Univ Of North Carolina Chapel Hill

NIH Research Projects · FY 2026 · 2026-04

An imbalance in the gut microbiome (i.e. dysbiosis) is broadly implicated in the chronic inflammation leading to Inflammatory Bowel Diseases (IBD). Naturally, the gut microbiome holds promise as a therapeutic target, yet it remains under-exploited due to limited tools available to precisely modify the functions of specific bacteria. Instead, most current bacteria-targeted strategies involve the use of either probiotics, prebiotics or wholesale change in the microbiome via fecal microbiota transplant, all of which suffers important drawbacks, including effects on non-targeted resident bacterial species. Bacteriophages (phages) represent ideal vectors for imparting precise genetic control over bacterial consortia, similar to viral vectors currently used for human gene therapy. However, current phage vectors, which can be categorized as either replicative or non-replicative, suffer from a number of shortcomings that preclude their use in vivo. Replicative vectors, which carry both transgenic DNA and genomic essential DNA for replication, are limited by a small transgene packing capacity, toxicity, and major risks for horizontal gene transfer. In contrast, non-replicative phage vectors (NRPV) are packed exclusively with transgenic DNA, which greatly increases transgene packing capacity while reducing the risks of horizontal gene transfer. Unfortunately, NRPVs suffer from very poor delivery efficiency (<0.2%) that have precluded their use to date. We have recently combined cutting-edge synthetic biology with phage engineering to develop a new category of NRPVs that can overcome these limitations, based on efficient self-recircularization of phage- injected linear cargo DNA within a bacteria host. As a result, DNA delivered by our self-circularizing NRPVs (scNRPVs) is (a) not at risk of exonuclease degradation, and (b) can replicate with the target bacterial host as they divide, leading to sustained retention and expression of transgenes. This improves delivery efficiency by orders of magnitude, with ~20% of E. coli transduced at just a 0.1:1 ratio of scNRPV:bacteria in vitro, and transduction efficiencies in vivo (>107 CFU/g) that rival replicative phage vectors. Building on these novel advances, we seek to engineer scNRPV that can reprogram the existing gut microbiome to secrete nanobody (Nb) formatted inhibitors of TNF and IL-23, important drivers of chronic inflammation in IBD. In Aim 1, we will engineer a P1-based scNRPV and the corresponding therapeutic phagemid it will deliver, encoding for secretion of Nbs against TNF and IL-23p19. In Aim 2, we will benchmark the efficacy of this therapeutic phagemid-packed P1 scNRPV treatment in a humanized microbiome-driven mouse model of IBD against controls, including systemic IV administration of the same inhibitors and oral delivery of live bacteria engineered to secrete these Nbs. If successful, the work will potentially advance a safe, effective, convenient and likely cost-effective strategy to treat IBD, while also laying the foundation for harnessing scNRPVs to reprogram the gut microbiome in situ for a variety of gastrointestinal indications.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY IMPG2 is a crucial extracellular matrix protein for maintaining photoreceptor structure and function. Mutations in IMPG2 are linked to two forms of visual impairment: juvenile-onset rod-cone dystrophy and adult-onset vitelliform macular dystrophy. While no treatment currently exists, packaging IMPG2 amino acid sequences into adeno-associated viruses (AAVs) offers promise for a sight-preserving therapy. We recently generated human retinal organoid (RO) and mouse models to enable us to rapidly engineer a gene augmentation therapy for IMPG2-associated retinal dystrophy (RD). The retinal organoids (ROs), grown from either patient-derived (human) induced pluripotent stem cells (hiPSCs) or gene-edited embryonic stem cells (hESCs), recapitulate the lack of photoreceptor outer segments observed in advanced IMPG2-RD. This fully penetrant phenotype provides a biomarker for assessing functional IMPG2 expression after AAV-mediated gene transfer. Although patient-derived ROs are tractable in vitro models of clinical relevance, their use in assessing viral vector designs for gene therapy development is best complemented by in vivo assessment of safety and efficacy in animal models. Accordingly, we will assess therapeutic safety and efficacy using the Impg2-knockout (KO) model mice, as these mice exhibit gliosis, subretinal deposits, photoreceptor degeneration, retinal detachment, and reduced electroretinogram (ERG) responses that are similar to the human condition. Here, we will accelerate a preclinical program to test our central hypothesis that gene augmentation can prevent retinal pathology in an IMPG2-RD mouse model and patient-derived ROs. To lay the groundwork for a clinical IMPG2 gene therapy, we will complete the following Aims: (1) Use Impg2-KO mice to define endpoints for preclinical trials, (2) optimize a gene therapy viral vector design using Impg2-KO mice and IMPG2 patient-derived and gene-edited ROs, and (3) establish preclinical gene therapy safety and efficacy in Impg2-KO mice. Synergistically employing mouse models and human ROs will accelerate the development of a gene therapy that will meaningfully improve the lives of individuals with IMPG2-RD. More broadly, this work will demonstrate the power of a dual-model platform to advance safe and effective therapeutics with high predictive value for treating inherited retinal disorders.

