Univ Of North Carolina Chapel Hill

NIH Research Projects · FY 2025 · 2022-05

Project Summary/Abstract Breast cancer is the most common type of cancer and the second leading cause of cancer death among women in the United States. With effective treatments and advancements in technology, the proportion of women who survive breast cancer five years and beyond is increasing. Despite the continued progress in survival, black women experience suboptimal five-year breast cancer specific survival, adverse cancer treatment effects (pain and swelling from lymphedema), and quality of life (QOL). Most interventions targeting physical activity (PA) have shown to improve QOL in predominantly white cancer survivors. There are critical gaps in our understanding of PA and QOL among post treatment black women with a history of breast cancer. First, there is not enough evidence to establish whether the effect of PA on QOL is smaller or larger in black women compared to white women. Second, there are limited descriptions of QOL concerns and experiences in relation to PA among black women. This study will address these issues in the following aims by: 1) investigating the effect of PA on social wellbeing, emotional wellbeing, and body image among post treatment black and white breast cancer survivors with lymphedema in the Women In Steady Exercise Research (WISER) Survivor Trial, 2) describing the QOL experiences and concerns in relation to PA among black women with a history of breast cancer in Pennsylvania using semi structured interviews and a narrative approach, and 3) assessing the association between PA, social, emotional, spiritual, mental, and physical wellbeing among black women with a history of breast cancer without lymphedema in the Black Women’s Health Study. The long term objective of this fellowship is to understand this association to increase the potential for medical and health professionals to recommend the use and promote the importance of PA to improve QOL among black women. Another long term objective of this fellowship is to increase awareness on the factors that influence QOL and PA, individual perceptions and descriptions of QOL, and unique QOL concerns and experiences to help improve QOL among black women breast cancer survivors who have worse health outcomes. This fellowship will help to inform clinical practice, refine exercise programs, promote the development of behavioral interventions, and advance scientific knowledge on QOL and PA among black women.

NIH Research Projects · FY 2026 · 2022-05

Multi-Site Neuroimage Harmonization for Personalized Brain Disorder Analysis Abstract Predicting the future progression of preclinical Alzheimer's disease (AD) such as subjective cognitive decline (SCD) is essential for drug development and timely intervention to prevent further cognitive decline. Multi-site mul- timodal neuroimaging data, while increasingly employed to augment sample size and improve statistical power for investigating SCD and AD-related disorders (ADRD), are susceptible to inter-site and inter-modality data het- erogeneity caused by differences in scanners/protocols, studied populations, and imaging modalities. Mitigating inter-site data heterogeneity, principled fusion of multimodal data, and precise interpretation of neuroimaging data can reduce bias in subsequent analyses and help avoid erroneous conclusions. In this project, we will develop a set of computational tools, powered by advanced machine learning techniques, for multi-site data harmoniza- tion, multimodal data fusion, and personalized/subject-specific neuroimage interpretation for SCD progression prediction. These tools will be evaluated extensively on 5,300+ subjects with multimodal data (e.g., magnetic resonance imaging, positron emission tomography, and cerebrospinal fluid) involving 79 imaging centers. We propose three aims. In Aim 1, we will develop both feature-level and image-level deep learning frameworks for multi-site data harmonization. Many studies ignore inter-site data heterogeneity by simply assuming a common data source. Our methods will allow feature-level harmonization for precision medicine and image-level harmo- nization targeting a broader range of applications. The developed models will be easy to train via unsupervised learning. In Aim 2, we will develop a framework to effectively fuse multimodal data for subsequent analyses with- out discarding subjects who lack certain modalities. Existing studies usually require modality-complete subjects, limiting their utility in multi-site studies where many subjects may lack one or several modalities due to patient dropouts or failed scans. Our models can be trained with modality-missing subjects, and thus are practical with considerably better adaptability. In Aim 3, we will develop a framework for fast and accurate neuroimage search to facilitate personalized analysis of SCD and ADRD. Interpreting neuroimaging data at the subject level is of- ten challenging due to the ever-increasing amount of imaging information. Our method will help overcome this difficulty by scalable neuroimage search for subject-specific progression prediction of SCD and ADRD.

NIH Research Projects · FY 2026 · 2022-05

ABSTRACT Arteriovenous fistulae (AVF) are the preferred mode of permanent dialysis vascular access because of better long-term survival and reduced infection risks as compared to dialysis grafts and catheters. Unfortunately, AVFs have a maturation failure rate (defined as inadequate diameter and blood flow for dialysis) of over 50% at 6 months, which results in multiple additional interventions, and also a prolonged period of tunneled dialysis catheter dependency with all of its attendant complications. Thus, AVF maturation failure results in a very significant morbidity, mortality and economic cost. We and others have previously demonstrated that AVF maturation failure occurs due to a peri-anastomotic venous segment stenosis characterized by the de-differentiation of vascular smooth muscle cells (VSMC) into a synthetic phenotype, which then results in an aggressive venous neointimal hyperplasia. We have also developed a unique expertise both in the biology of AVF maturation (Roy-Chaudhury) and in the signal transduction mechanisms involved in VSMC phenotypic switching (Xi). We now plan to apply this combined experience and expertise to study the signal transduction pathways responsible for AVF maturation failure. The overarching central hypothesis of this proposal, therefore, is that environmental modulation of the insulin receptor substrate 1 (IRS-1) signal transduction pathway plays a key role in VSMC phenotype switching which then results in neointimal hyperplasia and AVF maturation failure. We plan to address this central hypothesis through three specific aims. Specific Aim 1 will assess the impact of different combinations of hyperglycemia, uremia and genetic manipulation of IRS-1 and Kruppel like factor 4 (KLF-4) on signal transduction/VSMC phenotypic switch pathways using explanted venous (jugular) and arterial (carotid) VSMC from C57Bl/6 WT control mice. Specific Aim 2 will assess the impact of this same upstream manipulation on signal transduction pathways, VSMC phenotypic switch and clinical, hemodynamic and histological endpoints, in a validated mouse model of AVF stenosis at 2, 7 and 14 days, post-surgery. Finally, Specific Aim 3 will assess the impact of nutlin-3, an inhibitor of MDM2 mediated ubiquitination of p-53 (which inhibits VSMC phenotypic switching) on the in-vitro and in-vivo end points described in Specific Aims 1 and 2 respectively. If successful, this novel, innovative, mechanism driven and pre-emptive approach to the intractable problem of AVF maturation failure, could significantly reduce the clinical morbidity and economic cost associated with this unmet clinical need.

