated in 2023. Clear cell RCC (ccRCC) along with melanoma has traditionally been viewed as an immunotherapy responsive disease with a storied history of immunotherapy treatments including high dose interleukin 2 (IL2), interferon, and allogeneic stem cell transplant. Indeed, RCC was one of the first tumor types to garner FDA approval for PD1 immune checkpoint inhibition (ICI). However, unlike melanoma, most RCC tumors do not have a high tumor mutational burden (TMB) to potentially explain their immunotherapy responsiveness. We and others have sought to explain this unanswered question and have demonstrated that non-canonical tumor associated antigens like endogenous retroviruses (ERVs) may in part explain ICI response in RCC. Nonetheless, ERV expression is unlikely to fully explain ccRCC ICI response and only 25% of RCC patients respond to single-agent ICI. Therefore, further enhancing ICI response will be clinically meaningful. A collaboration between the Kim and Dominguez labs has uncovered another potentially robust source of tumor associated antigens - retained introns. We have noted that ccRCC tumors have the highest level of retained introns (RI) across all TCGA tumors, that RI levels are secondary to suppressed non-sense mediated decay (NMD) activity, and that one can subset ccRCC into RI-high and normal-like tumors. Moreover, we have found that mTOR signaling plays a key role in regulating NMD and intron retention and that mTOR inhibition can promote intron retention. Finally, our preliminary data demonstrates, in a clinical dataset, that ICI responsive tumors are enriched in a RI-high phenotype. In this proposal we will assess how NMD is regulated in ccRCC (Aim 1), determine the impact of suppressed NMD on ccRCC tumorigenicity (Aim 2), and determine the impact of NMD suppression and resultant enhanced intron retention on the tumor immune microenvironment and ICI response (Aim 3). Successful completion of our proposal will establish sound scientific premise for combining two FDA approved RCC therapies (mTOR inhibition and ICI) to promote expression of highly foreign neoantigens from retained introns (neo-RI-antigens), which should provoke a robust, antigen-driven immune response that can be leveraged to enhance immune checkpoint blockade.

NIH Research Projects · FY 2026 · 2024-03

PROJECT SUMMARY Social behavior comprises multiple distinct types of interactions that play a critical role in reproduction, survival, and over-all well-being. Dysfunction of the serotonin system has long been associated with social deficits present in a host of psychiatric and neurodevelopmental disorders, including depression, anxiety, schizophrenia, and autism spectrum disorders. It is therefore not surprising that therapeutics targeting the serotonin system, such as selective serotonin reuptake inhibitors (SSRIs), are commonly prescribed. Unfortunately, they are often ineffective in improving deficits in social behavior. Accumulating evidence supports the notion that alterations in chromatin remodelers and transcription factors play a critical role in the development of a host of disorders. Recent findings demonstrate that selective deletion of the chromatin remodeling subunit, Arid1b, in serotoninergic neurons results in social deficits in mice. Interestingly, rapid elevation of serotonin levels enhances sociability and promotes appropriate social behavior. These findings suggest that the speed and degree of serotonin enhancement is a critical regulator of its therapeutic effects. Think of the cooling effects of using a folding fan on a humid summer day in comparison to that of having central air conditioning on full blast. This analogy illustrates the difference in serotonin elevation due to SSRIs versus the potent serotonin releaser MDMA, used in our studies. Unfortunately, this effect is only temporary, and deficits resume when serotonin levels return to baseline. However, our preliminary data suggests that a simple 2-dose MDMA regimen can cause lasting increases in sociability in mice with this genetic deletion. The goal of this project is to identify the circuit, cellular, and molecular adaptations underlying this potential groundbreaking therapeutic phenomenon. By studying the neural mechanisms underlying sociability, we aim to shed light on a critically important element of the human experience, suggesting a novel approach to effective treatments for this devastating component of many neuropsychiatric disorders.

