Univ Of North Carolina Chapel Hill

NIH Research Projects · FY 2026 · 2026-06

Summary Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by loss of the maternal UBE3A allele, leading to intellectual disability, ataxia, microcephaly, and seizures. Only maternal UBE3A is expressed in mature neurons, as the paternal transcript is silenced by a long noncoding antisense RNA (UBE3A-ATS). This unique biology offers an unprecedented therapeutic opportunity of restoring UBE3A expression by activating the intact but silenced paternal allele, an approach being vetted in clinical trials using antisense oligonucleotides (ASOs) to downregulate UBE3A-ATS and, hence, unsilence paternal UBE3A. Despite promising clinical data, ASOs face limitations including uneven biodistribution, risk of hydrocephaly, and invasive delivery. In contrast, blood brain barrier (BBB)-penetrant small molecules offer even brain biodistribution, reduced invasiveness, and greater patient accessibility. Our lab recently identified that the BBB- penetrant small molecule (S)-PHA533533 potently unsilences paternal UBE3A/Ube3a in AS patient-derived neurons and mouse primary neurons. (S)-PHA533533 was designed to be a cyclin-dependent kinase 2 and 5 (CDK2 and CDK5) inhibitor; however, these kinases are not responsible for the unsilencing mechanism of action (MoA). Here, I aim to identify the MoA by which (S)-PHA533533 unsilences paternal Ube3a, allowing rational drug design away from CDK inhibition and toward enhanced on-target potency, improving therapeutic index for pediatric administration and advancing clinical candidate selection. Toward this goal, my lab developed a novel dual Ube3a reporter mouse that harbors a targeted knock-in following Ube3a containing NanoLuciferase for high throughput screening and nuclear-tagged superfolder GFP that enables nuclear sorting and rapid biodistribution assessments. Using this mouse model, I will explore the mechanism by which (S)-PHA533533 unsilences paternal Ube3a and will profile the structure-activity relationship of (S)-PHA533533 analogs, synthesized by our medicinal chemist collaborators. I will investigate the MoA through targeted ASO knockdown of known chemical interactors, a CRISPR whole kinome knockout screen, and a kinase chemogenetic inhibitor small library screen. I also aim to identify chemical modifications of (S)-PHA533533 that increase its potency and decrease its cytotoxicity, hence maximizing its therapeutic index. These experiments hold promise to develop a first-in-class, brain penetrant small molecule therapy for AS, ultimately improving quality of life for affected individuals and their caretakers.

NIH Research Projects · FY 2026 · 2026-06

Chlamydia trachomatis (CT) is a globally impactful sexually transmitted bacterial pathogen for which no vaccine is available. We and others have established the central importance of antigen-specific CD4 Th1 or Th1/Th17 cells producing IFN-γ in controlling CT and modulating innate inflammatory responses (e.g., IL-1α/TNF) that contribute to upper genital tract pathology. These studies informed development of a candidate vaccine, containing a conserved, immunoprevalent, immunodominant antigen for CD4 T cells and B cells, with highly targeted adjuvants for mucosal immunization to effectively induce protective immunity. However, the lack of easily quantified, early correlates of protection and the limitations of the C. muridarum mouse genital tract model, specifically its high sensitivity to immune-mediated oviduct damage and a shorter infection course compared to humans, undermines success in refining and testing T-cell focused vaccines. The goal of this proposal is to accelerate chlamydial vaccine development by identifying robust, early biomarkers predicting protection in mice and by establishing a mouse model that recapitulates infection chronicity and pathological changes seen during human infection. We will test our central hypothesis that cervical transcriptional immune responses to chlamydial challenge reflect infection and disease outcomes in mice by performing the following specific aims: (1) Profile cervical transcriptional responses to chlamydial infection and challenge. We will profile early cervical transcriptional responses to CM intravaginal challenge in three groups of mice: naïve, infection-immune (previously resolved infection with an attenuated or wild type CM strain), and vaccinated (immunized with recombinant vaccines and T-cell targeting adjuvants). Biobanked cervical swabs will be used, with data on vaccine immunogenicity, infection course, and pathology already being collected through a U01-funded grant. Causal mediation analysis of RNA-seq data generated as part of this study will identify genes, gene modules, transcription factors, and transcriptional responses unique or common to each group. Machine learning algorithms will identify predictive genes and gene modules to forecast time to infection clearance and pathology outcomes. (2) Evaluate Collaborative Cross (CC) mouse strains for vaccine testing. Our pilot studies have identified CC strains with diverse infection outcomes and pathology, providing a valuable platform for assessing vaccine candidates and identifying conserved, correlates of protection. To accomplish these aims, we have developed a simple and cost-efficient probe-based transcriptional profiling method, inspired by advancements in single-cell RNA sequencing (scRNAseq) technologies. This research integrates cutting-edge technologies and computational approaches to refine murine models and deepen our understanding of immune responses during early chlamydial infection. The identification of transcriptional biomarkers holds significant promise for translation into human vaccine studies, not only for chlamydia but also for other sexually transmitted mucosal pathogens.

NIH Research Projects · FY 2026 · 2026-06

Project Summary Epstein-Barr Virus (EBV) is etiologically linked to multiple aggressive B cell malignancies, including Burkitt lymphoma (BL), diffuse large B cell lymphoma (DLBCL), and post-transplant lymphoproliferative disease (PTLD). These lymphomas arise from germinal center B cells, where antibody diversification introduces uracils into DNA through activation-induced cytidine deaminase (AID). Under normal conditions, base excision repair (BER) and mismatch repair (MMR) resolve these lesions to maintain genome stability. However, persistent uracils promote mutations and chromosomal alterations that contribute to malignant transformation. Re-analysis of EBV-positive BL tumor sequencing reveals mutational signatures consistent with defects in both BER and MMR, suggesting that EBV may suppress uracil repair to promote lymphomagenesis while protecting its own viral genome. While EBV's effects on DNA damage signaling have been studied, its direct impact on uracil processing remains poorly understood. This K99/R00 proposal outlines a transition plan for Dr. Jessica Stewart to define how EBV suppresses uracil excision, alters DNA repair pathway utilization, and promotes mutagenesis. In the mentored phase (K99), she will (Aim 1) investigate how EBV suppresses uracil excision and identify viral gene products that impair uracil repair, and (Aim 2) dissect the function of FAM72A—a host factor upregulated by EBV that antagonizes nuclear uracil glycosylase UNG2—through structural studies, interactome mapping, and small- molecule screening. In the independent phase (R00), she will (Aim 3) define how unresolved uracils alter DNA repair pathway usage and identify repair vulnerabilities that support EBV-driven B cell transformation. Dr. Stewart's long-term goal is to establish an independent research program focused on how oncogenic viruses reshape host DNA repair networks to drive malignant transformation. Building on her expertise in uracil biochemistry and DNA repair, she will receive advanced training in viral recombination, structural biology, repair pathway analysis, and in vivo modeling of EBV-associated tumors under the mentorship of a multidisciplinary advisory committee with expertise in virology, DNA repair, and cancer biology. The outstanding research environment at UNC Lineberger Comprehensive Cancer Center will provide the resources, collaborations, and professional development needed to support her transition to independence. This work aligns with NCI's mission to define cancer mechanisms and inform therapeutic strategies for virus- associated malignancies.