NIH Research Projects · FY 2025 · 2022-05

ABSTRACT Cardiovascular disease is a main cause of death and disability in individuals with chronic kidney disease (CKD) but little is known on the genetic factors accounting for the increased cardiovascular disease burden in CKD. Genome-wide association studies have identified several loci for cardiovascular disease and subclinical atherosclerosis traits. Studies have also shown that genetic variants that regulate gene expression have important roles in complex traits. We propose to test regulatory regions of the genome associated with cardiovascular outcomes using approaches that integrate gene expression data to genome-wide genotypes. We will use the comprehensive clinical and biomarker data from the Chronic Renal Insufficiency Cohort (CRIC), a multi-ethnic and longitudinal study of individuals with CKD. CRIC has adjudicated cardiovascular events in all participants and the study has already documented a high burden of atherosclerosis and cardiovascular disease in CKD. We will perform genome-wide association studies of cardiovascular outcomes using dense imputed genotypes from multi-ethnic reference panels obtained from the Trans-Omics for Precision Medicine (TOPMed) Program to identify new loci in individuals with CKD (Aim 1). To identify putative causal genes associated with cardiovascular disease in CKD, we will use predicted gene expression approaches and expression quantitative trait loci from ancestry-matched datasets (Aim 2) and multi-tissues (Aim 3). This project uses innovative concepts and approaches by integrating transcripts and genotypes for gene discovery in a high-risk population for cardiovascular disease. This project aligns with NHLBI mission to reduce the burden of CVD.

NIH Research Projects · FY 2026 · 2022-04

ABSTRACT Dengue virus (DENV) vaccine development has been challenging because of the presence of 4 serotypes (DENV1-4) and the potential for vaccine enhanced severe disease. The leading live attenuated tetravalent DENV vaccines have been plagued by poorly balanced replication of vaccine components leading to variable efficacy and vaccine primed severe dengue disease in some children. The goal of this proposal is to develop novel recombinant DENV envelope (E) protein and virus like particle (VLP) vaccines that overcome barriers faced by live attenuated tetravalent vaccines. We have discovered that the DENV E protein produced as a secreted protein is a poor vaccine because it is a monomer that does not display major quaternary epitopes targeted by human neutralizing and protective antibodies (Abs). This proposal is based on new discoveries from our group about how structure based, computational approaches can be used to produce highly stable and properly folded DENV E dimers that are efficiently secreted from mammalian cells. We will use mouse models of DENV vaccination and infection to test if artificially stabilized DENV E dimers stimulate Ab responses that are similar to serotype-specific and serotype-cross-protective Ab responses in people exposed to primary and secondary wild type DENV infections. The stabilized E dimers will be further modified to test if large-scale resurfacing of the E dimer can be used to focus the immune response on epitopes recognized by potent neutralizing Abs, while eliminating responses to off target, disease enhancing epitopes. Finally, we will design membrane anchored variants of stabilized E dimers to promote the formation of dengue virus-like particle (VLP) vaccine candidates that better resemble mature infectious virions than VLPs made with current techniques. Our studies, which explore how to design and deliver recombinant E antigens to focus the host antibody response on important quaternary structure neutralizing epitopes, will stimulate new research directions in the field of flavivirus subunit vaccines.

NIH Research Projects · FY 2026 · 2022-04

Project Summary Exposure to the ambient air pollutant ozone (O3) is associated with cardiopulmonary morbidity and mortality, rendering it an important public health issue. Controlled exposure studies show that acute O3 exposure causes airway inflammation, epithelial injury, and a transient decrease in lung function. These studies have also demonstrated that subjects exhibit highly reproducible differences in O3 response, suggestive of gene-by- environment interactions (GxE). Candidate gene studies have provided evidence of GxE for a handful of genes, however, the role of genetic variants in the rest of the genome is largely unknown. This data gap limits our ability to identify susceptible individuals and gain insight into mechanisms by which O3 causes adverse effects. Here, we put forth a proposal to address this data gap using human bronchial epithelial cells (hBECs) in vitro. hBECs are the first cells of the respiratory tract to interact with O3, and we have shown that hBECs exposed to O3 in vitro upregulate the expression of key pro-inflammatory genes (e.g., CXCL8), mirroring the in vivo response. We hypothesize that variation in O3-induced inflammation is associated with differences in hBEC gene expression, and that inter-individual differences in gene expression at baseline and after O3 have a genetic basis, i.e., are expression quantitative trait loci (eQTL). Further, we hypothesize that some eQTL are caused by single nucleotide polymorphisms (SNPs) that affect chromatin accessibility (caQTL). In Aim 1, we will establish well- differentiated hBEC cultures, grown at air-liquid interface, from 300 banked lung tissue donors of both sexes and diverse ancestries, then expose them to O3 vs. filtered air (FA) and measure key hBEC O3 response phenotypes (e.g. IL-8 production, oxidative stress, lipid peroxidation, barrier function, and cytotoxicity). We will profile gene expression in FA and O3-exposed hBECs using both bulk RNA-seq and single cell RNA-seq to identify O3- induced/repressed genes and their cell-type specificity. After genotyping, we will map eQTL at baseline (mRNAFA), response eQTL (mRNAO3-mRNAFA), and QTL for all hBEC O3 response phenotypes, then use mediation analyses to identify SNPs and genes fitting a putative causal model: O3+SNP → [mRNA] → hBEC O3 response phenotype. In Aim 2, we will perform ATAC-seq to characterize how O3 alters chromatin accessibility in hBECs, then map baseline and response caQTL. We will perform multi-omic data integration (eQTL, caQTL, QTL) to identify gene regulatory models of O3 response, i.e., O3+SNP→chromatin accessibility→[mRNA]→hBEC O3 response phenotype. Finally, in Aim 3, we will validate novel genes and gene regulatory mechanisms underlying variation in O3 response in vitro and in vivo. We will determine how key SNPs affect gene regulation and whether knocking down the corresponding genes alters O3 response in vitro. For in vivo validation, we will test for association between SNPs of interest and O3-induced neutrophil recruitment in a dataset of 191 human volunteers exposed to O3. In total, our work will identify genetic variants and gene regulatory mechanisms that influence susceptibility to O3-induced airway inflammation.

NIH Research Projects · FY 2026 · 2022-04

Project Abstract Non-polio human enteroviruses (NPEVs) represent an existing and emerging threat to public health, especially to infants and children. With more than 100 NPEVs known and the high rate of mutation and recombination of these viruses, the risk for evolution of virulent strains is high. Because we cannot predict the serotype of any newly emerging strain, addressing this problem effectively will require pan-enterovirus solutions. All NPEVs encode an enzyme, which has been termed 2C. This enzyme is as well conserved as the enterovirus RNA- dependent RNA polymerase (RdRp). Indeed, inhibitors of 2C with activity against multiple enteroviruses have been known for decades, with even more reported over the past few years alone. A major obstacle to further development of these compounds is the absence of an established experimental framework to define mechanism of action and to guide design of pan-enterovirus activity. Two of the earliest inhibitors of 2C: guanidine hydrochloride (GuHCl); and 5-(3,4-dichlorophenyl)- methylhydantoin (hydantoin), revealed roles for 2C both in genome replication and virion assembly. Because 2C protein is a member of helicase superfamily 3, the prevailing view has been that 2C is a hexameric helicase that cooperates with RdRp by unwinding RNA structure during genome replication and by facilitating genome encapsidation during virion assembly. Unfortunately, only indirect evidence exists to support these views. Nearly five years ago, our laboratory initiated an effort to connect the biochemical and biophysical properties of 2C to its biological functions using poliovirus (PV) as our model. The advances made to date, all unpublished, have changed the way we think about structure-dynamics-function relationships of 2C, the subcellular locations in which 2C manifests its virion-assembly function, and the physical properties of the virus-induced membranes with which 2C must interact during infection. In this application, we propose to add Enterovirus A71 (EV-A71), Coxsackievirus B3 (CVB3), and Enterovirus D68 (EV-D68) to our studies of PV to establish unifying models for the biological functions of 2C that will provide a framework to establish 2C as a pan-enterovirus therapeutic target. We will do so by pursuing the following specific aims: Elucidate the quaternary structure and kinetic mechanism of 2C ATPase (Aim 1); Elucidate the impact of drug resistance on 2C ATPase activity and viral fitness (Aim 2), and Characterize sites contributing to genome encapsidation (Aim 3).

