Univ Of North Carolina Chapel Hill

NIH Research Projects · FY 2025 · 2025-08

While vaccines are readily available for SARS-CoV-2, there continues to be significant demand for prophylaxis that are potent and not at risk for viral escape to better protect vulnerable populations. In addition, there is emerging evidence that a number of bat sarbecoviruses and merbecoviruses can use human ACE2 (hACE2) as an entry receptor to infect human cells. Thus, there is also a need to advance effective immunoprophylaxis to protect against such zoonotic coronaviruses with pandemic potential. We have previously advanced an ACE2-immunodecoy as treatment for SARS-CoV-2 infections. Instead of the common approach pursued by many investigators to affinity mature ACE2 to enhance binding to SARS-CoV-2 Spike, we instead sought to optimize the linkage between the extracellular fragment of human ACE2 and IgG1-Fc (ALFc) to promote improved bivalent binding to SARS-CoV-2 Spike. Similar to other ACE2- decoys, ALFc is not susceptible to viral escape. Unlike other ACE2-decoys, the preservation of the full human ACE2 sequence means ALFc is likely active against all ACE2-targeted viruses. We have demonstrated that ALFc maintains picomolar activity (comparable to many of the previous leading monoclonal antibodies that received emergency use authorization) against all variants of SARS-CoV-2, and is highly effective in a hamster challenge model. Importantly, the ALFc has outstanding bioprocessing attributes, including stability at high concentrations and exceptional productivity using cGMP CHO production cell line. These attributes have led the U.S. Army to select ALFc to be advanced into clinical development over other ACE2 decoys; GMP materials for clinical trials and GLP tox studies are currently underway, and a Phase 1 clinical study is planned for 2H 2025. In this proposal, we build on the success of ALFc as an inhaled therapy to establish the efficacy of ALFc as a systemic immunoprophylaxis that can prevent severe pulmonary disease in vulnerable populations. Specifically, the ALFc currently in development possess wildtype IgG1-Fc. For sustained immunoprophylaxis lasting >6-9 months, it is essential to utilize Fc with enhanced affinity to FcRn, such as YTE, LS and DHS mutations. In this proposal, we will first produce and characterize ALFcYTE, ALFcLS and ALFcDHS(Aim 1). We will evaluate their activity against a panel of hACE2-targeting viruses, including emerging bat sarbecoviruses and merbecoviruses, using both pseudotyped alphavirus vectors in cell-lines (BSL-2) and infectious virus clones in well-differentiated cultures of human airway epithelial cells (BSL-3) (Aim 2). Finally, we evaluate the ability of ALFc to protect against infectious clones of SARS-CoV-2 and SHC014-CoV challenge in human ACE2 transgenic mice (Aim 3). Successful completion of these studies will likely advance an intervention for providing immunoprophylaxis against future SARS-CoV-2 variants as well as other hACE2-targeted coronaviruses with pandemic potential.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY Consistent with the research priorities of the National Heart, Lung, Blood Institute, this proposed study will investigate optimal treatment algorithms for patients with chronic limb threatening ischemia (CLTI). CLTI is the most severe, debilitating, and progressive form of peripheral artery disease. Successful treatment requires ongoing combinations medical, wound/podiatric, and endovascular or surgical vascular care. Despite the availability of multiple life- and limb-preserving treatments, success in improving health outcomes of patients afflicted with CLTI has been limited. Several patient factors influence the effectiveness of treatments over time: socioeconomic conditions, adherence to best medical therapy, degree of success with revascularization, and ability to attend postoperative vascular surveillance appointments. A lack of understanding of how these clinical and social factors affect CLTI treatment sequences and impact CLTI-free survival is a critical barrier to saving lives and limbs. The recently completed NHLBI-sponsored BEST-CLI randomized controlled trial with 1830 adult participants determined that surgical vein bypass is the most effective initial revascularization approach for patients with CLTI, but almost 10% required major vascular re- intervention, 10% underwent major limb amputation, and 33% died within two years. Our proposed research will use advanced analytics and machine learning to leverage the BEST-CLI trial data to identify the patient characteristics that associate with different disease trajectories and treatment patterns after the initial revascularization (Aim 1). Aim 2 will measure the effect of partial adherence to clinical follow-up visits on these clinical trajectories and CLTI-free survival. The identified patterns will define treatment tailoring opportunities- key decision points at which treatment decisions can be customized to individuals based on their unique clinical features. To address the non-clinical factors that influence treatment adherence and CLTI outcomes, Aim 3 is a prospective qualitative study, including semi-structured interviews and a user- centered design approach called journey mapping, that will identify facilitators, gaps and unmet needs that impact patients’ ability to adhere. This will inform where additional support should be integrated to make individualized, optimal treatment plans accessible to all patients. Our final output will include individually tailored, socially supportive treatment plans that improve the health of patients with CLTI. In the future, these candidate treatment algorithms will be tested with sequential multiple assignment randomized trials (SMARTs) to realize the goal of bringing precision medicine (“right treatment, right person, right time”) to CLTI care.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY Chronic inflammation is a hallmark of aging and plays a key role in the development of numerous neurological disorders. In the mammalian innate immune system, cyclic GMP-AMP synthase (cGAS) detects foreign or damaged endogenous DNA, synthesizes the second messenger 2’3’-cGAMP, and activates STING to promote the production of type-I interferons and interferon-stimulated genes. While recent studies suggest that activation of nuclear cGAS is critical in aging-related inflammation and neurodegeneration, the mechanisms by which nuclear cGAS is activated to drive chronic inflammation during aging remain poorly understood. Our preliminary findings reveal an unexpected link between chromatin regulation and cGAS activation, potentially explaining how cGAS contributes to aging-induced chronic inflammation. We discovered that cGAS, which is predominantly enriched in the nucleus and bound to nucleosomes in an inactive state, is released and activated by histone H4 N-terminal tail acetylation. Moreover, we found that BRD4, a known reader of H4 acetylation, binds acetylated H4-containing nucleosomes and further enhances cGAS activation. Since increased H4 acetylation is a hallmark of aging, we propose that aging-related histone hyperacetylation leads to the release and activation of nuclear cGAS, driving chronic inflammation and contributing to age-related diseases. Our central hypothesis is that specific patterns of histone H4 acetylation, along with their reader proteins, represent a novel regulatory mechanism that unleashes and activates chromatin-bound cGAS, contributing to inflammation and aging. If validated, these findings would introduce a new paradigm for understanding how nuclear cGAS drives aging and could pave the way for therapeutic strategies targeting H4 acetylation and BRD4 to control inflammation during aging. To test this hypothesis, we have assembled a multidisciplinary team with expertise in structural biology, biophysics, biochemistry, cell biology, chromatin biology, and epigenetics. Together, we will pursue three specific aims: (1) decipher the histone H4 acetylation patterns that regulate the activation of nucleosome-bound cGAS, (2) elucidate how H4 acetylation readers activate nucleosome-bound cGAS, and (3) investigate the physiological roles of H4 acetylation-dependent nuclear cGAS activation in cellular senescence and aging. This research, spanning from atomic structures and mechanistic insights to genetic models and animal pathology, offers an innovative concept and framework to advance our understanding of nuclear cGAS regulation in chronic inflammation. The potential findings could uncover a new paradigm at the intersection of epigenetics, innate immunity, and aging, and facilitate the development of cGAS-targeted therapies for age-related disorders.