NIH Research Projects · FY 2026 · 2024-03

Abstract In South Africa (SA), depression is common in adolescents and has numerous immediate and long-term negative consequences. High exposure to childhood adversity contribute to the mental health burden among youth in SA. Cash transfer (CT) programs to alleviate poverty and its sequela are an essential part of government social protection programs reaching millions of households in the African region. While there is a growing body of evidence that CTs are associated with better mental health outcomes in adults, there is less evidence as to the impacts among adolescents who have experienced childhood adversities. The overall objective of this proposal is to determine whether, how, and under what conditions cash transfers work to reduce depression among youth exposed to different adverse childhood experiences and identify potential combination interventions that could work synergistically to promote health and well- being among South African adolescent girls and young women (AGYW) with a high burden of childhood adversity and depression. Using extant data from a rich longitudinal cohort combined with community data sources, we propose a unique set of analyses to understand how CTs work to reduce depression for adversity-exposed youth and improve later social outcomes. In Aim 1, we will identify whether the longitudinal association between childhood adversities and depression differs depending on CT exposure. We will first use data from a randomized conditional CT (CCT) trial conducted among AGYW in rural SA that followed a cohort of 2,533 AGYW (HPTN 068, ages 13-20 at baseline) from 2011-2019. Depression was measured six times over 8 years capturing a critical developmental period across adolescence into early adulthood. Childhood adversities were assessed through community and family violence exposures, poverty indicators, and low parental engagement. Using data from the Agincourt Household Socio-Demographic Surveillance (AHDSS) in which the girls’ cohort is nested, we will also determine the impact of the government of South Africa’s Child Support Grant (CSG), a monthly unconditional CT (UCT) provided to poor households provided over time girls in the 068 cohort. In Aim 2, we will examine the processes linking adversities to depression, including mediation through cognitive, emotional, and stress processes, and use moderated mediation analysis to determine how CT exposure moderates these pathways. Finally, in Aims 3 and 4 we will use causal inference models to explore how combining CTs with interventions on mediators of the adversity- depression pathways could boost promotive impacts on depression and explore how reductions in depression could reduce longer term social outcomes such as teen pregnancy, intimate partner violence, educational attainment, and financial well-being. Taken together, we anticipate that findings from this robust set of analyses will inform our understanding of how CTs may be leveraged to improve adolescent mental health.

NIH Research Projects · FY 2026 · 2024-03

Endometrial cancer is the 4th most common cancer diagnosed and 6th leading cause of cancer death among United States (U.S.) women. Today, there are more than 891,000 endometrial cancer survivors in the U.S., making it the second largest cancer survivor group among women (after breast). Black women are more likely than White women to have endometrial cancer recur and are twice as likely to die. Disparities in endometrial cancer outcomes are multifactorial; contributors likely include, but are not limited to, higher prevalence of worse-prognosis biologic subtypes, variation in symptom recognition and receipt of guideline-concordant cancer treatment, and differential survivorship care. We propose a comprehensive approach to understanding endometrial cancer outcomes within a population-based survivorship cohort. The Carolina Endometrial Cancer Study (CECS) will prospectively recruit women with newly diagnosed endometrial cancer in North Carolina using the statewide Central Cancer Registry’s rapid case ascertainment program. Within the planned cohort of ~1,700 women, we aim to enroll ~667 Black women. Baseline data collection includes retrieval of tumor paraffin blocks and medical records for detailed diagnostic and treatment history, collection of buccal samples, and administration of questionnaires offered in written, phone, or online formats. We will conduct follow-up interviews every 18 months and retrieve medical records for any additional endometrial cancer treatment or reported disease recurrence. Our aims include: 1) To assess variation in the distribution of endometrial cancer histologic and molecular subtypes that are associated with poor prognosis among Black and White women evaluated by centralized pathology review; 2) To assess variation in presenting symptoms and receipt of guideline-concordant endometrial cancer treatment among Black and White women and; 3) To assess variation in experience and provider assessment of guideline-recommended symptoms for surveillance visits and survivorship care among Black and White women. The proposed cancer epidemiology survivorship cohort uses a population-based platform and combines detailed tumor biology and patient-reported survey data to investigate endometrial cancer biology, medical care, and experience. We collect detailed information on individual-level molecular tumor characteristics; behavioral and lifestyle factors; cancer treatment, follow-up care, and recurrence information abstracted from medical records; and have an established infrastructure to link participant records to administrative insurance claims and area-level social determinants of health and health system factors. The multidisciplinary investigative team and patient advocacy support facilitate investigation of not only the proposed aims, but create a resource and infrastructure for ongoing research to advance the science of endometrial cancer survivorship.

NIH Research Projects · FY 2026 · 2024-03

The NIDDK IBD Genetics Consortium (IBDGC) has led Genome-wide association studies (GWAS) that have determined >250 genomic loci associated with IBD. The vast majority of these loci, which can contain hundreds of variants, are in non-coding regions enriched for regulatory elements. As a result, determining both the casual variant and the mechanism by which this variation contributes to IBD is not known for most. A primary goal of this IBDGC Ancillary RFA is to fill this gap. In line with this goal, we hypothesize that most IBD GWAS loci contribute to disease by altering activity of regulatory elements defined by accessible, chemically modified chromatin resulting in changed gene expression and cellular function. Molecular quantitative trait loci (QTL) define genetic variants associated with cellular processes such as gene expression (eQTL), alternative splicing isoform usage (sQTL), and gene regulation (chromatin accessible caQTL). These analyses have great potential to suggest the missing mechanistic link between GWAS loci and the associated disease. Large-scale molecular QTL efforts in human tissues and cells have primarily used biological material from non-diseased individuals. While QTLs have been identified for some GWAS loci, the recent Gene-Tissue Expression (GTEx) consortium showed a surprising lack of ability to comprehensively determine GWAS-linked eQTL. We hypothesize this lack of success specifically for IBD is due to three primary factors: (1) only performing eQTL and sQTL and not QTL related to gene regulation; (2) performing analyses in samples from non-IBD individuals; and (3) limited sample size. We propose to address this challenge by first focusing on analysis of IBD patient derived tissue samples, and second performing both expression-based eQTL and sQTL analyses and chromatin-based caQTL analyses to better link genetic variants to gene regulatory mechanisms. To better annotate regulatory region activity, we will also determine genome-wide landscapes for four histone modifications (H3K36me3, H3K27ac, H3K27me3, H3K4me3) that have been linked to IBD. Based on QTL analyses, we will identify putative casual variants in IBD GWAS loci and investigate their functional mechanisms in intestinal epithelial cells using patient derived 2D intestinal monolayer systems. The successful completion of this project will significantly increase our understanding of how genetic variation contributes to the risk of developing IBD. .