NIH Research Projects · FY 2024 · 2022-04

Project Summary/Abstract The goal of this proposal is to investigate the role of a human microphysiologic intestine-on-a-chip platform as a precision medicine tool to model a devastating disease affecting premature infants known as necrotizing enterocolitis (NEC). We developed preclinical models of NEC using both organoids and a “NEC-on-a-chip” model system to recapitulate the intestinal environment of the human disease in vitro, gain new insights into disease pathogenesis and test the functional and clinical utility of our models to evaluate the efficacy of candidate therapeutics. Our NEC-on-a-chip model utilizes a combination of premature infant intestinal organoids along with human endothelial cells and patient-derived microbiota, to recreate critical aspects of premature gut pathophysiology. Our preliminary studies demonstrate that co-culture of these components on intestine-on-a- chip microfluidic devices produces clinical features seen in human NEC such as gut barrier failure with the breakdown of cellular tight junctions, decreased epithelial cell proliferation, a dramatic increase in the pro- inflammatory cytokine response, as well as a significant amount of cell death. In this proposal, we will use several multi-omic approaches to characterize our NEC-on-a-chip model and compare to the human NEC phenotype. To achieve this, we developed a multi-center NEC Biorepository, which consists of detailed clinical metadata corresponding to a plethora of human specimens, including intestinal organoids cultured from the biopsies of premature infants with or without NEC. Furthermore, we have created a high-throughput and high-content drug screening platform using premature intestinal organoids to identify drugs or compounds that inhibit the pathogenic inflammatory responses seen in vitro. Moreover, we will demonstrate the functional and clinical utility of our patient-derived NEC-on-a-chip model as a precision medicine platform to test the dosing, efficacy, and toxicity of candidate therapeutics. To successfully complete these studies, we established a multi-disciplinary team with the expertise of a Neonatologist, Cell Biologist, Pediatric Surgeon, Genome Scientist and Bioinformatician. Taken together, these studies will make a significant conceptual advance in our understanding of the multicellular interactions with the microbiome of the developing premature intestine and provide new model systems and preclinical platforms by which the identification and testing of therapeutics for NEC and other intestinal diseases can be performed in this vulnerable patient population.

NIH Research Projects · FY 2026 · 2022-04

Project Abstract Hepatitis B virus (HBV) remains endemic in sub-Saharan Africa (SSA), despite an effective vaccine. While perinatal transmission from mother-to-child has been the prevailing theory for continued HBV endemicity based on studies in Asia, limited evidence from SSA suggests transmission at the household- and community-levels is a more important driver of transmission in SSA contexts. Given that scale-up of HBV vaccination will be slow and insufficient to reach the World Health Organization goal of HBV elimination by 2030, additional prevention measures are needed for HBV control, which first require a better understanding of HBV transmission in SSA. The Democratic Republic of the Congo (DRC) has a national HBV prevalence of ~3.3%, which translates to approximately 3.5 million chronic infections in a setting where advanced hepatology care is essentially inaccessible. This proposal builds upon a strong research infrastructure (~20 years) between scientists at the University of North Carolina at Chapel Hill (UNC) and in DRC’s capital city, Kinshasa, to study HBV transmission using data and samples from an ongoing household-based case-control study and from the DRC’s latest national Demographic and Health Survey. The overall goal of this proposal is to improve understanding of HBV transmission in a low-resourced, sub-Saharan Africa setting. The specific aims of this proposal are: 1) Characterize the epidemiology of HBV transmission in households in urban Kinshasa, DRC, and identify associated individual, household, and community risk factors; and 2) Investigate evidence of community-level horizontal transmission using phylogenetic analysis. Through this research proposal and a carefully constructed training plan, the trainee will achieve the following fellowship goals: 1) develop a unique and interdisciplinary research skillset that integrates epidemiology, geography, genetics, and infectious diseases; 2) engage in meaningful clinical training that will enhance the trainee’s future clinical practice and the translation of research findings to clinically relevant interventions; and 3) develop professional skills that will facilitate a successful academic career as a physician-scientist.

NIH Research Projects · FY 2026 · 2022-04

ABSTRACT Chronic pain impacts a large proportion of the US population with estimates ranging from 10-40% of adults. Opioids and related medications are among the most frequently prescribed medications for treating chronic pain, albeit with considerable risks due to overdose, constipation, addiction and other serious side-effects. Over the past decades our understanding of the neural circuitry responsible for nociception and anti-nociceptive therapies has revealed several molecular targets that are potential therapeutic targets for non-opioid pain relieving medication. Among these are the Mas-related G protein coupled receptors (MRGPRs). The first MRGPR was discovered in 1986 and since then they have been found to encompass an ~40-member family of GPCRs that are highly localized to primary sensory ganglia. MRGPRs are divided into 9 major families (viz. MRGPRA through MRGPRH and MRGPRX) and, of these, the MRGPRX-family of receptors has been highlighted as a ‘primate-exclusive’ group enriched in human sensory neurons. We have recently shown that MRGPRX2 likely mediates the mast-cell dependent hypersensitivity responses caused by prescription opioids and related medications. We have also with collaborators reported that a polymorphism in MRGPRX4 mediates the preference for mentholated cigarettes among individuals with African ancestry. The mechanism(s) by which opioids and other drugs interact with MRGPR-receptors is unknown and here we will elucidate their mechanism(s) by structural biological investigation of these enigmatic receptors. Using these structures we will discover and optimize chemical tools with which to modulate their function. These studies will lead to an enhanced understanding of MRGPR-receptor structure and function. The findings may accelerate the search for medications devoid of MRGPR-mediated side effects and which may function as therapies for diseases linked to MRGPR-receptor dysfunction.

