Univ Of North Carolina Chapel Hill

NIH Research Projects · FY 2026 · 2023-06

Abstract: Rising antibiotic resistance in N. gonorrhoeae poses a serious, global public health threat. Effective control of N. gonorrhoeae is hampered by asymptomatic infections that allow transmission of the bacteria to uninfected individuals and immune evasion by the bacteria that has limited vaccine development efforts. Understanding the natural history of asymptomatic infection and the immunologic responses that are responsible for clearance of infection. We propose a longitudinal study with close surveillance and of follow up individuals with recent N. gonorrhoeae infection who are at high risk for re-infection. This study will provide a rich data set to understand pathogen exposure and infection outcome. It will also provide a set of biologic specimens to study the pathogen and host factors that contribute to infection clearance as well as asymptomatic carriage and/or progression to symptomatic infection. We will conduct analysis of anti-N. gonorrhoeae antibody and cellular immune responses to inform correlates of protective immunity against gonorrhea. Combined this project will provide important new information that will contribute to public health and vaccine development efforts to reduce the spread of N. gonorrhoeae.

NIH Research Projects · FY 2025 · 2023-06

PROJECT SUMMARY/ABSTRACT Breast cancer is the most common cancer and the second most common cause of cancer death in women. Most breast cancers are estrogen receptor (ER) positive. The primary cause of treatment failure and death in patients with ER+ breast cancer is resistance to endocrine therapy (ET). Novel therapeutics are needed to improve outcomes for patients with resistant tumors. Several findings demonstrate that the RET receptor tyrosine kinase alters sensitivity to ET. RET expression in ER+ breast cancer is associated with worse outcome and recurrent tumors that are resistant to ET express RET at higher levels than primary tumors. Preliminary data show that RET is overexpressed over time in breast cancer cells treated with ET and that inhibiting RET reduces ERK/MAPK activity and sensitizes ER+ cell lines and xenografts to ET. We have established and validated ER+ breast cancer organoids which we will use to dissect precise mechanisms of increased RET expression, how RET impacts sensitivity to ET, and how RET directs kinase signaling with ET treatment. We hypothesize that high expression of RET in ET resistant ER+ breast cancers drives tamoxifen resistance and is a therapeutic target to overcome resistance. To test this hypothesis, in Aim1 we will define reprogramming of regulatory elements at the RET promoter over time with tamoxifen leading to increased expression of RET. In Aim2, we will determine the efficacy of targeting RET to enhance response to ET in cell lines, organoids, and patient derived xenografts. Finally, in Aim3 we will determine how RET alters kinase signaling adaptation in response to tamoxifen using a functional inhibitor bead capture assay coupled with mass spectroscopy. Cumulatively, these studies will form a scientific basis to develop clinical strategies and select patients for RET inhibitor therapy. In addition to advancing scientific knowledge, this proposal provides training to a physician-scientist. Dr Spanheimer is a practicing surgical oncologist specializing in breast cancer with a background in molecular biology. His long-term goal is to combine his research and clinical expertise to develop an independently funded research program focused on therapeutic vulnerabilities of altered gene regulation in response to therapy. He benefits from established mentors with a strong track record of training independent scientists and an extremely supportive research environment. This proposal includes a structured career development plan and training in: 1) molecular biology of transcriptional regulation, 2) targeted therapeutics and translationally relevant breast cancer models, and 3) functional proteomics. Training will also include development of expertise in increasingly complex hypothesis driven experimental design, execution, and analysis. The proposal includes mentored experiential learning, course work and conference participation, frequent mentor meetings and a graded increase in research independence. Cumulatively, this will ensure at the end of the award period the candidate is ready to lead an independent translational research program.

NIH Research Projects · FY 2025 · 2023-06

PROJECT SUMMARY Plasmodium falciparum strains with resistance to first-line artemisinin-combination therapies (ACTs) threaten malaria control and elimination efforts across Africa, where 95% of the world's malaria cases and deaths occur. Artemisinin resistance is mediated by mutations in the pfkelch13 (K13) gene that have only recently impacted the region. Concerning K13 mutations have now been confirmed in Africa, including emergence and expansion of the candidate artemisinin-resistance K13 R622I mutation in the Horn of Africa (HoA). Increasing reports from the HoA by us and others also indicate that “diagnosis resistant” strains that escape detection by widely used rapid diagnostic tests due to deletions of the histidine-rich protein 2/3 (pfhrp2/3) genes are now established across the region. The dual emergence of drug and diagnostic resistance mutations threatens frontline test- and-treat strategies and may have profound impacts on malaria control. Improved understanding of the determinants of infection by R622I parasites is needed to inform clinical practice and policy decisions. In collaboration with the Ethiopian Public Health Institute, the technical arm of the Ethiopia Federal Ministry of Health, and leading academic partners, we will conduct surveys of people presenting to health facilities with falciparum malaria across Ethiopia and achieve the following Aims. In Aim 1, we will elucidate risk factors for infection by artemisinin-resistant P. falciparum, including whether the presence or absence of pfhrp2/3 deletions impacts risk. We will develop a clinical risk tool to help predict who may be infected by an artemisinin- resistant parasite. Such a tool could be used for targeted implementation of antimalarial treatment options designed to overcome resistance and prevent its spread, such as triple ACT that employs two partner drugs alongside an artemisinin derivative. In Aim 2, we will determine the impact of K13 R622I on drug resistance and parasite fitness in pfhrp2/3-deleted and intact parasites. In Aim 3, we will develop a predictive model of the future spread of artemisinin resistance within and out of the HoA, focusing first on development of data/models of human and parasite migration and then integrating in vivo data from Aim 1 and in vitro data from Aim 2. Together, these Aims will improve our understanding of the epidemiology and drivers of emerging artemisinin resistance in the HoA and produce tools that can be used by malaria programs to identify, predict, and respond to emerging drug-resistant strains in Africa.