NIH Research Projects · FY 2026 · 2026-04

PROJECT ABSTRACT Chikungunya virus (CHIKV) is an emerging mosquito-borne alphavirus that causes major epidemics of both acute and chronic arthralgia. Humans exhibit significant variation in CHIKV disease susceptibility, with outcomes ranging from severe debilitating arthritis to asymptomatic infection. There is growing evidence that polymorphic human genes contribute to variation in disease outcome, however, results from large unbiased genetic mapping studies have not been reported from CHIKV infected humans. Therefore, much of our knowledge of how specific host genes affect CHIKV disease susceptibility comes from mouse models of CHIKV-induced arthritis/myositis. Although standard inbred mouse strains (e.g. C57BL/6 mice) are a valuable resource for studying CHIKV pathogenesis, these mouse strains do not recapitulate many aspects of human genetic diversity, and therefore fail to reproduce the full range of CHIKV-induced disease phenotypes observed in human populations. Therefore, to broaden the phenotypic range of CHIKV-induced disease and study the role of host genetic variation in driving CHIKV disease outcomes, we have used the Collaborative Cross (CC) mouse genetic reference population. CC mice exhibit strain dependent variation in CHIKV disease susceptibility, with outcomes ranging from mild to severe disease, while one outlier strain, CC026, is completely resistant to CHIKV disease. Gene mapping studies identified a quantitative trait locus (QTL) on chromosome 8 (HrCHK1) that regulates susceptibility to CHIKV-induced joint swelling and arthritis. Therefore, as part of this exploratory R21 application, we propose to identify and validate the specific causal gene under HrCHK1 that regulates CHIKV disease outcomes, while performing additional focused mapping studies to identify the specific gene(s) that confer extreme disease resistance on the CC026 genetic background. These studies will significantly advance our understanding of how host genetic variation affects CHIKV susceptibility, while setting the stage for future mechanistic studies focused on understanding how specific gene variants impact CHIKV disease and whether these genes can be targeted to treat acute or chronic alphavirus-induced arthritis.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY/ABSTRACT The proposed project for a K23 Career Development Award will enable Dr. Camilia Kamoun to become an independent physician-scientist expert in patient-centered research on psychosocial health in early female puberty. Early female puberty is increasingly common, yet there is a lack of patient-centered tools to assess its psychosocial impact and guide treatment decisions. The proposed research aims to develop a patient-oriented outcomes (PROs) measure for early puberty, addressing a critical gap in evidence-based, patient-centered care. This research would positively impact public health given high rates of early puberty. Dr. Kamoun’s long- term goal is to become an expert in researching psychosocial health in pediatric patients with endocrine conditions, integrating bioethical inquiry to advance just, patient-centered care. Her strong research background, as well as bioethics training, make her an ideal candidate. The research has the following specific aims: 1) To characterize parental health concerns related to early female puberty, as well as parental experiences of its social and mental health impacts; 2) To understand parental prioritization of patient-reported health outcomes for early female puberty and explore their association with parental and child traits; and 3) To assess early female puberty-related PROs using adapted existing relevant PROMIS® measures. These aims will be accomplished through integrated mixed methods. They will lead to the development of a patient- oriented outcomes measure to use in a clinical trial to assess the effect of pubertal suppression treatment on psychosocial health in early female puberty, which will constitute the next steps in the research. In the last two years of the K23, Dr. Kamoun will develop an R01 or equivalent proposal to secure funding for this follow-up research. An interdisciplinary team of mentors and collaborators will guide Dr. Kamoun in accomplishing the following training goals: 1) To acquire advanced theoretical and practical knowledge of research methodologies used in patient-centered research; 2) To gain skills and knowledge in patient-oriented health outcomes research; 3) To acquire knowledge in peripubertal psychoneuroendocrinology and developmental psychology; 4) To deepen her bioethics expertise with a focus on pediatric, research, women’s health ethics, and the relationship between risks, values and ethical care. This training will include survey science coursework through the Odum Institute for Research in Social Science at UNC-CH and advanced bioethics training through the Children's Mercy Bioethics Center's Certificate Program in Pediatric Bioethics. Dr. Kamoun’s mentorship team will meet regularly with her to monitor progress, as well as to provide guidance in writing manuscripts and R01 and equivalent grant proposals. This K23 Career Development Award will provide Dr. Kamoun with the necessary training, mentorship, and research foundation to launch an innovative patient- centered research program that aligns with the Eunice Kennedy Shriver National Institute of Child Health and Human Development’s mission to improve child and adolescent health and the transition to adulthood.

NIH Research Projects · FY 2026 · 2026-04

Globally, over 50% of those infected with HIV are women, and annually, ~50% of all pregnancies are unplanned. Therefore, there is a critical need to promote female-controlled methods of multipurpose prevention technologies (MPTs) and delivery strategies that can be disassociated from the sex act. Long-acting (LA) formulations that provide sustained drug release over weeks offer several advantages, including relief from “pill fatigue” and better protection of health privacy. As such, LA delivery systems hold great potential to enhance compliance to HIV pre-exposure prophylaxis (PrEP) and help curb the global HIV epidemic. Amongst LA formulations currently in development or recently approved, injectable formulations provide several advantages over implantable devices that require an applicator (e.g. Trocar) or that are sex specific (e.g. vaginal rings, inserts). Injectable formulations are well tolerated by men and women, are efficacious for contraception, and have high patient acceptability and compliance1-4. Apretude, a LA injectable nanoparticle suspensions of cabotegravir (CAB), is the first FDA-approved for HIV PrEP5-7. Although effective, Apretude requires six (6) intramuscular (IM) injections per year after 2 once-monthly starter injections. Lenacapavir (LEN) is another LA injectable currently in Phase 3 clinical trials as a once-every-six-months subcutaneous injection for HIV PrEP8. Despite these advances in HIV PrEP, currently there are no LA injectable MPT formulations in development mainly because of limitations of current LA injectable formulations utilizing nanoparticle suspensions whereby two drugs cannot be combined into a single injection. In this R61/R33 grant and building on our strong preliminary data and current development, we propose a comprehensive evaluation and translation of a first-in-line injectable MPT that offers durable and sustained protection from HIV transmission, high efficacy of contraception, increased user compliance, and the ability to be removed in case of unanticipated adverse events or when considering discontinuation from the LA HIV PrEP and/or contraception. We will achieve this goal by optimizing and advancing a liquid MPT formulation utilizing excipients that form a biodegradable depot after subcutaneous injection (in-situ forming implant (ISFI)). We propose a comprehensive evaluation of this novel drug delivery approach using highly relevant rodent and non-human primate models of safety and pharmacokinetics to support a pre-IND application and meeting with the FDA, tech transfer and GLP manufacturing and scaleup, and initial IND-enabling studies to accelerate its clinical translation. With this cutting-edge combined approach using a unique and highly innovative ultra-long-acting coitally-independent MPT ISFI formulation we will address two significant global unmet needs (HIV and unplanned pregnancy) to make significant impact to global health.

NIH Research Projects · FY 2026 · 2026-04

PROJECT ABSTRACT Post-transcriptional mRNA modifications have a major impact on viral RNA stability, translation efficiency, and sensing by the host innate immune system. Therefore, understanding how RNA modifications affect viral replication and/or host innate immune sensing is essential for understanding virus/host interactions, while providing new insights into both the regulation of specific types of RNA modifications and their functional importance that are more broadly relevant to understanding RNA biology. ADP-ribosylation (ADPr) is an important post-translational modification of proteins, and several mammalian poly ADP-ribose polymerases (PARPs) are interferon stimulated genes (ISGs) that exert potent antiviral activity by placing mono-ADP-ribose (MAR) or poly- ADP-ribose (PAR) on essential viral proteins. While the effect of ADPr modification of proteins is well characterized, recent studies have found that several PARPs can ribosylate RNA in vitro and in cells, and cellular stress induces RNA ribosylation in mammalian cells. RNA ribosylation increases RNA stability but inhibits mRNA translation. In preliminary studies, we find that infection with chikungunya virus (CHIKV), an emerging alphavirus that causes severe debilitating arthritis in infected humans, results in increased levels of RNA ribosylation of both viral and host RNAs. We also demonstrate that a CHIKV mutant with diminished macrodomain-mediated ribosylhydrolase activity led to increased RNA ribosylation, and ribosylated viral RNA is translated less efficiently both within the cell and in cell free translation systems. Further analysis found that ribosylated RNA is less stable and induces a more robust antiviral response than unmodified RNA, and these effects are dependent upon expression of the host Zinc Finger Antiviral Protein (ZAP). Therefore, as part of this highly innovative R21 application we propose to further investigate the impact of RNA ribosylation on viral RNA translation efficiency, while also investigating ZAP’s role in sensing ribosylated RNAs to inhibit viral replication and initiate antiviral immune responses within the infected cell. These studies, which take advantage of our collaborative team’s expertise in RNA biology, translational control, molecular virology, and innate immunity will provide important new insights into a novel role for ribosylation in regulating viral RNA biology and innate immune control of viral infections.

