Univ Of North Carolina Chapel Hill

NIH Research Projects · FY 2025 · 2024-05

Antibiotic resistance in Neisseria gonorrhoeae has been rising over the last decade, leading the WHO and the US CDC to label the emergence of antimicrobial-resistant N. gonorrhoeae a serious public health threat. Development of a vaccine against N. gonorrhoeae is considered a critical step in prevention strategies to slow the spread of antibiotic-resistant N. gonorrhoeae. However, individuals infected with N. gonorrhoeae remain susceptible to repeat N. gonorrhoeae infection because they fail to develop effective protective immune responses. Our research has found that the PorB porin, the most abundant protein antigen in outer membrane vesicles (OMVs), suppresses the capacity of antigen-presenting dendritic cells to stimulate T cell proliferation when treated prior to addition of T cells. This immunosuppressive effect likely contributes to immune evasion by the bacteria and the failure to develop protective immune responses. Recently, N. gonorrhoeae infections have fallen in countries or regions that deployed mass vaccination campaigns with vaccines against N. meningitidis serogroup B made from OMVs, suggesting that these vaccines may offer partial cross-species protection against N. gonorrhoeae. However, these OMVs have very high levels of PorB (and a related porin, PorA). We hypothesize that because of the documented immunosuppressive effects of PorB, it is likely that these porins limit the immunogenicity of OMV-based vaccines. One possibility is that the immunosuppressive effects of PorB are due to its channel activity. To test whether decreasing or ablating the channel activity reduces the immunosuppression mediated by PorB, we propose in Specific Aim 1 to use a structural model of PorB to introduce cysteine (Cys) mutations at locations within the pore that would have a high likelihood of decreasing or ablating channel permeation following modification by Cys-directed chemical reagents and crosslinkers. We will establish the effectiveness of these different reagents to inhibit permeation by assessing channel activity in lipid bilayers and in multilamellar vesicles using established protocols. Porin mutants that are readily inactivated by sulfhydryl-directed reagents will be examined for their capacity to inhibit dendritic cell-mediated T cell proliferation. To test whether reducing the level of PorB in OMVs impacts immunogenicity of vaccination with OMV, in Specific Aim 2 we will create a strain of N. gonorrhoeae with regulated PorB expression. We will test whether OMVs containing decreasing levels of N. gonorrhoeae PorB exhibit reduced capacity to inhibit dendritic cell-mediated T cell proliferation and whether immunization of mice with these OMVs results in increased cellular immune responses against N. gonorrhoeae. These experiments will serve as an important step in the future development of more effective OMV-based vaccines.

NIH Research Projects · FY 2025 · 2024-05

PROJECT SUMMARY We propose the Eating Disorders Genetics Initiative 2 (EDGI2), a new collaborative R01 in response to PAR- 23-050 Clinical Studies of Mental Illness. Its single-site predecessors, EDGI1 (R01 MH120170) and ARFID-GEN (R56 MH129437) have been resoundingly successful. We now unite the four original EDGI1 sites with exceptionally productive global new sites to advance genomic discovery across all major eating disorders (EDs) to identify biologically, clinically, culturally, and therapeutically meaningful and actionable insights. Aim 1: EDGI2 extends our core business by increasing sample size, diversity, and ED phenotypes. Using our comprehensive harmonized online assessment battery, we will phenotype and bio-sample 20,000 new participants with anorexia nervosa (AN), bulimia nervosa (BN), binge-eating disorder (BED), avoidant/restrictive food intake disorder (ARFID), and controls. EDGI2 emphasizes co-production—with representatives from minoritized and marginalized communities, we will ascertain 30% of samples from underrepresented groups. We will also over- sample individuals with severe and enduring AN (SE-AN), whose DNA may be enriched for causative alleles. Aim 2: We will apply statistical genetic analyses to explicate heterogeneity and biology of EDs by: conducting standard GWAS analyses on diagnoses, trans-diagnostic behaviors, and continuous phenotypes including polygenic risk score (PRS), and rare variant CNV analyses; identifying clinically meaningfully patient subsets; and intensively evaluating our proposal that AN is a metabo-psychiatric disorders using LDSC, PRSet, pheWAS, and Mendelian randomization to clarify direction of causation. Aim 3: We will evaluate the relative roles of genetic and environmental risk and resilience factors to inform risk prediction by phenotypically characterizing cases and controls with high and low PRS for EDs and then by genotypically characterizing those with severe ED phenotypes. We will characterize distinct genetic or molecular groupings/patterns across cases and controls and phenotypically characterize identified molecular subtypes. Aim 4: To determine where in the body EDs “live”, we will identify brain cell types and anatomical regions implicated by genomic studies of EDs; predict genetically regulated gene expression (GREx) in brain, gut, adipose, and other ED-relevant tissues; use snRNAseq atlases to sharpen preliminary GTEx and TWAS analyses to identify brain cell types strongly implicated by the genomics of each ED; expand to relevant non-brain cell types (e.g., adipose, muscle, liver, salivary); and use dynamic GREx to model gene expression in ED-relevant contexts (e.g., sex, BMI, stress) enabling precise and personalized modelling of gene expression. Aim 5: EDGI2 will culminate in a Translational Summit uniting forward-thinking stakeholders from multiple sectors to develop a translational roadmap for evidence-based ED prevention and treatment. EDGI2 will yield critical knowledge about genetic and environmental risk for EDs, reveal mechanisms that potentiate or protect against genetic risk, and transition ED genetics from discovery to clinical translation.

