Univ Of North Carolina Chapel Hill

NIH Research Projects · FY 2025 · 2025-09

Asthma is a common and expensive chronic medical problem that incurs approximately $81.9 billion annually in health care costs, the bulk of which are attributable to emergency care visits and hospitalizations for asthma exacerbations. Most acute asthma exacerbations are triggered by respiratory viral infections and treated with systemic steroids as the standard of care to suppress inflammation. However, steroids do not target neutrophilic inflammation and mucus plugging, common problematic features of exacerbations. In addition, short courses of systemic steroids have multiple long-term adverse effects, exert broad immune suppression, and most importantly, failed to reduce hospitalizations due to viral exacerbations. To address the gap in steroid-sparing treatment options that can work quickly and effectively in asthma exacerbations, this pilot proposal will incorporate early intervention with the IL-1 receptor antagonist (IL-1RA), anakinra, as part of a home-based asthma action plan at the start of a moderate exacerbation with the goal of preventing severe exacerbations requiring systemic steroids. Anakinra is a recombinant IL-1RA with a fast onset of action and short half-life that is currently FDA-approved for the treatment of rheumatoid arthritis. Using a model of dust mite allergen inhalation in humans, we have shown that airway IL-1β associates with acute bronchoconstriction, eosinophil recruitment, and T2 cytokine production. We successfully and safely used anakinra pre-treatment to mitigate neutrophilic airway inflammation after environmental endotoxin challenge in healthy volunteers. We have also shown that IL-1RA treatment reduces rhinovirus-induced neutrophil chemoattractant release from airway epithelium and modulates mucin secretion without attenuating antiviral responses. We hypothesize that anakinra’s anti-inflammatory activity and fast onset of action without broad immunosuppressive effects make it an attractive candidate to test if using this steroid-sparing treatment during a moderate asthma exacerbation can prevent severe exacerbations. Our team has conducted hybrid decentralized observational studies and clinical trials in patients at high-risk for asthma exacerbations that have incorporated telehealth and digital health technologies and home-based sampling for inflammatory mediators. Leveraging this prior experience, the Anakinra Rescue Treatment for Moderate Asthma Attacks (ARTMA) pilot study will support the development of a multi-site hybrid decentralized double-blinded, randomized phase II clinical trial. The phase II trial will test if home-based administration of anakinra at the onset of a moderate exacerbation can prevent severe exacerbations requiring systemic corticosteroids and emergency care visits. We will determine the feasibility of recruitment, enrollment, and retention for a trial that requires self-administered injections (Aim 1); adherence to critical protocol operational tasks and rates of moderate exacerbations (Aim 2); and preliminary safety and efficacy of anakinra treatment during a moderate asthma exacerbation (Aim 3). This paradigm-shifting approach to asthma care has high potential to reduce morbidity and mortality and healthcare costs.

NIH Research Projects · FY 2025 · 2025-09

ABSTRACT Alzheimer’s disease and related dementias (ADRD) disproportionately impact Black Americans. Most people with ADRD and their family decision-makers prioritize comfort, yet burdensome interventions and lack of shared decision-making about goals of care are common in NHs with a high proportion of Black residents. Evidence supports systematic communication interventions to address practice variation in shared decisionmaking about treatment, with resulting difference in quality of care and outcomes. An experienced team of investigators proposes GOC ADVANCE (Goals of Care- Addressing Variation for Alzheimer's disease Nursing home Care at End of life), a clinical trial conducted in NHs with a high proportion of Black American residents. The over-arching premise is that GOC ADVANCE will improve communication and treatment decisions in latestage ADRD. Research design uses the RE-AIM framework to assess implementation and impact, in partnership with Community Advisors to optimize implementation. The Specific Aims are: Aim 1. To conduct a real-world efficacy cluster RCT (NIA Stage III) comparing 3-month communication outcomes among ADRD decision-makers in NHs randomized to the GOC ADVANCE intervention vs usual care. NHs with > 35% Black residents will be randomized to intervention vs. usual care (16 NHs, N=8 NHs/arm). Participants will be family decision-makers and NH residents with late-stage ADRD (n=300, 150 dyads/arm, >35% Black American). Communication outcomes ascertained in decision-maker interviews at 3 months are: Quality of Communication (primary), perceived goal concordance with NH clinicians (secondary), and Feeling Heard and Understood (secondary). Aim 2. To compare 6-month care management outcomes (secondary) between residents in NHs randomized to the GOC ADVANCE intervention vs usual care. Outcomes ascertained in decision-maker interviews are: % of decision-makers reporting new decisions for limitations on resuscitation, tube feeding, hospitalization, % with decisions to initiate comfort care or hospice, and number of hospital transfers per persondays. Aim 3. To evaluate the implementation of the GOC ADVANCE intervention. Guided by RE-AIM (Reach, Effectiveness, Adoption, Implementation and Maintenance), implementation will be evaluated for Black and White dyads using: 1. Quantitative measures (e.g., % decision-makers who viewed the video) and 2. Qualitative data obtained from semi-structured interviews with NH staff (n=16) and family decision-makers (total, N=32; Black, N=16; White, N=16) about their experience with the intervention.

NIH Research Projects · FY 2025 · 2025-09

ABSTRACT Respiratory problems during childhood, including reduced lung function and asthma symptoms, present a threat to healthy child development. There is increasing evidence linking prenatal and early childhood adversity, such as poverty, violence, or maternal depression, to multiple respiratory health problems over the lifecourse. Childhood adversity may be a promising target for prevention of respiratory problems, but has never been the focus of a randomized control trial. In addition, there is a dearth of longitudinal evidence on how childhood adversity impacts respiratory health from low resource settings, such as low-and-middle income countries (LMICs), where the majority of the disease burden lies. In this study, we propose leveraging an ongoing birth cohort with a randomized controlled trial of a maternal depression intervention to generate important evidence on how childhood adversity impacts child respiratory health. Specifically, we will test whether a maternal depression intervention is an avenue for improving child respiratory function. In addition, we will study how multiple adverse experiences from pregnancy through middle childhood affect respiratory health in early adolescence in a low resource setting. We will achieve this by expanding on the Bachpan study, a birth cohort of roughly 825 mother-child dyads in rural Pakistan (R01HD075875, PI: Maselko). Led by a strong and multi-disciplinary team, the Bachpan study is a birth cohort with a nested cluster randomized controlled trial (cRCT) of a maternal depression intervention. Building on our team’s successful track record in implementing the Bachpan cohort study from pregnancy through child age 8, this proposal will fund an additional data collection wave focused on lung function and respiratory symptoms at child age 11. The resulting unique dataset enables us to test several key hypotheses about the impact of common adversities (poverty, violence, and maternal depression) spanning multiple development periods (pregnancy, infancy, early childhood, middle childhood) on respiratory health at age 11, as well as the potential role of a psychosocial maternal depression intervention. Additionally, hair-derived markers of child hypothalamic-pituitary-adrenal (HPA) axis activity are available for a subset of the children from multiple time points, facilitating an analysis of potential physiological pathways through which adversities may shape respiratory health. This innovative and cost-effective study will allow us to capitalize on an existing study infrastructure, cRCT design, and extensive longitudinal dataset to: (1) test whether targeting maternal mental health may have benefits for child respiratory health, and (2) gain a holistic understanding of how childhood adversity and physiological regulation during varying developmental windows (prenatal, infancy, early childhood, middle childhood) relate to child respiratory function at age 11.