NIH Research Projects · FY 2026 · 2026-04

Advances in our understanding of the role of genetic variation in human diseases and the technologies for genomic analysis and therapy have the potential to revolutionize health care. Clinical sequencing has become a routine tool for diagnosis of patients with rare monogenic diseases, pharmacogenomics is increasingly used to optimize therapy, and deep analysis of the genomic aberrations in tumors is now routinely able to identify targetable mutations. Genomic approaches are now poised to be widely employed in screening for monogenic conditions, prenatal chromosomal disorders, and cancer. However, there are major barriers to the broad dissemination of these advances. Specialists with expertise in these areas are scarce and typically concentrated in academic or population centers, creating long wait times for outpatient consultations and potentially requiring patients to travel long distances to be seen. Rapidly evolving testing options and the complexity of the results make it difficult for non specialists to stay current with the knowledge required to make use of new technologies. The small amount of time permitted for routine visits and lack of focus on rare diseases in primary care means that most providers are ill-equipped to handle complex diagnostic or management questions for most monogenic conditions. Fragmentation of the U.S. healthcare system and lack of harmonized electronic health record systems for all patients prevents the broad use of computational decision support across the population. However, novel practice paradigms such as virtual care including electronic consults (eConsults) could serve as a mechanism to disseminate genomic medicine knowledge and expertise, increasing access to genetic testing and expert interpretation of genetic and genomic findings, and ultimately bringing the future vision of genomic medicine closer to reality. This proposal seeks to examine the implementation of genomic medicine eConsults through a multi-state network of experts linked via informatics infrastructure that facilitates communication between the referring provider and the consultant, informed by stakeholder input ranging from clinical providers to community members to administrative leaders. We will study the barriers and facilitators to the adoption of genomic medicine eConsults for clinical questions ranging from helping with the diagnostic work-up of a patient with suspected rare disease, interpretation of genetic test results and their implications for the patient, management of patients already diagnosed with a rare disease, and next steps for patients with positive/abnormal genomic screening results. Key outcomes will include patient and provider response to the use of eConsults, perspectives on the value of this approach by administrative stakeholders and payers, and understanding the conditions required for such a practice to be sustainable. Accumulation of a corpus of completed eConsults will also enable scaling and knowledge transfer through the use of modern AI technologies and dissemination into healthcare systems. The translational implementation science research herein will inform the expansion of genomic medicine eConsults broadly across the US.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY Oncogenic mutations in KRAS are nearly universal in pancreatic ductal adenocarcinoma (PDAC) and drive disease initiation, progression, and maintenance. Small molecules that inhibit mutant forms of KRAS (KRASi) and both mutant and wildtype RAS proteins (RASi) have recently emerged with the potential to transform the treatment landscape of PDAC. However, the mechanisms dictating efficacy and resistance to RAS inhibitors remain poorly understood. PDAC development and therapeutic response depends on co-evolution and interaction between tumor cells and the tumor immune microenvironment (TIME). This research proposal focuses on a major goal of our laboratories: to determine how remodeling of tumor-immune interactions contributes to efficacy and durability of RAS inhibition. We have developed immunocompetent mouse models that recapitulate seminal features of PDAC heterogeneity and found that while the KRASG12D inhibitor MRTX1133 and the pan-RASGTP inhibitor RMC-6236 both effectively inhibit the MAPK pathway and illicit potent tumor responses in pre-clinical studies, they result in distinct patterns of response and adaptation in tumor cells and the tumor microenvironment. We hypothesize that these differences result from poorly understood and understudied immune cell intrinsic roles of the RAS family that alter interactions between tumor and immune cells in response to RAS inhibition. Using a multidisciplinary and collaborative approach, this proposal integrates cutting-edge genetic models with innovative molecular and immunological methodology to delineate targetable immunological changes which define distinct patterns of response to KRASi and RASi in PDAC. We propose 2 aims that meet the research objectives of notice of special interest NOT-CA-24-016 (Exploratory Cancer Immunology Projects and Technologies (ExCITe)/PA-25-304, by addressing “fundamental aspects of tumor immunology and/or innovative ways to enhance anti-cancer immunity.” Aim 1 will leverage state of the art single cell technology and high dimensional spectral flow cytometry in mouse models of PDAC to comprehensively establish how TIME remodeling contributes to PDAC response and resistance following RASi/KRASi. Aim 2 will investigate immune-intrinsic roles for wild type RAS activity in the PDAC TIME through novel genetic approaches to determine how non tumor cells contribute to efficacy and resistance of RASi. Taken together, this proposal integrates expertise in PDAC pathobiology, tumor immunology, and applies novel genetic tools to unveil new mechanisms that underlie the efficacy and durability of RAS inhibition.