NIH Research Projects · FY 2025 · 2024-03

1 PROJECT SUMMARY/ABSTRACT 2 3 Inflammatory bowel diseases (IBDs) such as Crohn’s disease and ulcerative colitis are chronic inflammatory 4 disorders that cause damage to the gastrointestinal tract. There is no cure for IBD. Current therapies treat 5 inflammatory responses but do not target underlying causes. Research improving our understanding of 6 underlying causes of IBD can lead to improved treatment of disease. The intestinal epithelial barrier plays a 7 critical role in the development of chronic intestinal inflammation. There is increasing evidence that barrier 8 function and immune responses in IBD are influenced by genetic factors and confer disease risk. While over 200 9 genomic loci have been associated with IBD by genome-wide association studies (GWAS), only a handful of 10 these loci have known molecular mechanisms. Loci falling within non-coding regions suggests variants perturb 11 regulatory mechanisms by altering transcription factor binding and local chromatin structure but identifying exact 12 mechanisms and target genes remains challenging using GWAS alone. Mapping molecular quantitative trait loci 13 associate traits such as gene expression (eQTL) and chromatin accessibility (caQTL) with genetic variants, 14 provides evidence to functionally link variants to regulatory mechanisms and target genes. Mapping QTL in 15 diseased tissue specifically will identify regulatory mechanisms active in disease. I hypothesize that using a 16 QTL approach in colonic mucosa can reveal functional IBD variants and their regulatory mechanisms that may 17 be altered in the presence of disease. In Aim 1 I will map eQTL in IBD colon tissue to identify putative target 18 genes of IBD GWAS loci. In Aim 2 I will map caQTL in colon tissue to identify functional variants within regulatory 19 elements that may modulate expression of target genes by altering binding of transcription factors. In Aim 3 I will 20 determine the functional consequences of altered expression of CAMK2A, a putative IBD GWAS target gene, 21 on intestinal epithelial barrier function. Together, these aims will increase our understanding of the molecular 22 pathogenesis of IBD by uncovering previously unidentified regulatory mechanisms and target genes of IBD- 23 associated variants and provide novel biomarkers or candidates for therapeutic targets. This proposal seeks to 24 leverage the rigorous coursework, computational resources, collaborative environment, curated mentorship, and 25 access to clinical samples available at the University of North Carolina at Chapel Hill to provide the best possible 26 Ph.D. training in Bioinformatics and Computational Biology. This project will not only elucidate the functional role 27 of variants contributing to the molecular pathophysiology of IBD but will also provide the valuable experience 28 and training necessary for a career as an independent research investigator.

NIH Research Projects · FY 2026 · 2024-03

AI-Powered MRI Quality Control and Artifact Correction for Multi-Site Studies Abstract Magnetic resonance imaging (MRI), while commonly employed to investigate brain structure and function, is susceptible to imaging artifacts caused for instance by eye and head motion, hemodynamic changes, and mag- netic field inhomogeneities. Identifying images with questionable quality, correcting for artifacts, and discarding unusable images reduce biases in subsequent analyses, and therefore help avoid erroneous conclusions. In this project, we will develop computational tools, powered by artificial intelligence (AI), for image quality assess- ment (IQA) and retrospective artifact correction (RAC), catering to large-scale studies involving multiple imaging centers. In Aim 1, we will develop a deep learning framework for automatic, objective, fast, and accurate IQA of structural MRI data. IQA is typically performed via visual inspection by MRI technologists and can be time-consuming, subjective, and error-prone. Our method will complete IQA in milliseconds with high sensitivity and specificity. It will be designed to be easily trainable with a small amount of annotated data via semi-supervised learning. It can be used immediately after each scan to determine whether the acquired data are usable and whether re-scan is necessary. It can also be used in post-acquisition data curation to automatically identify usable images from huge image datasets. We will also develop a deep learning framework to rapidly generate derivatives, such as cortical surfaces, for inspection to ensure sufficient image quality for downstream analyses. In Aim 2, we will develop a novel RAC method to remove artifacts without requiring modification of sequences or mounting of motion markers. Existing RAC neural networks are typically trained in a supervised manner, requiring the scanning of the same subjects motionless and with deliberate motions. In contrast, our RAC method will be based on unsupervised learning, simply requiring the user to provide for training a set of clean and corrupted images, which can be from different individuals. Our method is therefore practical with considerably better adaptability. In Aim 3, we will develop techniques that will allow the methods developed in Aims 1 and 2 to be adapted to and optimized for different imaging centers, MRI scanners, and imaging protocols without requiring explicit exchange of imaging data across sites, which often requires data sharing agreements between institutions. The techniques developed in this aim will help overcome data sharing challenges for site-optimized IQA and RAC. Successful completion of this project will allow image quality assurance to be done automatically in large-scale, multi-site, and longitudinal studies, and increase the amount of usable data for improving statistical power.