NIH Research Projects · FY 2026 · 2022-04

ABSTRACT Glaucoma, a leading cause of irreversible blindness, is characterized by progressive degeneration of the optic nerve and retinal ganglion cells (RGC). Glaucomatous damage might be caused either by elevated intraocular pressure (IOP), which could mechanically stress the optic nerve, or by reduced blood flow, which could impair function of the optic nerve. Lowering IOP is the only available treatment for glaucoma, but many patients continue to lose vision despite successful IOP reduction. Vascular abnormalities independent of IOP can occur in glaucoma patients, such as vasospasm and hypertension. While vascular dysfunction is associated with glaucoma pathophysiology, it remains uncertain whether blood flow impairment can be a target for intervention. Normalizing blood flow is a compelling novel treatment strategy for glaucoma. Our laboratory pioneered the application of multiparametric MRI to image high-resolution lamina-specific anatomy, quantitative blood flow, and function of the retina and optic nerve in rodents and in humans. This includes volumetric blood flow MRI of the retina, choroid, and optic nerve head, as well as diffusion MRI to measure optic nerve axonal integrity. Moreover, we have compelling preliminary data that blood flow is reduced in an established animal model of glaucoma and that chronic, mild hyperoxia treatment improves retinal function in glaucoma, supporting a role for blood flow impairment in glaucoma pathogenesis. Herein, we will utilize our MRI methods to further investigate the role of vascular dysfunction in glaucoma pathology by assessing a treatment to normalize blood flow in glaucoma. The goals of this proposal are to use our novel ocular MRI methods in an established mouse glaucoma model to: 1) evaluate whether a novel treatment strategy to increase blood flow can prevent glaucomatous damage and 2) evaluate whether combined treatments to lower IOP and normalize blood flow provide additional protection against glaucomatous progression. Our central hypothesis is that blood flow dysregulation contributes to glaucoma pathogenesis, so treatments to normalize blood flow could prevent damage and ultimately preserve vision in glaucoma. The impacts of this study will be i) novel insight into glaucoma pathophysiology and into the contribution of blood flow abnormalities to irreversible structural and functional damage, ii) establish novel retinal and optic nerve MRI as a method that provides unique, clinically relevant information on volumetric blood flow, and iii) establish an innovative treatment strategy for glaucoma of normalizing blood flow. The ultimate impact of this work would be to prevent blindness and vision loss due to glaucoma.

NIH Research Projects · FY 2026 · 2022-04

PROJECT SUMMARY Colonic diverticulitis is a common (209 cases per 100,000 person-years) disease that is responsible for $5.5 billion dollars in health care expenditures annually. Diverticulitis is a leading indication for operations, hospital admissions, and ambulatory visits, with a greater burden of disease in women. Postmenopausal age women are at highest risk of developing diverticulitis when compared to either similar age premenopausal women or similar age men. The reason for this disparity is unknown but may be due to metabolic changes associated with menopause. Menopause is associated with the development of all components of metabolic syndrome including visceral fat accumulation, atherogenic dyslipidemia, insulin resistance, and hypertension. While there is compelling evidence that obesity increases diverticulitis risk, the mechanism for this association is unclear. We believe metabolic syndrome explains this association. Establishing a role for metabolic syndrome in diverticulitis risk would radically redefine this disease and open new lines of research to utilizing existing therapies that are currently used for the treatment of metabolic syndrome. Menopausal hormone therapy does not prevent postmenopausal metabolic dysfunction and is associated with an increased risk of cardiovascular events, particularly in women with preexisting metabolic syndrome. In limited work, menopausal hormone therapy use has also been associated with increased diverticulitis risk. Building on existing, high-quality evidence and our own preliminary data, the proposed application aims to demonstrate that metabolic syndrome and preclinical obesity biomarkers play a role in diverticulitis. Our central hypothesis is that diverticulitis is a metabolic disease. We plan to test this hypothesis using a large, ongoing, prospective cohort study (Sister Study) conducted by the National Institute of Environmental Health Sciences. This mature cohort of 50,884 women in the U.S. and Puerto Rico is well characterized with archived blood samples, sufficient follow up to observe incident diverticulitis, standardized data collection, and detailed covariates including reproductive characteristics. The aims of the proposed study are 1) to prospectively determine the association between metabolic syndrome (hypertension, type 2 diabetes, dyslipidemia, and central obesity) and incident diverticulitis, 2) to prospectively determine the association between menopausal hormone therapy and incident diverticulitis in postmenopausal women, and 3) to prospectively determine the association between obesity- related serum biomarkers in relation to incident diverticulitis. This is a novel approach to diverticulitis that diverges from the current paradigm and creates the potential for multiple new medical and behavioral strategies for diverticulitis treatment and prevention. Understanding the association between menopausal hormone therapy and incident diverticulitis creates the possibility of immediate change in prescribing hormone therapy to women at increased risk and will generate important insights into the biological mechanisms underlying diverticulitis.

NIH Research Projects · FY 2026 · 2022-04

PROJECT SUMMARY Elevated psychosocial stress – a hallmark of modern, fast-paced societies – has been repeatedly associated with altered immune function and increased coronary heart disease (CHD) risk, but the mechanisms underlying these associations are unclear. DNA methylation, one of the critical and most studied epigenetic processes in humans, has emerged as a key link between environmental exposures and human health. Our long-term goal is to elucidate the epigenetic and other molecular mechanisms through which psychosocial stress contributes to atherosclerotic disease. The overall objective of this application is to define the methylomic differences associated with stress both in whole blood and in distinct immune cell types and to determine how these differences can shape immune function and predict CHD risk. The central hypothesis is that stress drives methylomic patterns that epigenetically upregulate proinflammatory and other immune mediators across distinct blood cell types, thereby contributing to incident CHD. The rationale for this application is that determining stress-associated epigenomic patterns and their functional sequelae in peripheral blood immune cells can yield novel composite predictors and molecular targets that can be leveraged to enhance CHD prevention and treatment. The central hypothesis will be tested by combining large-scale analyses in human cohorts and mechanistic investigations in cell models. Three distinct but complementary specific aims will be pursued: 1) Identify stress-associated methylomic profiles in whole blood that predict incident CHD; 2) Define cell type- specific methylomic patterns that are associated with stress and predict CHD; and 3) Mechanistically dissect how stress epigenetically regulates monocyte function in culture. Aims 1 and 2 will leverage multiple large cohort studies that participate in the NHLBI Trans-Omics for Precision Medicine (TOPMed) program and have suitable psychosocial stress, whole-blood DNA methylation, and/or incident CHD data. Cell type-specific methylomic patterns will be deconvoluted using cutting-edge computational methods recently developed by the research team. Key epigenetic signals will be mechanistically dissected using cell models of monocytes and monocyte- derived macrophages undergoing exposure to physiological levels of stress hormones and targeted DNA methylation editing in culture. This interdisciplinary proposal is innovative as it will integrate large-scale association efforts that apply novel computational methods across multiple TOPMed studies with cutting-edge mechanistic work in immune cell models. The proposed research is significant as it is expected to yield innovative epigenetic predictors and actionable molecular targets that can be leveraged to enhance prevention and treatment of stress-associated CHD.