NIH Research Projects · FY 2026 · 2024-05

There is a clear need for a vaccine to protect against Chlamydia trachomatis (Ct), a sexually transmitted bacterium causing an ongoing epidemic associated with reproductive complications. IFNγ-producing CD4 T cells (Th1 & Th1/17 cells) are required for protection from Ct, which grows and replicates intracellularly, whereas antibodies provide complementary protection in the presence of IFNγ. Our studies of Chlamydia-infected women and mice have identified Chlamydial Protease Activity Factor (CPAF) as an immunoprevalent and immunodominant antigen for CD4 T cells and B cells, making it a strong vaccine candidate. Due to the tolerogenic nature of the female genital tract (FGT) and its lack of secondary lymphoid tissue, effective induction of protective cell-mediated immunity requires potent adjuvants and mucosal vaccination to imprint FGT homing or generate resident memory T cells. Our preliminary data indicate that intranasal immunization of female mice with CPAF conjugated to the TLR9 agonist, CpG, combined with the STING agonist, cyclic-di-AMP (CDA) in the squalene oil-in-water nanoemulsion AddaS03 (AS03), induces high levels of CPAF-specific CD4 T cells and protection from infection and pathology. Our novel covalent CPAF-adjuvant conjugation approach enhances antigen- presenting cell activation through coincident stimulation leading to the potential for dose sparing, reduced toxicity, enhanced immunogenicity, superior efficacy, and reduced cost of goods. This proposal incorporates a tiered approach to determine if refinements using innovative new generation TLR7/9 and STING agonists delivered via mucosal routes will enhance protection via the following specific aims: Aim 1. Complete product development activities of 2nd generation dual agonist CPAF vaccines. (i) Refine the multi-adjuvant CPAF-CpG+CDA+AS03 vaccine. (ii) Covalently conjugate TLR7, -9 and STING agonists to CPAF. (iii) Perform in-vivo formulation, toxicology, and preliminary immunogenicity analysis of candidate vaccines. Aim 2. Evaluate efficacy of the 2nd generation candidates in the female murine challenge model and immunogenicity in male mice. (i) Determine most efficacious vaccine regimen (candidate and route). (ii) Determine protection against female infertility and vaccine immunogenicity in males. (iii) Determine duration of humoral and cell- mediated responses by top candidate, and the contribution of additional boosting. Aim 3. Vaccine process development. (i) Optimize upstream production, downstream purification, and conjugation of CPAF. (ii) Develop analytical assays and qualify as suitable for intended use. (iii). Develop formulation and evaluate vaccine stability. (iv) Conduct a non-GLP toxicology assessment of the final vaccine candidate. Accomplishing these three Specific Aims will result in a Chlamydia vaccine candidate ready for tech transfer to a qualified CMO, GMP production, and early-phase human clinical trials.

NIH Research Projects · FY 2026 · 2024-05

SUMMARY It has yet to be determined whether human brain myeloid cells (BMCs) serve as an important reservoir for persistent HIV-1 (HIV) infection in the central nervous system (CNS). This is hampered by the challenges faced in accessing fresh human brains. Therefore, our current knowledge of HIV CNS reservoirs in humans is largely limited to in vitro microglia/macrophage models of HIV latent infections and animal studies from SIV-infected NHP or HIV-infected humanized mouse models. There is an urgent need for innovative HIV latency models of BMCs that are physiologically close to the cells in the human brain. By working with the “Last Gift” Program, we have established a platform to isolate, expand, and characterize BMCs derived from people with HIV (PWH) on antiretroviral therapy (ART). We showed that a near full-length HIV can be recovered from BMCs, which was replication-competent in both T cells and BMCs. Bioinformatics analyses predicted the R5 tropism of this BMC HIV strain, which was confirmed by in vitro infection in BMCs, during which BMC infection by this strain of HIV was effectively dampened by a CCR5 inhibitor, Maraviroc. Pseudoviruses of Env cloned from this strain of BMC HIV efficiently infected CD4low but CCR5high affinofile cells, supporting its M-tropism nature. Interestingly, human BMCs expressed the newly identified HIV latency gene Nurr1 as well as anti-apoptosis genes, including Bcl-2 and MCL1, which could be essential for the stable HIV reservoir in BMCs. With the needed expertise to successfully isolate CNS cells (CNS T cells and BMCs) from postmortem fresh brains, technical innovations of single-cell technique pipelines, and the unique and rare resource of the “Last Gift” cohorts, this proposal will define the mechanism underlying the stable replication-competent HIV reservoir in BMCs. We will isolate BMCs from the brains of ART-suppressed PWH. We will define replication- competent HIV through de novo infections in T cells and BMCs as well as BMC-QVOA and T cell-QVOA analyses. We will genotype BMC HIV by single genome amplification sequencing and phenotype it by Env- pseudoviral infections in cells expressing low levels of CD4. We will characterize the transcriptionally active HIV as a possible viral reservoir in BMCs (Aim 1). In Aim 2, we will define the survival signaling pathways that may be acquired in the latently infected BMCs. We will study latency reversal using epigenetic modulators in BMCs. We will define the mechanisms of the epigenetic regulation of BMC HIV. We will also test whether previously identified BMC transcription factors play essential roles in HIV latency in postmortem BMCs. In Aim 3, we will examine new tools to directly target the transcription machinery of HIV to control viral reservoirs and delay or prevent viral rebound, which may also limit immune activation. This proposal will address critical knowledge gaps in replication-competent HIV reservoirs in BMCs and underlying molecular mechanisms. The tools and BBB-penetrating small molecules used in this proposal could be developed into novel cure strategies to eradicate HIV from the CNS.