NIH Research Projects · FY 2025 · 2024-03

Abstract The CDC reports that ~10% of pregnant women drink alcohol (exposing the fetus to prenatal alcohol exposure) as do ~26% of 12th grade students (adolescent alcohol exposure). Either exposure alone induces a variety of persistent outcomes in cognition and proinflammatory signaling in humans and animal models. Prenatal alcohol exposure is a risk factor for adolescent and adult drinking, adolescent drinking is a risk factor for adult drinking, and adult drinking is a risk factor for prenatal alcohol exposure, thereby creating a cycle of exposure and use that can perpetuate alcohol use disorder and harmful drinking across the lifespan. Emerging studies show that two developmental insults (“double-hit”) in an individual exacerbate outcomes. We propose to test the hypothesis that the “double-hit” of prenatal + adolescent alcohol exposure worsens cognitive outcomes in rodent models and to investigate two potential mechanisms that underlie these effects: loss of the cholinergic neurons in the basal forebrain that are critical for cognition and gliosis indicative of neuroinflammatory priming. Dr. Mooney’s lab has experience with the prenatal alcohol exposure model and studying gliosis and Dr. Robinson’s lab has experience with the adolescent alcohol exposure model and the role of acetylcholine-positive neurons. This project will generate the “double-hit” model of prenatal + adolescent alcohol exposure in mice and rats. After phenotyping the effect of exposure on cognitive behavior, brain sections will be assessed for differences in cholinergic and glial phenotype. The models developed in this proposal will be of use to us and other researchers to investigate mechanisms that underlie or contribute to the cycle of alcohol use and exposure across the lifespan, and understanding the mechanisms will allow identification of therapeutic targets and optimal windows for interventions to break the cycle.

NIH Research Projects · FY 2026 · 2024-03

PROJECT SUMMARY Although it has been established that the gut microbiota influence normal physiology and transitions to disease, the roles played by microbial proteins in these complex molecular processes are still poorly understood. Through this project, we will examine the structures and functions of diverse gut microbial enzymes, modulate their activities with targeted small molecules, and unravel their roles in human disease. Over the last five years, we have elucidated the structures and functions of key microbial protein families, created gut bacterial enzyme inhibitors, and developed novel multi-omics approaches to examine gut microbial processes. Here we will focus on pathways that are unique to the gut microbiome, concentrating specifically on bile salt hydrolases, tryptophan-indole lyases, and -glucuronidases. Bile salt hydrolases convert amino acid-conjugated bile salts to free bile acids with direct effects on the host and the microbiota. We will unravel the diversity in structures and functions of bile salt hydrolases in the gut microbiome and pinpoint the roles these enzymes play in recurrent Clostridioides difficile infection. Gut microbial tryptophan-indole lyases, or tryptophanases, are the only source indole in humans. Indole is converted to the uremic toxin indoxyl-sulfate, which exacerbates kidney and heart diseases. We will characterize tryptophan-indole lyases in the human gut microbiome and will target these enzymes with novel, potent and selective inhibitors to block indoxyl-sulfate formation in animal models. Finally, -glucuronidases reactivate previously inactivated endobiotics in the gut including serotonin, dopamine, and estrogen. We will define the roles that gut microbial -glucuronidases play in the antenatal depression experienced by one in seven expectant mothers by evaluating their impacts on neurotransmitter and steroid hormone levels. Overall, this interdisciplinary project will employ the tools of structural and chemical biology, biochemistry, and multi-omics and will take advantage of human clinical samples and select mouse models. In summary, the proposed research program will define how gut microbial enzymes influence human disease toward the development of novel diagnostic and therapeutic paradigms.