NIH Research Projects · FY 2025 · 2022-03

Abstract: Autosomal Dominant Hyper IgE Syndrome (AD-HIES) is a rare genetic disease characterized by elevated IgE, eosinophilia, eczema, recurrent skin infections, and pneumonia. AD-HIES is most frequently caused by mutations in the STAT3 gene, leading to impaired TH17 cell differentiation and recurrent pulmonary infections, a major cause of morbidity and mortality in AD-HIES patients. Airway mucus obtained from AD- HIES patients is abnormally thick (hyperconcentrated), viscous, and adherent. The abnormal mucus properties are associated with chronic inflammation and mucus obstruction, resembling features observed in cystic fibrosis (CF) and primary ciliary dyskinesia (PCD). In CF and PCD, loss of the CFTR or motile cilia, respectively, leads to hyperconcentrated mucus, impaired mucociliary clearance (MCC), and chronic infection, suggesting candidate pathways for the pathogenesis of AD-HIES lung disease. Our preliminary in vitro and in vivo studies suggest both pathways are defective in AD-HIES: (1) CFTR transcription and function are downregulated; and (2) expression of ciliary shaft dyneins are also downregulated. These data led us to test the hypothesis that defective STAT3 perturbs mucus clearance in AD-HIES lungs. Three Aims are prepared to test this hypothesis. Specific Aim 1: STAT3 regulates CFTR-mediated airway surface hydration and mucus concentration. We will measure nasal PD, sweat chloride values in AD-HIES patients in vivo, and CFTR activity in vitro using primary AD-HIES human bronchial epithelial (HBE) cultures at baseline and after exposure to inflammatory stimuli. Therapeutic approaches aimed to improve CFTR expression and function will be assessed in AD-HIES HBE cells. Specific Aim 2: STAT3 is required for ciliated cell genesis, function, and mucociliary transport. We will image motile cilia ultrastructure in freshly collected nasal scrapes by TEM. Ciliary beat frequency and direction, waveform patterns, regulation of ATP/adenosine concentrations, and mucus clearance rate in the AD-HIES HBE cells will be measured. Therapies aimed to restore MCC and mucus hydration will be assessed for their efficacy in AD-HIES HBE cells. Specific Aim 3: AD-HIES is associated with airway mucus plugging and heterogeneous ventilation that can be quantified using advanced CT and MRI imaging techniques. To quantify the muco-obstructive phenotype in AD-HIES patients in vivo, we will perform quantitative imaging analyses by conventional CT, regional ultra- high resolution CT scan, and high-performance low field MRI to measure mucus plug, airway trapping and gas exchange distribution. This collaborative project combines the strengths of the NHLBI, NIAID, NIH Clinical Center, Johns Hopkins CF Center and UNC’s Marsico Lung Institute, to study AD-HIES lung disease. Data derived from this application should identify the molecular and cellular mechanism(s) of STAT3 in regulating MCC-mediated innate host defense, optimal imaging modalities for detecting mucus obstruction in AD-HIES subjects, and novel therapeutic options for restoring mucus clearance in AD-HIES subjects.

NIH Research Projects · FY 2025 · 2022-03

ABSTRACT Sedentary behaviors (SB) are biologically distinct but understudied cardiovascular disease (CVD) risk factors. National and international agencies have surmised that the level of evidence for an overall and dose-response association between SB and CVD mortality is moderate-strong. These agencies do not provide specific recommendations for breaking-up SB, though do call on the research community to facilitate policy development by establishing biological plausibility, identifying the optimal dose for SB substitution strategies, and conducting randomized clinical trials to test the efficacy of these strategies. Our goal is to identify mechanism-informed, socioecological-based SB substitution recommendations to mitigate CVD risk. Aim 1A will identify a feasible SB substitution strategy to prevent the adverse cardiovascular responses to prolonged SB. Adverse cardiovascular responses will be measured using aortic arterial stiffness (AS), a noninvasive test that predicts future CVD. To accomplish this aim, in 56 middle-aged (36-55 years) participants, we will measure aortic AS and associated mechanistic responses to the following over 4 hours: (i) SB with once/hour 5 min walk break; (ii) SB with once/hour 15 min stand break; (iii) SB with twice/hour breaks (alternating 5 min walk and 15 min stand); and (iv) SB with no breaks (control). These strategies were selected based on extensive prior work by our group, and because they are feasible, which is a key component of this proposal. SB reduction strategies will only decrease CVD risk if people are willing to adhere to future SB substitution recommendations. To increase the likelihood of feasibility and long-term adherence, Aim 1B will evaluate the determinants of SB using a socioecological model. This recognizes that behavior change is likely to be limited if the physical and sociocultural environments do not support the behavior change. To accomplish Aim 1B, a combined inductive-deductive qualitative approach will be used. Participants who complete Aim 1A will be participate in one of 6 focus groups (6-8 participants/group). Aim 2A will then test the feasibility of implementing the strategy in the real-world via an individualized single-arm 12-week intervention (n=40, 36-64 years). The mechanistic (Aim 1A) and qualitative (Aim 1B) data from Aim 1 will guide the intervention design. We will test the following feasibility domains: demand, acceptability, implementation, practicality, integration, and limited-efficacy. Lastly, Aim 2B will investigate which components of the intervention worked and which components did not work. All participants who complete Aim 2A will be asked to complete questionnaires pertaining to our behavioral model as well as participate in a focus group. The focus groups will be used to add context to the quantitative feasibility data. Specifically, we will address acceptability, adoption, appropriateness, sustainability, and the perceived socioecological determinants. Crucially, the outcomes from this proposal will be instrumental in facilitating the design of a subsequent clinical trial to test a mechanism-informed yet feasible SB reduction intervention, and in doing so directly support the development of SB policy.