NIH Research Projects · FY 2026 · 2026-06

Abstract: Astrocytes are structurally and functionally complex glial cells capable of exerting dynamic control over synapse development and maturation through direct interactions with thousands of neuronal synapses. Atypical astrocyte structure and function is a recurring phenotype in neurological disorders concurrently characterized by dysregulated synaptic function, including autism spectrum disorder, epilepsy, and Schizophrenia. Unfortunately, we lack a complete understanding of astrocyte cell biology, posing a significant barrier to understanding how astrocyte dysfunction might initiate or exacerbate disease-related synaptic dysregulation. To address this knowledge gap, we performed a reverse genetic screen to identify novel regulators of astrocyte development and identified protein tyrosine phosphatase receptor Z1 (PTPRZ1) as a significant regulator of astrocyte morphogenesis in vitro. PTPRZ1 plays important roles in numerous neurodevelopmental processes and is highly expressed in astrocytes during brain development; however, the astrocyte-specific function of PTPRZ1 is unknown. To investigate the astrocyte-specific function of PTPRZ1 in vivo, we developed a Ptprz1 conditional knockout mouse to delete Ptprz1 from postnatal astrocytes and found a significant decrease in excitatory synapse density in the visual cortex. We also observed abnormal perineuronal net (PNN) structure, suggesting a potential role for PTPRZ1 in cortical plasticity. Here, we propose a detailed investigation of the astrocyte-specific role of PTPRZ1 in cortical development to test the central hypothesis that astrocyte-derived PTPRZ1 is a critical regulator of both synapse development and cortical plasticity. In Aim 1, we will expand upon our recent work to define the primary mechanism through which astrocytic PTPRZ1 regulates excitatory synapse development. This will generate new insight into the underlying mechanisms of astrocyte regulation of excitatory synapse development. In Aim 2, we will investigate the role of astrocytic PTPRZ1 in regulating PNN structural formation and cortical plasticity. Notably, these experiments will characterize astrocyte-PNN and astrocyte-PNN- synapse interactions in unprecedented detail by developing a robust, scalable, multivariate image acquisition and analysis pipeline under the mentorship of microscopy and bioinformatic experts at UNC-Chapel Hill. Overall, the proposed work will significantly advance our foundational understanding of the regulatory role astrocytic PTPRZ1 plays in synapse development and cortical plasticity, while identifying potential mechanisms underlying disease-relevant phenotypes. The exceptionally collaborative training environment at UNC-Chapel Hill will enable multiple training opportunities across core facilities and within the co-sponsor's lab. The implementation of in vitro quantitative proteomics, advanced super-resolution microscopy, multivariate image analysis, and the ocular dominance plasticity assay will provide balanced and comprehensive training for the applicant to expand their technical skillset and grow as an independent neuroscientist.

NIH Research Projects · FY 2026 · 2026-06

Project Summary This proposal aims to tackle the critical issue of hallucinations in medical large vision language models (Med- LVLMs) in radiology to significantly enhance the reliability of using these models to analyze medical images and aid in clinical diagnosis. While generative AI has revolutionized medical imaging, concerns about hallucinations generating factually incorrect medical analyses persist. Most research on reducing hallucinations in LVLMs has concentrated on natural images, leaving the unique challenges of medical images largely unexplored. Two primary challenges impede progress: (1) the intrinsic disparity between natural and medical images, where medical analyses must prioritize abnormal findings rather than treat all visual information equally; and (2) the inadequacy of single-model approaches for accurately handling complex and nuanced radiological tasks. To overcome these challenges, the project proposes two specific aims: (1) developing a modality-aligned Med- LVLM that leverages medical-aware preference learning and knowledge-augmented retrieval. This approach enhances alignment between clinical descriptions and medical image features, prioritizes abnormal findings, and systematically evaluates hallucinations through a novel medical hallucination benchmark; and (2) implementing a multi-agent reinforcement learning (MARL) framework to collaboratively mitigate hallucinations in complex radiology scenarios. This framework employs specialized Med-LVLM agents engaging in structured debate and verification, thereby enhancing reliability, interpretability, and efficiency in complex diagnostic tasks. The project team, with extensive expertise in LVLMs, medical imaging analysis, deep learning, and clinical applications, is committed to openly releasing developed models, source code, and evaluation benchmarks, fostering broader adoption and advancement of reliable Med-LVLMs.

NIH Research Projects · FY 2026 · 2026-06

ABSTRACT This study will investigate whether colorectal (CRC) and cervical cancer (CC) screening programs could be improved by bundling outreach of at-home self-collection kits for CRC and CC screening for under- screened patients. Both CRC and CC are highly preventable through regular screening and treatment, yet more than 50% of cases are attributable to suboptimal screening. More than 40% of U.S. women report not being screened for both cancers at recommended intervals. Self-collected fecal immunochemical testing (FIT) is a widely used test which detects hidden blood in stool for CRC screening. Self-collection of cervico-vaginal cells for human papillomavirus (HPV) testing is a valid and accepted screening method for detecting high-grade cervical lesions and cancer. Although our previous research shows that mailed outreach interventions are effective in increasing CRC and CC screening coverage separately, the effectiveness of a novel 2-for-1 approach that bundles self-collection kits to improve outcomes for both screening programs remains to be seen. This trial will test if the bundled approach improves outcomes for both programs. Aim 1: We will enroll 2,499 women overdue for both CRC and CC screening at a large Federally Qualified Health Center in North Carolina, which serves a community with limited access to care (92% of patients at or below 200% of the Federal Poverty Level; 17% self-pay). Women will be randomly assigned to one of three groups: Arm 1: Receive a FIT kit (for CRC) and an HPV self-collection kit (for CC) at the same time. Arm 2: Receive one kit first, followed by the second kit one month later (either CRC then CC, or vice versa). Arm 3: Receive usual care (no kits sent). All participants will receive a study information letter. Arms 1 and 2 will be mailed the kits for at-home use to return by mail. Arm 3 will continue with the standard of care procedures provided by the clinic. The primary trial outcome will be the completion of both CRC and CC screenings within 9 months, defined as either a negative result from self-collected samples or an in-clinic screening. Secondary trial outcomes include opt-out rates, kit return rates, screening completion by cancer type, and follow-up procedures within 9 months. Aim 2: We will conduct telephone surveys both pre- and post-intervention to assess perceptions of screening efficacy, convenience, and commitment across arms. We hypothesize that these factors will mediate the effect of bundled outreach on screening completion. Aim 3: We will measure cost inputs for each arm and calculate the incremental cost per additional patient completing screening of bundled kit outreach as compared to sequential kit outreach and to usual care. This trial will provide rigorous evidence on whether (Aim 1), why (Aim 2), and at what cost (Aim 3), bundled provision can improve CRC and CC screening programs. If found to be effective, this scalable approach could have a large public health impact by substantially improving early cancer detection and reducing mortality among under-screened populations.