NIH Research Projects · FY 2026 · 2023-06

PROJECT SUMMARY Aortic Aneurysm (AA) represents a major cause of morbidity and mortality in the United States and continues to be a difficult management problem for cardiovascular surgeons. This disease weakens the vessel wall and leads to dilation that can progress to rupture in the absence of symptoms. At present, the diagnosis of aneurysm disease is highly dependent on costly, advanced imaging techniques such as computed tomography (CT) and magnetic resonance imaging (MRI). There are no point-of-care plasma biomarker assays currently available that either screen for AAs or follow disease progression to inform optimal timing for surgical intervention. To develop novel assays capable of diagnosing, locating, tracking, and assessing diameter (or risk) of AAs: We have assembled an extensive clinical plasma biorepository and selected instruments that are quantitative, scalable, reproducible, and able to be automated. Using this repository, as well as newly collected blood samples, we will test the hypothesis that quantification of aneurysm biomarkers enables enhanced biochemical monitoring for AA. In aneurysm tissue enhanced proteolysis results in pathological remodeling and progressive dilation. This breakdown of normally long-lasting matrix molecules, such as elastin and collagen, emphasizes the involvement of Matrix Metalloproteinases (MMPs), and their endogenous regulators, the Tissue Inhibitors of Matrix Metalloproteinases (TIMPs). These enzymes degrade all components of the vessel wall and are attributed to the development and progression of aneurysm disease. MicroRNAs represent a class of small non-coding RNA that regulate translation and a subset are secreted by aortic cells during progression of AA. Extracellular Vesicles (EVs) have been identified as critical mediators of cell-to-cell communication and extracellular matrix remodeling. EVs contain multiple MMPs, TIMPs, microRNAs, and the transforming growth factor (TGF)-ß, all which influence signaling pathways and contribute to degradation of the vascular wall. Experiments conducted by this laboratory show that when an aneurysm presents, a unique set of these circulating molecules also emerge. These signature profiles are different among AA location, subtype, and size. Accordingly, experiments and testing will demonstrate the following three aims. First, AA can be identified in plasma by profiling the MMP:TIMP ratio because it provides a unique metric of proteolytic activity within the aortic wall. Second, that the subset of microRNAs secreted from aortic cells under stress is correlated linearly to aortic diameter and pathological progression of AA. Third, circulating Extracellular Vesicle (EV) size, structure, and composition is altered in patients with AA subtypes and profiling them constitutes a diagnostic assay. Even if one aim should fail as a diagnostic assay, another can take its place; nevertheless, this study will provide mechanistic data and insight into upstream pathways involved in AA progression. Combined, this study will advance the development of a standardized screening assay for early diagnosis and risk stratification to mitigate life-threatening aortic complications.

NIH Research Projects · FY 2026 · 2023-06

ABSTRACT – OVERALL The induction of broadly neutralizing antibodies (bNAbs) against the HIV envelope glycoprotein (Env) is considered vital for an effective HIV vaccine. Rational vaccine design applying native Env-like trimers that target the respective germline B cell receptor have evolved as the most promising strategy. Yet, so far, bNAb precursor yields have not exceeded 50% of vaccinees. The goal of this Program aims to identify early determinants of bNAb precursor induction, with a focus on the role of adjuvants and host microbiota, utilizing broad and integrated omics approaches to decipher the mechanisms associated with bNAb development. In HIV infection, plasma bNAbs develop in a minority of adults and only after several years, whereas bNAbs in infants with HIV can be detected as early as one year post infection. Interestingly, bNAbs isolated from infants appear to require less somatic hypermutations to achieve similar breadth as bNAbs of adults, implying potentially different mechanisms of bNAb development. We present preliminary data that immunization of infant rhesus macaques (RM) with BG505 germline-targeting (GT)1.1 SOSIP trimers adjuvanted with the TLR7,8 adjuvant 3M-052 resulted in the induction of VRC01-like CD4 binding site bNAb precursors in 3 of 5 animals, a frequency comparable to that observed in adult RM (6 of 12). Plasma antibodies of infant RM also targeted a broader array of epitopes compared to adult RM, indicative of greater polyreactivity. Despite additional immunizations, the remaining 2 infant RM did not develop this neutralization signature, suggesting that early events are critical in driving bNAb development. In infants, early immunity is partially defined by the evolving microbiota. The polyreactivity of many, although not all, bNAbs, further supports a potential role of microbiota in bNAb development We hypothesize that the dynamic state of the infant immune system and microbiota can be exploited to optimize the induction of bNAbs by HIV vaccines. Leveraging the infant BG505 GT1.1 SOSIP vaccine model and applying systems biology approaches, we will identify how the developmental pathways of bNAb induction are altered by the modulation of the vaccine prime by different adjuvants (Project 1), the microbiome (Project 2), and the interactions between host immunity and microbiota (Biostatistics and Computational Analysis [BCA] Core). The Projects will be supported by the Nonhuman Primate (NHP) and the B Cell Cores, with organizational and fiscal support by the Administrative Core. In Aims 1 and 2, we will define differences in early immune responses and molecular signatures between vaccinees who do or do not develop bNAbs in response to BG505 GT1.1 SOSIP vaccination by modulating the vaccine prime via adjuvants (Project 1) and microbiota (Project 2). Aim 3 will develop modeling approaches that integrate immune, microbiome, and molecular signatures to predict the development of bnAb precursors. The results of the Program will identify critical determinants in the induction of bNAb precursors. In future studies, we will modulate these factors to optimize HIV vaccine strategies. The newly developed computational models will facilitate vaccine screening for the potential of bNAb development.

NIH Research Projects · FY 2026 · 2023-06

Project Summary: Developing disease-modifying therapies for neurodegenerative diseases has been challenging, in part because accurate statistical models to identify the optimal time for intervention do not exist. Models of how symptoms worsen over time (i.e., the symptom trajectory) before and after a clinical diagnosis can help identify that optimal time. These models can help pinpoint when a therapy could prevent a clinical diagnosis, or slow the disease after a clinical diagnosis. Yet modeling the symptom trajectory is not easy even for Huntington disease, a disease for which researchers can track symptoms in patients guaranteed to develop it. Like other neurodegenerative diseases, Huntington disease progresses slowly over decades, so studies that track symptoms often end before clinical diagnosis. This makes time to clinical diagnosis right-censored (i.e., a patient's motor abnormalities will merit a clinical diagnosis sometime after the last study visit, but exactly when is unknown), leaving researchers with the challenge of trying to model the symptom trajectory before and after clinical diagnosis without full information about when clinical diagnosis occurs. The challenge creates a unique statistical problem of modeling the symptom trajectory as a function of a right-censored covariate, time to clinical diagnosis. Tackling this problem by modeling the distribution for time to clinical diagnosis has long been thought to be the best strategy. For years, we and others worked to develop reliable distribution models, but we found that if the model is even slightly wrong, we get biased estimates of how the symptom trajectory changes as a function of time to clinical diagnosis. This bias causes problems for clinical trials because they are incorrectly powered to determine if a therapy modifies the disease course with statistical significance. We began seeking a strategy that estimates the symptom trajectory as a function of time to clinical diagnosis without needing to accurately model the distribution for time to clinical diagnosis. Our team developed such a strategy for a related problem: estimating a regression model that has a covariate measured with error. Like a right-censored covariate, when a covariate is measured with error, the covariate's true value and distribution are unknown. Rather than finding the correct distribution, our nontraditional strategy accurately estimates the regression model even when the distribution for the covariate is mismodeled. Our overarching objective is to develop a similarly robust strategy when we have a right-censored covariate, which requires tackling challenges in three new areas: noninformative censoring (Aim 1), informative censoring (Aim 2), and handling longitudinal measures of the symptom trajectory (Aim 3). Upon completion, our work will produce robust estimates of the Huntington disease symptom trajectory as a function of time to clinical diagnosis. The work is timely, given recent therapies that show potential for modifying the course of Huntington disease. Correctly powered clinical trials will enable researchers to test these therapies and determine if they modify the disease course. Our strategy could help design these clinical trials and push forward the science of Huntington disease and other neurodegenerative diseases.