NIH Research Projects · FY 2026 · 2025-08

Project Summary: Despite the success of antiretroviral therapy (ART), HIV remains an incurable infection, due to the presence of a persistent viral reservoir that is resistant to ART. This reservoir is widely disseminated throughout the body, including in solid tissues such as the central nervous system (CNS) where microglial cells constitute the primary reservoir. New cure approaches are needed that promote permanent silencing or inactivation of viral gene expression. In particular, the viral protein Tat plays a central role in driving viral gene expression, and secretion of Tat from infected microglia likely contributes to CNS toxicity and HIV-associated neurocognitive disorder (HAND). Thus, irreversibly inhibiting or inactivating Tat in brain resident microglia could represent an effective way to block viral reactivation and to limit virus-induced HAND. However, no antiviral drugs that target Tat or viral transcription are currently available for clinical use. In this proposal we aim to develop microglia-targeting lipid nanoparticles (LNPs) containing Cas9/sgRNA complexes that inactivate the viral Tat gene, leading to loss of Tat expression and permanent silencing of HIV proviruses. In a key breakthrough, we have recently identified a novel LNP formulation (MG-LNP) that is optimized for biomolecule delivery to microglia and we have demonstrated successful use of this formulation for CNS gene targeting in mice. MG- LNPs containing Cas9/sgRNAs against Tat will first be optimized in microglial models of HIV infection (Aim 1), followed by testing in ex vivo brain samples from SIV infected macaques (Aim 2). Finally, we will use a novel humanized mouse model of HIV CNS/microglia infection to test this approach in vivo, in the presence or absence of cannabinoid exposure (Aim 3). If successful, these tools will prevent the microglial reservoir from reactivating after therapy interruption and will also mitigate residual CNS pathogenesis from Tat expression during therapy.

NIH Research Projects · FY 2026 · 2025-08

PROJECT SUMMARY/ABSTRACT ABSTRACT Significant gaps remain in the study of women’s health and understanding the effect of biological sex differences on disease risk, pathophysiology, symptoms, diagnosis, and treatment. From birth through childhood and adolescence into reproductive age and beyond, women encounter barriers affecting their opportunities, outcomes, and quality of life. The mission of the University of North Carolina Building Interdisciplinary Research Careers in Women’s Health (BIRCWH) Program is to mentor and train early career investigators to become independent interdisciplinary translational science researchers who study high priority areas in women’s health, explore sex influences on health and disease and also incorporate research strategies to promote health across the lifespan. Our priorities are to address crosscutting interdisciplinary themes from the 2024-28 NIH-wide Strategic Plan for Women’s Health Research and continuous evaluation of scholar progress and program effectiveness. We propose the following aims: (1) Training and mentorship: Facilitate research skills training, holistic, interdisciplinary mentorship, and career development to catalyze the transition of promising women’s health investigators to independent researchers; (2) Team science and translational research: Support early investigators in conducting interdisciplinary team science-driven translational research that fosters their acumen to conduct innovative women’s health research across the lifespan. Core National Institutes of Health (NIH) research priority areas aligning with strengths at UNC include maternal health, metabolic disorders, behavioral health, infectious disease, and cancer; (3) Health across the lifespan and stakeholder engagement: Bridge the interaction between biological perspectives and external health factors by training the next generation of women’s health investigators in how research design can incorporate stakeholder engagement to study and improve women’s health outcomes; and (4) Evaluation and Continuous Quality Improvement: Provide comprehensive evaluation and continuous quality improvement to guide decision-making, program improvement, and outcomes/impacts assessment. Our experienced interdisciplinary mentorship team, along with UNC’s substantial institutional resources, will create a program which is ready to addresses the common challenges faced by early career investigators and ensure our program trains scholars whose research will address significant health issues women’s health, promote innovation, and improve the lives of women across the U.S.

NIH Research Projects · FY 2025 · 2025-08

ABSTRACT Endoscopy plays a vital role in the diagnosis and treatment of various medical conditions and is regularly performed millions of times every year. However, endoscopy is both challenging to perform and often time- consuming to analyze from the resultant videos. Thus researchers have focused on developing many assistive and intelligent techniques to aid physicians in conducting endoscopies and to analyze the data. These techniques all share a common fundamental problem of 3D perception, i.e. recovering the 3D structure of the surveyed organ and localizing the endoscope in it from the captured 2D videos only. However current 3D perception techniques perform poorly on real clinical data. One key reason for failure is the lack of high-quality training data with 3D supervision for training 3D perception systems with Machine Learning algorithms. Current 3D perception systems rely on simple virtual models that cannot model complex geometric and reflective properties of internal organs, e.g. airway. In this proposal, we focus on developing a generative AI-based phantom airway model that can generate arbitrary geometric shapes and reflective properties of the mucus-layered airway surface conditioned on covariates such as age, sex, weight, and abnormalities. We aim to learn this generative airway phantom model from n=300 CT scans and n=300 endoscopy videos of different patients captured at UNC Chapel Hill. We first focus on designing a novel neural architecture that can generate realistic shapes from global and local latent codes with covariates, and a novel loss function that trains this generative model from CT scans and endoscopy videos (Aim 1). We then develop a novel strategy that can render realistic endoscopy videos by optimizing the material reflectance property modeling the mucus layered airway surface (Aim 2). We will demonstrate the effectiveness of our proposed generative-AI airway simulator by training state-of-the-art 3D perception systems on our simulator and existing virtual airway model BronchoPose dataset, and testing these 3D perception models on n=30 paired endoscopy videos with associated 3D CT scans. In summary, our proposed generative-AI-based airway simulator aims to provide high-quality realistic training data for various 3D perception systems. This will help in significantly improving various assistive and intelligent technologies, e.g. semi-autonomous navigation, 3D visualization, guidance to unsurveyed regions, automatic extraction of geometric properties, etc., for conducting and analyzing endoscopy and will help in incorporating these technologies into successful clinical practices. While we focus on the airway, our approach is general and can be used for building simulators of other organs of interest for endoscopy, e.g. GI tract.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY/ABSTRACT Rapid brain growth and development throughout the first years of life and the fragility of the blood brain barrier cerebrovasculature render the early childhood brain (birth-age five) uniquely susceptible to chemical exposures. Children are exposed to pesticides, flame retardants, and other suspected and known neurotoxicants in air, water, and dietary sources through exposure opportunities that are either uniquely high in early life (e.g., fruit and vegetable consumption, air intake) or specific to this developmental window (e.g., breastfeeding, hand to mouth behaviors, crawling exposure to house dust, and sustained contact with baby products). Despite evidence linking prenatal chemical exposures to neurodevelopmental deficits, insufficient biomonitoring in early childhood limits our understanding of the early life chemical exposure landscape, and few studies have assessed changes in underlying neural substrates. My objective is to characterize the early life chemical exposome and its impact on structural and functional brain development during this critical period of brain growth. I propose to leverage the University of North Carolina Baby Connectome Project (BCP), a longitudinal study that maps brain growth and development in early life using serial structural and resting-state functional magnetic resonance imaging (MRI), paired with developmental assessments and repeated child urine specimens to measure environmental exposures. During the K99 phase, I will characterize longitudinal patterns in the untargeted early life urine exposome and their associations with structural brain growth (among 250 children contributing 540 scan-urine pairs between 0-5 years). During the R00 period, I will generate novel exposure data by launching a targeted investigation measuring biomarker levels of high priority contaminants identified in the K99 period, as well as emerging fungicides and organophosphate esters that have been prioritized for early life biomonitoring based on toxicologic evidence of neurotoxicity and uncertain exposure burden. I will use innovative mixture methods to estimate associations between these emerging exposure biomarkers, brain anthropometry, functional network connectivity, and developmental assessments. The proposed work combines omics technology, longitudinal neuroimaging, and innovative dimension reduction methods to establish mechanisms of chemical neurotoxicity. To be successful in the proposed work and launch my independent research career, I need to gain: (1) statistical skills for analyzing high dimensional exposomic data, (2) proficiency in interpreting neuroimaging data, and (3) professional skills to establish and maintain an independent research program. The K99 structured training plan and exceptional team of mentors and scientific advisors will help address each of these dimensions. This award will provide a critical foundation for me to launch an independent research career investigating the impacts of environmental exposures on child health and development. This study has significant public health impact because it can causally link chemical exposures with adverse effects, leading to earlier interventions and improved neurodevelopmental outcomes.