NIH Research Projects · FY 2026 · 2026-06

ABSTRACT The endometrium is crucial for successful embryo implantation and subsequent maintenance of the pregnancy. Until recently, assessment of endometrial receptivity has relied on invasive techniques such as endometrial biopsy. However, recent studies have shown that menstrual effluent exhibits similar properties to tissue obtained from an endometrial biopsy. The objective of this project is to examine whether alterations in endometrial receptivity affect fertility and risk of miscarriage by quantifying and analyzing menstrual effluent. We hypothesize that low menstrual volume, luteal phase bleeding, and alterations in the distribution of immune cells and cytokines in menstrual effluent will be associated with a decrease in the probability of conceiving in a given menstrual cycle (fecundability) and an increase in the risk of miscarriage. The proposed study will enroll 695 women from the community who desire to conceive, and measure, collect, and analyze their menstrual effluent. Participants will be actively followed throughout their attempts to conceive over the following twelve months. During that time, women will conduct standardized ovulation and pregnancy testing and complete a daily diary that captures bleeding patterns. Pregnancy follow-up will include ultrasound assessment for viability and a pregnancy outcome report. These methods will allow us to address our primary research aims: 1) Determine the extent to which endometrial proliferation and luteinization impact fecundity. To address this aim, we will determine the association between menstrual volume and bleeding patterns with a) fecundability and b) miscarriage. 2) Determine the extent to which the uterine immune microenvironment impacts fecundity. To address this aim, we will determine the association between mononuclear cells and cytokines in the menstrual effluent and a) fecundability and b) miscarriage. Our study is innovative in its use of menstrual effluent as a measure of uterine receptivity. Identifying non-invasive methods to assess endometrial receptivity and the uterine microenvironment could lead to new diagnostics and treatments for infertility and recurrent pregnancy loss.

NIH Research Projects · FY 2026 · 2026-06

ABSTRACT Approximately 5.3 million individuals in the United States used cocaine in the last year and 1.4 million met the diagnostic criteria for Cocaine Use Disorder (CUD). CUD is a devastating disease with significant consequences for affected individuals, their families and society, yet there are currently no FDA-approved treatments. Recently developed methodologies in tissue clearing and cell-specific labelling allow for unbiased interrogation of brain regions that are activated in response to cocaine and other drugs. These imaging techniques can advance our understanding of neural processes that contribute to addiction by identifying functional brain networks that are perturbed in response to repeated drug exposures. Previous studies have successfully used whole-brain c-Fos mapping along with functional connectivity analysis in cleared brains to identify patterns of activity that change in response to cocaine, methamphetamine, opiates and alcohol. These studies only considered a single genetic background, however, which could limit translational significance. Only about one in five people who use cocaine will go on to develop CUD suggesting that individual differences, including genetic factors, contribute to risk. However, little is known about genetic and neural mechanisms that drive the transition from cocaine use to CUD and why some individuals are more at risk than others. Identifying brain networks that are differentially activated in response to cocaine in genetically heterogeneous mice would inform our understanding of how individual genetic differences contribute to drug response and reward. These studies will reveal interactions between drug exposure and genetic background that could uncover unique mechanisms that increase risk for CUD and lead to novel targets for prevention and treatment.

NIH Research Projects · FY 2026 · 2026-05

Rapid, cost-effective, and noninvasive tools to monitor host-pathogen-microbiome interactions during Chlamydia trachomatis (CT) infection are urgently needed to identify correlates of protection and predict risk for reproductive tract damage—critical for advancing vaccine development and clinical care. Chlamydia trachomatis is a globally impactful sexually transmitted bacterial pathogen for which no vaccine is available, and predictive biomarkers for adverse outcomes are lacking. Prior research and our recent study indicate that chlamydia-microbiome and microbiome-host interactions can influence establishment of infection and spread to the upper genital tract. We previously demonstrated that total RNAseq can transcriptionally profile host, pathogen and cervicovaginal microbiome activity during human genital tract infection. However, this method requires high-abundance, only moderately degraded RNA and is cost-prohibitive for large-scale use. To overcome these limitations, we developed a simple and cost-efficient, probe-based transcriptional profiling method, inspired by advancements in single-cell RNA sequencing technologies, and demonstrated its feasibility using cervical specimens from experimentally infected mice. The goals of this proposal are to: i) evaluate probe-based transcriptional profiling as an effective and cost-effective alternative to total RNAseq for characterizing human clinical cervical specimens; ii) determine if this technique can simultaneously and sensitively profile chlamydial gene expression during natural infection while iii) monitoring cervicovaginal microbiome composition. We will complete the following specific aims: (1) Compare performance of probe-based RNA sequencing with total RNAseq for cervical brush specimens collected from women at high risk for C. trachomatis infection. Using previously collected, cervical brush specimens currently undergoing total RNAseq in an R01 funded study, we will perform parallel, probe-based profiling and compare outcomes for sensitivity and robustness, particularly in the face of low RNA quality and/or abundance. (2) Profile pathogen gene expression during natural cervical infection using probes targeting the global chlamydial transcriptome. We will use probes targeting the global chlamydial transcriptome to profile gene expression during natural cervical infection, generating RNA-seq libraries from cervical brush samples with varying chlamydial loads. (3) Determine if incorporation of 16S-targeting probes will support coincident CVM characterization during chlamydial infection. Chlamydial 16S and 23S rRNAs were sensitively and robustly detected in murine genital infection samples so we will extend this approach to determine feasibility for coincidental monitoring of co-pathogen abundance and to profile resident mucosal microbiota without need for separate 16S rRNA gene amplicon library pipelines. This approach integrates emerging RNA profiling technologies into a customizable, scalable pipeline that supports unbiased studies of mucosal immunity, pathogen burden, and microbiome composition, even in low-yield or degraded clinical samples. The successful development of this platform would accelerate determination of molecular correlates of protection or immunopathogenesis in humans after infection and has significant promise for vaccine evaluation not only for chlamydia, but also for other sexually transmitted mucosal pathogens.

NIH Research Projects · FY 2026 · 2026-05

Abstract This revised R21 application responds to PAR-23-056 / Co-infections and Cancer. Epstein-Barr Virus (EBV / HHV4) is a “known oncogenic agent” as defined by this PAR and the International Agency for Research on Cancer (IARC). The overall goal of this proposal is to develop a transgenic model and novel cell culture reagents for EBV-driven tumors. EBV-associated tumors include B, T, and NK cell lymphomas as well as epithelial lineage cancers. While reasonable models for EBV B-cell lymphomas exist, no animal model exists for EBV-associated epithelial lineage cancers, such as nasopharyngeal carcinoma (NPC) and gastric cancer (GC). The majority of EBV models are immunodeficient, as the immune response to cancer can only be partially modeled in culture, organoids, or humanized mice. We hypothesize that this new approach will generate new models that address these gaps in our knowledge and that will facilitate bench-to-bedside translation of new treatments. This hope is based on our recent success in developing a transgenic mouse for a related gamma-herpesvirus. This novel approach will allow us to study the role of EBV transcription, EBV microRNAs, and EBV proteins in vivo. In contrast to many EBV lymphoma models, the new transgenic mice will be (a) fully immunocompetent and (b) carry the entire complement of the viral genome, not just a single one. Thus, they will be helpful for therapy evaluation based on small molecules or immune modulation (PD1, PDL-1 inhibitors). This proposal will also derive novel cell lines for the preliminary assessment of small molecules that target evolutionarily conserved virus-host interactions and thereby reduce animal use.