NIH Research Projects · FY 2025 · 2025-09

Modified Project Summary/Abstract Section Preliminary evidence suggests that rates of unintended pregnancies may differ by sexual orientation, and there may be additional differences among subgroups of women within sexual orientation groups. For example, women who live in different states may experience differences due to varied access to reproductive health care from varying state policies. This project will combine data from two large national longitudinal cohorts to see how these differences in state policy contexts and demographic characteristics impact differences in unintended pregnancies and associated adverse pregnancy outcomes. The proposed research is an essential next step towards (1) elucidating the mechanisms that affect unintended pregnancies and their outcomes (2) identifying particular policies that promote health and wellbeing, and (3) improving pregnancy outcomes for all.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT There is a significant lack of evidence to guide care for patients with UC following a restorative proctocolectomy with IPAA. Specific evidence gaps include 1) an absence of reliable risk factors for recurrent or chronic pouchitis and 2) a lack of evidence-based approaches for the primary or secondary prevention of pouchitis and pouch-related disorders. The overarching hypothesis underlying this proposal is that rifaximin will be a safe, tolerable, and ultimately effective method of secondary prevention of pouchitis. In this proposal, we aim to 1) demonstrate the feasibility of recruitment, retention, and protocol fidelity of rifaximin as a method of secondary prevention of recurrence after an initial episode of acute pouchitis in a single-arm, open-label pilot study, 2) determine the safety and tolerability of rifaximin as a method of secondary prevention of recurrence after an initial episode of acute pouchitis in a single-arm, open-label pilot study, and 3) explore differences in microbiome profiles from whole genome sequencing of patients at specific time points during 12 months of rifaximin treatment following an acute episode of pouchitis and microbiota profiles from samples collected at the same time points from patients not treated with rifaximin following an episode of acute pouchitis collected in an ongoing study funded by my K23 award (external control population). We will carry out these objectives in a single-arm, open-label, pilot study, where patients will receive rifaximin for 365 days after an initial episode of pouchitis and appropriate treatment with 14 days of antibiotic therapy via a standard protocol. Patients will complete patient reported outcomes (PROs) and submit stool samples at pre-specified, serial time points to allow for both assessments of feasibility of rifaximin as a method of secondary prevention as well as tolerability of this therapy. Additionally, serial stool samples will allow for exploration of differences in the microbial profiles via whole genome shotgun sequencing among patients treated with rifaximin and stool samples submitted at serial time points in a separate prospective cohort funded by Aim 3 of my K23 award. Completion of these aims will demonstrate the safety and tolerability of rifaximin as a method of secondary prevention of pouchitis, explore the mechanisms underlying the potential role, and demonstrate the feasibility of a future multicenter randomized controlled trial. Furthermore, these proposed aims and their associated pilot data will allow me to pursue my ultimate goal of developing tailored interventions for those patients at the highest risk for developing chronic inflammatory conditions of the pouch and crafting strategies for the potential early prevention of these conditions.

NIH Research Projects · FY 2025 · 2025-09

ABSTRACT Women in low- and middle-income countries (LMICs) shoulder a disproportionate burden of cervical cancer, accounting for 85% of new cases and 90% of deaths worldwide. Women living with HIV (WWH) -70% of whom reside in Africa – are at especially high risk, with up to 6-fold increased likelihood of developing cervical cancer due to higher incidence and persistence of human papillomavirus (HPV) infection. Consequently, cervical cancer is the leading cause of cancer-related death for WWH in LMICs. Although the World Health Organization (WHO) recommends thermal ablation for treating cervical precancer, recurrence of cervical intraepithelial neoplasia grade 2/3 (CIN2/3) in WWH following ablation alone can reach 33% within a year of treatment. This high recurrence partly stems from thermal ablation’s inability to clear HPV infection in WWH, which is associated with up to 20-fold risk of CIN2/3 recurrence. This is a significant limitation and calls for urgent and accessible solutions to improve cervical precancer treatment outcomes in this population. Drawing on evidence from U.S-based randomized trials and a recent Phase I pilot study in Kenya, we propose to investigate the use of 5-Fluorouracil (5FU), an affordable, widely available chemotherapeutic agent, as a patient-administrated intravaginal therapy following thermal ablation to improve HPV treatment outcomes among WWH in Kenya. While 5FU’s safety and efficacy as a primary and adjuvant cervical precancer treatment have been demonstrated in high-income countries, no randomized trials have investigated its use as an adjuvant therapy following thermal ablation among WWH in LMICs, where the disease burden is greatest. This study will address this gap by conducting a pilot Phase IIa randomized placebo-controlled trial to evaluate the safety, adherence, and preliminary efficacy of self-administered intravaginal 5-fluorouracil (5FU) following thermal ablation in HPV-positive WWH. We will enroll 140 WWH in Kenya and randomize them 1:1 to receive either 5FU or a placebo after undergoing thermal ablation. Our aims are 1) to determine the safety of 5FU, including its effect on genital HIV viral shedding; 2) to evaluate adherence to the self-administered regimen using both self-reported data and ultraviolet light inspection of applicators; and 3) to determine preliminary efficacy by comparing type-specific HPV clearance rates between the two treatment arms at 24 weeks. The trial builds on a successful Phase I single-arm trial of self-administered 5FU in Kenya and leverages well- established partnerships with local healthcare facilities, research institutions, and the Ministry of Health (see letter of support). Findings will inform future Phase IIb or III trials evaluating 5FU as an adjuvant therapy for preventing CIN2/3 recurrence among WWH in Africa and other resource-limited settings. If proven safe, effective, and acceptable, self-administered 5FU could offer a widely scalable approach to improve secondary prevention of cervical cancer for millions of WWH globally, helping to move closer to the global goal of eliminating this preventable cancer.

NIH Research Projects · FY 2025 · 2025-09

Sickle cell disease (SCD) arises from a gain-of function mutation of hemoglobin (Hb) in which sickle hemoglobin (HbS) polymerizes, but only after it has delivered its oxygen, and become deoxy-HbS. These polymers wreak havoc inside the red blood cells (RBCs), resulting in rigid, adhesive, and fragile RBCs, then anemia, inflammation, and, with time, progressive vasculopathy. SCD comprises both homozygous sickle cell anemia (SCA, HbSS or HbSb0) and variant (HbSC or HbSb+). We will focus on SCA which is more common and has been historically most affected by low oxygen or ‘hypoxemia’. A decreased oxygen level, measured as a low saturation of Hb (SpO2), likely makes SCA worse due to the central role that deoxy-HbS plays in damage from sickle cell. An association between hypoxemia during sleep and impaired brain, genitourinary, and cardiopulmonary health has been described in children with SCA. Studies of sleep-associated hypoxemia in adults have been less informative, likely due to the inability of even well-designed single site studies to fully describe subtle comorbidities. In this proposal, we will examine the prevalence, impact, and response to treatment of hypoxemia during sleep in adults with SCA, the most severe form of sickle cell disease, at 4 institutions, encompassing dense urban sites (Philadelphia, Newark) and more heterogeneous sites (Birmingham and Chapel Hill, with significant rural outreach). This multi-site study will focus on patient reported outcomes, a cognitive screening test, clinical co-morbidities, routine clinical labs, echocardiograms to identify right to left shunts (which may contribute to this low oxygen), and cellular biomarkers. We want to understand the prevalence of, and impact of treatment for, sleep hypoxemia. A secondary aim will be to identify meaningful short term RBC and plasma biomarkers, which could be helpful in better identifying and managing this comorbidity. Significant barriers to multi-site prospective studies in SCD include a lack of coordination amongst centers, inconsistent and inadequate government and foundation support, and lack of access to a longitudinal prospective national registry. (None of which are true in parallel more supported diseases such as Hemophilia and Cystic Fibrosis). Recently, there has been a sustained effort, by affected individuals living with SCD and their health care communities, to comprehensively address complications from SCD in the modern era. The American Society of Hematology clinical trials network (ASH CTN), which facilitates intra-institution coordination, and the globin research network for data and discovery (GRNDaD) registry, which streamlines longitudinal deidentified data collection at multiple sites, are two new collaborative efforts that we are accessing in order to lower barriers to multi-site studies in SCD. We do not have many treatments for SCD; there is an urgent need to identify modifiable risk-factors, such as occult sleep hypoxemia, in adults. It is possible that evaluation for sleep hypoxemia may be an important part of improved health care for adults with SCA, and this proposal seeks to begin to answer that question.