NIH Research Projects · FY 2025 · 2023-06

ABSTRACT Task-shared mental health interventions are effective in low- and middle-income countries, yet they remain underutilized and the mental health treatment gap remains substantial. Innovative implementation strategies are needed to successfully integrate evidence-based mental health treatments into medical care in LMICs. A common component of many implementation efforts is a “champion” strategy which identifies and empowers an on-the-ground staff member as the implementation champion, in charge of focusing their colleagues’ efforts on implementation of the evidence-based treatment model. Yet a growing body of research, including our own work in Malawi and elsewhere, highlights that the champion’s success is strongly influenced by the strength of support from their line manager and other up-the-chain organization leaders, who are critical in aligning the organization’s climate and priorities in support of the implementation effort. Approaches to influencing leadership engagement to change organizational climate and align priorities has been developed over decades in the field of organizational and industrial psychology but only relatively recently applied to implementation science health research and primarily to implementation in high-income countries. The Leadership and Organizational Change for Implementation (LOCI) is a recently developed multi-level leadership coaching implementation strategy that has demonstrated effectiveness in changing organizational climate, aligning priorities, and enhancing mental health treatment model integration in the US and Norway, but has not been adapted to or tested in low-income country settings. LOCI has significant potential to address the gaps identified in our current research by aligning leadership priorities to support champions in advancing mental health integration. The objective of the present proposal is to test the impact and sustainability of supplementing the standard champion implementation approach with the LOCI leadership alignment strategy to achieve successful integration of an evidence-based, task-shared mental health treatment model into general medical care. We will use a cluster-randomized trial to evaluate the impact of the adapted leadership alignment strategy on integration of an evidence-based mental health treatment package into multiple medical care settings (NCD, HIV, and TB care), assessing proximal (climate), primary implementation (adoption, reach, fidelity), downstream patient mental health, and cost-effectiveness outcomes as well as sustainability after conclusion of the leadership alignment activities. Additionally, we will use the structure of the research project to further strengthen capacity among mental health researchers and policy makers in Malawi. Leadership alignment strategies are an understudied but essential ingredient for successful mental health integration efforts. This project will make a major contribution to our understanding of the role of leadership alignment in advancing evidence-based mental health integration in LMICs.

NIH Research Projects · FY 2026 · 2023-06

PROJECT SUMMARY Angelman syndrome is a severe neurodevelopmental disorder caused by maternal allele deletions of UBE3A. In neurons, the paternal allele of UBE3A is epigenetically silenced. Unsilencing the paternal allele of UBE3A offers a potentially transformative opportunity for treating Angelman syndrome. We recently discovered a small molecule that unsilences the paternal allele of UBE3A in neurons cultured from Angelman syndrome model mice or from stem cells derived from Angelman syndrome individuals. When delivered noninvasively to Angelman syndrome model mice, this small molecule leads to brain-wide neuronal UBE3A protein expression without observable toxicity. We hypothesize that our small molecule approach can reverse Angelman syndrome phenotypes in mice, justifying its advance towards additional safety studies and future clinical trials. Towards developing this approach as a non-invasive treatment for Angelman syndrome, we propose to (1) establish rescue of behavioral and electrophysiological phenotypes in Angelman syndrome model mice, (2) identify the mechanism of action by which our small molecule produces unsilencing of paternal UBE3A, and (3) perform structure-activity-relationship studies to improve efficacy and maximize favorable pharmacology. By advancing the first small molecule treatment of Angelman syndrome, this research may lead to therapy yielding profound lifelong benefits for this patient population.

NIH Research Projects · FY 2025 · 2023-06

Project Summary RNA is now recognized as a compelling therapeutic target because it lies upstream of all protein function and has cellular roles that go beyond protein translation. Similar to proteins, RNA molecules can fold to create complex tertiary structures that form binding pockets capable of specific small-molecule engagement. However, compared to proteins, few small molecules have been rationally designed to target RNA. The central challenges to developing RNA-targeting ligands are, first, the difficulty of identifying ligandable sites on RNA and, second, the lack of direct strategies for converting ligand binding into functional perturbation of mRNA stability, translation and regulation. Both of these challenges can be addressed by a new ligand-engagement technology developed in our lab. This technology enables nucleotide-resolution capture of ligand-RNA interactions via a high-throughput, cell-based screen of a small-molecule library versus an RNA library – the cellular transcriptome. In preliminary work, the ligand-engagement technology has been validated with photo- reactive probes in bacterial cells, and shown to be modular and applicable to diverse chemistries and biological systems. The first goal of this training and research proposal is to extend the technology to human cells and to develop chemistries that yield covalent adducts with RNA specifically at sites of RNA tertiary structures. The second goal of this proposal is to characterize the effects of covalent modification on gene expression for a subset of ligandable RNAs. Completion of these aims will create a concise strategy for linking small molecule engagement with RNA to direct functional modulation of gene expression. This multi-disciplinary project emphasizes training in the fields of technology development, RNA biology, and bioinformatics. Expertise in these fields, combined with my previous experiences as a chemical biologist and proteomicist, will position me at the forefront of RNA-targeted therapeutics development. I envision using this training as a launching point for an independent career as a scientific investigator and visionary leader with a research agenda focused on developing new technologies that modulate RNA function and impact human health.