NIH Research Projects · FY 2026 · 2024-05

PROJECT SUMMARY The goal of the Rheumatic and Musculoskeletal Disease (RMD) Epidemiology and Outcomes Training Program at the University of North Carolina is to provide state-of-the-art resources and a rich environment to train independent interdisciplinary researchers who will improve our understanding of the magnitude, etiology, impact, and treatment of RMDs, and who will assume leadership roles in RMD epidemiology and outcomes research. An estimated 1 billion prevalent cases and over one hundred thousand deaths were attributed to RMDs in 2017, which combined with the pending shortage of rheumatologists underscores the need for trained researchers to advance RMD epidemiology and outcomes research now and into the future. We propose to establish a robust training program in the University of North Carolina Department of Medicine’s Division of Rheumatology, Allergy, and Immunology (RAI) and the Thurston Arthritis Research Center (TARC) focused on epidemiology and outcomes research in RMDs to address the critical need for an enhanced interprofessional workforce trained to understand the etiology and clinical management of RMDs. This will directly address the objective of the NRSA T32 program to enhance research training opportunities for trainees interested in biomedical, behavioral, and clinical research relevant to the NIH mission. The UNC RMD Epidemiology and Outcomes Training Program will include pre- and postdoctoral trainees. It will include the following features: Clear core methodologic and content-related competencies to be met by trainees, and supported by the existing infrastructure at UNC and TARC, including our NIAMS-funded Core Center for Clinical Research; linkages to formal training programs in epidemiologic methods and biostatistics (from courses to full degree-granting programs) to provide a strong foundation in research design and analytic techniques, including those through the North Carolina Translational and Clinical Sciences Institute; emphasis on design, execution, analysis, and publication of research projects to enhance the ability of the trainee to conceptualize and think through research problems with increasing independence; experienced and dedicated mentors to guide the developing investigator. We will emphasize rigor and reproducibility, data science principles, and the responsible conduct of research in an intensive but supportive training program. The program will benefit from strong leadership, outstanding faculty from Schools and Departments across the university, and the strong research infrastructure of RAI, TARC, and UNC.

NIH Research Projects · FY 2025 · 2024-05

The prevalence of obesity continues to be higher among Black adults compared to other racial/ethnic groups in the United States, contributing to multiple health disparities. Strong evidence suggests modest weight loss achieved through lifestyle behavior changes can reduce the burden of obesity-related conditions like diabetes, cardiovascular health, and some cancers, yet current standard behavioral weight loss interventions are not optimized for weight loss among Black adults. Cultural adaptation of these interventions is recommended to improve weight and weight-related outcomes. Specifically, familial social networks are considered an important obesity contextual factor to target for Black adults, providing opportunities for provision of social support, resources for coping with stressors, and positive interdependence in achieving joint goals. In the few studies incorporating family members in weight loss interventions targeting Black adults, While this limited research shows promise, the field of family-centered research in obesity has several areas in need of additional research, including identifying the most effective combination of family support and behavior change strategies. Our research team has previously developed and implemented family-centered behavioral weight loss interventions for Black adults, including both couples and family member dyads. weight loss outcomes are enhanced. In these studies, we observed clinically significant short-term weight loss and improvements in hemoglobin A1c; family interactions; dietary, physical activity, and diabetes self-care behaviors; session attendance; and self-monitoring behaviors. Building on these preliminary studies of multicomponent interventions, we propose applying two innovative methodologies to optimize a family-centered behavioral weight loss intervention for Black adults. First, using the engineering-inspired, Multiphase Optimization STrategy (MOST) and a highly efficient experimental design, we will identify which levels and combinations of 4 intervention components yield the greatest weight loss at 6 months. Black adults (n=256 dyads, 512 individuals--index participant with %0, • 30 kg/m2; dyad partner with BMI • 27.5 kg/m2) will receive a core behavioral weight loss intervention and be randomized to 4 additional components: 1) number of family skills sessions (10 vs. 5), 2) delivery mode (in-person vs. online), 3) family communication/conflict skills training (yes vs. no), and 4) family cohesion skills training (yes vs. no). Second, by augmenting the optimization trial with Social Network Analysis (SNA), we will identify the types of interactions dyad members have with their larger social networks (both family and non-family) and how these interactions influence their health and weight loss behaviors. Evidence generated will yield an optimized family- centered intervention for Black adults that can be fully evaluated in a subsequent randomized controlled trial.