NIH Research Projects · FY 2026 · 2026-05

Myosin-X (Myo10) is a molecular motor crucial for the formation and function of filopodia, finger-like protrusions cells use interact with their surroundings in processes such as brain development, blood vessel formation, and the spread of cancer cells. We have shown that Myo10 localizes to the tips of filopodia, increases the number and length of filopodia, and moves within filopodia in a process known as intrafilopodial motility. Our generation of Myo10 knock-out mice showed that loss of Myo10 causes developmental defects in brain, eye, and blood vessels, but is not essential for survival of adult mice. Myo10 promotes tumor growth and invasion in many cancers, including breast, lung, and melanoma. Myo10 also has important functions in cell division, where it is required for spindle orientation and for clustering the excess centrosomes that are a hallmark of cancer cells. Myo10’s important roles in biology, plus the need to understand the fundamental cell biology of filopodia, make it essential to investigate the molecular mechanisms of Myo10 and filopodial function at the cellular and organismal levels. To fill these knowledge gaps, we will address the following: -How does Myo10 promote filopodia and what are its molecular cargos? -What are the functions of headless Myo10, a form of Myo10 that lacks the motor domain and is expressed in brain and stem cells? -Purify filopodia and use modern proteomics approaches to identify and quantify the full set of their molecular components, including the filopodial cytoskeleton, tip, and plasma membrane. -What are Myo10’s organismal functions in epithelial tissues such as kidney where it localizes basolaterally and in eye where KO results in major developmental defects. Because filopodia are a major cellular organelle whose purification has not been reported, we will combine our recent progress purifying filopodia with quantitative proteomics to identify the molecular components of filopodia. We will also take advantage of the extensive set of tools and techniques we have established to investigate Myo10 and filopodia, including Myo10 floxed and knock-out mice, KO and stable cell lines, and deletion and point mutant constructs. Although the other members of the MyTH4-FERM family of myosins in vertebrates have important roles in human physiology and disease at the tips of other protrusions based on actin bundles like epithelial microvilli and inner ear stereocilia, Myo10 is the MyTH4-FERM myosin present in filopodia and most mammalian cells and tissues. This research will answer fundamental questions about Myo10 and filopodia as well as investigating Myo10 functions at the organismal level in health and disease.

NIH Research Projects · FY 2026 · 2026-05

Project Summary/Abstract The Pathology Services Core (PSC) at the University of North Carolina at Chapel Hill (UNC-CH) is a shared resource for intramural and extramural biomedical researchers, that supports over 350 primary investigators and their labs. The PSC is committed to providing its users with high-quality, reproducible non-clinical and epidemiological histopathology and molecular pathology data. The PSC seeks NIH funding to acquire a 3DHistech Pannoramic 250 Flash III Digital Pathology Scanner (P250 Flash III) to continue this commitment to serving its users and to bring cutting-edge technology to UNC-CH. The rise in use of artificial intelligence technology to obtain quantitative data from microscopic images in a spatially relevant fashion for use in translational biomedical research has driven an explosion in the need for fast, high-resolution bright field (BF) and fluorescent (FL) slide scanning capabilities. Over the past four years, the PSC has processed over 51,000 digital slide scans. Some of these scans are for archiving or collaborating on images, but most are for downstream processing for advanced quantitative applications such as image analysis. Most of the IF microscopic slide scanning in the PSC is performed by a 15-year-old Aperio ScanScope FL. The manufacturer has discontinued support for this scanner as it is past its typical functioning lifespan, leaving the instrument inoperable and unfixable when it fails. Loss of the ScanScope FL means the PSC’s FL scanning capabilities would be decimated. After a comprehensive review of available cutting-edge digital scanning systems, the P250 Flash III was the optimal choice for our core facility because of its unmatched combination of high-speed throughput, automated slide handling (up to 300 slides), and superior fluorescence imaging resolution (up to 60x). We are requesting $395,744.46 in Federal Funds. We will supplement this with $50,000 from internal sources to cover multiple years of a service contract, which ensures the instrument remains fully operational to reliably meet the needs of UNC-CH researchers. Placement of the P250 Flash III within the PSC ensures immediate impact and optimal usage, as PSC provides comprehensive histology and digital pathology services from sample processing to advanced data analysis. This acquisition is supported by highly experienced technical staff and robust IT infrastructure. The new scanner will substantially enhance UNC’s research capabilities, ultimately contributing to significant advancements in Public Health.

NIH Research Projects · FY 2026 · 2026-05

Abstract Hepatocellular carcinoma (HCC) is the most common type of liver cancer and is projected to be the third leading cause of cancer-related death by 2035. HCC surveillance, defined as screening high risk individuals with abdominal ultrasound every 6 months, is associated with earlier detection, increased curative treatment receipt, and improved overall survival. National data demonstrate that only 25% of patients with cirrhosis receive adequate HCC surveillance and little progress to increase uptake has been made over the past decade. While the current clinical practice paradigm for HCC surveillance focuses on high risk patients with cirrhosis, the rapid increase in the prevalence of metabolic dysfunction associated steatotic liver disease (MASLD) will lead to a larger population at risk for HCC for whom the net benefits of further risk stratification and HCC surveillance are unknown. Given changes in chronic liver disease etiology and HCC epidemiology, emerging novel risk-stratification and surveillance tools, and the initiation of the first multisite trial of HCC surveillance in the United States, there is a need for research to better understand HCC surveillance practices to determine optimal care among patients at risk for HCC development. The long-term goal is to improve healthcare delivery and outcomes for patients at risk for HCC by creating a population-based surveillance registry that will facilitate the implementation of targeted interventions to improve risk-stratification and appropriate healthcare delivery of HCC surveillance. The objective of this application is to establish the feasibility of developing a population-based HCC surveillance registry and assessing our ability to identify at risk patients with MASLD. These objectives will be accomplished through the following specific aims: 1) Develop and implement the tools required to establish a population-based HCC surveillance registry; and 2) Determine the prevalence of MASLD and the performance of ICD codes, lab results, and radiology imaging reports to identify MASLD. The study is conceptually innovative as it is centered on the paradigm shift driven by changes in liver disease etiology that will significantly impact the risk of developing HCC and thus the benefits and harms of HCC surveillance. The proposed research is significant because it will lay the foundation for future research to identify gaps in HCC surveillance and opportunities for improvement. Novel frameworks and approaches are needed to evaluate the impact of the rapid changes in the epidemiology of liver disease etiologies on HCC risk, surveillance, and outcomes.