NIH Research Projects · FY 2025 · 2025-09

Outcomes in human papillomavirus (HPV)-associated cervical cancer are significantly worse in rural areas than in urban areas, with high-risk women living in rural areas being disproportionately affected. Complex, multifaceted access barriers in rural areas often result in delayed screening and late-stage diagnoses. HPV self-collection (HPVSC) can mitigate access barriers to cervical cancer screening among high-risk, rural women. However, barriers to using HPVSC kits remain. Intentional, coordinated efforts to engage trusted community messengers at both the individual (community health workers [CHWs]) and community levels (community-based organizations [CBOs]), may address access barriers to cervical cancer screening in rural communities. However, few studies have engaged both CHWs and CBOs synergistically as collaborators in interventions to address access barriers to cervical cancer screening in rural areas. The purpose of this study is to develop and test the feasibility and acceptability of a multi-level, community-engaged intervention that unities trusted CBOs (community-level) and CHWs (individual-level) to increase access to cervical cancer screening using HPVSC outreach among women living in a high-risk, rural county and improve navigation for follow-up screening. We aim to 1) Develop a community advisory board (CAB) to inform the development of a multi-level intervention designed to increase uptake of HPVSC kits and evaluate CAB capacity, function, and long-term sustainability; 2) Co-develop an intervention protocol with the CAB intended to reach rural women at high-risk for cervical cancer and improve completion of follow-up screening among women testing HPV-positive; and 3) Assess the feasibility and acceptability of the intervention protocol, and preliminary outcomes, HPVSC kit return and HPV positive screening rate, among high-risk, rural women. A one-group intervention evaluation design will be used to pilot test the feasibility and acceptability of the multi-level intervention and to assess the proportion of women who return HPVSC kits and screen HPV-positive. We will recruit 100 participants from a rural county in North Carolina. At the community-level, local CBOs will serve as HPVSC kit distribution sites. At the individual-level, trained CHWs will collaborate with CBOs to provide navigation throughout the HPVSC process: Specimen collection, kit return, result notification, and follow-up clinic-based screening for women testing HPV-positive. We will apply select domains from the RE-AIM framework to assess feasibility outcomes using predetermined parameters. Quantitative surveys will measure acceptability of intervention components and qualitative interviews will explore women’s and community partners’ experiences in the intervention. Findings from this study will provide insight on a novel multi-level, community-engaged intervention intended to increase access to cervical cancer screening using HPVSC kits and provide navigation to follow-up care in high-risk, rural communities.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT Phthalates are ubiquitous environmental endocrine-disrupting chemicals with a wide range of potential adverse health effects. Laboratory studies have identified developmental effects of phthalates on cardiovascular and adipose formation and growth, contributing to adverse cardiometabolic outcomes across the lifecourse. Human studies have only recently been able to noninvasively assess fetal cardiovascular and adipose development, and few studies have prospectively evaluated cardiometabolic outcomes following prenatal phthalate exposure. In the HPP-3D Study, 90% of pregnancies were exposed to phthalates and new chemicals used to replace phthalates (alternatives), highlighting the critical need for human studies to better understand the impact of these chemicals on cardiometabolic health. The overarching objective of this proposal is to investigate associations between prenatal phthalates and phthalate alternatives and fetal (Aims 1 and 2) and pediatric (Aim 3) cardiometabolic outcomes in the HPP-3D Study. With up to eight exposure assessment timepoints, this study has one of the most comprehensive characterizations of prenatal nonpersistent environmental chemical exposures to date. Utilizing innovative tools to repeatedly assess fetal cardiovascular outcomes and body composition, I will provide novel insight into associations between these well-characterized exposures and longitudinal fetal cardiometabolic development in the K99 phase. Building on this rich resource, I will employ a two-pronged approach to conduct follow-up of HPP-3D Study children in the R00 phase using electronic medial records (Aim 3a) and advanced cardiometabolic assessments during an in-person clinic visit on a subset of 40 children (Aim 3b). The proposal will incorporate innovative environmental mixture methods and will examine periods of susceptibility across pregnancy to appropriately quantify the human exposure experience, identify biological mechanisms, and improve targeting of future exposure investigations and interventions. With the majority of American youth having at least one cardiometabolic abnormality, there is a critical need to identify intervenable risk factors for adverse cardiometabolic development. This research will therefore provide crucial insights into the effect of endocrine-disrupting phthalates and phthalate alternatives on human cardiometabolic development, which will have implications for the etiology and prevention of cardiometabolic dysfunction. To be successful in the proposed work and launch my independent research career, I will build on my strong prior epidemiologic training with experiential and didactic professional development trainings in environmental and cardiovascular assessments and the conduct of clinical research. This training will take place within the interdisciplinary environment of the Intramural Research Program at the National Institute of Environmental Health Sciences with the support and mentoring of highly accomplished epidemiologists and physician-scientists. This career development award will launch my independent research career investigating the impact of environmental exposures on early cardiometabolic health.

NIH Research Projects · FY 2025 · 2025-09

ABSTRACT Dialysis vascular access is the Lifeline for the 500,000 plus patients currently on hemodialysis in the United States (3 million+ worldwide). Unfortunately, due to the complications associated with dialysis vascular access, it is also the Achilles Heel of hemodialysis. We and others have previously demonstrated that good early AVF blood flow (1 day - 6 weeks) is the most powerful predictor of AVF success and failure. In an attempt to optimize early blood flow profiles, we have previously developed a biodegradable magnesium stent that increases early AVF flow and diameter (at 1-2 weeks), but which also unfortunately causes later neointimal hyperplasia (NH) and stenosis because of a slow (and fixed) degradation rate (needed to prevent early collapse of the stent). The central goal of this proposal, therefore, is that the application of the Smart ArterioVEnous (SAVE) stent technology through a magnetically operated galvanic corrosion electro-chemistry loop will allow for the SAVE stent to switch from a non-degrading to degrading mode at a fixed early time point (likely 2 weeks), thus maximizing the early scaffolding and balloon dilation effect, but minimizing the later stenotic effect (due to neointimal hyperplasia). We aim to achieve this central goal through the following Specific Aims. In Specific Aim 1 we will detail the scaffold strength and degradation profiles of the smart stent on the bench. In Specific Aim 2 we will describe in-vivo technical feasibility, toxicity and degradation in a validated pig model of AVF stenosis. And finally, in Specific Aim 3 we will document the clinical efficacy of the SAVE stent compared to a standard Mg stent and a control AVF. In summary, the current proposal is both significant and innovative because it would allow us to get away from the current one size fits all paradigm for vascular access care to a future individualized and precision medicine approach where the SAVE stent could be switched to degradation mode only when the AVF flow is predictive of AVF success. We strongly believe that this series of high risk, high reward experiments targeting the intractable clinical problem of AVF maturation failure, could significantly reduce the morbidity, mortality and economic cost associated with vascular access failure, and most importantly, greatly improve the quality of life of our patients. Last but not least this is clearly a platform technology which could also be applied to other vascular beds (coronaries, carotids and peripheral arteries) and to non-vascular settings such as tracheal, hepatobiliary and ureteral stenoses as also to orthopedic applications (plates and screws).