NIH Research Projects · FY 2025 · 2023-06

Abstract. The intestinal epithelium (IE) lines the entire inner surface of the intestine, handling all of the body’s nutrient and fluid uptake while simultaneously serving as a barrier to toxic luminal contents and pathogens. To combat the damage human intestinal epithelial cells (hIECs) accumulate during homeostasis, cells on the villi (primary absorptive surfaces) are constantly replaced. Dedicated intestinal stem cells (hISCs) in crypts proliferate continuously to generate a steady stream of progenitor cells that collectively migrate towards the villi in one of the most expansive examples of collective cell migration in the adult body. Following IEC injury or loss, nearby IECs undergo a rapid collective migration called restitution to quickly repair the damage. Restitution driven by collective migration is an essential cellular process to preserve the barrier against luminal contents. Despite the importance of collective cell migration to intestinal function, little is known about how hIECs coordinate this process. The WNT-associatedPlanar Cell Polarity (WPCP) pathway, and in particular the cell surface protein VANGL2, has been increasingly implicated as a major player in the coordination of collective cell migration, but research is hampered due to a major deficit of physiologically relevant model systems for studying WPCP in higher organisms. Observations from my preliminary data indicate that: 1) sporadic overexpression of VANGL2 is sufficient to strongly impair collective migration, 2) VANGL2 is upregulated at the leading edge of an epithelial wound in scratchassays, and 3) a protein gradient of VANGL2 exists along the in vivo crypt-villus axis. Together these observations led me to hypothesize that the IE utilizes the WPCP pathway to coordinate collective cell migration. I will test this hypothesis using two aims. Aim 1 will establish a mechanistic role for WPCP in homeostatic migration, while Aim 2 will establish its role in wound healing. Both aims will use novel inducible genetic models of WPCP pathway perturbations to generate primary data. This will be used to train a computational reaction-diffusion model of WPCP polarity to decipher how local WPCP feedback can so strongly impact collective migration of large tissue regions. This study will fill critical technical and knowledge gaps by generating new culture models with primary human cells, uncovering novel mechanisms of how the hIE controls collective migration, and building novel computational models for studying collective migration and WPCP. My findings will be significant as VANGL2 and WPCP ligands are increasingly implicated in diverse health conditions including developmental defects, neurological and kidney disease, skeletal muscle and biliary duct regeneration, cancer metastasis, and chronic colitis.

NIH Research Projects · FY 2026 · 2023-06

Project Summary The overarching goal of this project is to understand at a mechanistic level the chromatin regulatory pathways governing gene expression. To achieve this objective, we use chemically controlled proximity to allow for temporal and special control over specific chromatin regulatory enzymes. Our research group has made contributions to understanding the interplay between the heterochromatin protein 1 gene repression pathway and other chromatin regulators. In addition, we have a drug discovery program that has identified inhibitors of heterochromatin gene repression. We also have developed bifunctional molecules that work with catalytically inactive dCas9 to recruit endogenous chromatin regulatory enzymes to any site across the mammalian genome. Three main goals of this research program are: 1. Explore how heterochromatin gene repression is governed by two distinct H3K9 methylation binding proteins, 2. Develop approaches to visualize dynamic heterochromatin gene repression in real time at the single cell level 3. Study chromatin dynamics in real time with bifunctional compounds to recruit endogenous enzymes to specific loci. Over the course of this grant our research group will continue to advance our understanding of the mechanisms of heterochromatin gene repression using unique chemically based technologies. We also will further advance areas we have pioneered developing bifunctional small molecules to explore the capture and retargeting of endogenous chromatin regulators as an approach to understanding mammalian genome regulation.

NIH Research Projects · FY 2025 · 2023-06

PROJECT SUMMARY/ABSTRACT Recently, remarkable progress has been made in cancer treatment employing adoptive cell transfer (ACT) of tumor-specific “killer”, CD8+ T cells. Various engineered T cells including chimeric antigen receptor T (CAR-T) cells, have shown great potential as new forms of cancer therapies. However, a hostile tumor microenvironment (TME) impedes T cell infiltration and survival and induces T cell dysfunction (i.e., ‘exhaustion’), making the beneficial effects of the therapy transient. Exhausted T cells (TEX) arise when T cells are stimulated by antigen for prolonged periods, which drives a defined differentiation process involving major transcriptional and epigenetic changes in T cells. Thus, there have been attempts to promote intratumoral T cell trafficking/proliferation but challenges with poor long-term survival and efficacy of adoptively transferred T cells in solid tumors still remain. Therefore, the goal of this proposal is to engineer T cells that better infiltrate and survive inside tumors to provide robust, durable anti-tumor T cell immunity. By combining (1) the expertise of the Dr. Kaech lab in effector and memory T cell development, (2) that of the Dr. Wang lab in integrative analysis of epigenomic/genomic data, and (3) that of Dr. Chung in protein engineering, this research will provide novel solution to the current limitation in ACT. Preliminary research generated epigenetic and transcriptional atlas of CD8+T cells and analyzed the transcription factor networks of the most tumoricidal, tumor-infiltrating “effector” T cell state, the long-lasting “resident-memory” T cell state and dysfunctional “exhausted” T cell state. Based on the understanding of T cell differentiation states, this proposal aims to design key transcription factor programs that drive desired T cell states and devise new methodologies to redirect T cell exhaustion state to toggle desirable effector and memory states and to temporally and combinatorically control the cell-state specific TFs of the adoptively transferred T cells in situ. This new class of T cell engineering platform is termed SMARTER (Specific Modifiers Assisted Reprogramming of T cell Engineered with Regulability). To generate SMARTER T cells, in Aim 1, a new platform will be devised to systemically identify novel cell-state-specific transcription factors. In Aim 2, synthetic machinery will be developed to rewire exhaustion signals to specific differentiation program. Lastly, in Aim 3, a clinically useable synthetic biology methods will be developed to enable temporal and combinatorial control of the cell- state-specific modifiers. This SMARTER platform will effectively transform T cells into “intelligent and tenacious soldiers”. These enhanced T cells will not only effectively infiltrate and kill cancer cells, but also retain the immunological memory of their “foes” and reside long-term at the tumor site, leading to complete remission.