NIH Research Projects · FY 2026 · 2026-05

Project Summary/Abstract The University of North Carolina at Chapel (UNC-CH) is requesting a Miltenyi UltraMicroscope Blaze with Lightspeed mode (Blaze). This is a light-sheet microscope that can take images of large, cleared tissue samples, with cellular resolution. It is ideal for imaging whole mouse organs, mouse tumors and human biopsies with high quality at high speed. This instrument will catalyze the research programs of twenty-four laboratories with funding from the National Institutes of Health, engaged in research in neuroscience, immunology, cancer biology and therapeutics, lung disease, kidney development, and vascular biology. Many of these projects cannot move forward without this new microscope. The Blaze light-sheet microscope will replace an obsolete system, a LaVision UltraMicroscope II (UM-II), that has significant limitations in terms of speed and optical quality, and which will no longer be eligible for a service contract from December of 2025. In detailed comparisons we measured the speed of the Blaze to be at least an order of magnitude faster than the UM-II in many relevant workflows, with equivalent or improved imaging quality. This makes feasible experiments that are currently out of reach because of prohibitively long imaging times. We are requesting a configuration of the system with the Lightspeed mode upgrade, that allows these fast imaging speeds, a full complement of lenses, and a custom configuration with five lasers (488, 561, 640, 685, 785 nm) that are well suited for imaging multiple fluorophores compatible with large, cleared tissue samples. The University is requesting $426,104.25 in Federal Funds, which it will supplement with $35,000 from internal sources to add software that will accelerate workflows. This microscope will be placed in the Microscopy Services Laboratory, a recharge core facility with a 30+ year history supporting the microscopy needs of the UNC-CH community. This core is strongly supported by the University, has deep expertise in the type of instrument being requested, and a strong track record training and assisting researchers. Many members of our User Group have experience with this form of microscopy, in the form of currently trained personnel and/or publications using our current microscope. The strong foundation of expertise in the core and User Group with this technology, as well as our experience during an extended demo with the Blaze give us great confidence that the new system will have a fast and very positive impact on many research projects. Ultimately, we expect this instrument will lead to important discoveries in multiple areas relevant to human health, and possibly to the development of new treatments.

NIH Research Projects · FY 2026 · 2026-05

Abstract The UNC Readiness And Preparation for Informatics and Data Science Careers, or RAPID program, is a 15- week program designed to inspire undergraduates to integrate data science tools into translational science that is rigorous and promotes health outcome optimization across populations. The program components include: 1) didactic training in data science and differential health outcomes in populations 2) mentorship to complete a research practicum, 3) interactions with established investigators who are applying data science tools across the spectrum of translational science and 4) development of a mentoring network comprised of peers, near-peers, staff and faculty. The program is delivered in a hybrid fashion with 2 weeks of preparatory work done by the participant before they arrive at UNC, followed by a 10-week residential summer intensive program. During the 10 weeks, participants are guided through each phase of a data science project from idea formulation to dissemination and are taught choices they can make to incorporate principles of population conscious analysis and rigor into each phase. Participants have the option of 3-weeks of support after they leave UNC to complete and present the research project. Eligible participants are rising sophomore and junior STEM majors. Innovative aspects of the program include use of a conceptual model that gives participants agency to choose their research topic, the application of data science skills in project-based learning, and interactions with community advisory boards to further reinforce communication skills and health outcome optimization across populations.

NIH Research Projects · FY 2026 · 2026-05

Giardia lamblia (Giardia) causes >300 million infections annually worldwide. In multi-site field studies Giardia consistently associates with impaired child growth and has also been associated with other cognitive developmental impairments in early childhood. The exact mechanisms, and specifically, which virulence factors are responsible for Giardia-induced growth faltering have been elusive. We hypothesize that secreted proteins, (e.g. proteases) made by intestinal dwelling trophozoites are key factors driving intestinal barrier injury and subsequent growth impairment during childhood giardiasis. Furthermore, we have found that antibodies directed towards these proteins occur in experimental Giardia infection and in humans from endemic settings. Although these antibodies are not known to prevent infection or facilitate clearance, we hypothesize that host antibody responses directed towards select proteins in the Giardia secretome can nonetheless support disease tolerance—children may be protected from growth impairment if these antibodies are present or recover catch-up growth if these antibodies are generated. We propose 3 Aims to rigorously examine Giardia proteases and antibody responses to proteases as potential therapeutic targets. First, we will use in vitro models of parasite-host interactions using both conventional intestinal epithelial cell monolayers as well as primary murine-derived intestinal epithelial cells. Studies will examine the roles of highly purified recombinant proteases alone and/or in combination with other secreted proteins or other parasite factors. We will test in these assays whether anti-secretome antibodies abrogate these effects. In our second aim, we will test the immunogenicity of secretome proteins and whether immunization prior to Giardia infection protects against growth impairment using gnotobiotic and conventional murine models that mimic childhood undernutrition. We will also use immunodeficient mice to determine if antibody-based therapy is sufficient to protect against severe weight loss. Finally, we have generated an initial multi-antigen panel including multiple Giardia proteins that we will expand upon and test in a child cohort at high risk of Giardia infections and Giardia sequelae. Serial banked sera from children will be used to examine the breadth, magnitude, and durability of serological repertoires to these antigens and we will model whether specific antibodies associate with measures of barrier function and growth outcomes in these children. Knowledge of the role of specific proteins in the Giardia secretome will advance understanding of basic pathogenesis with targets that are druggable. Completion of these aims will define virulence factors present in the Giardia secretome and provide a strong foundation for development of an anti-pathology vaccine or antibody-directed therapies to reduce the insidious impact of giardiasis on child development in LMICs.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY Targeted HIV latency reversal remains a significant obstacle to HIV cure strategies. Most strategies rely on activation or inhibition of host proteins due to the lack of expressed viral proteins. However, studies suggest single LRAs cannot overcome the heterogeneity of the viral reservoir and the multiple mechanisms which aid to maintain latency, driving the field towards combination LRAs which risk increased off-target effects. Bifunctional molecules, which bridge two molecular complexes not expected to interact, represent a rapidly expanding field and a new potential avenue for development of novel latency reversal agents. Towards this aim, we have sought to identify potential warheads for targeted HIV latency reversal. Latent HIV infection produces no detectable viral proteins and fully elongated HIV mRNA is rare. However, small abortive transcripts containing the viral RNA TAR, which is recognized by the arginine-rich domain of the viral protein Tat, are observed in cells from durably suppressed individuals. Peptides which mimic the arginine-rich domain of Tat and bind TAR with low nanomolar affinities have been reported, representing viable ligands for TAR as one half of a bifunctional molecule. A critical role of Tat is the hijacking of P-TEFb, a host complex necessary for processive transcriptional elongation and full viral replication. Current LRAs can modulate P-TEFb levels, but in the absence of Tat during latency there are no current strategies which mediate direct recruitment of P-TEFb to the HIV promoter. As such, a targeted therapeutic that directly recruits P-TEFb to the HIV LTR is an attractive strategy. We have recently observed that in contrast to the long-standing dogma, the bromodomain inhibitor family of LRAs does not release competition between Tat and BRD4 for P-TEFb. Rather, bromodomain inhibitors increase free, active BRD4/P-TEFb. This in turn triggers an altered transcriptional response which positively impacts viral activation in the absence of Tat. This transcriptional response is independent of the bromodomains. This is key to the development of bifunctional molecules, as the molecule must recruit relevant complexes but not interfere with necessary activity. Targeted recruitment of BRD4 to epigenetically silenced host gene promoters has previously been shown to activate transcription. These approaches used bromodomain inhibitors as warheads and have shown selective BRD4 binding and increased phosphorylated RNAPolII. We hypothesize that targeted recruitment of the endogenous BRD4/P-TEFb complex to the HIV LTR using TAR-binding peptides linked to a bromodomain inhibitor will result in selective viral activation. Towards this aim, we have generated a proof-of-concept molecule, Tat14-JQ1, a 14 amino acid peptide containing the RNA-binding domain of Tat conjugated to the bromodomain inhibitor JQ1. We demonstrate this molecule can induce HIV in cell models. Here we seek to define the mechanism and selectivity for a first-in-class targeted latency reversal agent, Tat14-JQ1, designed to recruit an endogenous transcriptionally activating complex directly to the HIV LTR for HIV cure strategies.