NIH Research Projects · FY 2025 · 2025-08

Glioblastoma (GBM) is the most common primary malignant brain tumor and is ultimately fatal. We have shown that targeting ferroptosis, iron mediated lipid peroxidation, is a promising and effective treatment strategy in GBM models. This regulated form of cell death is inhibited by glutathione peroxidase-4 mediated clearance of lipid radicals using glutathione as a substrate. Glutathione is a tripeptide containing cysteine. Levels of intracellular cysteine, and its homodimer cystine, are regulated by System Xc-, a cystine-glutamate antiporter that is highly expressed in glioma. Our group and others have shown that targeting System Xc- induces ferroptosis in glioma. Our published data has also demonstrated that dietary cysteine/methionine deprivation (CMD) enhances the effects of ferroptosis-inducing agents and provides a survival benefit in glioma models. System Xc- activity is therefore well poised to serve not only as a target, but also a biomarker of response to ferroptosis. Positron emission tomography (PET) imaging is an established technique for analyzing cancer progression based on metabolic activity. Fluorinated glutamate, (S)-4-(3-[18F]fluoropropyl)-l-glutamic acid or FSPG, is a sensitive tracer for detection of malignant brain tumors as shown by clinical PET imaging studies, and thus may be a useful and accurate biomarker of CMD and pharmacologic System Xc- inhibition in glioma. Indeed, our preliminary data has shown that brain sections from glioma-bearing mice on a chronic CMD diet demonstrate differential uptake of FSPG when treated ex vivo. My laboratory has therefore optimized in vivo FSPG quantification in orthotopic syngeneic murine gliomas using PET-CT to investigate this application. Additionally, radiation, which is standard of care in GBM, can itself induce ferroptosis. Our murine in vitro data suggests that CMD and radiation synergize to induce ferroptosis. We therefore aim to show in preclinical studies using human GBM models that CMD synergizes with external and brachytherapy radiation to enhance GBM cell death by ferroptosis. We hypothesize that FSPG PET-CT imaging accurately detects glioma response to System Xc- inhibition, and radiation synergizes with CMD to induce ferroptosis, resulting in glioma cell death. We propose to undertake the following Aims: 1) Validate FSPG tumor uptake as a non-invasive biomarker of glioma response to treatment with System Xc- inhibitors (CMD, erastin, sulfasalazine); 2) Show that CMD synergizes with radiation to induce ferroptosis in glioma. The K01 will provide me with focused training in radiopharmaceutical imaging and radiobiology to enable my transition to an independent investigator, as we work to advance this line of research into patient care, combining CMD and radiation with FSPG PET-CT monitoring.

NIH Research Projects · FY 2025 · 2025-08

Project Summary Biomedical research increasingly leverages multi-modal data, including genomic, multi-omics, medical imaging, and clinical narratives, to advance precision medicine. The integration of these diverse data types is significant because it enables a comprehensive understanding of complex diseases, such as cancer and Alzheimer's disease, by combining the genetic, physiological, and clinical aspects of patient health. Such rich multi-modal data offer unparalleled opportunities for advancing precision medicine and improving health outcomes. However, the field faces several daunting challenges: (1) Complex and Heterogeneous Modalities: The integration of complex data types, such as high-dimensional genomic data and high-resolution medical imaging, is challenging due to significant noise and data misalignment, necessitating sophisticated data imputation and denoising methods. Moreover, significant multi-modal interference and suboptimal integration performance arise from substantial data heterogeneities, which is one of the key limitations of existing multimodal methods. It necessitates innovative use of advanced regularized optimization and network architecture designs to alleviate such issues. (2) Reliance on Single-Modality and Incomplete Multi-Modal Data: Traditional and emerging multi-modal frameworks often fail to effectively synthesize complex datasets. Single-modality approaches miss interconnected insights, while multi-modal methods struggle with cross-modal interactions and optimal performance, especially lacking the ability to cope with incomplete or missing multi-modal data that are ubiquitous in practice. (3) lnterpretability: Existing multi-modal models often neglect essential cross-modal interactions and rely on posthoc explanations, lacking mechanistic interpretability. To bridge these significant gaps via a novel multi-modal learning framework, we propose the following aims. Aim 1: To illuminate the black box of biomedical multi-modal data fusion: Toward effective and interpretable multi-modal biomedical Al. Aim 2: To address incomplete biomedical multi-modal data via retrieval-based methods: Toward robust multi-modal clinical classification and prediction. Aim 3: To bridge missing modalities in multi-modal biomedical data via optimization-based methods: Toward flexible integration with arbitrary modality combinations. Aim 4: To assess and validate the proposed multi-modal learning framework through integrative analysis of ADNI data for Alzheimer's Disease and TCGA data for cancer. Throughout the experiments, to verify our proposed methods, we will use performance metrics like ACC, Macro-F1, ARI, c-index, and AUROC, evaluating them on datasets including ADNI, Patch-seq GABAergic neuron, multi-omeATAC + gene expression BMMC, TCGA, ABIDE, and Duke Breast. The proposed methods are expected to accelerate biomedical research and improve healthcare by enhancing multi-modal data integration, overcoming analysis challenges, and providing valuable insights into the molecular and physiological processes underlying complex diseases, leading to more effective and tailored therapeutic strategies.