NIH Research Projects · FY 2026 · 2023-05

Persistent infection with high-risk HPVs cause multiple human cancers; however there are no antivirals to treat these diseases. An increased understanding of the virus-host interactions that regulate the viral life cycle may reveal novel approaches for therapeutic development. Upon infection, HPV genomes transiently amplify to 50- 100 episomal copies per cell that are stably maintained. Epithelial differentiation triggers productive replication, resulting in amplification of viral genomes to 100s-1000s of copies/cell. We have shown that the ATM-dependent DNA damage response (DDR) promotes recruitment of homologous recombination (HR) repair factors (e.g. BRCA1, Rad51) to HPV genomes to facilitate productive replication. Despite an increase in cellular double-strand breaks (DSBs) upon differentiation, HPV genomes are preferentially repaired, though the mechanistic basis for this is unknown. We recently demonstrated that the DDR ubiquitin ligase RNF168 is specifically required for viral genome amplification upon differentiation. RNF168 is recruited to DSBs by ATM signaling. RNF168 plays a critical role in the DDR by catalyzing histone ubiquitination to recruit DNA repair proteins, including 53BP1 and BRCA1, both of which localize to HPV replication foci. How HPV uses RNF168 activity to drive viral replication is unclear, although several recent studies have implicated RNF168 in HR repair. The HPV E7 protein interacts directly with RNF168, disrupting repair at cellular DSBs. E7 may sequester RNF168 from cellular DSBs to direct RNF168 activity to viral chromatin, promoting preferential recruitment of HR factors to viral DNA upon differentiation. However, RNF168-mediated 53BP1 recruitment to DSBs poses a block to HR initiation that HPV must overcome. BRCA1 recruitment to post-replicative chromatin in S/G2 phases antagonizes this block by redistributing 53BP1. We have found that 53BP1 is redistributed at HPV DNA foci upon differentiation, implicating BRCA1 in promoting HR initiation on viral chromatin. Interestingly, our preliminary studies indicate that DNA-PK, a kinase critical for error-prone non-homologous end joining (NHEJ), may contribute to viral genome amplification by repressing cellular DSB repair pathways that could interfere with HR factor recruitment to viral DNA. We hypothesize HPV reshapes the cellular DNA damage response upon differentiation to support HR on viral chromatin. In this proposal, we will test if RNF168 promotes productive replication through HR factor recruitment to viral chromatin and determine if the E7-RNF168 interaction facilitates this process. We will also determine if the HPV-mediated increase in RNF168 protein stability influences viral replication. We will determine if BRCA1 monitors the state of post-replicative viral DNA to direct repair to HR by removing 53BP1. Additionally, we will define the interplay between HR and NHEJ during productive replication by determining if DNA-PK activity provides a cellular environment that protects HR factor recruitment to viral DNA. Understanding how HPV directs HR activity to viral DNA at the expense of cellular DNA repair will provide insight into mechanisms of viral replication and pathogenesis and may identify novel therapeutic targets to disrupt the viral life cycle.

NIH Research Projects · FY 2026 · 2023-05

ABSTRACT Alzheimer’s disease (AD) is one of the predominant causes of disability and dependency among older people, and the sixth leading cause of death in the United States. Late-onset AD is the most common form, with more than 99% of AD cases occurring after age 65. The strongest genetic risk factor for developing late-onset AD is carrying the APOE4 allele. Apolipoprotein E (APOE) is primarily expressed by glial cells in the brain and is the major protein component of lipoprotein particles secreted by astrocytes and microglia. Lipoprotein particles provide a bidirectional mechanism of lipid transport between glia and neurons. Many recent studies suggest that a disequilibrium in nervous system lipids is associated with increased risk of developing AD. However, the mechanisms by which APOE4 affects cellular lipid homeostasis are incompletely understood. We recently discovered that in glia, APOE can traffic to cytoplasmic lipid droplets (LDs) rather than undergoing secretion on lipoprotein particles. We hypothesize that APOE plays previously unrecognized roles in cellular lipid metabolism by acting directly on LDs in astrocytes and microglia. Astrocytes play important roles in metabolizing peroxidated lipids, while microglia are the primary innate immune effector cells of the central nervous system. In Aim 1, we will test the effect of modulating APOE in astrocytes on cellular lipid composition, metabolism, and lipid peroxidation. In Aim 2, we will test the effect of modulating APOE in microglia on cellular lipid composition, metabolism, and inflammation. In Aim 3, we will fill a key knowledge gap by developing a community resource visualizing and quantifying LDs in various brain regions and cell types in mice of different genotypes and ages. Together, these studies will lead to new insights about the cellular and molecular mechanism by which expression of APOE4 leads to increased risk of late-onset AD. This work could also lead to the identification of novel drug targets for preventing and treating AD.

NIH Research Projects · FY 2026 · 2023-05

Project Summary Our program, “Preventing Infant Infection with Implementation Science in Malawi”, PRI3SM, will conduct 3 clinical studies to address incident maternal HIV infections during pregnancy and breastfeeding and (re)engage pregnant and breastfeeding women with HIV frequently missed by traditional HIV care. Our research projects will be supported by an Administrative Core, an Implementation Science Core and a Data Science and Analytical Core. Our accumulated experience with EMTCT research in Malawi since 2002; established local partnerships; cross disciplinary expertise in clinical research, epidemiology, implementation and behavior science; and our synergistic projects put us in a superb position to impact MTCT by addressing the following aims: Aim 1. (Research Program) Conduct 3 synergistic research projects focused on addressing gaps in the EMTCT cascade that collectively expand HIV treatment and prevention in pregnancy and postpartum to avert maternal and infant infections.Aim 1a. Project 1 (PrEP in Pregnancy) To evaluate maternal and infant safety of PrEP regimens in pregnancy and breastfeeding. Cabotegravir (CAB) injectable PrEP represents a substantial advance over daily oral PrEP7 and could dramatically reduce new maternal infections. But CAB has not been systematically studied in pregnant and lactating women. We will establish a national registry of CAB and TDF/FTC PrEP users who become pregnant alongside a safety cohort of pregnant women receiving PrEP to compare pregnancy and infant outcomes. Aim 1b. Project 2 (Postpartum Prevention Package) To optimize post-partum HIV prevention including PrEP uptake and persistence among at-risk lactating women to prevent primary HIV infection and subsequent infant infection using a novel integrated task-shifting intervention strategy including partner engagement and testing, PrEP, and community outreach. Aim 1c. Project 3 (PAC-Man) To evaluate reach and effectiveness of a novel community-based service model, the “Point-of-care (POC) Active Case-finding & Management” (or PAC-Man) model to identify and test infants missed through routine facility testing and determine effectiveness and measure implementation outcomes including, adoption, implementation, sustainability, and cost per pediatric HIV case identified. AIM 2. (Admin Core) Create a robust administrative structure to implement and integrate research protocols efficiently and effectively, support the Implementation Science and Data Science and Analytical Cores, and nurture existing rich partnerships with the sponsor, Ministry of Health and HIV PEPFAR implementing partners. Aim 3. (Support Cores) To establish robust Implementation Science and Data Science and Analytical Cores to provide support to the study projects, support Ministry of Health program evaluation, and facilitate engagement of early-stage investigators through existing D43 capacity building programs. Broadly, we expect to identify successful implementation strategies with the potential to achieve elimination of pediatric HIV in Malawi and beyond.