NIH Research Projects · FY 2026 · 2026-04

MASTL Kinase in DNA Repair and Treatment Resistance in Oral Squamous Cell Carcinoma Abstract Microtubule Associated Serine Threonine kinase-Like (MASTL) has been shown to promote mitotic progression by suppressing protein phosphatase 2A coupled with targeting subunit B55 (PP2A/B55). Interestingly, MASTL is commonly upregulated in human cancer. In oral squamous cell carcinoma (OSCC), MASTL expression is associated with cancer progression, tumor recurrence, and adverse patient survival. Upregulation of MASTL renders OSCC cells resistant to DNA damage treatments, attenuating post-treatment cell death while promoting cell survival and proliferation. Depletion or inhibition of MASTL significantly enhanced the tumor response to cisplatin in OSCC mouse models. These findings prompt us to hypothesize that MASTL is a potentially effective drug target for OSCC therapy, especially in combination with existing chemoradiation which eliminates cancer cells via induction of DNA damage. However, the precise role of MASTL in mediating DNA damage resistance is still largely unclear; specific strategies to target MASTL kinase in cancer are lacking, representing two major hurdles to the clinical development of MASTL targeting. Our preliminary studies unveiled novel functions of MASTL in DNA repair. MASTL promotes, and B55 suppresses the repair of DNA interstrand crosslinking (ICL) caused by cisplatin. Our data also implicated the MASTL-B55 module in DNA double strand break (DSB) repair via homologous recombination (HR). In Aim 1, we will further investigate these new functions of MASTL, in the context of Fanconi anemia gene pathway that mediates ICL repair and cisplatin resistance, and Rad51- dependent HR that is of strong clinical relevance to treatment responses to chemoradiation and inhibition of poly (ADP-ribose) polymerase (PARP). In Aim 2, we will explore a novel strategy to target MASTL kinase by disrupting its C-terminal domain. This idea, supported by our preliminary data, may guide the development of new and highly selective therapeutic tools for MASTL targeting. Together, our studies will lead to new mechanistic understanding of MASTL-PP2A/B55 in DNA repair and propel the development of new therapeutic strategies to overcome treatment resistance in OSCC.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY Stable HIV reservoirs remain a significant challenge for the eradication of HIV-1 (HIV). While several anti- HIV latency strategies have been proposed to control HIV reservoirs, few have proven effective in reducing the size of the HIV reservoir in clinical settings. This suggests that our current understanding of how HIV achieves its persistent infection is limited and underscores the need for the development of alternative innovative tools for HIV cure. Recently, we and others characterized a unique integrated stress response (ISR)/ATF4 signaling pathway that is essential for HIV transcription and early seeding of HIV. Conversely, when ATF4 is knocked down, HIV transcription is inhibited. We further defined ATF4 as a new transcription factor of HIV, exploited by HIV for its own transcription after the recruitment of ATF4 to the ATF/CREB consensus site at the 5’ HIV long-terminal repeat. ATF4 induction leads to HIV activation from latency, indicating that ISR/ATF4 signaling activation promotes HIV transcription while the suppression of ISR signaling is associated with the establishment of HIV latency. Of note, prolonged activation of ISR/ATF4 signaling also induces cell death, mediated by ATF4 binding to the promoter of the CHOP gene, an essential protein driving apoptosis during persistent ISR/ATF4 activation. In a primary CD4+ T cell model of latency, prolonged ISR/ATF4 signaling activation disrupts latent HIV and selectively induces apoptosis in HIV+ CD4+ T cells, without affecting bystander HIV-negative CD4+ T cells. Notably, using viral outgrowth assays, we discovered that prolonged ISR/ATF4 signaling activation reduces replication-competent HIV by up to 2,300-fold in resting CD4+ T cells isolated from people with HIV receiving suppressive antiretroviral therapy (ART). Therefore, we hypothesize that the suppression of ISR/ATF4 signaling is essential for HIV persistence. This will be tested through three specific aims: Aim 1: Investigate how activation of the ISR/ATF4 signaling pathway eliminates HIV-latently infected T cells and brain microglia. Aim 2: Elucidate the unique mechanisms by which ISR/ATF4 signaling controls the stable HIV reservoir for the establishment of HIV latency. Aim 3: Determine the effectiveness of activating ISR/ATF4 signaling in eliminating HIV reservoirs in the hu-BLT mouse model of HIV latency in vivo.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY This application aims to develop advanced ultrasound systems that enable precise imaging, targeting, and delivery of neurotherapies with real-time feedback control. The current standard in ultrasonic neuromodulation currently relies on MRI both to target the ultrasound focus and to assess the brain’s functional response. However, being in the magnet bore typically requires anesthesia, which limits the range of observation of neuromodulatory effects, especially for realistic behavioral scenarios which do not occur in a magnet. Furthermore, fMRI operates on the order of minutes, which is slow compared to the natural time scale of the neurovascular response (tens to hundreds of milliseconds) thus impairing the ability of MRI to appropriately sample neurological responses. Our proposal focuses on developing techniques to resolve the persistent challenges of a) identifying relevant brain circuits b) targeting multiple locations within brain circuits, and c) establishing real-time closed-loop interaction between the imaging and neuromodulatory systems. These objectives are achieved with functional imaging and neuromodulation to dynamically and reconfigurably target multiple locations in the brain using next-generation volumetric ultrasound tools. Volumetric circuit-level interaction with closed-loop feedback should provide better control over spatial and temporal targeting. Even simple behaviors arise from the simultaneous activation of multiple regions in the brain. Thus, the ability to simultaneously stimulate multiple regions within a brain circuit should allow for better modulation of function where it is needed and offer more control over behavioral outcomes compared to conventional, focused or static approaches. Functional ultrasound (fUS) imaging, which has been recently developed, measures transient changes in blood volume at high spatio-temporal resolution (100 μm, 100ms), fills the gap between whole brain imaging and microscopy. To achieve a leap in performance, functional ultrasound imaging will be combined with super-resolution ultrasound imaging to provide quantitative imaging of the local hemodynamics and neurovascular response (velocity, flow, microvascular organization). Whole brain and multifocal beamforming and algorithms will be designed for a programmable ultrasound system to detect functional activity in real time. A multifocal neuromodulatory array will be designed and integrated directly into the imaging system for co- registered targeting. Validation and characterization of the imaging sequences, circuit-level targeting, and feedback control between the volumetric imaging and therapeutic neuromodulatory systems will occur in small animals before translating to large animals. Our approach is developed in a partnership between UNC for the imaging and acoustical development and with Vanderbilt for validation and deployment in clinically relevant large animal models. If successful, these techniques will offer the possibility of high-spatiotemporal resolution and non- invasive volumetric closed-loop neuromodulation in awake and behaving animals, providing a powerful platform for neuroscientific investigation and precision therapy.