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT Chronic pain in youth is often undertreated and/or neglected, leading to long-term consequences across the lifespan. The most common chronic pediatric orofacial pain complaint is temporomandibular disorder (TMD), a broad term which encompasses pain and/or dysfunction in the masticatory muscles, temporomandibular joint, and/or their associated structures. TMD pain affects up to 30% of adolescents, yet there is a general absence of studies concerning treatment strategies for its management in pediatric populations. Adolescents with TMD pain exhibit significant variability in their levels of pain and pain-related disability and distress, which is influenced by individual psychosocial factors and underlying physiology. To develop personalized, patient-oriented treatment approaches, it is crucial to identify distinct patient subgroups based on clinically relevant features, including physiologic outcomes, pain characteristics, and psychosocial factors, to determine which subgroups are more responsive to treatment. Physical self-regulation (PSR) is a biobehavioral intervention that directly targets the physiological and psychosocial elements that characterize individuals with TMD pain, through increasing a patient’s ability to individually self-regulate his/her physical and psychological state. The novel use of PSR in adolescents with chronic TMD pain holds promise for a personalized treatment regimen customized to an individual patient’s specific phenotypic profile. The long-term objective of our proposed research program is to identify subgroups of adolescents with chronic TMD pain who are more likely to respond to PSR treatment. A critical first step is to characterize individual phenotypic differences among adolescents presenting with chronic TMD pain. This application proposes to characterize physiologic processes associated with chronic TMD pain in adolescents using heart rate variability, salivary stress hormones and inflammatory cytokines, and quantitative sensory testing (Aim 1) and evaluate patient-reported outcome measures of pain characteristics and psychosocial factors using validated questionnaires (Aim 2) in order to identify distinct subgroups of adolescents with chronic TMD pain (Aim 3). Altogether, data generated from these aims will be used to guide the design and implementation of a randomized controlled trial to evaluate the efficacy of PSR among subgroups of adolescents with chronic TMD pain. Integration of a tailored, behavioral change intervention such as PSR has the potential to significantly improve the quality of life in not only adolescents with chronic TMD pain, but also youth suffering from other chronic pain conditions. Our interdisciplinary team is uniquely qualified to conduct the proposed work as we have the necessary experience, expertise, and facilities required to achieve our aims. This application includes collaboration between experienced and junior faculty across multiple disciplines to ensure the rigor and translation of our findings.

NIH Research Projects · FY 2025 · 2025-09

Obesity remains a critical public health concern. Digital web- and mobile-delivered behavioral weight loss (BWL) interventions with little or no human support are low-cost approaches to adult obesity treatment with 30- 60% of participants achieving 5% weight loss at 6 months. Newer, adaptive intervention approaches have provided alternative treatments to participants who are struggling (non-responders), but few have been tested and have universally used early weight change as an indicator of treatment response. This focus on early weight change obscures the importance of proximal behavioral goals, including the impact of adherence to prescribed dietary recommendations on weight change, and there remains a gap in understanding what types of intervention components can directly target and improve dietary adherence. To fill this gap and inform precision intervention approaches, and in response to NOT-OD-21-100 (NOSI: Improving Patient Adherence to Treatment and Prevention Regimens to Promote Health), we will use an innovative design that uses a factorial trial, as part of the Multiphase Optimization Strategy (MOST) framework, to optimize dietary adherence for non-responders in a mobile BWL intervention. Our team developed a standard mobile-delivered BWL program (core BWL) that is automated except for a brief kick-off session with staff. The core BWL includes daily calorie goals and smartphone-based calorie tracking (dietary self-monitoring; DSM). In our pilot trial, participants identified as non-responders in the first 8 weeks (participants who had 2 consecutive weeks with < 3 days/wk of DSM and calorie goal adherence; 64% of sample) achieved -2.5% (SD=4.8) weight loss at 6 months compared to -11.0% (SD=8.0) among responders. Thus, in the proposed trial we will recruit N=580 adults to participate in the 6-month core BWL program and will use DSM data to continually evaluate and identify participants who are non-responders (< 3 days/wk DSM and calorie goal adherence in prior 2 weeks) over the first 8 weeks. At the time participants are identified as non-responders (~ 65% of sample; N=377), they will be randomized in a factorial trial to receive or not receive each of 4 additional intervention components that specifically target improved dietary adherence: 1) switching to a simple dietary approach, 2) adding autonomous goals + planning modules, 3) adding just-in-time (JIT) messages, and 4) adding 3 coach sessions. Assessments will occur at baseline, 4 weeks (brief), 8 weeks (brief), 3 months, and 6 months to accomplish the following aims: 1) Determine the combination of additional intervention components that maximize dietary adherence among non-responders; 2) Conduct mediation analyses to test the relationships between the additional components and hypothesized mediators (self-regulation, perceived competence, relevance, supportive accountability); and 3) Conduct moderation analyses to identify for whom the additional components are most effective and predictors of early response. Our findings will inform the development of an optimized adaptive intervention that maximizes adherence to prescribed dietary recommendations.