NIH Research Projects · FY 2026 · 2022-03

Project Summary Manifestations of enterovirus infections are variable, with several severe illnesses such as meningitis, acute flaccid myelitis (AFM), myocarditis, and neonatal sepsis. Poliovirus vaccines are near perfect at preventing severe illness by generating strong, circulating antibody responses. However, the polioviruses represent only three of the more than 100 enteroviruses capable of causing human disease. Recently approved vaccines for enterovirus A71 are demonstrating that other enterovirus diseases, in this case hand, foot, and mouth disease, can be prevented by vaccination as well. Our previous work shows that monoclonal antibodies that cross-react to all clades of enterovirus D68 can protect infected mice from AFM-like disease, and even treat disease after onset. Rather than try to make 100 vaccines to cover each enterovirus, we propose to understand the qualities of the human antibody response that could provide cross-reactive immunity across many enteroviruses. With this knowledge, immunogens can be designed that preserve the B cell epitopes that stimulate cross-reactive antibodies. We first aim to determine the degree of cross-reactivity of enterovirus antibody responses at a B cell level. We will complement seroepidemiology studies of hundreds of healthy adults, looking to see what proportion of them have naturally made antibody responses to the four species of enterovirus, with studies of stimulated memory B cells from the peripheral blood mononuclear cell compartment. The latter will allow us to see how many individual B cells in healthy adults produce antibodies that cross-react between enterovirus species, a knowledge gap with no existing data. Second, we aim to determine the molecular details of enterovirus species cross-reactivity using human mAbs. We will create human hybridomas that produce monoclonal antibodies (mAbs), screening and selecting for mAbs that bind to multiple enteroviruses. Antigen-binding fragments of the mAbs, in complex with virions from all immune-reactive enteroviruses, will be used for cryo-electron microscopy studies to obtain atomic resolution maps of antibody epitopes, detailing at a molecular level the determinants of cross-reactivity. Third, we aim to determine mechanisms of antibody action utilizing human primary cell infection models. As we investigate which stage of the viral life cycle different mAbs disrupt to exert function, using ex vivo differentiated human epithelial cell cultures will preserve the natural cell surface receptors used by viruses during in vivo human infection. The knowledge gained from these studies will allow detailed understanding of how cross-reactive antibodies bind to enteroviruses and how they function. In turn, the mAbs can be used to functionally validate that candidate immunogens preserve these cross-reactive B cell epitopes. Finally, some mAbs could later have potential for direct use in humans, either as prophylactic or therapeutic agents. This is an especially important consideration for populations such as the immunocompromised, who may not be able to generate strong antibody responses upon vaccination.

NIH Research Projects · FY 2026 · 2022-03

Adeno-associated virus (AAV) vectors have been applied in clinical trials in patients with different disorders. Although successful in clinical studies, one of major concerns for broader AAV vector application for patients is high prevalence of neutralizing antibody (Nab). In the general human population, over 95% of individuals have been infected by AAV and, on average, approximate 50% of them have Nabs. Several approaches have been explored to evade AAV Nabs, including epitope masking with PEG or exosome, different serotype of AAV vector, rational design and combinatorial mutagenesis of the capsid in situ, as well as biological depletion of Nabs (empty capsid utilization, B cell depletion, plasma-apheresis and IgG cleavage enzymes). Generally, these approaches have low efficiency or side effects or AAV tropism change. Therefore, it is imperative to develop ideal strategies to evade Nabs, but without a change in tissue tropism from capsid engineering or negative side effects from pharmacological treatment. Recently, we have developed a vector independent protein based strategy to universally block Nabs and demonstrated that this approach is effective against a broad range of pre-existing Nab concentrations by use of a unique mycoplasma derived protein and it’s analogues, termed Protein-M. Protein-M is able to interact with immunoglobulin from any species without antigen dependence. We have found that protein M protected AAV vector neutralization over 100 fold in vitro and 1000 fold in mice with adoptive transfer of Nab positive serum, so far, the most effective strategy to evade AAV Nabs. However, the wild type protein M is structurally unstable at body temperature (37°C), making it challenging for clinical application. The protein unfolding at body temperature may correspond with decreased Nab blockade when using the protein in vivo. In order to improve PM stability, we have rationally designed in silico a library of 150 individual protein mutants engineered for improved thermal stability. At least 10 mutants were identified with enhanced thermal stability and high biological activity. In this proposal, we will further characterize the efficacy of these mutants in vitro and in mice with adoptive transfer of Nab positive serum (Aim 1). Next, we will study the role of protein M in AAV re-dosing in mice with pre-immunization (Aim 2). Then we will move forward to a disease model to test the ability of the best protein M variants to block AAV Nabs in animals for phenotypic correction with AAV vector mediated gene delivery (Aim 3). The long term objective is to develop a more effective strategy to evade Nab activity in future gene therapy with AAV vectors in patients with Nabs.

NIH Research Projects · FY 2026 · 2022-03

Most older adults experience changes in immune system function which lead to chronic elevations in inflammation biomarkers. Chronic inflammation leads to elevated risk of many age-related disorders, including Alzheimer’s disease and related dementias (ADRD); however, the exact mechanisms remain unclear. There is a higher burden of both ADRD and chronic inflammation in African American populations, likely in large part due to social determinants of health (SDOH) and psychosocial stress. Pro-inflammatory innate and adaptive circulating immune cells, and inflammation related genes in these cell types, may be associated with an increased risk of mild cognitive impairment (MCI) and dementia among community-dwelling older African Americans. We propose to characterize the circulating proportions of monocytes, T and B cell, and innate lymphocytes (>50 cellular phenotypes) and gene expression in immune cells in ~1440 African American participants enrolled in the well-characterized population-based Jackson Heart Study, using samples collected and stored at the upcoming Exam 4 (2021-2023). We will then evaluate associations of immune cells and inflammation pathway gene expression with age, psychosocial stress and SDOH, plasma biomarkers of Alzheimer’s disease neuropathology, magnetic resonance imaging (MRI) based neurodegeneration and cerebrovascular disease measures, and MCI and dementia. We will examine these relationships both cross-sectionally and longitudinally, using previously funded RNA-sequencing and immune phenotyping data at the Jackson Heart Study baseline exam (2000-2004), and assess differences by sex, given known sex differences in immune system function. We hypothesize that pro-inflammatory cell types and transcripts will be associated with MCI, dementia, and its risk factors and that inflammation may statistically mediate associations between higher psychosocial stress/SDOH burden and risk of MCI/dementia. We will also use data from immune cells to identify putative target genes and biological mechanisms for dementia risk variants, especially for variants more common in African versus European ancestry populations. This study is responsive to PAR-19-070 , as well as the January 2021 NIA approved concept calling for increased study of adaptive immunity in ADRD. It will add unique immune function and RNA sequencing data to one of the largest ongoing cohort studies of aging African American adults, with longitudinal phenotyping over 20 years. The generated data will be made widely available to the scientific community through appropriate public repositories (such as dbGaP) and can be used to address how immune cells and their gene expression influence risk of both dementia and other important disease outcomes in aging African Americans, cross-sectionally and longitudinally. Identification of specific and non-invasive inflammation biomarkers associated with MCI and dementia risk will improve our understanding of disease biology and help inform selection of putative anti-inflammatory therapeutics for ADRD.