NIH Research Projects · FY 2026 · 2026-05

Project Summary Alcohol use disorder (AUD) is a pressing public health issue and treatments are much needed. Glucagon-like peptide-1 receptor agonist (GLP-1RA) compounds (e.g., Ozempic, Wegovy, Mounjaro) have been receiving tremendous media attention for their dramatic weight loss effects. With this popularity have come media and anecdotal reports from clinicians and individuals using these medications of decreased alcohol use and changes in sensitivity to the subjective effects of alcohol. The rapid market expansion of GLP-1RA compounds and their derivatives presents an opportunity to identify which may be most efficacious for clinical trials in individuals with AUD. Therefore, in this application we developed a preclinical screening pipeline focused on two key aspects of alcohol drinking with translational importance – alcohol subjective/interoceptive effects and alcohol reinforcement in the context of an alternate reward choice. We will evaluate the long-acting and FDA approved compounds semaglutide (GLP-1RA; which is currently in clinical trials for AUD) and dual GLP-1RA and glucose-dependent insulinotropic polypeptide (GIP) agonist tirzepatide, and the triple (GIP, GLP-1R and glucagon) agonist retatrutide. Additionally, the mechanisms by which GLP-1RAs reduce drinking remain poorly understood, with the salience network and activity in its key hubs emerging as promising targets for investigation. In this application, we will evaluate the effects of GLP-1RAs on alcohol interoceptive effects (Aim 1) and drinking behavior in the context of an alcohol vs. sucrose concurrent choice self-administration procedure (Aim 2). Finally, we will use functional MRI to assess the effects of the most efficacious GLP-1RA on salience network activity with and without alcohol, and fiber photometry to measure neural activity in salience network circuitry during the alcohol vs. sucrose choice self-administration procedure (Aim 3). Overall, we hypothesize that GLP-1RA compounds will reduce the interoceptive effects of alcohol and will shift drinking away from an alcohol reinforcer, and that these behavioral outcomes are related to blunted activity of the salience network and salience network circuitry. These reverse translational studies will provide important information regarding the effects of GLP-1RAs on key themes emerging from patient reports (alcohol subjective/interoceptive effects and alcohol reinforcement) which is a highly innovative strategy to help inform future clinical studies.

NIH Research Projects · FY 2026 · 2026-05

Project Summary/Abstract Rapid adaptation has been implicated in a wide range of biological processes relating to human health, ranging from antibiotic resistance in bacteria to insecticide resistance in mosquitoes. However, accurately detecting the genomic signatures of rapid adaptation remains a challenging task in evolutionary biology that has been historically limited by a lack of genomic data and sufficiently accurate methods for analyzing such data. Machine learning tools offer great promise for population genetics due to their unrivaled capacity for detecting high-dimensional signatures of natural selection and their ability to account for demographic histories which may produce signatures that mimic that of selection. Nonetheless, even modern machine learning tools suffer from two significant limitations: 1) their capacity to distinguish between hard and soft sweeps which is vital for understanding the pace that an organism can adapt and 2) they can experience drops in accuracy in the presence of severe model mis-specification (e.g., when the true demographic history of a population is unknown or incorrectly inferred). Indeed, there is no method capable of accounting for both limitations simultaneously. The proposed research will first develop a method capable of detecting and distinguishing between multiple modes of selection while explicitly accounting for model mis-specification, and then apply this method to populations of the yellow fever mosquito to explicate the genomic underpinnings of rapid adaptation to insecticides (Aim 1). Next, long-read sequencing data will be used to explore the role of structural variation (genomic variation >50bp) in rapid adaptation (Aim 2). The final aim will develop the first machine learning tool to detect an understudied form of rapid adaptation, namely adaptive tracking, where fluctuating selective pressures result in repeatable adaptive shifts in allele frequencies over seasonal and sub-seasonal timescales. A multi-year field-based experiment will then be conducted where the southern house mosquito will be exposed to both oscillating environmental and insecticide-based directional selection. The novel machine learning tool will then be applied to this dataset to characterize the targets of fluctuating selection in a major disease vector and assess whether the presence of strong direction selection alters the degree, tempo, and targets of adaptive tracking (Aim 3). Dr. Ketchum has assembled a team of expert mentors who will help broaden her knowledge in machine learning, insect genomics, and mosquito rearing protocols. Dr. Ketchum’s primary mentor, Dr. Dan Schrider has pioneered some of the first applications of machine learning tools to population genetic datasets and so is perfectly suited to help Dr. Ketchum achieve her research goals. The K99 phase of the award will take place within the Department of Genetics at UNC Chapel Hill which is an intellectually stimulating environment with ample opportunities to participate in journal clubs and seminar series and collaborate with other research groups. This training will help Dr. Ketchum successfully complete her proposed research and aid her transition to principal investigator of an internationally recognized lab that studies the genomic architecture of adaptation.