NIH Research Projects · FY 2026 · 2026-04

A Trial of Upadacitinib for Non-responsive Eosinophilic esophagitis (ATUNE) ABSTRACT Eosinophilic esophagitis (EoE) is an immune-mediated chronic disease defined by abnormal infiltration of eosinophils into the esophageal mucosa, leading to dysphagia, progressive esophageal stenosis, and food impaction. The incidence and prevalence are rising dramatically, and EoE is now a major cause of upper gastrointestinal morbidity. EoE has a complex pathogenesis due to multi-faceted immune profiles, perturbation of structural cell function, and infiltration with other inflammatory cells. Optimal therapeutic options must address this underlying immune complexity, but few therapies target EoE pathogenesis, and treatment non- response and disease relapse are frequently encountered. Uncontrolled and treatment-resistant EoE leads to progressive fibrostenosis due to activated fibroblasts which generate a unique pathogenic extracellular matrix. Fibroblasts isolated from esophageal biopsies of patients with difficult to treat active EoE have predicted enrichment of interferon response which rely on JAK/STAT signals. Accordingly, treatment of EoE esophageal fibroblasts with the JAK1/2 inhibitor ruxolitinib decreases production of the eosinophil chemotactic cytokine CCL26/eotaxin-3. Our preliminary work with in vivo spatial transcriptomics demonstrates that esophageal biopsies have abundant transcripts for JAK1, STATs, and regulators of JAK1 activation. Upadacitinib, a specific JAK1 inhibitor, was superior to IL-4Rα blockade with dupilumab in atopic dermatitis, a disease with significant pathogenic overlap with EoE. These data provide the framework and feasibility for our central hypothesis that JAK1 inhibition with upadacitinib will treat steroid-resistant EoE and improve architectural and immune cell dysfunction in EoE. To test this hypothesis, we will perform a proof of concept randomized, placebo-controlled clinical trial of upadacitinib in topical steroid-resistant EoE subjects and assess disease response with validated clinical outcome metrics. We will also generate novel mechanistic data by investigating in vivo effects of upadacitinib on tissue structural cell transcriptomes and functions, spatial localization, and tissue cell neighborhoods comprised of fibroblasts and immune cells. The specific aims are to 1) evaluate the efficacy of upadacitinib versus placebo for improving clinically important disease activity outcomes in patients with EoE; and 2) understand the effects of JAK inhibition on tissue inflammation and remodeling. This proposal will have a major clinical impact for the large number of refractory EoE patients without current treatment options, provide data for planning a pivotal trial, and elucidate the role of the JAK/STAT pathway in EoE. Given the strong scientific premise, our expert multidisciplinary team with a proven track-record in EoE, clinical trials, and translational research conduct, is uniquely situated to successfully complete this study.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY Intrinsically disordered proteins, or IDPs, have numerous essential roles in cellular signaling and regulation. In many ways, IDPs are ideally suited for carrying out important regulatory roles in complex environments. IDPs do not adopt a single stable structure in isolation, are highly dynamic, and can engage multiple binding partners in a context-dependent manner. In addition, IDPs are highly responsive to the environment and can undergo changes in abundance, structure, dynamics, and interactions in response to chemical changes. This flexibility in form and function makes IDPs extremely efficient and adaptable regulators of biological processes. However, the precise physicochemical basis of these behaviors and the relationships between IDP conformational ensembles, sequence, dynamics, and function are poorly understood. Critically, even less is known about the mechanisms by which highly flexible IDPs achieve functional specificity through interactions with other cellular components. Growing evidence suggests that multivalency, or the linkage of multiple binding motifs in a single polypeptide chain, is a key feature that enables IDPs to carry out highly specific yet environmentally tunable functions in the cell. At present, the few systems for which the molecular features driving multivalent interactions have been well-described comprise a combination of disordered and folded domains, presenting a challenge for establishing a direct link between disorder and functional specificity achieved through multivalency. To address this gap, we are studying the fully disordered CITED family of transcriptional regulators as ideal model systems for dissecting the relationships between the molecular features of IDPs and specific biological functions. The CITED proteins differ in size, sequence, and domain organization but all share a highly conserved C-terminal activation domain required for transcriptional regulation. The C-terminal activation domains of all CITED proteins are implicated as molecular hubs for binding a multitude of cellular factors but the mechanistic basis of how these conserved segments selectively engage different molecular partners is not known. Further, the role of the variable N-termini and distinct compositional biases of the CITED proteins in regulating the proteins’ conformational ensembles, dynamics, and functions has yet to be elucidated. The overarching goals of this research program are: (1) to determine the mechanistic basis of molecular selectivity in protein-protein interactions involving IDPs, and (2) to understand the relationships between sequence compositional biases, environmental responsiveness, and functional specificity. As IDPs have a multitude of important roles in human health, the insights gained through this research will aid in establishing a new framework for considering functional specificity in the context of highly dynamic systems and will guide the design of new strategies for controlling the behavior of IDPs in a therapeutic context.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY Nitric oxide (NO) is the focus of intense research primarily because of its wide-ranging roles in human physiology and disease. The rising interest in NO research demands analytical techniques that can accurately and precisely quantify NO concentrations and production rates in vivo. The objective of this project is to design, fabricate and study the analytical performance of a needle-type NO sensor in a swine model as a function of diabetes disease state. Implantable NO sensors with robust performance characteristics will allow the ability to probe how diabetes disease state influences NO levels, which will guide future diagnostics and management of the disease. To establish this notion, we will subcutaneously implant the NO sensors for acute periods (<7 d) in swine to quantify basal NO levels in tissue as a function of disease state (i.e., healthy vs. diabetic). Additionally, we will ascertain the best practices for calibrating such devices in vivo while also establishing the use of light (e.g., wavelength, intensity, duration) to access and quantify the available NO reservoirs (e.g., S-nitrosothiols) found in tissue which liberates NO through the breakdown of S- nitrosothiols (e.g., S-nitrosoglutathione, S-nitrosocysteine, S-nitrosoalbumin). The new knowledge generated by this research may someday facilitate improved diabetes diagnostics and management by establishing the influence of basal NO levels within tissue on favorable wound healing, for example. However, implantable NO microsensor technologies may prove useful in other biomedical applications as well, including oncological, chronic inflammation, and infections.

NIH Research Projects · FY 2026 · 2026-04

SUMMARY/ABSTRACT Type 1 diabetes (T1D) is characterized by the T cell-mediated destruction of the insulin producing b cells in the islets of Langerhans. Currently, there is no cure for T1D, highlighting the ongoing need for immunotherapies that effectively suppress b cell autoimmunity long-term for disease prevention and treatment. Recently, T follicular helper cells (Tfh) have been implicated in promoting the diabetogenic response. Notably, persistently high levels of Tfh correlate with nonresponsiveness to CTLA4-Ig therapy in T1D patients. This observation suggests that it is necessary to tolerize Tfh to effectively suppress T1D. With this in mind, we propose to exploit the inherent plasticity of Tfh to limit their fitness and function, while promoting Tfh conversion into functional regulatory T cells (Treg). To achieve this, we will evaluate the efficacy of coreceptor therapy (CoRT), using low-dose nondepleting (ND) Ab specific for CD4 to induce Tfh de-differentiation and conversion into Treg. Our prior work has demonstrated that high-dose CoRT has potent in vivo effects on the properties of murine and human effector T cells (Teff), restoring b cell tolerance in NOD mice, and blocking pathogenic Teff activity in humanized mice. This R21 proposal outlines two Specific Aims. In the first Aim, we will assess the efficacy of low-dose CoRT to promote de-differentiation of murine and human Tfh and subsequent conversion into Treg, as well as investigate mechanisms that regulate this process. In the second Aim we will define the pathogenic versus suppressor function of CoRT-induced, de-differentiated murine and human Tfh. Through this work, we aim to establish a novel approach to both selectively block the pathogenic activity of autoreactive Tfh, while enhancing protective immunoregulation. In addition to T1D, this approach will be applicable to other autoimmune diseases and pathologies where Tfh play a role.