NIH Research Projects · FY 2025 · 2025-09

ABSTRACT Child neurodevelopment (ND) is significantly impacted by nutrition in early life, a time of rapid growth and intricate development of the neurological system. In low resource settings, we now know that meeting nutrient recommendations alone is not enough to support optimal child growth and ND—a key driver of malnutrition and poor ND is environmental enteric dysfunction (EED), a subclinical intestinal condition of chronic inflammation and increased permeability. Therefore, to reduce the burden of poor ND, novel nutritional interventions are needed that incorporate this new understanding of intestinal health. Rice bran is a food with known prebiotic properties, important nutrients and phytochemicals, and has been shown to decrease biomarkers of intestinal damage and improve child growth. In addition, common beans provide essential amino acids and contain fiber, folate, iron and zinc that might further slow the progression of EED. In addition to appropriate nutrition, psychosocial stimulation in early childhood may have positive effects on ND, independent of nutrition. A caregiver training implemented by members of our research team resulted in higher quality caregiving and improved child ND in high-risk children in other low-resource settings. The potential benefits of combining this caregiver training with an “intestinal health-targeted” nutritional intervention on child ND are not known. Together with US academic partners, the Fundación para la Salud Integral de los Guatemaltecos (FSIG) has shown the feasibility of rice bran supplementation at the study site and has adapted the performance-based Mullen Scales of Early Learning (MSEL) to this context, revealing a high burden of poor child ND. In the proposed study, our multi-disciplinary team plans to conduct a randomized controlled trial with a 2X2 factorial design to understand the individual and combined effects of an intestinal health-targeted nutritional intervention and a caregiver training on child ND. We will integrate Guatemalan trainees in psychology, nursing, and nutrition into this research to build local capacity in child ND research. 400 Guatemalan mother-infant dyads will be randomized into 4 groups: 1) 100 children will receive 18 months of nutritional supplementation with “Frijolatole Plus,” a porridge (‘atole’) containing complete protein from common beans and maize, micronutrients, and rice bran as a prebiotic agent to support intestinal health and nutrition, 2) 100 will receive the Mediational Intervention for Sensitizing Caregivers between 12 and 24 months of age, 3) 100 will receive both interventions, and 4) 100 will form an active control group. Our primary outcome is ND at 24 months, as assessed by the MSEL. To accelerate future research on child ND in the region, we will contribute to international efforts to develop the WHO’s Global Scales of Early Development (GSED), as well as foster a cadre of Guatemalan students on their path to future research on child ND in the region.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT Platelets are small anucleate blood cells that coordinate the hemostatic response to vascular damage through the formation of a platelet plug. Our lab has previously shown the rapid activation of the primary platelet integrin, ⍺IIbβ3, by the small GTPase Rap1 and its effector Talin is essential for platelet plug formation. This response must be tightly controlled as hypoactive platelets can cause prolonged bleeding while hyperactive platelets are associated with thrombotic disease. Platelets also play a crucial role in inflammation and immunity. Platelets are among the first cells recruited to sites of inflammation to aid in the recruitment of neutrophils and scavenge bacteria to prevent dissemination to other organs. Additionally, neutrophils exit the blood vessel between endothelial cells and leave behind gaps in the endothelium. Recent evidence shows single platelets adhere and migrate on the inflamed endothelium to plug the holes to prevent bleeding into the surrounding tissue, in a process known as inflammatory hemostasis. Overactivation of platelets and immune cells in areas of inflammation can lead to immunothrombosis, or the formation of thrombi in response to pathogens or damaged cells. Thus, a better understanding of the molecular mechanisms underlying platelet migration at sites of inflammation may lead to the development of new treatments for immunothrombosis. Platelet migration also relies on integrin activation; however, the mechanisms appear to be different than platelet plug formation. Our lab and others have shown that Talin1, but not Rap1 or ⍺IIbβ3, is required for inflammatory hemostasis. Previous studies also demonstrated that 1 and 3 integrins are functionally redundant in inflammatory hemostasis. Based on these foundational studies, I hypothesize that the coordinated formation and turnover of multiple integrin-ligand connections is critical to platelet function in inflammation. My preliminary data show that Talin1 is required for platelet migration, while Rap1 is dispensable for migration but plays a role in the establishment of platelet polarity. Additionally, my studies are the first to show that platelets, like other migratory cells, can cycle integrin engagement and migrate on a diverse array of surfaces, including fibronectin, vitronectin, and low concentrations of fibrinogen. The seminal questions that my proposal seeks to address in two aims are: (1) how do key regulators of platelet integrin affinity facilitate platelet migration and polarity required for bacterial scavenging and inflammatory hemostasis?, and (2) which integrin receptors, ligands, and binding motifs enable platelet migration in vitro and in vivo? Successful completion of this work will provide novel mechanistic insights on how platelet adhesive signaling at sites of inflammation differs from that at sites of mechanical injury, information that is critical for the development of novel therapies that target platelet function in inflammatory disease conditions.

NIH Research Projects · FY 2025 · 2025-09

ABSTRACT Sapovirus (SaV), a genus in the Caliciviridae family alongside norovirus, is increasingly recognized as an important cause of acute gastroenteritis (AGE) in childhood. SaV ranked second among all enteric pathogens in its contribution to AGE incidence in children under 24 months of age in a large multi-site birth cohort study. While vaccines against rotavirus have lowered the burden of childhood AGE and a pediatric norovirus vaccine is in Phase III trials, currently, there are no vaccines against SaV. A major challenge to SaV vaccine development is that there is little known about natural immunity to serve as a guide for vaccine-elicited immunity, including what levels and types of antibodies (Abs) protect against infection. This may be due to the fact that human SaVs are not readily grown in cell culture, hindering infectivity studies and antigen production. Dr. Nordgren at Linköping University has recently implemented SaV cultivation in his lab and has provided as proof of concept that convalescent sera can protect against SaV infection. Our team is uniquely poised to substantially advance the understanding of natural neutralizing immunity to sapovirus with our biobank from field epidemiology research in Nicaragua and state-of-the-art laboratory techniques to measure neutralizing Abs. Leveraging an NIH-funded birth cohort of 444 children in León, Nicaragua, this project aims to characterize the kinetics of neutralizing Abs to SaV in longitudinal serum and stool samples collected from 50 children experiencing a SaV gastroenteritis episode during the first two years of life. In addition, we will test whether polyclonal sera neutralize homotypic and heterotypic SaV, and compare neutralizing Ab levels between children who do and do not develop SaV AGE episodes. We will also determine the correlation between neutralizing Ab levels and levels of IgG and IgA as determined by enzyme immunoassays (EIAs). Together, this unique collaboration and sample set allows us to advance analytic tools to better understand the immunology of sapovirus in children. Most importantly, this project will generate a new tool that will be shared with the scientific community and is fundamental for the understanding of natural humoral immunity to SaV.

NIH Research Projects · FY 2025 · 2025-09

Endometrial cancer (EC) is increasing in frequency and mortality and harbors one of the largest health disparities in US cancers. To address this disparity, we propose the Cancer Health Disparities SPORE in Endometrial Cancer that is comprised of a multi-disciplinary translational research team and a comprehensive approach to studying disparities in EC that incorporates both social and biological factors into the study design of each of our three Projects and makes use of three unique EC patient cohorts as well as novel pre-clinical mouse and organoid models. The overall mission of our SPORE is to define key biological factors (epigenetic aging in Project 1; microbiome and innate immunity in Project 2; metabolic reprogramming and allostatic load in Project 3) alongside measurable social factors that may drive more aggressive behavior or lead to worse EC outcomes (treatment response, survival). Our hypothesis is that disparities influencing social and biological factors are fundamental drivers of poorer outcomes for women with EC, including the inter-related biological factors of epigenetic age acceleration, microbial dysbiosis, a heightened innate immune system, metabolic reprogramming and increased allostatic load. To address this hypothesis, we will leverage the on-going Carolina Endometrial Cancer Study (CECS) as our first patient cohort, a NC state-wide population-based prospective study of >1,700 EC patients with survey and medical records data collection, acquisition of tumor samples, and ongoing follow-up to collect data on treatment response and survival. CECS integrates tumor biology with measurable clinical and social data as potential contributors to worse outcomes in EC patients, and this study is central to Projects 1 and 2. In addition, we will make use of a second patient cohort which is a prospective study of EC patients undergoing programmed cell death protein-1 (PD-1) inhibitor immunotherapy treatment (PROMOTE) and includes the collection of tumors, blood, rectal swabs and stool, which are to be analyzed in Project 2. Our third patient cohort consists of banked tumor/blood from EC patients at both UNC and MD Anderson for analysis in Project 3. To complement these patient cohorts, we plan more mechanistic studies in pre-clinical models, including a unique germ-free EC mouse model (Project 2) and EC organoids (Project 3). These three Projects are supported by four integrated Cores, including an Administrative Core, a Biospecimens/Pathology Core, a Biostatistics/Bioinformatics Core and a Community Outreach and Engagement Core as well as a Developmental Research Program and Career Enhancement Program for the next generation of ideas and investigators. By combining these three Projects into a single program that share both key resources (patient cohorts, four Cores) and critical clinical, social and biological measures, we will identify the most impactful factors for biomarker and therapeutic target development and immediate translation into clinical interventions to improve outcomes in EC patients.