NIH Research Projects · FY 2026 · 2026-05

PROJECT ABSTRACT. Human adolescent binge drinking is associated with lasting deleterious effects on the brain, including induction of proinflammatory HMGB1 signaling, degeneration of basal forebrain cholinergic neurons (BFCNs), and impaired adult cognitive flexibility, increasing risk for later AUD development and alcohol- related dementia. BFCNs, which are crucial for cognition due to their vast projections to various brain regions (e.g., hippocampus), mature during adolescence paralleling development of executive function. Adolescent intermittent ethanol (AIE), a preclinical model of human adolescent binge drinking, recapitulates induction of proinflammatory HMGB1 signaling, reductions of BFCNs (e.g., ChAT+, TrkA+), and lasting adult cognitive deficits in adulthood. We discovered AIE-induced BFCN marker loss is reversible in adulthood through a mechanism involving increased occupancy of the epigenetic repressive marker H3K9me2 at cholinergic gene promoters. However, the mechanism underlying, and the consequences of, prolonged AIE-induced epigenetic suppression of the BFCN phenotype are unknown. Our preliminary data reveal AIE and neuroinflammation increase the H3K9 methyltransferase Ehmt2 in the adult basal forebrain, and ChAT+ BFCN loss is reversible by Ehmt2 inhibition suggesting cholinergic genes regulated by Ehmt2 could be novel targets to reverse persistent neuropathology caused by adolescent binge drinking. BFCNs are dependent on hippocampal retrograde NGF transport for maintenance of the cholinergic phenotype, which is disrupted by AIE and proinflammatory signaling. The direct contributions of basal forebrain HMGB1 signaling and reduced hippocampal NGF to reversible epigenetic suppression of the BFCN phenotype is unknown. We propose to test the overarching hypothesis that AIE induction of proinflammatory HMGB1 signaling causes reversible Ehmt2-mediated epigenetic suppression of the BFCN phenotype resulting in long-lasting adult cognitive deficits. Employing pharmacological, transgenic, and viral vector approaches, studies in Aim 1 will investigate male and female basal forebrain HMGB1 proinflammatory signaling involvement in Ehmt2-mediated epigenetic suppression of the BFCN phenotype and resulting behavioral flexibility deficits in adulthood. Employing pharmacological and NGF sequestration approaches, studies in Aim 2 will investigate contributions of AIE-induced HMGB1 proinflammatory signaling to reductions of male and female hippocampal NGF and consequent epigenetic suppression of the BFCN phenotype in adulthood. Employing pharmacological, transgenic, multiomic, and electrophysiological approaches, studies in Aim 3 will investigate the transcriptomic and chromatin accessibility changes in epigenetically suppressed BFCNs following AIE and determine HMGB1 involvement in AIE-induced alterations in physiological functioning of epigenetically suppressed BFCNs. The proposed studies on HMGB1-epigenetic regulation of BFCN phenotype and adult behavioral flexibility deficits explores novel neuroplastic mechanisms with broad therapeutic implications.

NIH Research Projects · FY 2026 · 2026-05

Project Summary G-protein-coupled receptors (GPCRs), the largest superfamily of human membrane proteins, are primary targets of about 1/3 of currently marketed drugs. GPCRs can couple with specific subtypes of heterotrimeric G proteins and β-arrestins, followed by dissociation of the intracellular proteins to regulate various downstream signaling pathways in the cell. GPCR–G protein/arrestin interactions can be modulated by ligands that bind allosteric sites with divergent sequences and conformations. Allosteric modulators provide advantages over traditional agonists that often cause off-target side effects due to binding to conserved “orthosteric” sites. Furthermore, biased agonists shift conformational ensemble of GPCRs to preferentially bind certain G proteins or β-arrestins and selectively activate a subset of the downstream signaling pathways. The allosteric modulators and biased agonists have thus emerged as promising candidates of selective GPCR drugs. Recent fluorescence experiments showed that the lifetime of GPCR-G protein complexes determine the efficiency and selectivity of G protein coupling to GPCRs. However, these experiments are expensive, time-consuming, and limited to a small number of GPCR-G protein systems. On the other hand, computational modeling, in particular Molecular Dynamics (MD), is a promising approach to explore protein interactions with GPCRs. We hypothesize that quantitative characterization of the lifetime and dissociation kinetics of GPCR–G protein/arrestin complexes will facilitate drug design of GPCRs. However, it is extremely challenging to predict protein dissociation kinetics using existing MD simulation methods, due to the large system size and gap between simulation and biological timescales. Based on successes of the Protein-Protein Interaction–Gaussian accelerated MD (PPI-GaMD) and related simulation methods the PI’s lab has developed with prior NIGMS R01 support, we will address the following challenges: (1) Develop a new Selective Deep Boosted MD (SDBMD) method that integrates powerful enhanced sampling and Deep Learning to predict the dissociation kinetics and lifetime of protein complexes more efficiently and accurately. (2) Benchmark new simulation methods on model GPCR-G protein complexes with published experimental kinetics data. (3) Predict changes in the dissociation kinetics and lifetime of adenosine and muscarinic GPCR-G protein complexes upon binding of GPCR allosteric modulators and biased agonists, and validate simulation predictions with fluorescence and cellular functional assays through collaborations with world-leading experimentalists. We will develop an innovative computational tool for predicting protein dissociation kinetics and obtain a quantitative picture of the dissociation kinetics and lifetime of GPCR-G protein/arrestin complexes. The research will greatly facilitate computer-aided design of selective GPCR drugs. Our long-term goals are (1) to develop robust computational methodologies to quantitatively characterize biomolecular recognition in disease-associated cellular signaling pathways and (2) to design effective drug molecules targeting important GPCRs.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY Cellular immunotherapies are treatments in which a patient’s own immune cells are reprogramed to recognize and destroy tumor cells. These approaches utilize ex vivo engineering and expansion via synthetic receptors to target immune specificity toward tumor antigens, followed by reinfusion into the patient. This approach has been demonstrated as a potentially curative treatment for certain classes of hematopoietic malignancies and is being further developed to target other diseases including solid tumors. In these treatments, synthetic receptors drive the formation of an immune synapse, a specialized structure through which the immune cell secretes cytotoxic granules to destroy the tumor. Thus, developing and evaluating effective treatments depends on understanding how synthetic receptors organize within and regulate synapse formation. However, current flow cytometry-based and in vitro cytotoxicity assays, which are essential components of cellular immunotherapy research and development, do not provide a detailed view of synapse formation or structure. Although this can be accomplished by high-resolution microscopy, current implementations are limited in spatial resolution, in the number of molecules they can detect simultaneously, and in the throughput at which they can acquire data. To overcome these limitations, we will develop new fluorescent probes to simultaneously visualize many proteins at once in immune cells, tumor cells, and at the immune synapse with resolutions ranging from one micron to tens of nanometers (Aim 1). In parallel, we will utilize computer vision and machine learning to develop “self- driving” microscopes that can automatically capture population-level statistics about immune and tumor cells together with high-resolution information about the structure and organization of immune synapses (Aim 2). Together, we believe that these technologies will allow researchers to profile the expression levels, subcellular distributions, and nanoscale organization of dozens of cellular proteins in single cells and at immune synapses. Automation through computer vision will dramatically increase data throughput compared to a human operator, leading to more significant sample sizes and greater reliability. Overall, we envision that these new capabilities will improve our ability to understand, intelligently design, and functionally evaluate a wide range of cell-based cancer therapies.