NIH Research Projects · FY 2026 · 2023-05

Social isolation and its subjective counterpart loneliness—well established as risk factors for poor physical and mental health—have been rising at alarming rates in the US, especially among young adults. Mechanistic understanding of how best to build social connectedness to ameliorate social isolation is sorely needed to redirect life trajectories toward health and well-being. In creating this foundational knowledge, populations who face higher disease burden—Black/African American young adults, Latino/Hispanic young adults, and those with lower subjective social status—merit special focus because persons in these at-risk populations often face unique challenges in initiating social interactions, including economic inequality. The broad, overarching objective of this work is to conduct basic experimental research on social connectedness to test whether, how, where, and for whom health communication messages can motivate in-person interactions to reduce young adults’ social isolation and loneliness. Our multi-disciplinary team brings together expertise in social psychology, emotion science, communication science, and health disparities and will carry out a 6-week randomized controlled trial—the Keep Social RCT—using our innovative and ecologically valid simulated social media platform and a suite of rigorous repeated measures of social behavior, loneliness, and other health-relevant outcomes. This program of research is designed to meet three specific aims. SPECIFIC AIM 1 is to optimize health messages about the value of social connectedness for young adults (ages 18-29) from populations who face higher disease burden and then conduct the Keep Social RCT to build a rich empirical platform. This aim will be met using a human-centered process to design health communication messages that include peer imagery and stories for an online experiment with 500 at-risk young adults. Messages that receive highest ratings for encouraging in-person interactions in this online experiment will be selected for the Keep Social RCT, which is placebo controlled with behavioral, survey, and implicit assessments repeated over six weeks. SPECIFIC AIM 2 is to analyze theory-driven mechanisms through which health communication messages in the Keep Social RCT may reduce young adults’ social isolation and loneliness to identify intervention targets. This aim will be met with longitudinal statistical modeling to test whether and how the experimental health communication messages improve social connectedness. SPECIFIC AIM 3 is to extend data analyses of the Keep Social RCT to identify regional and person-level moderators of reduced social isolation and loneliness to identify where and for whom effects are largest. This aim will be met with advanced statistical modeling to illuminate the conditions under which our health communication messages most effectively ameliorate social isolation and loneliness in young adults who face higher burden of disease. Taken together, this research will provide a framework to identify intervention targets to guide subsequent translational work undertaken to reduce health disparities in the US.

NIH Research Projects · FY 2026 · 2023-05

In the more than 40 years since the discovery of the Ebola virus (EBOV) there has been an increase in both the frequency, size, and duration of Ebola outbreaks. The 2014-2016 outbreak that devastated West Africa evolved within the span of months into a global humanitarian crisis, infecting over 28,600 people and killing more than 11,300 - eclipsing all previous outbreaks combined. Moreover, in the six years since the end of the West African Ebola epidemic, there have been seven additional outbreaks in Guinea and the Democratic Republic of Congo (DRC). The recurrence of Ebola in Guinea and the DRC and the detection of the Ebola virus in a bat in Liberia, make it clear that this pathogen is persistent and will be the cause of recurrent outbreaks of varying scales across West and Central Africa. While the West African epidemic has ended, the clinical concerns of EVD survivors persist including the longevity of immune protection against repeat infection and the mechanisms underlying the persistent and debilitating somatic complaints reported by an overwhelming majority. The primary objective of this proposal is a rigorous characterization of the protective and pathologic effects of the EVD survivor immune response in one of the largest EVD survivor cohorts. Specifically: • AIM I will characterize the humoral immune response to EBOV infection by measuring antibody levels and neutralizing capacity - a key correlate of protection, and assessing the memory immune response in seronegative EVD survivors from 1 to 10 years following acute infection • AIM II will investigate autoimmune activation as a mechanism underlying post-Ebola complications We will conduct this work in the context of close and strong working relationships with healthcare leaders and Ebola survivor representatives in West Africa, and well-developed infrastructure for clinical research that we have established in Liberia and Sierra Leone where we have recruited, enrolled, and longitudinally followed and sampled more than 700 EVD survivors and over 1,000 household contacts. The proposed work will provide a much-needed longitudinal characterization of the humoral immune response, evaluation of the memory immune response to EBOV infection, and investigation of autoimmune activation as a mechanism underlying the long- term complications of surviving EVD. With seven outbreaks, including the second largest Ebola outbreak ever, occurring in the 6 years since the West African epidemic, the question is not if another large outbreak will occur but when. This study will ensure that the world is better prepared for the next epidemic through an improved understanding of the durability of the humoral immune response to infection, an improved understanding of the clinical complications of EVD, and through the implementation of clinical research platforms in areas that are likely to see a recurrence of EVD.

NIH Research Projects · FY 2026 · 2023-05

PROJECT SUMMARY/ABSTRACT Alzheimer’s disease (AD) is a leading cause of dementia among the elderly and the most prevalent age- related neurodegenerative disease, affecting ~56 million individuals worldwide. Despite of its high heritability (estimates ranging 60-80%) and many genetic variants (residing in tens of loci across the genome) identified from genome-wide association studies (GWAS), our knowledge of the underlying genetic mechanisms remains limited. Uncovering pathophysiological mechanisms underlying AD proves to be highly challenging. To advance our mechanistic understanding of AD, we will first acquire and harmonize various in-house, protected and public data, encompassing bulk and single cell RNA-seq data, GWAS summary statistics, array genotyping and whole genome sequencing data, as well as functional genomic data. We will then analyze them using a suite of computational methods and bioinformatics tools to generate cell-type-specific mechanistic hypotheses. These hypotheses will be validated through experimental technologies. Our validations will be carried out in iPSC-derived neural cells (particularly excitatory neurons and microglia), as well as in iPSC-derived brain organoids involving diverse cell types including neurons, astrocytes, and microglia. In these iPSC-derived cells and organoids models, we will leverage CRISPRi as well as knock-in experimental technologies to perturb the most promising putatively causal regulatory DNA elements, and evaluate the impact by measuring a cascade of molecular and cellular phenotypes including gene expression and AD related physiological phenotypes.

NIH Research Projects · FY 2025 · 2023-05

ABSTRACT Biological membranes create compartments within cells and demarcate the outsides of cells from their insides. Beyond their role as physical barriers, lipid membranes also are used as platforms to organize biological processes essential for life: Membrane surfaces are unique for the exceptional ability to coalesce, organize, and regulate biological complexes necessary to transmit information between cells and among cellular compartments. Certain of these biological complexes are core nodes that coordinate diverse inputs into conserved outputs. One such core node is organized and orchestrated by the phospholipase C gamma (PLC-) isozymes in response to diverse transmembrane receptors including a host of receptor tyrosine kinases and immune receptors. We will study this core node as a “Rosetta Stone” to learn the inherent and emergent properties of signaling at biological membranes. By systematically and quantitatively comparing how properties of this core node and associated cellular responses are altered for different classes of input receptors and in different cell types, we will derive fundamental and guiding principles about how cells and tissues execute precise signaling within the physical-chemical constraints of their biological membranes. This goal will be accomplished using a highly collaborative and interdisciplinary approach: Detailed structural, biophysical, and biochemical studies of purified proteins and complexes will guide complementary studies of reconstituted nodes on self- assembled lipid bilayers or re-engineered in cells to be controlled and imaged with light. Data from these studies will inform computational models based on a newly-developed frameworks describing core nodes operating at membranes that will be used to predict signaling kinetics, efficiency, and dynamics in response to changes in core components, inputs, and feedback regulation. Together, these studies will reveal critical insights into the function and regulation of the PLC- isozymes downstream of multiple receptor types. These studies will also advance our overall goal of a deeper, yet more parsimonious, understanding of signaling at biological membranes.