NIH Research Projects · FY 2025 · 2024-05

Project Summary/ Abstract Significance: Urinary tract infections (UTIs) are the most common infection during pregnancy. While these infections are typically minor, they are associated with an increased risk of preterm birth, low birth weight, pyelonephritis and sepsis. Despite this, there is insufficient evidence comparing the different antimicrobial treatment regimes. This lack of comparative effectiveness data is particularly concerning given the increasing prevalence of antimicrobial resistance in urinary pathogens. As a result, medical organizations have been unable to provide up to date guidance to patients and providers on best practices for treatment. Specific Aims: The proposed project will not only directly clarify the treatment options; it will also develop tools for future researchers to investigate similar questions. The first aim is to compare the safety and effectiveness of the most common antimicrobials used to treat UTIs during pregnancy, as well as to assess whether antimicrobial choice should be influenced by the patient’s symptomaticity. The second aim of this study is to develop and validate algorithms for the identification of UTIs during pregnancy. Successful development of these algorithms will allow researchers to identify UTIs in large health care data sources. Approach: In Aim 1, we will conduct a cohort study comparing the safety and effectiveness of the five most commonly prescribed antimicrobials for UTIs in US pregnancies. The data source for this study will be the University of North Carolina (UNC) Health System electronic health records (EHR). Approximately 14,000 people who received one of the five most common antimicrobial treatments will be compared on several maternal and perinatal outcomes including: preterm birth, low birthweight, pyelonephritis, spontaneous abortion, stillbirth, maternal sepsis, prescriptions for additional courses of antimicrobials, and antimicrobial switching. We will then examine heterogeneity in antimicrobial effectiveness and safety between people who are symptomatic versus asymptomatic. For Aim 2, we developed two algorithms containing diagnosis and procedure codes that we hypothesize will accurately identify symptomatic and asymptomatic UTIs. We will then manually review patient charts and assess how well the algorithm correctly classifies patients. Fellowship Information: The applicant is a PhD student in Epidemiology at UNC Chapel Hill and a predoctoral fellow at the UNC Center for Pharmacoepidemiology. Mr. Kahrs proposes a training plan that will equip him with the tools to launch a successful career in comparative effectiveness research for pregnant people. This training plan will take place in a thriving collaborative research environment, guided by an established team of interdisciplinary mentors. The outputs from this fellowship will not only help guide clinical care for pregnant people but will assist Mr. Kahrs in his journey towards becoming an independent investigator.

NIH Research Projects · FY 2025 · 2024-05

Project Summary Background: Climate change is driving changes in the thermal environment around the world, with especially strong impacts being felt on tropical islands. The range of temperatures that species can endure (thermal tolerance) will be a determining factor for persistence in the face of climate change. Animals can also mitigate the effects of changing environmental conditions by behaviorally preferring suitable refugia (thermal preference). The genetic determinants of thermal tolerance and how they relate to the genetics of thermal preference remain largely unknown. With this work, I will work to bridge this gap and enhance understanding of the basic biology of thermal physiology and behavior. Significance: The research that I propose will draw upon our lab’s historical datasets of the island’s natural history and its fly community, coupled with a novel combination of classic physiology and behavior experiments with cutting-edge genomic approaches in the lab to study how animals respond to a changing world. Specific aims: In the first aim, I will measure the thermal niches of the São Tomé drosophilids (Drosophila yakuba, D. santomea, and the continental outgroup D. teissieri) and dissect the genetic basis of thermal tolerance in sister species of Drosophila. In Aim 2, I will seek the genetic basis of thermal preference among the São Tomé drosophilids. In Aim 3, I will be positioned to answer the question whether thermal tolerance and behavior are controlled by similar regions of the genome, and thus evolutionarily linked, by comparing the genetic basis of thermal traits uncovered in the first two aims. Methods: I will rear flies in environmental chambers across conditions ranging from 13 to 30°C, which spans the range of temperatures that flies are exposed to on the island and measure survival and reproductive output as proxies for thermal tolerance. I will use custom-designed chambers that expose the flies to a thermal gradient. Flies will be free to move to regions within the gradient that they prefer, and I will track their movement using video tracking techniques. I will use a genome-wide association studies (GWAS) to identify regions of the genome that are associated with thermal tolerance and preference. Finally, I will quantify the amount of polygenic overlap among the physiological and behavioral traits to test whether thermal physiology and behavior are under similar genetic control. Expected outcomes: The work that I am proposing here will provide a novel and comprehensive understanding of the adaptive mechanisms that allow the São Tomé drosophilids to adapt to changing environmental conditions, and it will provide valuable baseline analyses for ongoing long-term studies of drosophilid evolution.

NIH Research Projects · FY 2025 · 2024-05

PROJECT SUMMARY/ABSTRACT This proposal presents a five-year research career development program focused on the neurobiologic mechanisms responsible for oral cancer pain. The candidate is a clinician-scientist and is firmly committed to a career in translational research studying the neurobiology of orofacial pain in pediatric patients. The outlined proposal builds on the candidate’s previous basic and clinical research skills by integrating patient-oriented translational research. Under the mentorship of Dr. Brian Schmidt at New York University, the candidate will have the opportunity to work with a research program that defined the clinical phenotype of a painful orofacial condition, and developed a paradigm that allows investigators to test nociceptive mechanisms responsible for the phenotypic features of the painful condition. The proposed research and career development plan will position the candidate with a unique set of cross disciplinary skills that will enable her transition to independence as a translational scientist focused on the clinical management of orofacial pain in pediatric patients. The incidence of oral cancer is rapidly increasing in the United States. More patients are afflicted with oral cancer than melanoma, cervical cancer, or ovarian cancer. Orofacial pain is one of the most common initial symptoms of oral cancer and often leads to the diagnosis of oral cancer. However, the character, severity, and unique features of oral cancer pain widely differ between patients. There is currently no effective and lasting treatment available to alleviate suffering from oral cancer pain. Clinical and preclinical data suggest that cancer causes pain through the secretion of mediators that activate and sensitize nociceptors; however, the specific contributions of nociceptive mediators and their mechanisms of action (i.e., responsible receptors) are unknown. The foundation for this proposal is based on preliminary studies demonstrating that oral cancer patients experience preoperative sensitivity to capsaicin (i.e., chemosensitivity) and report greater functional (i.e., mechanosensitivity) pain. The outlined experiments will test the hypothesis that the quality of pain experienced by oral cancer patients is dependent on the level of activation of specific channels on nociceptors. The overall objectives of this proposal are to 1) develop and validate assays to quantify mechano- and chemosensitivity in oral cancer patients, and compare the sensitivities to healthy subjects, and 2) determine the receptor subtypes responsible for nociceptive behavior in an oral cancer mouse model. The knowledge gained from the proposed research holds considerable promise for the development of novel, non-opioid treatment strategies that specifically address the unique pain experienced by individual patients. Successful completion of the proposed training plan will provide the candidate with the skills and experience necessary to direct an integrated clinical and laboratory research program to address pain-related challenges in pediatric dental patients.