NIH Research Projects · FY 2026 · 2026-05

Modified Project Summary/Abstract Section Lassa virus (LASV) is a persistent global public health threat that infects 2.7M and kills more than 5,000 individuals each year, principally in Nigeria, Liberia, and Sierra Leone. Annual outbreaks of Lassa fever (LF) contribute to more infections and deaths than all outbreaks of filoviruses, including Ebola virus, combined and is the most common cause of imported viral hemorrhagic fever to non-endemic countries. The permanence of LASV in the rodent reservoir in West Africa, coupled an expansion of their range and numbers have led to a steady increase in LF in this region. Despite the burden of LASV infection in West Africa there remain substantial gaps in our understanding of fundamental aspects of this emerging infection including host humoral and cellular immune responses to LASV, their potential protective and pathologic roles in LASV-related disease, and longterm complications of LF. The overarching objective of the proposed studies is to rigorously characterize the longitudinal humoral and cellular response to LASV across the spectrum of illness severity, identify the longerterm consequences of both LASV infection and LF, and evaluate the role of sustained immune activation as a pathogenic mechanism underlying LF and LASV infection sequelae. Specifically: Aim I: Characterize and compare the humoral and cellular immune responses following subclinical LASV infection and LF. AIM 2: Describe the prevalence, characteristics, and natural history of long-term clinical complications of LASV infection and LF and explore their association with host, viral and immune response factors. The findings of these investigations will have direct and practical value for the design of trials of LASV vaccine candidates and potentially identify strategies to prevent and treat longer-term sequelae of LASV infection. We will conduct this work in the context of close and strong working relationships with healthcare and community leaders in a hyperendemic region for Lassa fever and well-developed infrastructure for clinical research that we have established in Liberia where we have recruited, enrolled, and longitudinally followed and sampled more than 5000 participants including 79 patients with acute LF, 68 with subclinical LASV infection and 61 survivors of severe LF as well as hundreds of uninfected seronegative controls. The proposed work will provide a muchneeded longitudinal characterization of the humoral and cellular immune responses, evaluation of the long-term complications of subclinical LASV infection/severe LF and investigation of sustained immune activation as a mechanism underlying the long-term complications of surviving subclinical LASV infection/severe LF. With yearly outbreaks, this study will ensure that the world is better prepared through an improved understanding of the durability of the humoral and cellular immune responses to infection and of the clinical complications of LASV infection across the spectrum of disease severity.

NIH Research Projects · FY 2026 · 2026-04

Summary Funding is requested for the registration fees and travel costs of invited speakers and discussion leaders as well as registration fee support for graduate students, postdocs, and early/mid- career scientists with an emphasis on first-time attendees at the 2026 12th Symposium on Hemostasis at the University of North Carolina (UNC) at Chapel Hill. The theme of the 2026 Symposium is novel perspectives on classically understood pathways. The program is designed to bring together experts to present their most recent cutting- edge findings centered on defining novel mechanisms and innovative therapeutic advances in hemostasis and thrombosis. Recent studies suggest that coagulation proteins and platelets are tied to numerous pathological processes through mechanisms both dependent and independent of their traditional roles in hemostasis and thrombosis. Our invited speakers will present their latest and emerging work across a spectrum of basic science and clinical topics where coagulation proteins and platelets play a functional role, including cancer, infection and immunity, acute injury, and pregnancy. Priority will be placed on highlighting both the role these proteins play as disease modifiers, as well as the utility of employing or targeting these factors for diagnosis and therapy. A major goal for the 12th Symposium on Hemostasis is highlighting the translation of basic research findings into the clinical practice. Over 80% of our invited speakers will be presenting at this conference for the first time, and 30% represent early career faculty. In addition to invited speakers and discussion leaders, attendees will be selected by invitation and from submitted applications. They will be chosen to represent a broad, interdisciplinary spectrum of research topics. Additional efforts will be committed to recruiting first-time attendees as speakers in the ‘Hot Topics’ session and as poster presenters. An intended strength of this meeting will be the interaction and networking of young scientists in the field with the discussion leaders and the speakers. Collectively, the specific aims for the 12th Symposium on Hemostasis are to: (i) provide an environment that facilitates lively and open discussions between early career, mid-career, and established scientists that fuels the process of scientific discovery in the hemostasis and thrombosis community; (ii) provide a platform of support for the careers of junior scientists, including predoctoral and postdoctoral trainees, to ensure growth of the field; (iii) promote collaborative and interdisciplinary scientific research that opens channels of long-term interaction and networking; and (iv) provide a mechanism for clinicians to earn continuing medical education credits in the areas of hemostasis, thrombosis, and hematology. Through these specific aims the 12th Symposium on Hemostasis will reveal the next chapter of discovery and innovation for hemostasis and thrombosis research while helping to establish and build on the collaborative relationships necessary to push the field forward.

NIH Research Projects · FY 2026 · 2026-04

Background: Lutzomyia sandflies are the primary vectors of Leishmania in the neotropics. Leishmania infection manifests as multiple diseases, some of which are lethal. During the past 20 years, the distribution of Leishmania-carrying sandflies has spread, with significant increases in the number of reported cases of leishmaniasis disease (1–6). Given the contemporary geographic range of Lutzomyia sandflies, over 350 million people are at risk of leishmaniasis. Nearly 1.5 million cases are reported annually (1, 3, 5, 7, 8), in what is likely an underestimate of infection burden (7, 9–14). Understanding the processes that lead to genetic and phenotypic variation in sandflies influences the ability to monitor and predict vector spread and control. Aims and Approach: In this proposal, we leverage our expertise to advance sandfly management using integrative analyses of insecticide resistance (IR). We have the necessary permits and facilities to collect and work with sandflies, enabling us to rapidly initiate and efficiently complete the proposed work. Aim 1 will generate pangenome graphs with highly contiguous reference genomes for five vector species. This will enable the detection of loci under selection across sandfly species and establish a sandfly community genomic resource. Aim 2 will build on our preliminary data and expertise ecological and evolutionary genetics to sample natural variation and map alleles associated with pyrethroid resistance – one of the main strategies for controlling sandflies – in Lutzomyia evansi. This work will provide insights into the genetic basis of IR in a genetically understudied disease vector. Long-term goal: Our research program focuses on evolutionary and population genetics in insects. We are now applying our expertise to systems relevant to human health. This proposal launches an integrative research program combining population genomics, lab experimentation, and field sampling to generate genomic resources and foundational knowledge for Lutzomyia sandfly vectors. The outcomes—quantifying IR and identifying its genetic basis—will improve understanding of Lutzomyia adaptation to control strategies. Our preliminary data, necessary permits, and expertise in sampling and analyzing natural variation enable us to efficiently complete the proposed work on time. Health-relatedness: Leishmania disease burden is substantial, with estimates that over 12 million individuals are currently infected (8, 15). This disease burden is projected to grow as global trade, and travel facilitate range expansion of vectoral Lutzomyia species. Identifying genomic regions under selection – and specifically those involved in IR – using innovative approaches contributes significantly toward understanding and ultimately projecting leishmaniasis risk in contemporary and in novel geographical areas as sandfly vector populations continue their expansion toward the US.