NIH Research Projects · FY 2026 · 2025-08

Project Summary/Abstract Cancer immunotherapy has become one of the pillar therapies in treating cancer patients, exemplified by immune checkpoint inhibitors (ICI) (e.g., anti-PD1). While ICIs have significantly improved the prognosis of cancer patients, the response rate to ICI monotherapy remains low (10-20%) for many types of cancer, such as head and neck squamous cell carcinoma (HNSCC). Some variability may be explained by human papillomavirus (HPV)- vs. carcinogen-induced, tumor antigen-specific T cell responses in HPV+ or HPV− HNSCC, reflecting a unique disease opportunity to investigate ICI responsiveness. Thus, it is vital to better understand the mechanisms underlying heterogenous responses to ICI and to identify new targets that may sensitize HNSCCs to mono- and combination immunotherapy. In this application, we propose to focus on T cell phenotypes associated with clinical response, dynamic changes in specific T cell receptor (TCR) clonotypes, and TCR clonotype-specific transcriptomic changes in response to ICI treatment, using HNSCC patient samples from an ongoing clinical trial at our institution and detailed studies using murine HNSCC models. Using HCC 18-139 trial samples, we will compare tumor infiltrating lymphocytes (TIL) and peripheral blood lymphocytes (PBL) from pre- and post-treatment samples and examine TCR dynamics and T cell phenotypes in blood (minimally invasive and readily accessible) and in tumors in the context of ICI-induced anti-tumor immunity. Our mouse model allows functional validation among distinct TCR clonotypes correlating with ICI responses, and permits manipulation of novel potential targets to enhance clinical responsiveness as well as lay the groundwork for future clinical trials. Our proposed studies will identify cellular and molecular markers to better predict ICI responses in HNSCC patients treated with different combinations of ICIs and would facilitate finding novel mechanisms of differential ICI responses using transcriptomic differences in distinct clonal TCR-bearing T cell populations. A unique strength of our proposal is integration of human clinical trial samples and mouse models as a more powerful platform to uncover mechanistic insights that are translatable into the clinical setting.

NIH Research Projects · FY 2025 · 2025-08

Phenotypic tolerance to antibiotics is a major cause of antibiotic drug failure. Non-heritable mechanisms that confer antibiotic tolerance have long been associated with cells that maintain a diminished metabolic rate. The presence of a small number of cells in a low activity level within a large population of susceptible cells poses formidable technical challenges for analysis because any bulk measurement will average out the small signal produced by the tolerant cells with the strong signal of the larger and more active population. Single cell measurements that can identify the activity level of single cells and link them with the transcriptomic signature of these cells can solve this problem and address fundamental open questions about how these low activity cells arise and persist. For starters, such measurements can determine whether cells in this state all share a signature transcriptomic profile or if multiple different gene expression states are correlated with low activity. Additionally, measurements of transcriptomic activity in cells that have lower activity levels can predict what metabolic genes these cells express and pinpoint whether there are weaknesses that can be exploited therapeutically. In this proposal we aim to first develop a single cell technique that will report the translational rate and transcriptome of thousands of individual bacterial cells. We will then explore the level of translational and transcriptomic heterogeneity in Staphylococcus aureus cells that were passaged in a model that mimics chronic infections and long-term antibiotic recalcitrance. Our data will determine whether an increasing percent of the S. aureus population is found in a low-activity state upon continuous infection and the presence of antibiotics.

NIH Research Projects · FY 2025 · 2025-08

The battle against bacterial infections is pivotal to modern medicine, allowing for safe medical procedures ranging from surgeries to organ transplants. However, despite the arsenal of effective antibiotics available, treatment failures persist in the absence of detectable antibiotic resistance, posing a significant challenge in the clinical management of diseases like Staphylococcus aureus bacteremia. S. aureus infections, despite showing in vitro sensitivity to common antibiotics such as vancomycin and daptomycin, often require prolonged treatments in vivo, with a substantial fraction of treatment failures attributed to poorly understood mechanisms of antibiotic tolerance. Our research aims to dissect the role of neutrophil extracellular traps (NETs) in promoting antibiotic tolerance in S. aureus. We hypothesize that NETs modulate bacterial metabolism, thereby enhancing bacterial survival against antibiotic treatments. We propose to explore the mechanisms underlying neutrophil-induced antibiotic tolerance and the potential therapeutic benefits of inhibiting NETosis through targeted interventions. This study is structured around two specific aims: First, we will delineate the mechanism through which neutrophils induce antibiotic tolerance in S. aureus. We will evaluate the role of NETosis in antibiotic tolerance using the NETosis inhibitor Cl-amidine and assess the contributions of various neutrophil effectors like DNA, calprotectin, myeloperoxidase, and antimicrobial peptides. Additionally, we will measure S. aureus metabolic responses such as ATP levels and respiratory activity in the presence of purified NETs. Second, we will investigate the impact of inhibiting neutrophilia and NETosis on the efficacy of antibiotics in a murine bacteremia infection model, using B6 mice treated with Anti-Ly6G antibodies to deplete neutrophils and PAD4-/- mice, deficient in NETosis. Furthermore, the effectiveness of dexamethasone in enhancing antibiotic clearance will be evaluated. Understanding the mechanisms that underlie antibiotic tolerance in vivo is crucial for addressing the high rates of treatment failure in bacterial infections. Our study aims to uncover the role of neutrophils and NETs in this context, potentially leading to novel therapeutic strategies that combine immunotherapy with traditional antimicrobial treatments to improve outcomes in bacterial infections. This could significantly impact clinical practices by reducing the duration of antibiotic therapies and reducing the evolution of antibiotic resistance.

NIH Research Projects · FY 2025 · 2025-08

Pain is a multi-layered experience. It typically begins with nociception, the process by which noxious sensory signals are communicated through the peripheral and central nervous system. Peripheral signals are carried by various somatosensory neurons residing in the dorsal root ganglia (DRG) and trigeminal ganglia (TG). With the advent of innovative techniques like optogenetics and chemogenetics, researchers can now selectively modulate the activity of different classes of DRG neurons, offering insights on their specific roles in pain transmission. However, a comprehensive functional mapping of each molecularly defined DRG neuron types, especially in the context of chronic pain, has yet to be conducted. Furthermore, the effect of chemogenetic inhibition of DRG neurons on pain-induced neuronal activity in the brain has never been studied, leaving a gap in understanding the contribution of these primary afferent neurons to pain experience. I have successfully conducted the in vivo validation of a novel peripherally restricted designer receptor exclusively activated by designer drug (DREADD), in collaboration with Dr. Bryan Roth. This new tool enables us to use chemogenetics to inhibit DRG neurons without off-target effects. In this proposal, I aim to use this DREADD to: 1) establish a comprehensive functional map of molecularly defined DRG neuron types, 2) interrogate how distinct DRG neuron types can change the representation of pain in the brain, and 3) record and identify the cerebral neurons that directly respond to these peripheral manipulations. To create this functional map, I will combine our novel DREADD with mouse genetic tools to inhibit distinct classes of DRG neurons and assess their role in various types of pain. Then, to pinpoint the different brain structures that shut down their activity following peripheral inhibition, I will employ iDISCO+ whole-brain clearing, c-FOS immunostaining, and light-sheet microscopy. Lastly, to accurately record changes in the neuronal activity of relevant brain regions and identify antinociceptive neurons, I will combine two-photon in vivo microscopy with spatial transcriptomics. Altogether this project will determine whether different classes of DRG neurons can differentially contribute to acute and chronic pain experiences through the modulation of different neuronal ensembles in the brain. This research will occur in Dr. Grégory Scherrer’s laboratory at the University of North Carolina at Chapel Hill, an ideal environment for innovative research in the neurobiology of pain. With mentorship and guidance from esteemed neuroscientists Drs. Roth, Zylka, Ross, Schnitzer, and Ariel, this endeavor will greatly enrich my expertise in pain research, immersing me in cutting-edge techniques and concepts while filling critical gaps in knowledge in the pain field. Ultimately, this project will pave the way for my transition to an independent faculty position, ideally initiating my own laboratory program studying pain and associated comorbidities with a unique but holistic focus, the DRG-brain axis.