NIH Research Projects · FY 2025 · 2025-09

ABSTRACT During brain development, neurons undergo dramatic growth and branching to establish the intricate morphology required for neural network connectivity and function. This cellular expansion involves a substantial and rapid increase in neuronal surface area and therefore requires extensive insertion of material into the plasma membrane. Defects in neuronal morphogenesis can result in improper synaptic connectivity, neurodevelopmental disorders, and psychiatric syndromes. Insertion of membrane material is facilitated by SNARE-mediated exocytosis. Two SNARE proteins, Vesicle-associated membrane protein (VAMP) 2 and VAMP7, are enriched in the embryonic brain and are associated with distinct vesicle populations even prior to synapse formation. While knockout studies in mice have shown that both VAMP2 and VAMP7-mediated vesicle fusion are required for proper neuronal morphogenesis, the specific mechanisms regulating the trafficking and fusion of these vesicles during development is not known. My preliminary data reveal that VAMP2 and VAMP7 mediate non-synaptic exocytic events that cluster in different areas of the developing neuron, suggesting the existence of distinct regulatory pathways governing their distribution and fusion. Additionally, my preliminary data indicate that VAMP2-mediated exocytosis is sensitive to Ca2+ chelation, whereas VAMP7-mediated exocytosis is not, mirroring the differential Ca2+ sensitivity of VAMP2 and VAMP7 vesicle pools observed at the synapse of mature neurons. This suggests a potential role for Ca2+ signaling in the regulation of VAMP2 and VAMP7- mediated exocytosis during neuronal morphogenesis. Endoplasmic reticulum (ER)-PM membrane contact sites, key regulators of Ca2+ signaling, may also be involved in this regulatory process. The goal of this proposal is to investigate the regulation of VAMP2 and VAMP7-mediated exocytosis during neuronal morphogenesis using hypothesis driven science coupled with unbiased proteomic analysis. I will utilize total internal reflection fluorescence (TIRF) microscopy and advanced image analysis techniques to quantitatively define the interplay between SNARE-mediated exocytosis, Ca2+ signaling, and ER-PM membrane contact sites during neurite outgrowth in stage 2 developing neurons. Using a proximity biotinylation approach I will define the interactome of VAMP2 and VAMP7 during neuronal morphogenesis, providing insights into the molecular machinery regulating their trafficking and fusion. These findings will advance our understanding of the complex regulation of exocytic membrane trafficking during neuronal development. Successful completion of this proposed research will provide advanced training in live cell microscopy, the development of advanced image analysis pipelines, proteomics, and bioinformatics.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT Metabolic programming is a critical regulator of inflammatory responses. Prior work has shown that changes in metabolism drive changes in macrophage activity. These metabolic changes are not only a consequence of polarization but also drive macrophage function. Downregulation of fatty acid oxidation within pro-inflammatory macrophages leads to enhanced lipid synthesis, including production of pro-inflammatory lipid mediators. The majority of these studies have been performed in bone marrow-derived macrophages (BMDM), and questions remain as to how metabolism regulates the activity of lung macrophages during influenza A virus (IAV) infection. Within the lungs, macrophages play a critical role in host defense and mediate lung inflammation and resolution. Lung macrophages can be classified as tissue resident alveolar macrophages (AM), interstitial macrophages, and monocyte-derived macrophages. Recent work has demonstrated significant differences in the metabolism of AM and BMDM. Unlike BMDM, pro-inflammatory AM do not upregulate glycolysis, and in fact upregulation of glycolysis is associated with a pro-repair or pro-fibrotic phenotype. Our preliminary data indicate that there are significant differences between AM and BMDM not only in glycolysis but also in lipid metabolism. AM have a higher concentration of metabolites involved in fatty acid oxidation and have higher mRNA expression of the enzymes Cpt1a and Cpt2, which are rate limiting enzymes for fatty acid oxidation that act sequentially to transport fatty acids from the cytosol into the mitochondrial matrix where fatty acid oxidation occurs. In addition to serving as a source for ATP, lipid metabolism also generates lipid mediators that have important roles in cell signaling, cytokine production, and apoptosis. Thus, our proposal focuses on understanding how changes in lipid metabolism alter the activity and function of lung macrophages during homeostasis and injury. Our hypothesis is that fatty acid oxidation is critical for resolution of lung injury by modulating the activity of lung macrophages and reducing production of pro-inflammatory lipid mediators. In Aim 1, we will determine the role of fatty acid oxidation on lung macrophage activity during IAV infection. We will utilize LysM-Cre Cpt1afl/fl mice, which have a macrophage-specific deficiency in fatty acid oxidation. After inoculation with IAV, the clinical and inflammatory responses and severity of lung injury will be assessed at multiple time points. Lung macrophage subsets will be isolated and their transcriptomes profiled by RNAseq. In Aim 2, we will determine how fatty acid oxidation regulates the metabolic activity of lung macrophages by performing unbiased metabolomics on isolated lung macrophage subsets during IAV infection. The extracellular microenvironment will be assessed by determining the metabolome of the bronchoalveolar lavage fluid. These studies build upon work done in my K08 award and expand our focus to fatty acid oxidation and lipid metabolism. These data will serve as a foundation for an R01 proposal aimed at understanding how changes in metabolism regulate lung macrophage activity during injury.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY I am an Assistant Professor at the University of North Carolina-Chapel Hill (UNC) School of Medicine and part of the UNC Kidney Center. I am a clinician and researcher taking care of patients with autoimmune kidney diseases with a specific interest in antineutrophil cytoplasmic autoantibody (ANCA) vasculitis. The current treatment paradigm for ANCA vasculitis includes prolonged courses of immunosuppression. This approach is effective but is associated with long term complications such as infections and malignancy. There is an established cohort of patients with ANCA vasculitis enrolled in our registry. A subset of patients discontinue therapy and remain off treatment without relapse, termed Long-Term Remission Off Therapy (LTROT). These patients have been off therapy for at least 12 months and we have shown return of B cells. However little is understood about the autoantigen specific B cells in long term remission off therapy or differences in BCRs which indicate tolerogenic vs. pathogenic clonal populations. The first research aim is to define immunological remission in terms of the underlying BCRs and the immunophenotype of autoantigen specific B cells in the context of total B cell population. My goal is to identify markers of long-term immunological remission which can be validated in future studies as a clinical tool. The second research aim is to develop therapies to remove autoantigen specific B cells as a proof of concept study for future pre-clinical studies. My central goal is to build innovative clinical tools which can minimize immunosuppression for patients with ANCA vasculitis. I have developed a comprehensive career development plan integrating mentoring and training activities with basic and translational research. My mentorship team includes Dr. Ronald Falk, a world-renowned physician- scientist expert in ANCA vasculitis and co-mentor Dr. Benjamin Vincent, who will mentor me in translational immunogenetics training. My advisory team includes an ANCA B cell expert and a nanoparticle formulation advisor. I will train to develop nanoparticles as a selective therapy for autoantigen specific B cells. My training will focus on lab-based research training supplemented by formal training activities including coursework, national workshops, participation in national and international meetings, as well as instruction in scientific communication and academic leadership. The focus of my training is on immunology, immunogenetics, and nanoparticle drug development. My research aims and career development are supported by a world-class environment at UNC which offers ample resources for junior faculty, including an established vasculitis clinic with dedicated research coordinators for patient recruitment. My translational aims are to define long term remission in the context of B cells and develop targeted nanoparticle therapy for ANCA vasculitis. My proposed K08 research aims, mentorship team, career development plan, and collaborative research environment will catalyze my scientific productivity and provide me with the necessary training to become an independent investigator.