NIH Research Projects · FY 2026 · 2022-02

ABSTRACT Influenza and pneumococcal infections occurring in individuals with glomerular disease are preventable contributors to excess healthcare utilization, morbidity, and mortality, and occur at a rate approximately 30 times higher among individuals with glomerular diseases compared to the general US population. Vaccination is a powerful and cost-effective method to reduce infectious burden, however, vaccine immunogenicity and effectiveness have not been adequately studied in this high-risk patient population. Vaccination may not yield protective or sustained immune responses in individuals with glomerular disease as a result of exposure to immunosuppressive medications, altered immune cell function, and urinary loss of immunoglobulin and complement factors. As a result, there remain pressing questions regarding whether these antibodies confer in- vivo protection from influenza and pneumococcal infection. Evidence gaps that need to be addressed in preparation for pragmatic trials focused on infection-prevention measures in this population include frequency of administration of recommended vaccines, pervasiveness of infectious complications, and rates of influenza and pneumococcal vaccine seroconversion and seroprotection. Prior studies have been limited by small sample size, insufficiently characterized cohorts, and the use of assays that measure non-opsonic, and thus potentially non- functional, antibodies. The objective of this proposal is to describe the association of influenza and pneumococcal vaccination with influenza and pneumococcal infections and describe functional vaccine immunogenicity in patients with glomerular disease. Three projects have been proposed to achieve this objective: an analysis of influenza and pneumococcal vaccine use and effectiveness in a nationwide healthcare claims database (MarketScan®), a study examining vaccine immunogenicity in the multicenter NIDDK-sponsored Cure Glomerulonephropathy (CureGN) study, and creation of a multicenter cohort to examine 23-valent pneumococcal vaccine immunogenicity in children with nephrotic syndrome. The primary hypothesis is that, independent of kidney function, rates of influenza and pneumococcal infection and suboptimal vaccine response will be higher in individuals with active glomerular disease, greater immunosuppression exposure, greater proteinuria, and younger age. Dr. Glenn’s career development goals include gaining advanced training in statistical methods and epidemiologic study design, with a focus on the analysis of longitudinal datasets, healthcare claims data, and multicenter vaccine immunogenicity studies. Dr. Glenn will receive mentorship from Dr. Amy Mottl and Dr. Ronald Falk, both experts in the field of glomerular kidney disease. Additionally, Dr. Glenn will have a scientific advisory committee comprised of experts in vaccine immunogenicity, infectious disease, healthcare claims data analysis, and epidemiology. This work will inform the development of an R01 application in which Dr. Glenn leads a pragmatic trial investigating pneumococcal vaccination strategies among children with nephrotic syndrome.

NIH Research Projects · FY 2025 · 2022-02

TAM receptors are receptor tyrosine kinases with important regulatory roles in cells. These receptors are essential to maintaining cellular homeostasis through the clearance of apoptotic cells and through control of inflammatory and immune responses. Linked to their important regulatory roles, dysregulation of TAM receptors is implicated in numerous disease states including cardiovascular disease, hereditary blindness, autoimmune disorders, chronic inflammation and cancer. While there is growing interest in TAM receptors as therapeutic targets, their multiple roles in homeostatic processes create challenges for developing therapeutic strategies. Understanding TAM receptor activation mechanisms is important for further investigation of the potential development of targeted therapies. While these receptors are commonly believed to be activated through classical receptor-induced dimerization, my preliminary work presents the first in-depth study of the biochemistry and suggests that this simplified view may not be applicable to TAM receptors. Importantly, to fully understand how TAMs are activated, I intend to utilize a combination of structural, biophysical and biochemical approaches to investigate TAM oligomerization and cross-talk with other receptors. These studies will guide the development of informed theories of TAM receptor activation and provide important insights that may be used for the development of new therapeutics in cancer and autoimmune diseases.

NIH Research Projects · FY 2025 · 2022-02

ABSTRACT The lack of diversity in the United States genomics workforce is a critical multifaceted issue that highlights disparities for underrepresented people in access to training, job acquisition, and healthcare. We propose Educational Pathways to increase Diversity in Genomics at UNC Chapel Hill (UNC EDGE) to help address this problem by developing and implementing a new sustainable undergraduate training program in genomics. The primary aims for UNC EDGE are to (1) expose early career freshmen and sophomores to the breadth of careers available in basic genome sciences, genomic medicine, and genomics and society; (2) provide the foundational research skills & knowledgebase required to make an informed career decision; and (3) help students develop a supportive multi-tiered community mentoring framework to guide their career trajectory. Our central objective is to provide students with the tools, knowledge, and support to build self-efficacy and informed decision making required for sustainable advancement in a career in genomics. North Carolina (NC) has a high level of ethnic diversity [10.1 million people, ~33% from underrepresented communities], a large proportion of rural regions (80%), a low rate of completion of higher education among underrepresented groups (14-20%), and increasing disparities in health and healthcare. NC is also home to a burgeoning biotechnology enterprise and the University of North Carolina at Chapel Hill (UNC), a global leader in genomics research and Precision Medicine. Both entities have historically low proportions of people from underrepresented, underserved, and disadvantaged backgrounds working in genomics. Over the course of this 5-year project, UNC EDGE will use a tailored curriculum to bridge the gap between the stellar genomics research environment at UNC and underrepresented (UR) undergrads from surrounding NC communities, as well as students across the United States. Our primary objective for long-term outcomes is to increase the number of these UR students that choose and are stably retained in a genomics research career. This will increase access to lucrative job opportunities in academia and biotechnology, and increase inclusion and innovation in research & healthcare. In addition, increasing entry of well-trained underrepresented professionals into the genomics workforce gives them the opportunity to become stakeholders in the research and healthcare decisions that affect their community; an outcome that we hope will ultimately help improve disparities in healthcare as genomics becomes a greater consideration in Precision Medicine.

NIH Research Projects · FY 2026 · 2022-02

Project Summary/Abstract: The objective of this K08 Mentored Clinical Scientist Career Award Application is to provide Dr. Alena Markmann with a strong foundation in human immunology and the latest methods for studying human immune cells before launching her independent research career on the human immune response to RNA viruses. Dr. Markmann is an Assistant Professor of Medicine, tenure track, at the University of North Carolina -Chapel Hill (UNC) School of Medicine with a joint appointment in the Department of Microbiology and Immunology. The candidate has expertise in and a strong track record of publications on antibody structure, antibody-antigen interactions and antibody neutralization of viruses. By strengthening her knowledge of adaptive immunity to RNA viruses and mastering the latest methods for analyzing antigen specific B cells, Dr. Markmann will study how the human immune response to emerging flaviviruses like dengue and Zika can suppress viral infection and disease or enhance viral replication and exacerbate disease. The candidate and her mentor Dr. Aravinda de Silva have designed a training plan that includes a rigorous research component along with didactic instruction, networking and presentation opportunities, team management skills as well as manuscript writing and grantsmanship. Together these skills will establish the methods and principles necessary for successful career development. Flaviviruses are enveloped positive stranded RNA viruses that pose a growing threat to the human population and cause millions of infections annually. They are vector-borne, transmitted by ticks and mosquitoes, and cause a spectrum of disease manifestations including febrile illness, encephalitides that can cause lifelong complications, Congenital Zika Syndrome and dengue hemorrhagic fever and shock syndromes. For the most part, flaviviral infection result in a neutralizing protective antibody response against the infecting virus, that can last for years after infection. The four dengue viruses however are very similar antigenically and in many cases, result in generating a broad cross-neutralizing antibody responseto dengue virus serotypes that individuals have not yet been exposed to. Thus far, no one has identified the viral target site of these broadly neutralizing dengue antibodies that exist in the serum. Furthermore, though we know of a few major targets of the Zika protective antibody response from studying memory B cells, we do not know what the serum targets are. Preliminary results suggest that in the case of Zika serum antibody responses, binding targets are correlated with known strongly neutralizing memory B cell-derived antibody targets. Thus, we hypothesize in Aim 1, that serum antibody responses will mirror memory B cell responses, but will likely come from a smaller number of B cell clones and be less cross-reactive with other flaviviruses. In Aim 2 we will identify the viral binding targets of broadly cross- neutralizing dengue antibodies from the serum. These studies will result in the ident ification of critical protective viral targets to both dengue and Zika viruses from the serum antibody compartment in order to inform successful vaccine design.