NIH Research Projects · FY 2026 · 2024-05

PROJECT SUMMARY Infertility affects about 15% of couples, and ovulatory dysfunction is a primary cause with unclear etiology. Studies have found that certain chemicals are reproductive toxicants and impair female fertility. However, these studies are limited to a small number of known environmental chemicals, and there are major gaps in understanding of the impacts of simultaneous exposures to thousands of chemicals (i.e., the exposome) on ovarian function and female fertility. Thus, there is a critical need to evaluate how complex chemical exposures target reproductive organs, to determine potential underlying mechanistic pathways in the metabolome, and to identify important sources of exposures to inform opportunities for prevention and clinical intervention. This research project leverages an integrated exposomics–metabolomics approach to evaluate associations between cosmetic use, chemical exposure biomarkers, ovarian health biomarkers, and female fertility outcomes. Untargeted high-resolution mass spectrometry analysis will concurrently measure up to 100,000 environmental chemicals and endogenous metabolites in human samples of blood and follicular fluid, the latter of which is a localized reproductive biofluid that directly encapsulates oocytes in the ovaries. During the K99 phase, we completed a study evaluating the associations of the untargeted chemical exposome and metabolome in follicular fluid with the reproductive outcome of ovarian reserve (retrieved oocyte count) among a group of 82 patients undergoing egg retrieval for assisted reproduction in Atlanta, GA. During the R00 phase, we will continue our research progress on two studies. First, we will create an untargeted exposome annotation database that includes novel cosmetic ingredients and their biotransformation products and then will develop machine learning algorithms for classifying chemical signatures in the exposome that represent various cosmetic usage habits, based on blood samples from 4,188 women in the Sister Study. This will provide a key resource for other ‘omics health studies, including our own, to retrospectively assess cosmetic exposures in banked biologic samples. Second, we will leverage a sub-cohort of ~350 women in the EARTH study who underwent assisted reproduction in Massachusetts to investigate associations between cosmetic uses, the untargeted chemical exposome, the metabolome, and fertility/birth outcomes using longitudinal samples of both blood and follicular fluid. This study also offers an independent cohort for evaluating shared risk factors and metabolic pathways identified in the previous K99 fertility study. The research in the R00 phase will support the discovery of emerging chemical exposures contributing to infertility, identify their potential biologic pathways of action, improve our understanding of the distribution of chemicals into reproductive organs, identify product sources of harmful chemical exposures, and inform future grant proposals of understudied reproductive health conditions.

NIH Research Projects · FY 2025 · 2024-05

PROJECT SUMMARY Eating disorders (ED) and non-eating disorders internalizing-spectrum disorders (nonED-INT; e.g., major depressive disorder, generalized anxiety disorder, social phobia, obsessive-compulsive disorder, posttraumatic stress disorder) have major public health importance due to their prevalence and significant personal and societal costs. These disorders often onset during adolescence and co-occur. Despite years of psychiatric research, detection and prevention strategies for ED and nonED-INT are not optimal. Little is understood about the developmental course of ED and nonED-INT symptoms, particularly their co-development, and the degree to which shared vs. unique genetic and phenotypic factors underlie ED and nonED-INT risk. In this study, we will elucidate the taxonomy of ED and nonED-INT symptoms: clarifying their joint (i.e., as an overarching internalizing dimension) and specific developmental course and identifying genetic and environmental predictors. We will leverage the rich genomic and phenotypic data from two large and well-characterized cohorts - the Adolescent Brain and Cognitive Development (ABCD) and the Avon Longitudinal Study of Parents and Children (ALSPAC) cohorts. We will deliver developmental models of ED and nonED-INT symptom course, explicate their joint and specific risk (genetic and environmental), and assess differences in models across samples and race/ethnicities. We propose three specific aims: First, using ABCD and ALSPAC data, we will empirically identify trajectories of ED and nonED-INT symptoms across development for each cohort and assess stability of the models across sex, race, and ethnicity. Second, using multi-trait genomic methods, we identify unique and common genetic risk across ED and nonED-INT phenotypes. Finally, we will determine genetic and phenotypic longitudinal predictors of ED and nonED-INT trajectories in each cohort and elucidate the stability and robustness of a predictive model based on both genetic and early-life risk indicators. In the short-term, our results will lend clarity to the taxonomy of ED and nonED-INT. In the long-term, improved understanding of developmental pathways will aid early intervention and identification of high-risk youth.