NIH Research Projects · FY 2025 · 2025-09

Next generation sequencing and other -omics technologies have spurred the development of precision medicine, but this field is still in its infancy for alcohol use disorder (AUD). Transcriptomic studies have established that alcohol use causes widespread changes in brain gene expression. Brain gene expression profiles can identify alcohol-dependent human subjects and mice and can be used to repurpose pharmaceuticals that reduce excessive alcohol consumption in rodents. However, it is not possible to obtain brain samples from living patients, which limits the translational potential of this approach. Routine blood testing has long been a part of medical care. Blood genomic profiles could potentially be used to non-invasively determine whether a patient is at risk for AUD, provide data-driven diagnosis of AUD, stratify the heterogeneous AUD patient population for clinical trials, select optimal therapy, and monitor treatment response and disease progression. As a first step toward these goals, Dr. Ferguson analyzed gene expression patterns in paired blood and brain samples from mice subjected to chronic intermittent ethanol (CIE) exposure, a mouse model of alcohol dependence. Blood gene expression signatures of CIE predicted a pharmaceutical that reduced alcohol drinking in mice, and predictive models built from blood profiles distinguished between CIE and air-exposed mice with high accuracy. These results lead to the hypothesis that blood can serve as a proxy for brain tissue in molecular-based diagnostic or therapeutic tools and advance personalized medicine approaches for AUD. However, it is not known whether there is a biological signature of AUD in blood from a human population. Furthermore, there is a need for biomarkers to predict and monitor treatment success and it is unknown whether blood gene expression profiles might be useful in this regard. The CIE blood signature used in the previous study assayed the transcriptome only at a single time point. Therefore, the dynamics or ongoing transition of important gene regulatory functions were not investigated. These gaps in knowledge will be addressed in proposed Aims by analyzing blood profiles (1) across multiple time points throughout alcohol withdrawal in humans (Aim 1), (2) across multiple time points through the development of CIE-induced alcohol dependence in mice (Aim 2), and (3) before and after treatment in humans and mice (Aim 3). The overarching hypothesis is that genomic profiles from blood will improve the clinical management of AUD including diagnosis, prognosis, and predicting treatment response. These Aims and the accompanying training plan were designed to build on Dr. Ferguson’s previous research experiences and facilitate new scientific training in clinical alcohol research and biostatistical analyses of longitudinal data, time-to-event outcome data, and treatment effect estimation. The proposed Pathway to Independence Award will generate new knowledge about a relatively unstudied area in alcohol research and enable Dr. Ferguson to establish a solid framework for building a successful research program as an academic translational neuroscientist in the alcohol field.

NIH Research Projects · FY 2025 · 2025-09

TITLE: Defining Intercellular Heterogeneity in Cell Cycle Quiescence SUMMARY Cancer cells proliferate inappropriately, yet they also routinely exit the cell division cycle. Cells that exit the cell cycle to a reversible arrest are quiescent (or dormant or “slow cycling”). Quiescent cells can resist most cancer therapies, including immunotherapy, and thus are a major driver of cancer relapse. Until recently, the field has been dominated by the notion of a binary “proliferation-quiescence” decision implying that only two states exist. However, evidence indicates a spectrum of quiescent states range from shallow quiescence to deep quiescence. Deep quiescent cells re-enter the cell cycle less quickly or easily than shallow cells. Nonetheless, there is little information about the relationship between quiescence depth and tumor progression or sensitivity to treatment. Existing technological barriers prevent us from evaluating the relative quiescence depth of individual cancer cells both in culture and in tissues. Current tools can provide a snapshot of cells at the time of analysis or give information about prior cell divisions, but there are few options for measuring the history of cells in tumors or tissues and no existing tools for analyzing quiescence depth heterogeneity. In this pilot project we will test newly-generated quiescence depth biosensors. Our goal is to determine how single-cell biosensor signals correlate with true quiescence depth. We have already generated a series of genetically-encoded cell age and quiescence depth biosensors. Preliminary tests in cultured cells indicate correlation among signal, absolute time since the final cell cycle (cell age), and metrics of quiescence depth. We propose to define the accuracy and dynamic range of these biosensors in a variety of cancer cell lines. We will then deploy them in xenograft experiments to determine quiescence depth of single cells within a tumor. We will also test for correlation of biosensor signal with response to selected anti-cancer therapies. Finally, we will use the biosensors to isolate cells of varying quiescence depths for unbiased transcriptome and proteome analysis. We will determine which endogenous genes and proteins characterize quiescence depth and seek novel cancer cell vulnerabilities to exploit. Success will provide a means to evaluate quiescence heterogeneity in both normal and tumor cells. Validating the biosensors will inspire future construction of a biosensor mouse for analyzing both spontaneous tumors and the non-transformed cells in their microenvironments. The potential impacts of this work are 1) unprecedented insight into heterogeneity among non- proliferating tumor cells, 2) endogenous quiescence depth indicators, and 3) new therapeutic strategies to target quiescent cancer cells.

NIH Research Projects · FY 2025 · 2025-09

ABSTRACT Despite intensive prevention efforts from federal and state agencies, suicide remains a leading cause of mortality in the United States (US), increasing by 36% between 2000-2022. In 2023 alone, 49,303 Americans lost their lives to suicide. The impact of suicide is particularly high among vulnerable populations such as adolescents and formerly incarcerated individuals. Although much research has focused on causes and predictors of death from suicide, progress in suicide prevention has been hampered by data linkage and methodological challenges. While national mortality rates are known, entities with the potential to implement large suicide prevention initiatives – insurers, health systems, and departments of corrections – lack the linked data to monitor suicide mortality in their populations, establish benchmarks, and create an evaluation framework for prevention efforts. Many individuals who die from suicide have had recent contact with a health insurance, health care, or correctional system, representing critical missed opportunities to implement suicide prevention measures. Funded from 2020-2025, our original “INSPIRE” grant (R01MH124752) established a living suicide mortality surveillance system in North Carolina (NC) by securing all necessary data approvals and completing individual-level linkages between state death records and large datasets on four key populations covering 10-22 years depending on the data source: the publicly insured (NC Medicaid), privately insured (large single private insurer), a large integrated health system (UNC Health), and releasees from the Department of Adult Corrections. We have updated these linkages annually and have used this surveillance system to define benchmarks of suicide mortality in each population; evaluate policy impacts; identify risk factors for suicide mortality, attempts, self-harm, and suicidal ideation; and predict short and long term risk of suicide outcomes . Having invested the expertise, resources, and time to establish the INSPIRE living surveillance system and demonstrate its potential, RFA-MH-25-135 now provides an opportunity to untap the full potential of this surveillance infrastructure and further advance suicide prevention efforts. Over the next five years, we will enhance the surveillance system by continuing annual updates, including additional important populations (older adults), and performing enhanced cross-population linkages. We will utilize the established system to evaluate the impact of several recent suicide prevention efforts in NC and build risk assessment tools tailored to specific sub-populations and suicide mortality subtypes. Finally, we will move this research beyond Big Data as we engage end users (clinicians and health administrators) to plan implementation of the risk assessment tools into health care settings where they can be best utilized to connect people in mental health crisis with the help they need to prevent suicide-related outcomes.