NIH Research Projects · FY 2025 · 2023-05

Project Abstract Over 50 million Americans experience chronic pain annually, which has led to increases in opioid prescription rates. While effective analgesics, opioids produce harmful side effects like euphoria and physical dependence, which has led to a nationwide opioid epidemic and a need for efficacious analgesics that lack harmful side effects. Understanding how opioids impact the nervous system is important to distinguish the neural circuits driving opioid analgesia from circuits underlying unwanted side effects. Opioids target the mu opioid receptor (MOR), an inhibitory G-protein coupled receptor expressed by neurons throughout the brain. Neurons in the periaqueductal gray (PAG) express high levels of MOR and, upon electrical or morphine stimulation, produce both analgesic and rewarding behaviors. Distinguishing opioid-dependent PAG circuits driving analgesia from rewarding circuits may reveal a powerful, non-addictive therapy for pain relief. Characterizing the composition and organizational connectivity of the PAG is necessary to target distinct opioid-dependent circuits. PAG neurons vary in function, location, and molecular composition, but have not been comprehensively characterized using single-cell approaches. The PAG relays sensory and affective information to and from various brain structures during opioid use, but the configuration of presynaptic inputs and projection targets of opioid-sensitive MOR+ PAG neurons is unknown. Understanding the composition and organization of opioid- sensitive neural circuits is important to discern where opioids act to produce analgesic and rewarding effects. In preliminary single-cell RNA-sequencing (scRNAseq) experiments I identified 14 PAG transcriptionally distinct neuron subtypes that expressed various levels of the gene encoding MOR (Oprm1). In Aim 1, I will use spatial transcriptomics to determine the distribution and cellular heterogeneity of Oprm1+ PAG neurons. I will then resolve the architecture of opioid-sensitive circuits in the PAG using input-output circuit mapping. In Aim 2, I will first determine whether PAG neurons can be genetically classified based on their projection target using retro-seq. I will also use inhibitory chemogenetics during sensory, affective, and motivational behavior assays to investigate whether PAG neurons with different projection targets contribute to specific opioid- induced behaviors. The combined molecular, spatial, and circuit data generated from these experiments will provide a means to manipulate specific PAG circuits and reveal which neurons are receptive to opioids. Furthermore, results from loss-of-function behavioral assays will demonstrate whether specific PAG circuits preferentially contribute to the sensory or affective effects of opioids. The proposed research will be conducted under the mentorship of Dr. Gregory Scherrer. Dr. Scherrer has extensive experience integrating mouse genetics, functional neuroanatomy, and complex behavioral assays to investigate the neural circuits underlying opioid behaviors. Collectively, this project will help me develop into an independent researcher and provide the research community with resources for investigating opioid circuits.

NIH Research Projects · FY 2026 · 2023-05

ABSTRACT Ultrasound is one of the most widely used medical imaging modalities worldwide, with recent usage growth attributed to swift technology advancements in complementary subdisciplines. Ultrasound technology development continues to advance at lighting pace, with new capabilities rapidly maturing as the latest contributions from a wide spectrum of interdisciplinary fields converge. In concert with ultrasound’s inherent safety, cost efficiency, and portability (which make it the only accessible imaging modality to much of the world’s population), the potential for advanced ultrasound to dramatically impact patient care is enormous. However, to fully realize this potential, such exciting innovations must become commercially available. Therefore, it is vitally important to prepare the next generation of ultrasound engineers to develop ultrasound innovations that are clinically meaningful and commercially relevant. To meet this critical need, the Unified Medical Ultrasound Technology Development (UNMUTED) pre-doctoral training program combines clinically- oriented, world-class instruction in the physics and engineering of medical ultrasound technology development with preparation for commercial translation. Importantly, training is done in the context of The Research Triangle Park region of North Carolina, a prominent biotechnology hub and home to an unrivaled consortium of ultrasound technology experts. By participating in the UNMUTED predoctoral training program, trainees will uniquely gain the collaborative, technical, and commercialization skills necessary to transition their work from advanced research and development to commercially available products that meaningfully impact patient care. Specific Aim #1 is to give trainees first-hand experience communicating and collaborating with physician scientists to identify new ultrasound applications that meet clinically important needs. Specific Aim #2 is to provide trainees an unparalleled foundation in the physics and engineering of medical ultrasound to move from initial ideation, to feasible implementation, to clinical validation. Specific Aim #3 is to prepare trainees to commercially translate advanced ultrasound technologies through a combination of didactic training and mentorship by ultrasound entrepreneurs and industry experts. Additional professional skills development, including in effective written and oral communication, scientific rigor, and the responsible conduct of research, will be a highlight of the training experience. UNMUTED will be administered by the University of North Carolina at Chapel Hill (UNC) and North Carolina State University (NCSU) Joint Department of Biomedical Engineering and directed by Dr. Caterina Gallippi, a Professor in the UNC, NCSU Joint Department of Biomedical Engineering and a seasoned expert in medical ultrasound technology development with extensive experience in doctoral education. Dr. Gallippi will be assisted by two Associate Directors and a Senior Advisory Committee.

NIH Research Projects · FY 2026 · 2023-05

SUMMARY Microbial plaque biofilms that form at and below the gum line are the perpetrators of periodontal diseases, which are a class of diseases associated with non-resolving inflammation that results in soft and hard tissue destruction. Periodontitis is characterized by an unending cycle of chronic inflammation which leads to tissue destruction and prevents wound healing but cannot control the biofilms microbial dysbiosis. Under conditions of systemic inflammation, these host factors are amplified leading to more severe and refractory periodontal disease conditions. As such, periodontal diseases are affected by and can be risk factors for a number of systemic health issues such as diabetes. Current treatment of periodontitis involves mechanical removal of supra- and sub-gingival bacterial plaque and calculus and is often accompanied by the use of locally administered adjunctive therapies aimed at restoring microbial homeostasis. Current adjunctive therapies do not address the need to break the unending cycle of chronic inflammation and restore tissue homeostasis. Thus, there is a profound need to develop an adjunctive therapeutic that: a) possesses broad-spectrum activity against biofilms with minimal toxicity to mammalian cells; b) provides anti-inflammatory activity; and, c) promotes tissue healing. Due to its antibacterial and immunomodulatory functions, nitric oxide (NO) is an attractive adjunctive agent in the treatment of periodontal diseases. In the proposed research program, we will synthesize, characterize and evaluate nitric oxide-releasing hyaluronic acid (HA) as a multi-action NO-release system. Upon release, the NO will serve as a broad-spectrum antibacterial and pro-wound healing agent. The macromolecule that remains (HA) will then further serve to mitigate immunmodulation and wound healing. We will evaluate the efficacy and associated mechanisms of this multi-action therapeutic (e.g., NO: antibacterial, HA and NO: immunomodulatory, and NO and HA: pro-wound healing). We propose this approach will reduce the frequency of and/or augment clinical interventions and promote improved resolution of disease. We aim to: 1) synthesize nitric oxide-releasing hyaluronic acid nanomaterials and formulations, showing the influence of NO- releasing HA on antibacterial and antibiofilm action, mammalian cell cytotoxicity, and inflammation in various oral delivery formulations; 2) delineate the mechanisms modulating microbial dysbiosis, immune dysfunction and tissue-stasis; and, 3) test in vivo therapeutic efficacy in preventing and/or halting periodontal disease progression.