NIH Research Projects · FY 2025 · 2024-05

Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. ABSTRACT The number of men living with and beyond a prostate cancer (PCa) diagnosis exceeds 3.3 million and is rapidly increasing in the United States. An estimated 30% of PCa survivors develop comorbid conditions (e.g., hypertension, heart diseases, and stroke). Comorbidity is the leading cause of mortality for PCa survivors, surpassing mortality caused by PCa itself. A healthy diet protects survivors from comorbidities and improves PCa survival outcomes, yet few PCa survivors adhere to a healthy diet. Moreover, PCa is often considered a “couple’s disease,” as in both survivors and their partners (i.e., spouses or cohabiting partners) perceive the threats of PCa to their health and life, which may, in turn, increase their receptivity to adopting a healthy diet. Within an intimate relationship, it is likely that one’s diet is influenced by both self-perceived and partner-perceived threats. However, these interdependent relationships have not been examined among PCa survivor and partner dyads. Furthermore, the connection of perceived threats to diet may be influenced by factors at dyadic (e.g., relationship quality) and neighborhood (e.g., area deprivation index and food access) levels. In addition, after PCa survivors and partners perceive the threats of PCa, little is known about how they communicate and collaborate to adopt a healthy diet. To address these knowledge gaps, we propose a multi-method study to investigate the process through which PCa survivors and partners adopt and maintain a healthy diet during the PCa trajectory. Adopting the Actor-Partner Interdependence Model as the analytic model, in Aim 1 we will examine the interdependent relationships between perceived threats and diets and their changes over time. We will use data from 280 dyads of PCa survivors and partners in the Prostate Cancer Education & Resources for Couples (PERC) study (1R01NR016990-01A1). We will also assess how these relationships are moderated by dyadic relationship and neighborhood conditions. For Aim 2 we will recruit 20 dyads of PCa survivors and partners at the University of North Carolina Medical Center and conduct dyadic interviews supplemented with one-to-one interviews to determine how they communicate and collaborate to adopt and maintain a healthy diet. This study aligns with the research lenses of prevention and health promotion in NINR’s 2022-2026 strategic plan. This proposed study, combined with the training plans for career development, serves as my initial step towards becoming an independent behavioral and nurse scientist to develop and test couple-based behavioral interventions for cancer survivors and partners.

NIH Research Projects · FY 2026 · 2024-04

Alcohol use disorder (AUD) affects approximately 14.1 million people in the United States. Despite the prevalence of this disorder, we lack a thorough understanding of its underlying neurobiological mechanisms. One of the major mechanisms believed to contribute to the development of AUD is the dysregulation of central stress systems (Brady & Sonne, 1999). Whereas acute alcohol elevates stress hormones, chronic alcohol intake results in diminished hypothalamic pituitary adrenal (HPA) axis function characterized by a reduced physiological response to stress (Stephens & Wand, 2012). Corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus of the hypothalamus (PVNCRH) are essential for initiating the HPA axis response. Moreover, PVNCRH neurons and HPA hormones show distinct adaptations to chronic stressors, excessive alcohol, and withdrawal from alcohol (Bryon Adinoff et al., 2003; Sivukhina et al., 2006). For example, AUD and abstinence both blunt hormonal HPA axis responses to stress, but basal cortisol production is hyperactive during acute withdrawal and hypoactive during protracted abstinence(B. Adinoff et al., 1998; Stephens & Wand, 2012). While much of the field has focused on the role of PVNCRH neurons in initiating the hormonal response to stress, recent studies have revealed these cells are also critical for stress-linked behaviors that are independent of stress hormone actions (Kim et al., 2019). These include active defensive behaviors (escape), social approach and perseverative, grooming behavior. These studies indicate that PVNCRH neurons orchestrate complex behaviors and highlight new opportunities to probe for how disruptions in local signaling and changes in afferent drive to PVNCRH neurons following alcohol consumption may affect behavior. In addition, preliminary studies from the Bains lab have found that PVNCRH neurons can track the valence of contexts over a scale of time that outlasts behavior. Changes in the activity of these neurons following alcohol exposure may contribute to aberrant patterns of behavior that drive chronic alcohol consumption. Here, we propose to use a multi-faceted approach integrating machine learning based behavioral analysis, cell type specific genetic manipulations, in vivo imaging and ex vivo slice physiology to begin to unravel the role of PVNCRH neurons in alcohol use disorders. We will test the central hypothesis that alcohol drinking leads to heightened activation of PVNCRH neurons driving persistent increases in stress behaviors and that PVNCRH neurons play a critical role in alcohol consumption.

NIH Research Projects · FY 2025 · 2024-04

Project summary/Abstract Adolescence is a developmental period marked by risk-taking behavior and exploration, and over 60% of 12th-graders in the US reported trying alcohol. In fact, 16% of 12th graders reported binge drinking, or consuming 5+ drinking in a session. While human studies show that adolescent binge drinking impacts cognitive performance and neural signals via MRI, it is difficult to tease apart antecedent factors that may lead to binge drinking from the consequences of the resulting alcohol exposure on the developing brain. We and others have used animal models to show that binge-levels of alcohol exposure is sufficient to reduce cognitive and behavioral flexibility in conditioning tasks. Moreover, these behavioral changes are associated with a variety of neurochemical, physiological, molecular and epigenetic changes in the brain. We have reported that adolescent intermittent ethanol (AIE) exposure resulted deficient reversal learning, in that rats perseverated on a previously reinforced choice instead of shifting to a different choice. We also found that AIE-exposed rats exhibited reduced functional connectivity, measured with resting-state fMRI, among regions of interest that underlie behavioral choice. Finally, we and others have reported AIE-induced increases in perineuronal nets (PNNs, extracellular matrix structures that encapsulate parvalbumin (PV)-expressing interneurons) in frontal regions such as the orbitofrontal cortex. This is important as PV+ interneurons contribute to gamma oscillations that would be reflected in functional connectivity measures. However, it is unknown whether AIE-induced increases in PNNs contribute to the AIE-induced behavioral and functional connectivity deficits. This project addresses that knowledge gap by enzymatically degrading PNNs in the OFC of AIE-exposed rats and measuring subsequent effects on reversal learning and functional connectivity MRI. To our knowledge, the resulting data will be the first to link PNN integrity in the OFC to behavioral flexibility and functional connectivity. These data will contribute to our understanding of the mechanisms by which AIE persistently disrupts behavior and brain circuit function and lay the foundation for strategies to ameliorate these effects.