NIH Research Projects · FY 2026 · 2024-03

PROJECT SUMMARY Increasingly, consumers are vaping cannabinoids such as cannabidiol (CBD) or CBD-derived tetrahydrocannabinols (THCs), such as Delta-8-tetrahydrocannabinol (∆8-THC) and other THC isomers. Like in nicotine-containing e-liquids, flavoring chemicals are intentionally added to THC vaping liquids to make them more appealing for customers. In addition, metals, terpenes, pesticides, and microbial products have also been identified in commercially available THC vaping liquids. Chemical stability studies indicate that THCs can readily oxidize. Specifically, CBD and Δ8-THC have been shown to oxidize to their reactive quinone (CBDq and Δ8- THCq). Contaminant metals, such as Cu and Fe, catalyze the oxidation to Δ8-THCq. Similarly, flavoring chemicals like furanone compounds, providing a fruity flavor, have been shown to be pro-oxidants. However, the extent to which vaping liquid constituents, like metals and flavoring chemicals, oxidize THC isomers to reactive electrophilic quinones or other oxidation products and whether they pose a significant risk for lung health is completely unknown. Quinones, such as CBDq and Δ8-THCq, are Michael acceptors capable of covalently modifying biological molecules, especially proteins containing thiol groups. We hypothesize that 1) constituents like flavoring chemicals and metals, increase vaping-induced oxidation of THC and 2) the resulting quinone oxidation products cause airway epithelial cell toxicities through protein modification. Aim 1 will identify vaping- induced oxidation products and determine how vaping liquid constituents (metals, flavoring chemicals) affect the oxidation of THC isomers. Aim 2 will use our newly developed in vitro Vaping Product Exposure System (VaPES) to expose differentiated human bronchial epithelial cells (HBECs) to 1) commercial liquids, 2) lab-made liquids containing specific constituents, or 3) specific oxidation products. Aim 2 will link pro-oxidant constituents with protein adduction to cellular thiol groups and biological responses. Alkyne-tagged CBD and Δ8-THC analogues have been prepared for use in “click” cycloaddition to identify protein adduction of inhaled oxidant. In addition to specific targets, major proteins in the overall “adductome” will be identified, this uncovering novel cellular targets and biological pathways affected by inhalation of THC oxidation products. Aim 3 will collect nasal mucosal samples from non-vapers and frequent THC vapers and examined for a) tissue-level gene expression, b) untargeted metabolomic and proteomic profiles, and c) chemical biomarkers of exposure. Integrate multi-omic computational data analysis will be applied to uncover dysregulated immune pathways in the nasal mucosa of THC vapers. Data obtained from this grant will identify constituents of commercial THC vaping products impacting oxidation, toxicity, and normal functions of the airway mucosa in vitro and in vivo. To better understand the interaction between vaping-induced oxidation of THC products, signaling cascade initiation, and respiratory mucosal immune signaling, the translational and integrated multi-omic analysis proposed here, is critical for advancing the safety of THC vaping products.

NIH Research Projects · FY 2025 · 2024-03

PROJECT SUMMARY / ABSTRACT For decades, the analysis of Alzheimer’s brain pathology has remained, by and large, unchanged, with the detection of Aβ plaques and tau tangles representing the hallmarks features of Alzheimer’s disease (AD) that are intimately linked to cognitive decline. This traditional analysis of AD brain is very qualitative and limited by the slow and tedious “one-at-a-time” approach to detect individual markers of interest in the brain. This lack of innovation has posed major limitations in achieving more rapid, comprehensive, and quantitative views of dementia. Recently, a technology was developed called cytometry time-of-flight (CyTOF) imaging mass cytometry (IMC) and its potential for translational applications, especially neurodegenerative diseases, is remarkable. The reason for this is that we can now analyze all cell types and structures in a single experimental design. We can also quantify and mine these data to provide spatial insights into how the brain degenerates over time to establish a “brain signature” of aging and dementia. Such multiplexed analysis of a large panel of human brain samples will provide rapid quantitative insights that will inform our understanding of AD pathophysiology. In this study, we developed a “brain vulnerability and resilience” panel suitable for probing mouse and human brains, with particular emphasis on immune factors that have been implicated in AD. By probing their abundance, cell-type specific accumulation, and spatial proximity in relation to plaques and tangles, we will provide global insight into AD progression. We hypothesize that the ensemble of spatial information, gleaned from 45+ simultaneous markers of interest, will point to specific microglia subpopulations that drive or suppress brain pathology. In Aim 1, we will generate a comprehensive brain signature of aging and AD by employing IMC on a panel of human brains to derive in situ spatial information of brain health and resilience, providing a thorough assessment of disease trajectories. The inclusion of normal aged brains will also allow us to delineate the earliest stages of age-related brain changes, a timeframe that is more amenable to eventual therapeutic interventions. We will then validate the emergence of these spatial signatures using well characterized AD mouse models that show either slow- or fast-progression towards cognitive decline. In Aim 2, we will develop an automated bioinformatics approach for multi-sample IMC data to segment brain cell types and define their cellular microenvironments. We will also develop machine learning approaches to summarize the spatial patterns and predict clinical outcomes. This proposal is a highly innovative merging of unique experimental and computational strengths; it is significant since it represents a conceptual leap in how we image, visualize, and quantify brain data; and it has enormous clinical implications, since it could highlight multiplexed imaging coupled with predictive modeling to determine which patients transition from the normal to diseased state. Given that immune mediators often circulate peripherally, our study provides a foundation for the use of IMC to discover future biomarkers as readouts for immune dysfunction.