NIH Research Projects · FY 2026 · 2022-02

Project Summary/Abstract Glioblastoma is the most common primary brain tumor and one of the deadliest forms of cancer. Recently, we found that biocompatible matrices significantly improve the transplant of tumor-homing neural stem cells into the post-surgical GBM cavity allowing them to deliver anti-cancer gene products that suppress tumor recurrence. Yet, the optimal scaffold figuration that maximizes tNSC transplant, migration, drug release, and subsequent GBM kill remain unknown. Using clinically relevant human tNSCs, matrices, and mouse models of GBM resection/recurrence, we have found that 3D architecture and scaffold composition markedly enhance tNSC persistence in the surgical cavity. Here in, we hypothesize that optimizing features through unique 3D printing of custom designed scaffolds will achieve superior suppression of post-surgical GBMs by tNSC therapy. Leveraging Continuous Liquid Interface Printing (CLIP), a novel continuous fabrication method with high spatial resolution, we propose to fabricate a panel of 3D matrices with different architectural, biophysical, and mechanical response features design rationally selected to improve tNSC therapy. We will define the impact of each design feature on tNSC persistence, homing and killing in vitro and in vivo, then test a final optimized matrix incorporating the most beneficial features into a single matrix using surgical resection models of patient-derived human xenografts in immune-depleted mice and syngeneic GBM allografts in immune- competent animals. We propose to undertake the following Aims: 1) Utilize CLIP to fabricate a panel of 3D printed matrices with varied design features; 2) Define the impact of 3D design features on tNSC efficacy for post-operative GBM; 3) Investigate the efficacy and safety of 3D matrix/tNSC therapy in immune-competent models of GBM resection/recurrence. The results of our study will generate a therapeutic tNSC/scaffold transplant strategy capable of robust GBM killing that can be translated for human patient testing. It will also uncover the scaffold features that regulate different aspects of tNSCs, allowing us to modulate tNSC cancer therapy through matrix design.

NIH Research Projects · FY 2026 · 2022-02

ABSTRACT Child care centers ─ and their providers ─ are critical partners in public health efforts to address today’s obesity epidemic. Diet and physical activity (PA) habits are formed early, influencing immediate and long-term obesity risk, and both centers and providers play key roles in forming children’s weight-related habits. Yet, the standard paradigm of child care-based obesity prevention initiatives primarily target only center directors to change organizational-level policies and practices; failing to recognize the needs of the child care providers. These providers suffer disproportionally high prevalence of obesity and research has shown that providers’ own poor eating and PA behaviors reduce their confidence and ability to model and promote healthy lifestyle behaviors to the children in their care. However, information regarding the effectiveness of improving provider health behaviors or whether such improvements elicit meaningful change in the child care environment and the children in their care is limited. Leveraging our team’s expertise with implementing evidence-based behavior change and weight loss interventions, the proposed study will integrate an evidence-based weight management intervention for child care providers into Go NAPSACC’s existing childhood obesity prevention program (Go NAPSACC+). Go NAPSACC+ program will be assessed using a clustered randomized controlled trial to evaluate if improving child care providers’ health behaviors elicit meaningful change in dietary and PA behaviors in 2-5-year-old children in their care and the child care environment. We will recruit 84 centers, including 168 providers, and 672 2–5-year-old children to participate in the evaluation. Centers will be randomly assigned to 1) standard “Go NAPSACC” or 2) “Go NAPSACC+” (with a provider weight management component). Outcome measures will assess impact on dietary intake and PA behaviors of 2-5-year-old children at 6 months (primary aim) and 12 months. Secondarily we will compare the impact of the intervention on centers’ implementation of healthy weight practices and the effect on provider-level weight, diet quality and/or PA at 6 and 12-months. Extensive process analysis, guided by the RE-AIM framework, will document the fidelity of the interventions, challenges and barriers to effective implementation, and use of program specified activities. If successful, findings will provide a highly implementable, scalable, and sustainable strategy that would enhance the standard paradigm of early childhood obesity prevention initiatives.

NIH Research Projects · FY 2026 · 2022-02

The goal of this application for the NHLBI K01 Career Development award is to provide Deshira Wallace, MSPH, PhD, with the essential training to become an independent researcher in cardiovascular health and health disparities affecting US adult populations. Dr. Wallace puts forth a comprehensive research proposal and career development plan integrating training in and application of sociological theories, social epidemiology, cardiovascular health, and advanced quantitative and qualitative methods. Cardiovascular disease (CVD) is highly prevalent among specific United States (US) subgroups, such as Latinos. Yet, studies have shown that CVD prevalence varies within this multiethnic group, and these within-group disparities may be driven by different exposures due to the experiences reported by these groups. For example, studies have established that within-group CVD disparities exist for Latinos by country of origin, nativity, and years residing in the US. However, there is limited research on subgroup analysis according to poorly measured demographic variables like race and ethnicity, which can be measured in multiple ways, may result in differential outcomes. To begin improving demographic variable measures among a multiethnic group such as Latinos, the specific aims are to (1) Explore the experiences of multiethnic adults in the US; (2) Construct a multi-item demographic variable; and (3) Compare trajectories of cardiovascular risk scores over time among multiethnic adults to assess differences by a new latent demographic variable. Aim 1 will use in-depth interviews and focus groups to help identify specific, measurable, and modifiable risk factors influencing cardiovascular health and actionable in healthcare settings. Aim 2 (factor analysis) and Aim 3 (mixture models) will use data from an existing multiethnic dataset. To complement the scope of the proposed research study, the proposal includes four career-development and training goals: (1) Deepen theoretical understanding of sociological theories and apply them to qualitative and quantitative research methods; (2) Develop quantitative skills in latent class and mixture modeling analysis of longitudinal, epidemiological data; (3) Integrate social and biological science approaches to address causal factors that influence cardiovascular health; and (4) Strengthen scientific writing and grantsmanship skills. The proposed K01 supports the NHLBI’s focus on investigating factors that account for differences in health among populations. Findings from the proposed research will impact public health by using a multi-method approach to provide novel information to improve demographic measures to better understand disparities in cardiovascular health and inform tailored prevention and treatment strategies. This project will be carried out at the University of North Carolina at Chapel Hill, which offers exceptional resources and mentoring to train Dr. Wallace to execute the proposed K01; it also provides resources to augment faculty to successfully transition as an independent researcher.