NIH Research Projects · FY 2025 · 2024-04

Abstract: Dry mouth (xerostomia) is one of the most common and severe toxicities that patients experience after radiotherapy (RT) for head and neck cancer. Xerostomia results from RT-induced damage to the salivary glands and is associated with difficulties in chewing, swallowing, speaking, as well as increases in occurrence of dental carries, all decreasing the patient’s quality of life. Existing methods to prevent xerostomia are often not very helpful to the patient, difficult to implement, and can cause additional toxicities. In an attempt to reduce the morbidity of treatment, dose-reduced chemoradiotherapy regimens where patients with favorable-risk HPV-associated tumors are treated with 60Gy (Chera 2019) compared to the conventional 70Gy have been introduced. While dose reduction has led to an overall improved symptom profile, xerostomia remained the most severe patient-reported toxicity. Thus, additional methods to minimize RT- induced xerostomia are needed. Data suggest that salivary stem/progenitor cells, which preferentially reside within the large salivary ducts, have the potential to regenerate salivary glands post-injury. Our hypothesis is that dose sparing of the stem cells within the parotid ducts will improve patient outcomes compared to conventional parotid sparing (i.e., attempting to limit the mean dose of the contralateral parotid gland to less than 26Gy). In order to evaluate the utility of parotid ductal sparing formally, we will conduct a randomized double-blind trial. Patients with oropharyngeal squamous cell carcinomas will be randomized to receive parotid ductal sparing (using MRI-sialography to identify the ducts) or conventional parotid sparing RT.

NIH Research Projects · FY 2026 · 2024-04

Adults in the US have high rates of obesity, diabetes, and nonalcoholic fatty liver disease. These diseases are partially driven by intake of sugar-sweetened beverages (SSBs). Warning labels on product packaging are a widely used public health strategy that could reduce SSB intake. Initial research on SSB warnings is promising. However, the effects of SSB warnings on behavior in realistic settings in the US are unknown. Our overarching objective is to estimate the impact of sugar warnings on SSB purchases. In Aim 1, we will examine the impact of sugar warnings on SSB purchases in an RCT with adults in North Carolina (n=543). The RCT will take place in the Mini Mart, a small convenience store designed to conduct research studies, allowing for experimental control in a realistic setting where participants spend actual money on real products. Participants will be randomly assigned to one of two trial arms: SSBs with sugar warning labels or SSBs with neutral control labels. At each of four visits over four weeks, participants will shop for beverages for their household. We will estimate the impact of sugar warnings on the primary outcome: total sugar purchased from SSBs as well as secondary outcomes, such as purchases of juice or drinks with non-caloric sweetener. Additionally, we will identify the psychological mechanisms explaining how sugar warnings influenced beverage purchases using in-depth qualitative interviews with a subset of RCT participants and longitudinal survey data from the RCT. In Aim 2, we will evaluate new sugar warnings implemented in Mexico in 2020 to examine whether warnings were associated with reduced SSB purchases in the real world. We will use a longitudinal panel of 9,300 households over 5 years (2017-2021), with weekly beverage purchases linked to nutrition data. Using structural demand models, we will estimate the changes in SSB purchases after Mexico's sugar warnings were implemented. We will also estimate how much of the changes in SSB purchases were attributable to changes in consumer behavior (e.g., consumers switching products) or industry response (e.g., the food industry lowering the sugar content of beverages to avoid warning labels). This evaluation will allow us to move beyond the lab to understand how consumers react in the real world over a longer time, and also to measure the additional effects of warning policies on SSB purchases via changes to the products themselves. Together, the two studies will provide estimates of how sugar warnings could affect SSB purchases as well as mechanisms of the impact of sugar warning policies.