NIH Research Projects · FY 2025 · 2024-02

Abstract More than 90% of individuals experience a substantial traumatic stress exposure (TSE) in their lifetime. While most individuals recover following TSE, a substantial subset develop chronic musculoskeletal pain (CMSP). Despite growing evidence that mechanisms driving CMSP are vastly different in men and women, sex-specific mechanisms that drive the transition from acute to chronic pain following TSE remain poorly understood. This lack of knowledge is an important barrier to the discovery of novel therapeutics for the prevention/treatment of CMSP. The proposed work will help address this barrier by evaluating sex-specific, highly influential microRNA (miRNA) regulatory mechanisms affecting CMSP development. Experiments will center on miR-19, a miRNA repeatedly demonstrated to have an important sex-dependent influence on the pathogenesis of chronic pain and related neuropsychiatric disorders. Based on substantial preliminary data from the investigative team, experiments will evaluate the overarching hypothesis that miR-19 drives CMSP development differently in men vs. women via sex-dependent effects on circadian rhythm biology and TLR4-driven innate immune responses. Proposed experiments will leverage the translational research expertise of the study team by performing causation and mechanistic studies using both human cohort data and animal model systems. Human cohort data analyses will include first-in-kind transcriptomic, physiologic, and neuroimmune data collected as part of the AURORA study, a forty-million-dollar study that enrolled thousands of men and women trauma survivors and followed them prospectively over the course of one year. Objective accelerometry-based measures of circadian rhythmicity, measures of immune cell profiling/intracellular signaling (via mass cytometry), RNA and microRNA sequencing data, cytokine profiles of AURORA samples, and self-report pain and quantitative sensory testing of study participants will provide a unique opportunity to comprehensively evaluate study hypotheses. In addition, results from human cohort analyses will be supported by miR-19 knock-down, rescue, and gene expression studies in a well-validated and robust animal model of TSE-induced enduring stress induced hyperalgesia. By the end of the award period, we will have gained important new insights into sex-specific mechanisms of CMSP development and will elucidate exciting new therapeutic strategies for men and women.

NIH Research Projects · FY 2026 · 2024-02

The current study proposal is a mechanistic ancillary grant application that will leverage the infrastructure of an actively enrolling, NIH-funded, multi-site R01 research project (1 R01 AR078396-01A1). This proposal is time-sensitive because the parent R01 is currently recruiting and enrolling patients at UNC-Chapel Hill and Virginia Tech and if delayed beyond the proposed start date, the resulting sample size loss will negatively impact the power of our expanded and more comprehensive prognostic models. The parent R01 is actively recruiting patients with first-time (primary) ACL reconstructions (ACLR) to participate in a single visit to collect clinical data, patient reported outcomes, muscle strength and kinetic loading data using in-shoe wearable sensors. This session is scheduled at the time when patients are released from medical care by their physician to return to unrestricted physical activity. After the data collection session, patients are followed for 18 months via monthly electronic surveys to determine engagement in physical activity, perceived function, and occurrence of a second ACL injury. The parent R01 grant submission did originally not include motion capture due to high cost, time-burden to research participants and lack of access of the equipment required to collect kinematic data in a clinical setting. Since the parent R01 was awarded, an opensource markerless motion capture technology became available, presenting a unique opportunity to capture lower body kinematics using clinically accessible methods. The current ancillary study proposal will benefit the parent R01 tremendously through the addition of kinematic data in a clinical setting, which was not possible when the parent grant was submitted, and at a much lower cost and shorter time-line than submitting a separate grant application. In this ancillary proposal, we will utilize markerless videography while participants enrolled in the parent R01 perform jump-landing and hopping procedures. We will record and calculate joint kinematics from the ankle, knee, and hip in the sagittal and frontal planes, using two iPads in positioned within the testing area and processed using an NIH-supported open-source data capture technology (OpenCap.ai). The resulting movement data will be analyzed using advanced multi-joint approaches to derive kinematic features that will enable our research team to develop predictive models for second ACL injuries using lower body kinematics and joint coordination. The kinematic data will be combined with the existing kinetic-loading data collected from wearable in-shoe sensors (Parent R01) to develop a comprehensive mechanistic prognostic model for second ACL injury risk after primary ACLR. This highly innovative proposal will advance the understanding of mechanisms of risk for second ACL injuries through inclusion of multi-joint movement coordination during unilateral and bilateral landing tasks. The ability to detect subtle movement coordination features in a natural and unrestricted environment will empower clinicians and scientists to track progress, identify risk and optimize outcomes over the course of rehabilitation using clinically accessible and open-source technologies.