NIH Research Projects · FY 2025 · 2025-08

While it is well established that healthy eating and physical activity habits are formed early and influence immediate and long-term chronic health condition risk, there is an absence of available and accessible prevention and control programs for families of young children with Down syndrome, who have disproportionately higher rates of chronic health conditions compared to their typically developing peers. The development of early childhood interventions tailored to address health behaviors for this population are essential and would provide significant improvement in their overall well-being and quality of life. Therefore, the goal of this R61/R33 project is to evaluate an adapted healthy lifestyle program, HomeGrown, specifically tailored for families of young children with Down syndrome for its feasibility (R61 Phase) and efficacy (R33 Phase) in improving practices around healthy eating and physical activity. The proposed project is highly responsive to RFA-OD-22-010 seeking clinical trial development for co-occurring conditions in individuals with Down syndrome. As part of the R61 phase, feasibility of conducting a randomized control trial will be assessed with 38 primary caregivers of a young child (2-6 years old) with Down syndrome. Participants will be randomized (1:1), stratified by child's biological sex (male/female) and age (2-3; 4-6 years old), to either the HomeGrown intervention or a waitlist control (6-month delayed start). The primary outcome is feasibility of the HomeGrown program characterized by accrual, engagement, and retention rates. Secondary study measures consist of children's diet quality and physical activity and families' use of evidence-based healthy eating and physical activity practices. In the R33 phase, the efficacy of the HomeGrown program will be assessed with 208 primary caregivers with a young child (2-6 years old) with Down syndrome. Participants will be randomized (1:1), stratified by child's biological sex (male/female) and age (2-3; 4-6 years old), to either the HomeGrown intervention or a waitlist control (6-month delayed start). The primary outcomes measures will assess children's diet quality and physical activity between baseline and post-intervention; secondary outcomes include families' use of evidence-based healthy eating and physical activity practices. Guided by the RE-AIM framework, process data collected in both phases will be used to assess reach, representativeness, adoption, and satisfaction. Measures for both phases will be collected at baseline (0 months) and post-intervention (6-months). The proposed study fills key research gaps in health promotion initiatives for families of young children with Down syndrome, who are underrepresented in nutrition and physical activity research and underserved in clinical practice.

NIH Research Projects · FY 2025 · 2025-08

Abstract Improving Affordability in Cancer Care through Economic Screening and Support (I-ACCESS) is a proposed screening assessment and referral program to proactively identify cancer-related financial hardship in patients with cancer at diverse clinical settings and connect those at-risk with education, counseling, and resources. The objective of this study is to pilot and refine I-ACCESS across diverse clinical practice settings to yield a process that directly aligns with consensus standards of care and practice guidelines to assess patients for financial hardship and provide financial resources and support. In Aim 1, we will characterize the context of the context of geographically and demographically diverse clinical practice settings to prepare for I-ACCESS implementation through interviews with up to 30 clinical leaders and frontline staff. Assessment constructs will focus on understanding structural characteristics (including information technology infrastructure), available resources, culture, compatibility, relational connections, communications, and access to knowledge. These data will inform the creation of tailored process maps to outline processes and procedures to prepare each site for I-ACCESS implementation and elucidate when, how, and by whom I-ACCESS screening should be done. In Aim 2, we will implement I-ACCESS and determine the effectiveness of the screening tool in facilitating patient referrals for financial hardship counseling. Using a pre-/post-approach, we will examine whether I- ACCESS screening increases the number of financial counseling and oncology social work referrals (primary outcome) within two large healthcare systems and a network of community-based practices. We will also examine counseling dispositions, receipt of services among those referred to financial support, and the predictive accuracy of the screening tool (secondary outcomes). In Aim 3, we will assess the implementation of I-ACCESS across diverse clinical practice settings using a sequential mixed-methods, multi-stakeholder evaluation. Informed by the Practical, Robust, Implementation and Sustainability Model (PRISM) framework, we will analyze approximately 225 patient and 25 clinician surveys to gather feedback on I-ACCESS delivery, procedures, and barriers/facilitators to implementation. Based upon survey findings, we will then focus on key implementation determinants and outcomes through in-depth, semi-structured interviews with up to 40 stakeholders. Stakeholders will include patients, caregivers, healthcare providers, financial counselors, clinical support staff, and hospital administration at participating clinical sites. Findings from this study will inform future large-scale, multi-site hybrid effectiveness-implementation research to assess the scalability of I-ACCESS across care delivery settings and its integration with ongoing care.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY/ABSTRACT A Career Development Award in AI-Assisted Ultrasound for Early Pregnancy Localization This research addresses the challenge of evaluating women in early pregnancy presenting with signs and symptoms concerning for ectopic pregnancy, particularly in resource-constrained settings where access to pelvic ultrasound is limited. Despite pelvic ultrasound being the diagnostic mainstay for pregnancy localization, many low- and middle-income countries and rural areas of the United States face substantial barriers to this technology, owing to the high cost of equipment and need for trained staff. Consequently, ectopic pregnancy diagnosis may be missed or delayed, increasing maternal morbidity. Importantly, diagnosis of an intrauterine pregnancy effectively eliminates the possibility of an ectopic pregnancy, and achieving this diagnosis with transabdominal pelvic ultrasound reduces the need for transvaginal pelvic ultrasound assessment. This proposal outlines an innovative strategy to evaluate women presenting with non-specific symptoms of ectopic pregnancy. Point-of- care ultrasound (POCUS) devices offer a cost-effective alternative to traditional cart-based machines. Novel ultrasound collection procedures enable providers without formal ultrasound training to conduct evaluations. And deep learning artificial intelligence (AI) models analyze sonographic data to make diagnoses. My long-term career goal is to become an independent investigator leveraging evolving AI and ultrasound technology to improve obstetric outcomes. To achieve my career goals and objectives, I need additional mentorship and training in (i) applied data science with a focus on deep learning, (ii) clinical trials design and implementation, and (iii) research communication and collaborative global health partnerships. I will leverage this training and the resources of my mentors to achieve my scientific objective: to develop a novel strategy to evaluate early pregnancy localization using advancements in deep learning and ultrasound technology. I will pursue this objective through three specific research aims: (1) develop an AI ultrasound tool using transabdominal POCUS “blind sweeps” to diagnose intrauterine pregnancy; (2) develop an AI ultrasound tool to a) guide a clinician with minimal training to perform transvaginal ultrasound assessment and b) diagnose intrauterine and extrauterine pregnancy; and (3) pilot the use of these AI ultrasound models to localize early pregnancies in women presenting with signs and symptoms of ectopic pregnancy in both Lusaka, Zambia and Chapel Hill, North Carolina. I am well-positioned to achieve these aims given the vast institutional resources available to me through the University of North Carolina at Chapel Hill, along with an internationally-renowned team of mentors and advisors, including Drs. Jeffrey Stringer and Michael Kosorok, who have a history of collaboration in the burgeoning field of AI- assisted obstetric ultrasound. The proposed research is innovative and significant, and the results have the potential to significantly improve the diagnostic evaluation of ectopic pregnancy in the most vulnerable pregnant populations.