NIH Research Projects · FY 2025 · 2025-09

Injury-related fear after anterior cruciate ligament (ACL) injury significantly contributes to decreased return to sport, decreased physical activity engagement, and increased secondary ACL injury in previously high functioning, physically active individuals. Injury-related fear is also associated with poor jump-landing movement patterns and worse self-reported knee function in patients after ACL reconstruction (ACLR). While injury-related fear can be modified using psychological interventions, we have not comprehensively characterized how, when, and what types of injury-related fears (e.g., fear of movement, reinjury, avoidance) impede recovery. Furthermore, there is limited evidence regarding patient perceptions of injury-related fear and their perceived consequences on recovery outcomes. Failure to identify what types and when these fears are present throughout ACLR rehabilitation, and how patients perceive these fears to impact their recovery, will significantly inhibit our ability to effectively intervene with robust and effective psychological interventions aimed to mitigate secondary ACL injury risk. We hypothesize that patients follow three separate trajectories, including favorable (i.e., decreases in fear that are maintained), unfavorable (i.e., unresolved fear at clearance for return for activity), and variable trajectories (i.e., decreases in fear likely due to direct intervention prior to return to activity). Identifying these trajectories will enhance intervention effectiveness for future clinical trials using psychological interventions to mitigate secondary ACL injury risk and improve long-term knee joint health. Consequently, there is a critical need for high-quality longitudinal studies to characterize injury-related fear, both quantitatively and qualitatively, in patients after ACLR. Therefore, the objective of this study is to characterize injury-related fear in patients post-ACLR. A total of 50 patients will complete surveys to assess injury-related fear at important clinical timepoints, including pre-operatively, and at 2-, 4-, 6-, and 9-months post-ACLR. A subset of 15 patients at 9- months post-ACLR will complete semi-structured interviews to identify patient perceived impacts of injury-related fear on recovery outcomes and discuss interventions that could be used to reduce injury-related fear after ACLR. The central hypothesis is that multiple trajectories will exist for injury-related fears (i.e., fear of movement, fear of reinjury, and fear-avoidance beliefs) which will be supported qualitatively through patient interviews. The findings from this proposal will address a gap in knowledge by providing a clear understanding of how injury- related fear changes over time in patients after ACLR. This proposal will also position an aspiring independent clinician scientist with pertinent data that is needed to support future NIH grant applications and the trajectory of her independent research career.

NIH Research Projects · FY 2025 · 2025-09

Aggressive B-cell lymphomas are increasingly common but underdiagnosed in people with HIV (PWH) in Malawi. In 2013, we established the Kamuzu Central Hospital (KCH) Lymphoma Study, a prospective observation cohort of pathologically confirmed lymphomas in Malawi that includes uniform diagnosis, standardof-care therapy, and five-year clinical and laboratory follow-up for participants. We have shown that treating lymphoma in PWH is safe and effective, and the Lymphoma Study has become a leading regional resource for clinical and translational research studies of HIV-associated lymphomas. However, current diagnostic strategies are prohibitively expensive which limits the reach of effective lymphoma care, and the pivotal genomic studies from our group are primarily being performed outside of Malawi. Herein, we propose longread nanopore sequencing approaches that require minimal capital investment, and limited lab infrastructure to molecularly diagnose and subclassify common aggressive B-cell lymphomas in PWH. The proposal builds on our work in HIV-associated lymphomas, cutting-edge expertise in long-read nanopore sequencing, and, most critically, and research infrastructure at the UNC-Project Malawi research site. We aim to develop effective, resource-appropriate diagnostic tools and subsequently investigate implementation of nanopore sequencing across a network of sites while performing ongoing clinical, computational, and economic assessments. This project builds capacity to perform advanced molecular characterization of HIV-associated lymphomas in Malawi and leverages ongoing clinical, research, and training programs.

NIH Research Projects · FY 2025 · 2025-09

Project Summary Candidate: Simon M Gray, MD, PhD is a fellowship-trained board-eligible Gastroenterologist committed to im- proving the lives of patients with inflammatory bowel diseases (IBD) by understanding the causes of IBD. As a Clinical Instructor of Medicine at the University of North Carolina at Chapel Hill, he is focused on developing strategies to maintain durable IBD remission by understanding triggering events and preventing IBD therapy failure. The specific training objectives of this K08 are to develop expertise in 1) bioinformatic analysis of micro- bial metagenomics and host transcriptomics datasets and 2) statistical modeling of complex datasets. This train- ing will be led by an expert team of 5 mentors/advisors, including R. Balfour Sartor, MD and Timothy Hand, PhD. Environment: UNC-Chapel provides the ideal environment for the proposed research. The NIDDK P30-funded Center for Gastrointestinal Biology and Disease is a community of scientists with synergistic interests and skills in mucosal immunology, gut microbes, and multi-omics that provides a rich reservoir of mentors and advisors who will guide Dr Gray to accomplish the proposed research. UNC hosts the NIH National Gnotobiotic Rodent Resource Center, which is a critical resource for Dr Gray’s germ-free mouse studies. UNC has demonstrated its strong commitment to Dr Gray’s career by providing salary and project support to develop his research program. Research: Over 50% of IBD patients who achieve remission with immune-targeting drugs suffer therapy failure within 3 years despite maintaining therapeutic drug levels. I have developed a first-of-kind pre-clinical mouse model of experimental colitis remission and relapse to study the causes and mechanisms of IBD therapy failure. This model is clinically relevant because it integrates key features of human IBD (human microbes, FDA IBD therapy, a trigger-diet to elicit relapse) in colitis-prone Il-10-/- mice that mirror human IBD. IBD is caused by abnormal CD4+ T-cell mediated immune responses to gut microbes. IBD flares are strongly associated with the pathogenic gut bacterium C difficile. I use human IBD patient derived stool with or without C difficile to induce colitis in ex-germ-free Il-10-/- mice. This replicates clinically relevant disease because I found that 23% of my IBD patients are colonized with C difficile. After developing colitis, Il-10-/- mice achieve disease remission when treated with anti-IL-12/23 monoclonal antibodies, a 1st line FDA-approved human IBD therapy, even with the presence of toxigenic C difficile. Critically, feeding these mice in remission a diet associated with human IBD flares triggers recurrent gut inflammation despite continuing anti-IL12/23 IBD therapy. This therapy failure is associated with a >10-fold expansion of C difficile in the gut. I hypothesize that diet triggers C. difficile to induce chronic gut inflammation, despite anti-IL12/23 blockade, by shifting mucosal immune responses to uninhibited (non-IL12/23) inflammatory pathways driven by expanded CD4+ T cell clones reactive to dominant resident bac- terial antigens. Aim 1 will define the role of C difficile in therapy failure, aim 2 will identify the non-IL12/23 immune pathway(s) mediating therapy failure, and aim 3 will identify the CD4+ T cells expanded in IBD therapy failure.