NIH Research Projects · FY 2026 · 2023-05

Project Summary/Abstract Accumulating evidence has identified nucleus accumbens astrocytes as salient targets of drug abuse. For example, numerous studies indicate that rat self-administration of multiple drug classes results in impaired glutamate homeostasis, as well as decreased structural features and synaptic colocalization of nucleus accumbens astrocytes. Preliminary data for this proposal reveal that male rat accumbens astrocytes exhibit striking (~40%) reductions in surface area, volume, and synaptic colocalization 45 days after 10 days of long- access (6h/d) cocaine self-administration. These findings suggest loss of physiological function of astrocytes as regulators of neural circuits. However, the mechanism(s) driving these observations are unknown, as are the consequences to neural function. We hypothesize that astrocyte pathology underscores the neural adaptations and increased measures of craving observed across prolonged abstinence (also known as incubation). Accordingly, the goal of this proposal is to define the relationship between cocaine self- administration and the onset of astrocyte dysfunction in the nucleus accumbens, as well as the relationship between astrocyte dysfunction, synaptic transmission, and behavior. Aim 1 will assess the effects of operant cocaine self-administration on evoked Ca2+ responses in accumbens astrocytes as a function of both self- administration and abstinence, and will determine the functional significance of astrocyte Ca2+ to cocaine seeking behaviors. Aim 2 will examine how cocaine self-administration affects the ability of astrocytes to negatively regulate excitatory synaptic transmission in D1 and D2 receptor-positive medium spiny neurons. Lastly, Aim 3 will establish the role of dopamine and G protein-mediated astrocyte signaling in the pathological effects of cocaine on accumbens astrocyte structure. For each aim, we will evaluate endpoints as a function of time across abstinence. These objectives will collectively be accomplished by leveraging a multimodal approach that spans cellular physiology to circuit analysis and animal behavior, combining rat cocaine self- administration with high-resolution imaging of fluorescently-labeled astrocytes, acute slice imaging of Ca2+- labeled astrocytes using a photoconvertible Ca2+ indicator (astro-CaMPARI2), astrocyte DREADD stimulation, astrocyte Ca2+ depletion using an astrocyte-expressed PMCA2 Ca2+ pump, whole cell patch-clamp electrophysiology, neuronal subtype-specific analyses using Drd1a-Cre and Drd2-Cre transgenic rats, and fluorescent imaging of an adenosine biosensor GRABAdo. Collectively, these studies will define the relationship between astrocyte dysfunction across abstinence from cocaine self-administration with neural physiology and behavior.

NIH Research Projects · FY 2026 · 2023-05

ABSTRACT Periodontitis is a male-dominant, heterogeneous, inflammatory disease of the bone and tissues supporting the tooth. It is one of the most prevalent non-communicable chronic diseases, with ~50% prevalence in the American population. Currently, there are no adjuvant therapies available to treat the 20-25% of “hyper-inflammatory” patients that progress to tooth loss despite appropriate standard of care. In support of this current proposal, inflammasome modulation has been proposed to treat several inflammatory diseases. Inflammasome is required for processing of pro-interleukin (IL)-1, pro-IL-18, and Gasdermin-D into their mature, functional forms. Despite the common knowledge that IL-1 is sexually dimorphic and a marker for periodontal inflammation, its role as a direct driver of disease development in both females and males is not clear. We find that inflammasome activation has both a protective and destructive effect on periodontal tissue that is differentially regulated between the sexes. Our data suggest the existence of sex-based distinct pathways of periodontal bone loss. This study will expand our current knowledge on the role of inflammasomes in periodontal inflammation and tissue destruction in females and males. We propose to build upon our findings to develop the below aims: Aim 1: Define the impact of biological sex in inflammasome activation during periodontal disease development and progression. Aim 2: Define the relationship between inflammasomes and periodontal tissue repair. Aim 3: To use a new strategy to target inflammasomes for preventing murine periodontitis. 1

NIH Research Projects · FY 2025 · 2023-05

ABSTRACT American children are exposed to violence at a shockingly high rate. Over one in eight have had the maltreatment they experienced confirmed by the authorities, and at least one in four have witnessed inter-parental violence. Although formal institutions such as social service providers, child welfare, and law enforcement agencies are intended to protect families, these institutions may be seen less as family protectors than as agents of surveillance, punishment, and family separation—especially in vulnerable communities. The overall goal of this research is to understand how contact with formal institutions shapes family violence experiences and their consequences for children. It will also allow the principal investigator, Dr. Tasseli McKay, the opportunity to build the measurement expertise, analytic skills, and methodological tools needed to conduct impactful, long-term research on the implications of mass incarceration for family violence. The project consists of five studies, combining primary qualitative interviews and mobile surveys with youth and parents in contact with punitive institutions (such as juvenile and criminal legal systems) and secondary analysis of survey and administrative data. It will generate (1) Estimates of the bidirectional relationship between institutional contact and childhood family violence exposure (Aim 1, K99 phase); (2) New, validated measures of institutional contact that capture objective institutional contacts and subjective experiences of institutional responsiveness (Aim 2, K99 phase); (3) A qualitative assessment of how institutional contacts and institutional responsiveness inform family violence disclosure decisions among affected family members (Aim 3, R00 phase); (4) Estimates of the influence of institutional contact events and institutional responsiveness on help-seeking intentions and service utilization (Aim 4, R00 phase); and (5) A quantitative assessment of the respective roles of institutional contact events and institutional responsiveness in shaping the relationship between childhood exposure to family violence and involvement in violence during the transition to adulthood (Aim 5, R00 phase). The project will produce advances in conceptualization, measurement, and analytic methods that lay a foundation for new research on institutional contact as a social determinant of child health and well-being and help inform sound public policy and public health intervention for the most common and impactful forms of violence: those within the family.