NIH Research Projects · FY 2026 · 2025-08

PROJECT SUMMARY Misregulation of the 15q11-q13 chromosomal region is particularly consequential for neurodevelopment. Maternal copy number increases in 15q11-q13 cause duplication 15q (Dup15q) syndrome, a major subtype of autism spectrum disorder, while maternal (but not paternal) 15q11-q13 deletions cause the neurodevelopmental disorder Angelman syndrome (AS). There are ~20 genes in the 15q11-q13 region, but only UBE3A is expressed exclusively from the maternal allele in mature neurons, hence it is thought to be the main genetic driver for AS and Dup15q syndrome. Motor deficits are among the earliest and most impactful clinical phenotypes in AS and Dup15q syndrome, although the precise manifestation differs by disorder. We currently lack an understanding of how UBE3A misexpression alters neural circuit dynamics to impair movement control. Here we will test the central hypothesis that the motor phenotypes resulting from UBE3A misexpression are caused by altered dynamics in specific neural circuits. We will use mouse models to identify the impact of varying Ube3a copy number on motor brain networks during the acquisition and production of a skilled reach-to-grasp movement that requires planning, action sequencing, sensory-guided corrections, and adaptation. Accordingly, this project will identify rules that govern the complex relationship between Ube3a gene dosage, motor deficits, and distributed brain network formation and function. Finally, we will test a translationally relevant gene therapy to normalize UBE3A expression in relevant motor circuits and restore typical motor function. Towards these goals, we will complete three aims: (1) establish the impact of Ube3a copy number on skilled movements, (2) establish the impact of Ube3a copy number on distributed neuronal dynamics, and (3) causally link circuit-specific normalization of UBE3A expression to neural dynamics and skilled movements. The successful completion of these aims is expected to guide the development of safe and efficacious therapeutic approaches for ameliorating motor deficits in Angelman and Dup15q syndromes.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY Treatment options for Alzheimer’s disease (AD) have been elusive, in large part because the molecular and cellular mechanisms underlying AD pathogenesis remain unclear. Recent studies have identified various cis-regulatory elements (CREs) associated with AD, including 75 genomic regions identified by genome-wide association studies (GWAS) and thousands of genomic regions with altered chromatin architecture in postmortem brains from individuals with AD. These CREs are thought to influence AD pathogenesis by affecting gene regulation in a cell type-specific and age-dependent manner. Therefore, it is crucial to study how AD-associated CREs orchestrate gene expression at single-cell resolution. To achieve this, we propose a scalable platform, single-cell Massively Parallel Reporter Assays (scMPRA), to investigate how AD-associated CREs regulate gene expression across different cell types. The scMPRA platform combines high-throughput sequencing and barcoding technology with single-cell RNA-sequencing to simultaneously assess the regulatory effects of thousands of CREs in a cell type-specific manner. We will apply scMPRA to in vivo mouse brains from two well-established AD models, which recapitulate both shared and distinct pathological aspects of AD, along with age-matched littermate controls. This will allow us to examine the regulatory effects of CREs within an intact physiological context, accounting for natural cellular interactions and aging processes, thereby offering new insights into the genetic architecture of AD. Upon completion, we aim to establish a novel genomic toolbox for identifying cell type-specific CREs, pinpoint cell types critical for aging and AD pathogenesis, and understand gene-environment interactions in the context of AD.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY/ABSTRACT This project will support software development and community engagement for the CARDINAL open-source software infrastructure, which aims to provide a unified platform for simulating all major aspects of cardiac function. The prevalence of cardiovascular disease continues to drive research studies, with methodologies and scales ranging from wet-lab experiments and animal studies to large-scale clinical trials. While these experimental research approaches provide powerful tools for interrogation, yielding critical insights into cardiac function and disease, in silico computational models provide a critical resource for integration, enabling the synthesis of complex, multifaceted data into a predictive physics-based framework. Given the complex etiology of disease and variability in clinical measurements, distilling this information to identify the optimal approach to personalized treatment remains a significant challenge. Predictive computational models of the heart, capable of capturing all critical aspects of cardiac function, serve as powerful synergistic tools that can assimilate clinical information and drive predictive studies of heart function in response to treatment. A core challenge, however, remains that effective development of cardiac computational models is hindered by the lack of available tools, forcing modelers and researchers either to limit the scope of their studies or invest significantly in infrastructure development. Indeed, although substantial scientific, engineering, and medical research has gone into modeling cardiac dynamics, no open-source simulation frameworks currently provide integrated modeling capabilities addressing all major aspects of heart function. The absence of comprehensive, open-source simulation tools addressing the entire spectrum of heart function poses a significant barrier to advancing cardiovascular research. The CARDINAL software framework aims to address this critical gap in the research software ecosystem. This software development project specifically focuses on performance enhancement, containerization, and community engagement activities that are aligned with the Building Sustainable Software Tools for Open Science (RFA-OD-24- 010) program. Aim 1 will optimize the computational performance of CARDINAL to enable scalable and efficient simulations of cardiac dynamics by enhancing core modules and integrating performance portability libraries. Aim 2 will improve the portability and ease of deployment of CARDINAL across diverse computing environments by developing containerized versions and providing pre-compiled binaries for major operating systems. Aim 3 will foster community engagement and sustainability of CARDINAL by developing comprehensive documentation, creating tutorials and example projects, establishing support channels, and conducting outreach activities to build an active user base. Through these efforts, CARDINAL will provide a robust, scalable, and user-friendly tool that supports advanced research in cardiovascular medicine, ultimately contributing to the development of personalized treatment strategies and improving outcomes for patients with cardiovascular disease.