NIH Research Projects · FY 2026 · 2026-04

Precision medicine aims to accurately classify patients to improve diagnosis, intervention selection, and prognosis. The All of Us Research Program (AoURP) collects an array of data types from participants, including surveys, electronic health records (EHRs), physical measurements, wearable devices, and biosamples, offering valuable insights into health trajectories. However, certain aspects of a participant’s life remain missing in the collected data, which can limit the accuracy of research and care. To address this gap, we propose the creation of the All of Us Center for Linkage and Acquisition of Data (CLAD) to supplement existing data sources using passive data streams and deploy integration strategies to "put the patient back together again" and more deeply assess health outcomes. This team brings together collective experience leading large initiatives involving data acquisition, linkage, harmonization, quality assurance, pipelines and platforms, governance, and security. We will design and implement a data collection, linkage, and integration strategy that lays a foundation for a variety of AoURP data linkages for identified, and de-identified data integration, including person-level linkages such as with mortality, residential history, and administrative claims, and geocoded data pipelines to enable linkages with environmental and economic data. The CLAD will acquire and process new data linkages and geocoded data in a cloud-based Data Linkage Platform (DLP), guided by our experience formulating researcher-ready datasets with scientific utility. Our CLAD team will perform data quality assurance, repair, and standardization checks to ensure accuracy and robustness of data-driven research. This endeavor will align data with interoperability standards and clinical terminologies, extend them where necessary, and create a data quality dashboard for every data change and data health check. We will also explore new methods of clinical data acquisition to mitigate data missingness by comparing data provided from recruitment sites with EHR data from Health Information Networks. CLAD data sources and novel analytical methods, such as probabilistic models, will be used to reveal patterns of care, health outcomes, and potential interventions for common, chronic, and genetic diseases.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY Metabolic stress in the tumor microenvironment (TME) has emerged as a barrier to CD8+ tumor infiltrating lymphocyte (TIL) antitumor function in solid cancers. The integrated stress response (ISR) is an evolutionarily conserved pathway intrinsic to all mammalian cells poised to sense and respond to diverse metabolic stressors. However, it is poorly understood how the ISR integrates and regulates CD8+ TIL function in the stress of the TME. Activating transcription factor 4 (ATF4) is the central node of the ISR. In states of chronic stress, persistent ATF4 activity results in loss of cell metabolic homeostasis. Our recent work demonstrated that hypoxia in the TME enforces chronic ATF4 activity in CD8+ TILs, resulting in robust loss of tumor control. Pharmacologic inhibition of ATF4 enabled complete response to immune checkpoint inhibitor (ICI) therapy in therapy-resistant mouse models. However, the mechanism through which chronic ATF4 programs loss of CD8+ TIL metabolic homeostasis in the hypoxic TME remains elusive. Here we reveal preliminary data that position ATF4 as the central TME stress-responsive regulator of lipid metabolism in CD8+ TILs. We find that chronic ATF4 activity transcriptionally programs lipogenesis in CD8+ T cells, resulting in robust accumulation of intracellular lipid stores that we have previously shown govern CD8+ TIL cell metabolism. Due to elevated risk factors of alcohol and tobacco use, head and neck squamous cell carcinomas (HNSCCs) are a tumor type predominantly afflicted by hypoxia and lipogenesis across the TME and ICIs show only modest efficacy in HNSCC patients. Our preliminary data show that CD8+ TILs isolated from ICI therapy-resistant HNSCC patients display a gene signature indicative of chronic ATF4 activity. This proposal will test the central hypothesis that chronic ATF4 activity orchestrates steatosis in CD8+ TILs and serves as a primary metabolic checkpoint for ICI response in HNSCC patients. Aim 1 of this proposal will use T cells deficient in ISR kinases, mouse models with varied expression of ATF4, and CD8+ T cells isolated from HNSCC patients paired with metabolic imaging, scRNA-seq, CHIP-seq, metabolomics, lipidomics, and Seahorse bioanalysis to define the mechanisms upstream and downstream of chronic ATF4 activity that regulate steatosis in CD8+ TILs. Results from this aim will establish a radical new paradigm for ISR regulation of CD8+ TIL metabolism. Aim 2 of this proposal will use single-cell spatial transcriptomics, single-cell ultrahigh-plex spatial phenotyping, and pharmacologic inhibition of the ISR to determine the association between ATF4-regulated lipogenesis and ICI response in HNSCC patients. Results from this aim will elucidate a regulatory network of chronic ISR activity and metabolic fate in human CD8+ TILs, providing new avenues for clinical trial development.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY Our overall vision and long-term goal are to obtain a more complete understanding for how cellular signaling pathways, in particular G proteins and integrin receptors, control platelet adhesion and plug formation in hemostasis and thrombosis. Furthermore, we aim to elucidate aspects of the signaling machinery that function differentially in hemostasis versus thrombosis (both arterial and venous). The conceptual framework is that human thrombotic diseases result from an otherwise protective mechanism gone awry, and that disease-induced changes to platelet reactivity (priming) are a major contributor to thrombotic disease. A detailed understanding of platelet activation pathways is critical for the development of novel antithrombotic therapies, and for the identification of new biomarker assays for a prothrombotic state. Over the last two decades, my lab has utilized state-of-the-art in vitro and in vivo approaches to redefine our understanding of the molecular mechanisms regulating platelet reactivity in circulation and at sites of vascular injury. Key findings include the identification of tightly balanced G protein networks, an integrin activation complex that is unique to platelets, and injury-specific contributions of platelets to vascular integrity and thrombotic complications. The proposed work will focus on several areas within the general conceptual framework outlined above: (1) studies on G protein networks and integrin affinity regulation in platelets; (2) studies on the role of platelets in venous thrombosis pathogenesis and novel antithrombotic strategies; (3) development of novel assays to measure levels of primed platelets in different diseases; and (4) studies to better understand and correct defects in platelet count and function associated with inherited and acquired platelet disorders. Exciting preliminary findings include the identification of a novel G protein network in platelets, the establishment of new assays to monitor an elusive intermediate affinity conformation in platelet integrins, and a critical role for intermediate affinity integrins in thrombocytopenia and/or thrombosis associated with platelet disorders and cancer. In summary, the proposed studies will investigate significant knowledge gaps in basic platelet biology and provide a new understanding for how disease states like cancer affect platelet reactivity and platelet plug formation. Our studies have high translational relevance in the areas of antithrombotic therapy, biomarker development, and transfusion therapy.

NIH Research Projects · FY 2026 · 2026-04

ABSTRACT: Obesity is prevalent among adults (>40%) and children (~20%) in the U.S. and is expected to increase dramatically in the next 25 years. Addressing the obesity epidemic is vital for public health because of its wide range of comorbidities including deadly conditions such as stroke, hypertension, diabetes, heart disease, liver disease, sleep apnea, pregnancy complications, and cancer. Most clinical interventions for obesity target individuals who are already obese. However, a growing body of research demonstrates that obesity can be caused by adverse events during development that drive irreversible effects on metabolic programming. This work highlights a critical need for preventative measures to address the obesity epidemic. Vitamin D is an essential nutrient that has recently been implicated in obesity. This has the potential to impact a large population since up to 80% of pregnant women are deficient in vitamin D (VDD) and emerging studies implicate this may disrupt developmental programming of metabolism and increase offspring susceptibility to obesity later in life. This proposal will leverage our novel mouse model of VDD-induced adiposity (a naturally genetically divergent Collaborative Cross (CC) mouse lineage) to model the human condition so we can better understand the developmental mechanisms driving obesity and target them for effective interventions. The mouse serves as a vital model for studying this important question not only because of its conserved vitamin D biology but also because mouse research allows us to avoid ethical limitations that inhibit studying VDD in human pregnancy and provides control over environmental and genetic confounders present in human populations. The proposed study aims to: (1) Determine the importance of vitamin D sufficiency during pre-, peri-, or post-conceptional windows of development in driving the accumulation of adiposity and risk of obesity-related comorbidities later in life; and (2) Define the developmental timing of VDD-induced transcriptional dysregulation and investigate its role in disruption of metabolic programming. Addressing these gaps in our understanding of the role of VDD in developmental mechanisms of obesity will help determine the relative importance of VitD monitoring and timely interventions for VDD during pregnancy to protect offspring metabolic health so that effective guidance can be developed.