NIH Research Projects · FY 2026 · 2024-02

ABSTRACT Glioblastoma represents the most common primary malignant brain tumor with a median survival of less than 2 years. Despite extensive molecular characterization, precision oncology has had little penetration in clinical neuro-oncology, suggesting that novel therapies are needed. Many cancers, including glioblastoma, display accelerated protein synthesis associated with upregulation of major oncogenic pathways, including RTK/RAS, PI3K/AKT, MYC and β-catenin/WNT. In preliminary studies, we find that increased translation is heterogeneously distributed between tumor cells. Translation is regulated by post-transcriptional modifications of transfer RNAs (tRNAs). The human genome encodes ~500 tRNAs that recognize 61 codons for 20 amino acids, on which more than 100 types of tRNA modifications have been identified. Dysregulation of tRNA modifications is prevalent in cancer and often leads to altered tRNA abundance or function, resulting in global or codon-biased translational reprogramming. We performed a CRISPR screen of tRNA regulators to reveal critical dependencies in glioblastoma. Preliminary results suggest that tRNA regulators that integrate metabolites may be critical to glioblastoma growth. Dietary restrictions have been proposed as oncologic interventions. For example, high levels of methionine are required for the growth of many cancers, and dietary methionine restriction enhances cancer treatment through one-carbon metabolic remodeling. To date, dietary interventions for glioblastoma treatment have not been successful, of which the most studied approach is the ketogenic diet, based on the hypothesis that glioblastoma cells cannot utilize ketones efficiently and must rely on glucose as primary energy source. However, response rates have varied in different trials, limiting effective clinical translation. We recently found that dietary lysine restriction inhibits tumor growth through epigenetic remodeling of endogenous immune responses in preclinical studies. Here, we propose to interrogate metabolic rewiring and the cellular response to microenvironmental nutrients to regulate cellular translation in glioblastoma to inform the development of effective dietary intervention strategies.

NIH Research Projects · FY 2026 · 2024-02

Although evidence-based cancer screening protocols exist for several common cancer types, an estimated 70% of cancer deaths are due to cancers for which no early detection test is yet available. Multi-cancer early detection tests (MCDs) seek to fill this gap using advances in cell-free DNA detection to identify multiple cancer types from a single blood draw. This new approach to cancer screening has the potential to revolutionize early detection and reduce cancer mortality. MCDs are rapidly moving toward general commercial availability, and studies are urgently needed to improve our understanding of the risks and benefits associated with these tests and how best to implement them appropriately and effectively. To address these gaps the National Cancer Institute seeks to create the Cancer Screening Research Network (CSRN). At the University of North Carolina Lineberger Comprehensive Cancer Center, we have formed a multi-disciplinary team that is highly qualified and eager to join the NCI CSRN as the CSRN North Carolina Hub (CSRN NC Hub). Our extensive research experience in cancer screening trials and NCI clinical trials infrastructure, and our screening research affiliations both with UNC Health, our statewide health system, and with Federally Qualified Health Centers (FQHCs), demonstrates our capacity to enroll a large, comprehensive and representative populations. Our overarching aim is to accelerate research on emerging cancer screening technologies in partnership with the CSRN. In this application, we propose to (1) establish CSRN NC Hub infrastructure and linkages to build capacity for future, larger studies of MCDs and other novel cancer screening tests; and (2) enroll a comprehensive and representative participant population and conduct the Vanguard feasibility trial. We will build a population-based recruitment hub in North Carolina representative of the state’s population. For the Vanguard trial, we will enroll 2000 participants from two selected UNC Health sites and one FQHC, using a mix of innovative recruitment and retention methods demonstrated to be effective in our prior studies. Based on experience, we believe the CSRN NC Hub is exceptionally well-positioned to support the critical CSRN goal of recruiting a screening-eligible population representative of both NC and the US. As part of the CSRN, the NC ACCESS Hub will significantly contribute to the rapid evaluation of emerging cancer screening technologies and future studies of MCDs and other novel screening technologies that will yield high quality evidence to inform the use of these tests in clinical practice across US populations.

NIH Research Projects · FY 2026 · 2024-02

SUMMARY/SCOPE OF WORK BACKGROUND AND SIGNIFICANCE: Thrombotic diseases are the leading cause of death and disability worldwide. Genetic, environmental, and pharmacological factors, as well as acute and chronic inflammatory diseases, are linked to exacerbated thrombosis. Despite this heterogeneity of etiology and risk factors, thrombosis pathogenesis converges on a common pathway culminating in the conversion of soluble fibrinogen to an insoluble fibrin matrix that serves as the primary structural component of blood clots. However, there are currently no therapeutic approaches that directly modulate fibrinogen. RATIONALE: Thrombosis risk and severity are increased substantially with elevated circulating fibrinogen levels and other perturbations that promote the formation of a dense fibrin network that is resistant to degradation. This proposal is based on the concept that fibrin(ogen) can be directly targeted to produce porous fibrin clot structures with poor red blood cell retention and enhanced susceptibility to fibrinolysis with the ultimate goal of reducing thrombosis across diverse settings regardless of other confounding sequelae. The central hypothesis is that specific and selective reduction of circulating fibrinogen levels or directed suppression of fibrin matrix formation significantly protects against venous and arterial thrombosis while maintaining hemostatic potential. SPECIFIC AIMS: Innovative studies will be performed using (i) a newly developed lipid nanoparticle delivery system of a small interfering RNA (siRNA) that knocks down fibrinogen to any desired target level and (ii) genetic and pharmacological strategies (mRNA delivery) utilizing a customized fibrinogen variant (fibrinogenLOCK) that suppresses fibrin polymerization. These approaches will be used to uncover the contributions of fibrinogen and fibrin matrix formation in the development of venous and arterial thrombosis as well as to hemostasis and platelet plug formation. The specific aims are to: (1) Determine the changes in venous and arterial thrombus formation following targeted reduction in circulating fibrinogen or selective suppression of fibrin matrix formation; (2) Determine qualitative and quantitative changes in bleeding and platelet plug formation during hemostatic challenges following fibrinogen reduction or suppression of fibrin matrix formation; (3) Determine the efficacy of fibrinogen reduction or introduction of fibrinogenLOCK in mitigating thrombosis during endotoxemia (acute inflammation) and sickle cell disease (chronic inflammatory disease). EXPECTED OUTCOMES AND DELIVERABLES: This work will provide novel mechanistic insight into how quantitative and qualitative changes in circulating fibrinogen or fibrin matrix formation alters thrombogenesis. Moreover, the proposed studies will provide essential preclinical data on a novel management strategy for thrombotic disease across diverse etiologies. We expect to demonstrate that knocking down fibrinogen or introducing a polymerization-suppressing fibrinogen mutant mitigates thrombosis without impairing hemostasis, even in the context of pro-thrombotic acute and chronic inflammatory diseases.