NIH Research Projects · FY 2025 · 2025-08

The proposed study focuses on developing a novel bivalent vaccine to combat Chlamydia trachomatis (CT), a leading sexually transmitted bacterial infection which can spread to the upper genital tract of women and cause pelvic inflammatory disease, infertility, and chronic pelvic pain. No FDA-approved vaccine exists for CT, and due to its largely asymptomatic nature, many infections go undetected and untreated, increasing prevalence and risk for sequelae. This project builds on promising preliminary findings using a vaccine formulation combining Chlamydial Protease Activity Factor (CPAF), a conserved and immunodominant antigen, with a Stimulator of Interferon Genes (STING) agonist, ADU-S100, in murine models. This vaccine elicited robust CD4 T cell responses and significantly reduced bacterial burden but fell short in preventing oviduct pathology. To enhance efficacy, the study proposes a bivalent vaccine incorporating CPAF and the chlamydial Major Outer Membrane Protein (MOMP), a key target for opsonizing antibodies, conjugated with a novel STING agonist (CL1151) via click-chemistry. The central hypothesis posits that the bivalent vaccine will generate synergistic Th1 immunity and antibody responses critical for reducing bacterial load and preventing pathology. Specific aims include: (1) Determining whether a bivalent CL1151-conjugated vaccine improves protection over monovalent CPAF-CL1151, and elucidating the contribution of CD4 T cells and opsonizing antibody to protection. (2) Determine the downstream molecular mechanisms induced by the STING adjuvant, CL1151, in protection, including assessment of the roles of TNFα and type I interferon signaling. Experimental methods involve priming and boosting mice with various vaccine formulations, monitoring bacterial burden, and evaluating immunological responses via ELISpot and intracellular cytokine assays. Additional studies will investigate protective mechanisms through adoptive transfer experiments and gene knockout mouse models. Findings aim to clarify mechanisms of vaccine-induced immunity and establish a foundation for advancing a protective CT vaccine. This work addresses critical gaps in CT vaccine development and holds potential to mitigate the global burden of chlamydial infections.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY High-grade serous ovarian carcinoma (HGSOC) manifests with peritoneal metastases in over 75% of patients. Despite aggressive treatment, including cytoreductive surgery and platinum-taxane chemotherapy, the remaining metastases almost inevitably give rise to chemoresistant recurrences for which no curative treatments exist. There is an urgent need for complementary strategies to address resistance in these residual tumors. Altering cell membrane lipid composition has emerged as one such strategy. This proposal aims to utilize photodynamic alterations of cell membrane lipids to promote chemotherapy penetration and efficacy in preclinical models of peritoneal metastases. This will be achieved by combining two clinically viable approaches: 1) Co- delivery of easily oxidizable polyunsaturated fatty acids (PUFAs) with lipophilic photoactivatable molecules (photosensitizers) and 2) Induction of lipid peroxidation within cancer cell membranes that occurs downstream of photochemically-generated reactive oxygen species (ROS)—photodynamic priming (PDP). This approach is based on a hypothesis that lipid pathology initiated by incorporating PUFAs into membrane-forming phospholipids, followed by exposure to photochemically-generated ROS, will synergistically “prime” cells for subsequent chemotherapeutic eradication. Intraperitoneal light delivery, proven feasible in University of Pennsylvania trials, allows integration of the proposed strategy within the current standard of care. In this approach, PUFA and photosensitizer would be administered prior to cytoreductive surgery, during which light- irradiation would photodynamically alter cell membranes to enhance response to postoperative chemotherapy. During the mentored K99 phase, Dr. Overchuk will investigate the effects of free PUFA, PDP, and combinations on carboplatin efficacy in orthogonal models of HGSOC. As a clear path to independence, Dr. Overchuk will develop a lipoprotein-mimetic nanoparticle to harness natural lipid trafficking mechanisms for codelivery of PUFAs alongside a photosensitizer. Upon her transition to the R00 phase, Dr. Overchuk will compare PDP using free versus nanoencapsulated PUFAs and photosensitizers with respect to tumor selectivity and carboplatin enhancement. A mentoring committee will guide Dr. Overchuk’s research and facilitate her transition to independence. As primary mentor, Dr. Imran Rizvi will train Dr. Overchuk in physiological models of HGSOC peritoneal metastasis. As co-mentor, Dr. Alexander Kabanov will provide specialized training in nanoformulation development. Drs. Robert Chapkin (PhD), Victoria Bae-Jump (MD/PhD) and Huang Chiao (Joe) Huang (PhD) will bring further expertise in membrane therapies, lipid metabolism, clinical management of HGSOC and translational photomedicine. To summarize, this proposal aims to address key barriers to treating peritoneal metastases with a mechanistically distinct approach and establish a cancer-agnostic platform translatable to a wider variety of malignancies. The mentorship provided by this K99/R00 Award will allow Dr. Overchuk to pursue this clinically relevant research and enable her transition to an independent career.

NIH Research Projects · FY 2025 · 2025-08

ABSTRACT Staphylococcus aureus (S. aureus) is a leading causative agent of life-threatening bloodstream infections. The increasing prevalence of antibiotic-resistant strains (e.g., methicillin-resistant S. aureus), as well as understudied mechanisms of antibiotic tolerance, highlights the necessity of identifying strategies to better combat S. aureus virulence. Fibrinogen is a monomeric plasma glycoprotein which polymerizes to form a fibrin matrix following proteolytic cleavage by the coagulation protease thrombin. The physiological role of fibrin(ogen) is in hemostasis and vascular repair following blood vessel injury. However, S. aureus has evolved an extensive repertoire of virulence factors that engage host fibrin(ogen), including the bacterial coagulases ‘staphylocoagulase’ and ‘von Willebrand factor-binding protein’ that hijack host prothrombin to catalyze fibrin polymerization. The coagulases, along with key bacterial fibrin(ogen)-binding proteins (FBPs; e.g., clumping factor A) support the formation of a ‘fibrin shield’ around the pathogen to promote protection from the host and antibiotic therapies in the bloodstream. The central hypotheses of this proposal are that (i) S. aureus fibrin shield formation and function is driven by bacterial binding of circulating fibrinogen followed by coagulase-mediated fibrin polymerization, and that (ii) disruption of fibrin shield formation with novel fibrinogen variants (e.g., nonpolymerizable or non-S. aureus- binding variants) will result in increased bacterial susceptibility to antibiotic treatment during the course of a bloodstream infection. Preliminary in vitro studies suggest collaborative roles for each coagulase and other FBPs in fibrin shield formation. Moreover, a major mechanism of protection induced by the fibrin shield is induction of an antibiotic-tolerant state. In vivo studies support critical roles for coagulases and FBPs in S. aureus virulence in a murine model of intravenous infection and demonstrate the capacity for fibrinogen variants to disrupt fibrin(ogen)-dependent S. aureus virulence and improve host infection outcomes. The studies proposed will 1) determine the contribution of S. aureus-mediated fibrin(ogen) binding and fibrin polymerization to pathogen virulence in the bloodstream and 2) evaluate the efficacy of fibrinogen variants, which lack key S. aureus binding motifs, in disrupting S. aureus fibrin shield formation in vivo as a therapeutic strategy to increase bacterial susceptibility to antibiotic therapies. In vitro analyses of fibrin shield formation and function, mechanisms of fibrin(ogen)-mediated S. aureus antibiotic tolerance, and in vivo murine models of bloodstream infection will build upon preliminary results to rigorously investigate the role of fibrin shield formation in S. aureus pathogenicity and antibiotic tolerance as well as examine the potential for novel fibrinogen-directed therapeutics in improving infection outcomes. The UNC Blood Research Center, Department of Biochemistry and Biophysics, and Integrative Vascular Biology Training Program (NIH T32 fellowship) provide an outstanding environment to successfully complete the proposed work. The completion of this F31 fellowship will play an instrumental role in reaching my goal of becoming an independent researcher.