NIH Research Projects · FY 2026 · 2026-03

ABSTRACT Less than half of people with HIV (PWH) in the US are retained in outpatient HIV care, impeding access to life- saving antiretroviral therapy and increasing transmission risk. Hospitalizations are common among PWH, particularly PWH not engaged in care. An inpatient admission is an opportunity to link hospitalized PWH, either newly diagnosed or previously diagnosed but not in care, to outpatient HIV care following discharge. However, interventions to improve linkage to outpatient HIV care have been largely unsuccessful. Prior studies have been limited by fragmented data sources, often restricted to a single health system, cross-sectional data, or with insufficient variables to comprehensively examine complex risk factors influencing post-discharge care engagement. We propose to integrate complementary data sources that capture the full HIV care continuum among hospitalized PWH and collect qualitative data from key informants to investigate individual-, hospital-, community-, and policy-level determinants of post-discharge HIV care engagement. We will conduct this study in North Carolina (NC), where academic-public health partnerships have a proven track-record of using HIV surveillance data to inform public health interventions, improving care outcomes and interrupting transmissions. We will combine electronic health records (EHRs) from three of the largest health systems in NC with HIV surveillance data, including statewide viral loads, for the years 2018-2024. PWH will be matched across the data sources using highly accurate novel techniques that do not require sharing sensitive identifying data. Our study will include 34 hospitals that care for 80% of hospitalized PWH in NC. Care continuum outcomes and differences across hospitals will inform sampling for our qualitative work, engaging PWH, healthcare providers and administrators, and staff from community-based organizations involved in supporting engagement in HIV care for PWH. Our specific aims for this three-year grant are: 1) Characterize HIV care engagement pre- and post-discharge among hospitalized PWH; 2) Identify patient- and hospital-level predictors of post-discharge linkage to care; and 3) Explore key informants’ perceptions of factors that influence post-discharge linkage to care. In Aims 1-2, integrated EHRs capturing >600 in- and outpatient sites in all 100 NC counties and statewide HIV surveillance viral load data enables us to examine the full HIV care continuum among hospitalized PWH – diagnosis, linkage, retention, and viral suppression. Our collaboration capitalizes on clinical, epidemiological, and public health expertise at three academic institutions and the NC Division of Public Health, and leverages established partnerships with community-based organizations, local health jurisdictions, and community advisory boards. Combining HIV care continuum outcomes, predictors of care engagement following hospitalization, and a comprehensive examination of contextual determinants at individual, community, organization, and policy levels, we will identify modifiable targets from which we can develop tailored, multi-level interventions for subsequent testing.

NIH Research Projects · FY 2026 · 2026-03

The candidate, Erica Brenner MD, MSCR, is a pediatric gastroenterologist with training in epidemiology and qualitative methodology. Dr. Brenner’s long-term goal is to become an independently funded physician scientist focused on clinical trials and patient-centered research to improve women’s health for patients with inflammatory bowel disease (IBD). Dr. Brenner’s short-term goals are to: 1) train in psychometrics with a focus on developing and validating patient-reported outcome measures (PROMs), 2) acquire the necessary didactic and experiential training to design and conduct clinical trials, and 3) amass the professional training and conduct the preliminary studies required to successfully compete for R01 (or equivalent) funding. The proposed research activities, career development plan, mentorship team, and institutional environment are strategically designed to assist the applicant in achieving these aspirations. The overarching goal of the proposed work and subsequent research is to improve pain management in IBD by re-evaluating the use of non-steroidal anti-inflammatory drugs (NSAIDs) among women with Crohn’s disease (CD) and primary dysmenorrhea (painful menses without underlying pathology). Although patients with IBD commonly experience pain, they typically avoid NSAIDs due to concern for exacerbation of IBD, particularly CD, albeit based on weak data. Women with CD frequently experience dysmenorrhea, which may be debilitating, and thus represent an ideal sub-population to re-evaluate NSAID use in CD. The proposed aims for this K23 award will pave the way for a much-needed randomized control trial (RCT). In Aim 1, Dr. Brenner will develop PROMs for women with CD that capture primary dysmenorrhea severity while accounting for CD symptom overlap, using qualitative interviews followed by validation work in a two-center, prospective, longitudinal cohort. In Aim 2, Dr. Brenner will conduct a single-center pilot study to inform the design of a subsequent RCT to compare ibuprofen versus acetaminophen for primary dysmenorrhea treatment among women with CD. Dr. Brenner’s training goals include 1) PROM development and 2) the design and conduct of RCTs. Dr. Brenner will achieve these goals through the proposed advanced coursework and practical research experience, in addition to engaging in academic skill building activities. Dr. Brenner’s mentorship team, including a world- renowned health service researcher (Kappelman; primary mentor), an internationally recognized PROM development expert (Reeve; co-mentor), an epidemiologist and trialist (Baron; advisor), a gastroenterologist specializing in women’s health in IBD (Long; advisor), and a gynecologist with expertise in women’s health (Bryant; advisor), will guide Dr. Brenner through the proposed work. The environment at UNC, which includes the North Carolina Translational and Clinical Sciences Institute, the National Institutes of Health-funded Center for Gastrointestinal Biology and Disease, and the larger university community, will provide an ideal atmosphere for Dr. Brenner to pursue the above research and career development activities.

NIH Research Projects · FY 2026 · 2026-03

ABSTRACT This comprehensive research program is focused on revolutionizing the treatment of Glioblastoma (GBM), a highly aggressive brain tumor that currently has limited and largely ineffective treatment options. GBM is known for its devastating impact on patients, often leading to poor prognosis and survival rates. The proposal brings together a multidisciplinary team of experts from various fields, all working towards a common goal - to significantly enhance the efficacy of Chimeric Antigen Receptor (CAR) T-cell therapy using innovative translational biomaterials. The team is driven by a central hypothesis that the strategic use of biomaterial strategies can substantially enhance the effectiveness of CAR therapy. This enhancement is expected to promote epitope spreading, a process that currently limits CAR therapy. The proposal is structured into three distinct but interconnected research projects (RPs), each addressing a unique aspect of the overall goal. The first project (RP1) focuses on the integration of CAR T cell and CAR Natural Killer T (NKT) cell therapy with a specially designed nanofibrous acetalated dextran (Ace-DEX) scaffold that has uniquely tunable release rates. The second project (RP2) is centered on optimizing a Multifunctional Alginate Scaffold for T Cell Engineering and Release (MASTER) system for in situ generation of CAR cells. The third project (RP3) is dedicated to the development of CAR NKT cells, a promising new avenue in immunotherapy. In addition to these research projects, the proposal also includes three cores and three advisory boards. The cores are designed to provide essential support for research projects and include: Core 1: Administrative (Admin) Core; Core 2: Bioinformatics & Immunology; Core 3: Animal Models. They aim to integrate the goals across all projects, identify significant changes in cells of the immune system during GBM development and treatment, and develop pre-clinical mouse models for rigorous testing of these therapies. Our program will be overseen by three advisory boards: The Internal Advisory Board, the Clinical Advisory Board, and the External Advisory Board. The ultimate goal of this proposal is to address the significant challenges in treating GBM and transform the efficacy of CAR T/NKT cell therapies with biomaterials. By achieving this goal, the team hopes to significantly improve the prognosis for GBM patients and contribute to the ongoing efforts to find a cure for this devastating disease. The significance of this proposal lies not only in its potential impact on GBM treatment but also in its potential to advance the field of immunotherapy as a whole.