NIH Research Projects · FY 2026 · 2024-02

Worldwide, there are an estimated 300 million individuals who are carriers of the sickle cell β-globin gene (a condition known as ‘sickle cell trait’ (SCT)). While generally regarded as a benign condition, SCT has been shown to be associated with venous thrombosis and chronic kidney disease. We propose that harsh biophysical conditions within venous thrombi or in the inner renal medulla induce sickling of SCT red blood cells (RBCs) that promotes activation of coagulation and reduced RBC deformability while increasing RBC adhesiveness. To test this hypothesis, we will use both human SCT blood samples as well as heterozygous (AS) Townes sickle cell mice to study the RBC-dependent mechanisms that lead to venous thrombosis and chronic kidney disease. We have established that AS mice develop larger experimental venous thrombi than control animals. Additionally, like their human counterparts, AS mice manifest early onset glomerular hyperfiltration and albuminuria with age- dependent reduction in glomerular filtration rate. Sub-contracts with the University of Alabama at Birmingham and Johns Hopkins University will augment the recruitment of human subjects with SCT at UNC Chapel Hill. Blood from all subjects will be analyzed in the UNC Blood Research Center using a panel of laboratory assays that mimic the biophysical environments encountered by RBCs in the kidney or within newly formed blood clots. The mouse model studies will be used to test the ability of anti-sickling, anti-thrombotic and anti-adhesive therapies to prevent/reduce enhanced venous thrombosis and renal dysfunction observed in the AS mice.

NIH Research Projects · FY 2025 · 2024-02

Summary UNC-IMSD The long-term goal of the Initiative for Maximizing Student Development at the University of North Carolina at Chapel Hill (UNC IMSD) is to contribute to diversifying the leadership of biomedical science. We work towards this goal through an integrated suite of synergistic junior scientist development programs focused on biomedical PhD students from groups under-represented in the sciences due to historical exclusion. Our approach is a comprehensive, personalized, start-to-finish program led by a team of expert PhD-trained Directors and dedicated faculty who work to support the scientific, personal, and professional development of UNC biomedical PhD students from under-represented groups (URGs). We provide activities targeted to empower URG students and enhance both scientific identity and self-efficacy at key transition points in their graduate training to increase the likelihood that they persist to degree completion and in their chosen scientific careers. UNC IMSD is embedded in the UNC Office of Graduate Education, an institutionally-funded administrative unit that coordinates development, recruitment, and extensive support for 15 PhD programs. Leadership in this Office consists of multiple PhD-trained program Directors, including the two Directors of IMSD, whose full-time roles are to facilitate student success and to inspire continual improvement in graduate education practices in collaboration with the faculty PIs. The substantial resources devoted to graduate education at UNC through this Office provide numerous advantages to IMSD participants and members: i) ready access to expert advisors who have been through similar training , ii) a large and supportive community of peers from similar backgrounds and experiences, iii) individual academic support at key transitions (e.g. coursework, critical literature analysis, rotation and thesis lab selection, qualifying exams), and iv) customized professional development opportunities. Since 2006 the IMSD has financially supported 196 participants; 60 are still enrolled and on track to graduate, and 107 have graduated with a PhD (>85% retention). Participants published 308 peer-reviewed publications, 137 as first authors. Moreover, during this period an additional 64 graduate students were affiliated members of the IMSD community and benefitted from the program. As an R25-supported program since 1996, we institutionalized and broadly disseminated multiple successful innovations developed over many years. These elements benefit all graduate students – from under- represented and well-represented groups – and include faculty mentor training and a dedicated wellness counselor. We also engaged in scholarship of graduate admissions, graduate training, and workforce diversity; our studies have been published and have had impacts beyond UNC. In the proposed next phase of UNC IMSD as a T32, we have the following core Objectives: 1) develop and recruit high potential students from URGs, 2) facilitate academic and degree progress to PhD completion, 3) foster a community of thriving future scientific leaders, and 4) promote an inclusive training environment and cultural change.