NIH Research Projects · FY 2026 · 2025-08

Abstract Proposed is the development of a novel injectable material platform for breast reconstruction capable of time- controlled in-body curing, precisely mimicking the viscoelastic mechanics of surrounding tissue. This advanced solvent-, catalyst, and eventually reaction-free approach prevents leaching and enables minimally invasive surgery, improving the biocompatibility profile that overcomes the long-term health risks of currently marketed products. The focus on breast reconstruction is inspired by the alarming numbers of American women affected by breast cancer (1 in 8), with many undergoing lumpectomy or mastectomy. The significant quality of life (QOL) reduction in the aftermath of cancer survival can be addressed by breast reconstruction, as underscored by the Women’s Health and Cancer Rights Act of 1988 and President’s Executive Order on Advancing Women’s Health Research and Innovation from 03/18/24, which enforces insurance coverage of all reconstruction stages. Current implant options are mainly bifurcated into silicone gel- and saline-based devices. However, customers choose between silicone gel’s enhanced mechanical performance yet significant safety concerns or saline’s safer yet unnatural feel and disfigurement. Currently, all implant strategies demand substantial improvement due to a lack of tissue-like mechanics, uncontrolled leaching, capsular contracture (affecting 25%), and rupture (affecting 35%), entailing additional invasive explantation surgery for as high as 70% of all patients after 10 years. The proposed design-by-architecture platform will directly address the current implant shortcomings by merging 1) solvent-free, 2) minimally invasive, 3) cured within tailored time without using a catalyst, 4) leachable-free, and 5) tissue-mimetic mechanics, thus breaking the unsafe (status quo) aspects of breast reconstructive surgery. Preliminary data indicates these solvent- and leachable-free materials provide unprecedented biocompatibility, resilience, and longevity by remaining mechanically invariant over time, in contrast to FDA-approved technologies identified as not lifetime devices. As advised by clinicians, curing time is adjusted to 1-4 hours to allow continuous injection while avoiding disfigurement. A 9-month in vivo implantation study supports the biological safety of the proposed materials and curing procedures. We will advance breast reconstruction technology by optimizing its formulations, curing chemistry, and biocompatibility profile. Specific Aims include: 1) Conceptualization of network designs for efficient implantation; 2) Optimization of catalyst-free controlled crosslinking schemes for variable curing rate; 3) Replicating breast tissue mechanics; and 4) Biological evaluation of materials and curing protocols. The proposed technology will not only advance breast reconstruction but, given adjustable curing times and mechanical tunability, it enables translation into other types of reconstruction applications such as HIV-associated lipoatrophy of the face, buttocks, burns, tumor removal, and bodily injuries.

NIH Research Projects · FY 2025 · 2025-08

ABSTRACT In Kenya, like most low- and middle-income countries (LMICs), rapid urbanization and changing food environments are leading to increased access to energy-dense nutrient-poor foods that are contributing to rising rates of obesity and the burden of nutrition-related noncommunicable diseases. Adolescence is a critical lifecycle period for the prevention of obesity, and an opportunity to establish lifelong habits for healthy eating. Adolescent girls are particularly at risk for overweight and obesity, and women in urban Kenya have more than double the rates of obesity compared to men. Although there is widespread agreement on the need to improve adolescent girls’ dietary practices in LMICs, effective obesity prevention interventions are lacking, particularly in sub-Saharan Africa. With the mentorship and training proposed in this K01 application, I will pilot test theory- based adolescent obesity prevention intervention components for girls in an urban informal settlement in Kenya. In Aim 1, I will follow a community-engaged process to refine school-based adolescent obesity prevention intervention components that were designed based on our previous formative research. In Aim 2, I will conduct a pilot multiphase optimization strategy (MOST) study to determine the feasibility of recruitment, randomization, intervention delivery, retention, and data collection procedures, and the acceptability of intervention components in preparation for a future fully-powered factorial trial. In the pilot MOST study, 8 secondary schools will be randomized to one of eight combinations of intervention components, and data will be collected from students at baseline; after the 3-month intervention; and after a subsequent 3-month follow-up period. My aims are linked to training objectives that will advance my conceptual knowledge and skills in obesity research, the design of adolescent obesity prevention interventions, and MOST. This research will provide preliminary results to inform a future trial testing a multicomponent adolescent obesity prevention intervention for girls in urban Kenya. My mentoring team has expertise in the design of adolescent obesity prevention interventions, global obesity research, and the design and analysis of MOST and factorial trials, as well as extensive experience mentoring early career investigators. This research will generate novel insights into the design of school-based adolescent obesity prevention interventions in urban LMIC settings. The K01 will help me achieve my long-term career goal of becoming a leader in adolescent obesity prevention intervention research. With the support from this award, I will transition from conducting intervention research focused on undernutrition to creating an independent research program that is building the evidence base for effective obesity prevention interventions. The proposed mentorship, training, and research activities will generate data needed to develop a competitive R01 application to identify effective obesity prevention interventions for adolescent girls in urban areas.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY / ABSTRACT People living with HIV (PWH) often exhibit a spectrum of cognitive, motor and mood symptoms, together referred to as HIV-associated neurocognitive impairment (HIV-NCI). HIV-NCI is estimated to affect over 40% of PWH and is more common as PWH age. HIV can enter the CNS within days of initial infection, and individuals with suppressed plasma viral loads might still have detectable HIV in their cerebrospinal fluid (CSF) for up to a decade, leading to inflammation within the CNS and subsequently HIV-NCI. Inflammation is believed to start very early in the disease process and precede overt clinical signs and symptoms of NCI. Identifying biomarkers of neuroinflammation related to presence of HIV virus in the CNS could help detect PWH who are now experiencing the neuroinflammatory effects of HIV. While incompletely understood, HIV-NCI is believed to be linked to chronic inflammatory processes in PWH, since immune responses may lead to both repair and damage in the CNS. Chronic inflammation may also contribute to changes in brain structure and altered connectivity. Our own prior work of 21 PWH ages≥50 shows that heightened segregation in the brain correlates with inflammatory biomarkers in PWH, while higher CSF NfL is related to higher markers of neuroinflammation or microglial activity. Our findings highlight the potential relationship between inflammation, neurodegeneration and functional connectivity (FC). Our overall goal in this proposal is to determine if the impacts of FC deficits, neuroinflammation, neurodegeneration or greater white matter hyperintensity (WMH) volume in HIV-NCI are mediated by CNS HIV viral persistence. We aim to (1) evaluate the specific contribution of HIV in the CNS to associations with inflammation, brain structure and function and cognition, and (2) examine whether detectable HIV RNA in the CSF mediates the associations between inflammation and neuronal injury, cerebrovascular disease and Alzheimer’s pathology in older PWH. Leveraging our team’s expertise in the fields of neuroHIV, biomedical imaging and virology, we leverage an existing research infrastructure and banked biospecimens from an existing cohort of older PWH at UNC. We will examine if the associations between fluid biomarkers of inflammation using next-generation proteomics and multimodal MRI markers of aging differ in PWH age≥50 with detectable vs. undetectable HIV RNA in CSF. We will also examine if the associations between biomarkers of inflammation and biomarkers of neuronal injury (NfL), cerebrovascular pathology (WMH volume) and AD pathology (NfL, phosphorylated tau217) are differentially impacted by presence of HIV within the CNS. The results of this study will provide an understanding of the mechanistic pathways by which viral presence in the CNS affects brain function and connectivity and neuroinflammation and provide potential future therapeutic targets to reduce the burden of HIV-NCI.