NIH Research Projects · FY 2026 · 2026-03

ABSTRACT Candidate: I am a fellowship-trained Geriatrician and physician-investigator at the University of North Carolina (UNC). As an Assistant Professor of Medicine, I have developed expertise in quality improvement, observational research, and secondary analysis of clinical trials. My long-term goal is to establish an independently funded research program that develops, tests, and implements scalable interventions to prevent hospital-associated disability in older adults, including people with dementia (PwD). For this K23 application, I propose training in 1) adapting interventions for PwD, 2) clinical trial methodology, and 3) implementation science. Environment and Mentorship: As a premier research institution, UNC is an ideal setting for the proposed research. The Division of Geriatric Medicine and surrounding Health Affairs Campus is home to accomplished clinical scientists leading research to improve care for older adults and PwD. I have established collaboration with my primary co-mentors Drs Hanson and Batsis and have support from mentors and advisors with expertise in clinical trials, exercise for older adults, and implementation science. They have committed to guide this research and support my career development. Furthermore, UNC has demonstrated strong institutional support for my career by providing the salary support necessary for developing this proposal. Research: In the U.S., Alzheimer’s Disease and Related Dementias (ADRD) affects an estimated 6.9 million people, a population projected to double by 2060. Approximately 32% of PwD are hospitalized each year, and they are seven times more likely than individuals without dementia to acquire a hospital-associated disability, resulting in a loss of independence in at least one activity of daily living. Hospital-associated disability reduces quality of life, increases caregiver strain, and heightens the risk of nursing home placement and premature death. The overarching goal of proposed research is to develop and pilot test ACTIVE-AD—ACTIVity and Exercise for hospitalized people with ADRD to address the gap in effective, scalable, and sustainable strategies to tailor hospital care for PwD. Following the NIH stage model, our specific aims are to: 1) adapt an existing hospital- based exercise program for PwD, 2) assess ACTIVE-AD’s feasibility in 30 PwD-caregiver dyads, and 3) identify and address implementation determinants. The project's scientific and training aims will establish ACTIVE-AD’s feasibility and equip me with the expertise to lead an R01-funded efficacy trial (NIH Stage Model 2). This work aligns with the National Institute on Aging's objectives and the National Plan to Address Alzheimer's Disease's advocacy for nonpharmacologic trials to slow cognitive and physical function decline in PwD.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY Alzheimer’s disease (AD), hypothesized to begin in midlife before symptoms appear, is the leading cause of dementia in the United States resulting in loss of cognitive function and eventual death. AD has a higher prevalence in non-Hispanic Black and Hispanic adults compared to non-Hispanic White adults and is expected to increase at a greater rate in non-Hispanic Black and Hispanic populations than non-Hispanic Whites. Although these health disparities for AD exist, little research has been done into the genetic epidemiology behind AD, particularly polygenic risk scores (PRS), for these populations. PRS has poorer performance in populations different than the populations included in large-scale genetic analyses. Since the majority of genetic summary statistics used to construct PRS come from European populations, PRS tends to perform worse in non-European populations. Along with other scientific and clinical uses for PRS, an improved PRS instrument could be used to provide a better understanding of metabolomic changes in midlife associated with high AD genetic risk. Metabolomic changes may provide insight into AD mechanisms as either part of the AD pathogenesis pathway or as biomarkers indicating early AD development. Here, we propose to evaluate multiple methods for AD PRS construction in diverse populations and use the best-performing PRS to examine the relationship between AD genetic risk and metabolomics in midlife. Aim 1 will construct AD PRS for diverse populations by first using summary statistics available in published GWAS with a focus on newly available GWAS with predominantly African ancestry populations. Various PRS methods will be assessed to construct the best possible PRS in diverse testing cohorts, with a focus on participants with significant genetic similarity to African reference populations. Then, aim 2 will use the AD PRS as the exposure for the metabolite analysis in >25,000 participants from NHLBI Trans-Omics for Precision Medicine (TOPMed) with untargeted metabolomics. The use of the PRS instead of cases and controls will provide advantages such as increased power due to increased effective sample size since, in middle-aged TOPMed cohorts, most individuals have not developed AD at the time of metabolite measurement. This method also has the ability to identify metabolites associated with a higher genetic risk burden in midlife before AD develops. Genetic causal inference methods will be utilized to assess metabolites associated with AD incidence. The results of this study will provide a more predictive AD PRS for diverse populations and a better understanding of midlife metabolite changes associated with AD genetic risk. Ms. Drzymalla’s mentoring team, who has experience in AD, genetics, and metabolomic epidemiology as well as PRS and causal inference methods, will provide guidance for the completion of the research and training plans. Ms. Drzymalla will receive training on AD pathogenesis, genetic computation methods, metabolomic epidemiology, and causal inference methods as well as take part in professional development activities to develop the skills to become an independent researcher at the intersection of genetics, epidemiology, and AD.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY Enteroendocrine cells (EECs) are rare sensory cells scattered throughout the gastrointestinal epithelium that interface between environmental stimuli like nutrients and microbes and the body's response, secreting over 20 distinct hormones that act locally and systemically. Our lab uses EEC-deficient mice and human intestinal organoids to uncover the intestinal functions regulated by EECs and uses these models as a blank slate to test the roles of individual EEC-derived products on intestinal physiology. EECs are often dysregulated in metabolic and gastrointestinal diseases, such as inflammatory bowel disease (IBD), although their roles in disease pathogenesis remain unknown. Many of these diseases are associated with impaired function of the intestinal epithelial barrier, allowing undigested food, microbes, metabolites, and toxins to cross the epithelium, triggering local and systemic inflammation. Tight junctions are essential for barrier integrity and are composed of several proteins which are supported by sphingolipids called ceramides, best characterized in the skin. In the intestine, barrier proteins are often reduced in IBD, along with several species of ceramides. Similarly, loss of ceramides within the intestinal epithelium exacerbates chemically-induced colitis and supplementation of ceramides improves colitis in mouse models. We discovered that several species of ceramides are reduced or absent in EEC-deficient mouse small intestine. Moreover, EEC-deficient human intestinal organoids display increased barrier permeability and upregulate an inflammatory gene signature. In preliminary experiments, we found that EEC-deficient mice also display impaired barrier function with increased permeability and markers of inflammation. When challenged with oral ingestion of dextran sulfate sodium (DSS), which classically induces colitis, EEC-deficient mice displayed significantly greater weight loss compared to controls. These data led us to hypothesize that EECs promote a strong barrier by regulating ceramide abundance and may be effective therapeutics for inflammation-mediated barrier dysfunction. Our first aim is to determine the role of EECs in the structure-function relationship between tight junctions and ceramides using in vitro human intestinal organoid cultures. Our second aim is to define the role of EECs in DSS-induced disease progression and recovery, and to test the role of the EEC hormone PYY in protecting the gut against DSS-induced damage. Our third aim is to perform targeted analysis of sphingolipid metabolic pathways of human intestinal organoids and murine intestine to define the mechanism by which EECs participate in ceramide biosynthesis in homeostasis and in disease. We expect that restoration of exogenous PYY to EEC-deficient models will improve barrier function and mitigate the severity of DSS-induced disease by increasing the abundance of ceramides within the epithelium. These experiments will define a new role for EECs in maintaining gastrointestinal homeostasis, uncover a novel mechanism regulating barrier integrity in health and disease, and provide a basis for future therapies aimed at repairing a leaky gut.