NIH Research Projects · FY 2026 · 2024-04

PROJECT SUMMARY / ABSTRACT The proposed research plan will offer critical insight into the cellular and molecular mechanisms that drive the pathogenesis of myotonic dystrophy type 1 (DM1). One prominent feature of DM1 is debilitating, progressive skeletal muscle weakness, for which there is no cure or effective treatment. Skeletal muscles from patients with DM1 exhibit abnormalities in alternative splicing, a post-transcriptional mechanism that enables one gene to produce two or more protein isoforms. As a result, many protein isoforms are inappropriately expressed in DM1 muscles. The alternative splicing of the clathrin heavy chain (Cltc) gene is mis-regulated in skeletal muscles from DM1 patients, resulting in aberrant protein isoform expression during postnatal development and adulthood. Cltc mis-splicing reduces muscle contractile function in mice. CLTC is the main player in clathrin mediated endocytosis, yet also serves as a scaffold for cytoskeletal and endosomal components. The objective of this proposal is to determine the mechanisms by which the mis- regulation of Cltc splicing during development causes muscle weakness. The overall hypothesis is that Cltc mis-splicing, which blocks the inclusion of a 21-nucleotide micro exon during postnatal development, prevents protein scaffolding events that are critical for neonatal muscles to mature into muscles capable of supporting adult contractile needs. Aim 1 will determine the mechanisms by which Cltc mis-splicing disrupts the formation of transverse tubules, structures that are required for contraction and are abnormal in DM1 muscles. Aim 2 will define how Cltc splicing regulates the endo-lysosomal trafficking of ubiquitinated proteins, which is responsible for the downregulation of ion channels and membrane receptors. Aim 3 will determine the functional impact of Cltc mis-splicing on skeletal muscles with different cell type compositions; the pathology of DM1 and other muscle diseases is often cell type specific. Together, these studies will expand our understanding of the role alternative splicing plays in muscle health and disease. One exciting possibility is that Cltc mis-splicing could be redirected by antisense oligonucleotides to treat DM1. These studies will provide outstanding training for the applicant, whose long-term goal is to lead an academic research team. Through this work, she will master skills that are critical for her scientific development including primary muscle cell culture, live-cell trafficking studies, in situ hybridization, muscle contractility studies, molecular cloning, and versatile computational skills. The applicant will undergo exceptional training from her sponsor, co-sponsor, and collaborators at the University of North Carolina at Chapel Hill. She will receive additional support from the institutional environment through research core facilities, topical group meetings, and her department. The proposed research and training plan will build a very strong foundation upon which the applicant will develop her independent research program.

NIH Research Projects · FY 2026 · 2024-04

ABSTRACT While there have been significant gains in malaria control, mainly focusing on Plasmodium falciparum (Pf), Plasmodium vivax (Pv) has been expanding to fix the niche left behind. This phenomenon could be due to the formation of dormant liver forms, called hypnozites, sequestration in extravascular spaces, and early mosquito transmission of sexual staged parasites. Pv was thought to be absent from Africa due to the high prevalence of Duffy- negativity, an antigen on human erythrocytes that was thought to be required for Pv infection. There has been a paradigm shift in this belief due to multiple reports of Duffy-negative invasion throughout the African continent. Despite these reports, there has not been a definitive invasion pathway identified for Pv that facilitates Duffy-negative invasion. This proposal aims to support a promising MD/PhD student's career development and scientifically help us understand the mechanisms that govern Pv Duffy negative invasion through a dual in vitro and in vivo approach, utilizing cutting edge genomics and computational tools to understand the molecular mechanisms of Duffy-negative invasion at the single cell level. By investigating Pv invasion utilizing an in vitro model inhibited by invasion blocking monoclonal antibodies, a novel line of Plasmodium knowlesi that can invade Duffy-negative erythrocytes, and single cell RNA sequencing (scRNAseq) (Aim 1), we will identify invasion pathways that are upregulated to facilitate alternative invasion pathways at the level of the malaria cell cycle stage. We will validate these pathways through isolating Pv samples from an ongoing study in Duffy-positive and Duffy-negative individuals (Aim 2). This work will provide key insights into Pv pathogenesis that will inform malaria control strategies and public health interventions globally. In addition to the scientific training the trainee will gain, he has organized a group of scientific and clinical mentors that will guide his professional development to become a unique clinical scientist at the intersection of infectious disease and maternal health. His training in bioinformatics, clinical practice, and global health research will allow for gains in the understanding of the immense clinical burden of infectious disease in pregnancy, specifically malaria in pregnancy, and a foundational education in his career as a physician scientist.

NIH Research Projects · FY 2026 · 2024-04

ABSTRACT Only about 1% of the mammalian genome encodes for protein yet 80% is transcribed, suggesting that noncoding RNA has many roles in gene regulation. Our research program aims to delineate those roles and the mechanisms involved. Over the next five years, our focus will be the study of long noncoding RNAs (lncRNAs) that function to repress transcription. The most potent repressive lncRNA, Xist, silences transcription across one entire X chromosome during the essential process of X-inactivation. Yet the mechanisms by which Xist and other lncRNAs repress transcription are insufficiently understood. Indeed, at the level of RNA sequence, it is unclear what distinguishes repressive lncRNAs from those that lack repressive activity. This same lack of clarity extends to lncRNAs of all functional classes. Thus, it remains nearly impossible to predict the function of lncRNAs from analyses of their sequence content, stifling progress in the field. At the same time, lncRNAs play critical roles in health. Abnormal expression of genes that lncRNAs target for repression can drive genetic disorders such as Angelman and Rett Syndromes, as well as cancers and autoimmunity. Moreover, uncharacterized lncRNAs are found throughout mammalian genomes, including in regions linked to phenotypic variation and disease, hinting that lncRNAs with therapeutic relevance remain to be discovered. Additionally, we have discovered that many intron-containing RNAs closely resemble known repressive lncRNAs. Although introns are better known for their roles as substrates in the context of splicing, our data raise the intriguing possibility that intronic portions of the nascent transcriptome mediate lncRNA-like regulatory effects. Over the next five years, our research program will reveal fundamental insights into lncRNA biology and transcriptional control that are relevant across cell types and organisms. We expect to determine how RNA sequence and structure confer repressive function to lncRNAs; define new connections between nascent RNAs, RNA processing, and epigenetic regulation; delineate new mechanisms through which RNAs use RNA-binding proteins to control transcription; and identify how the regulatory functions of lncRNAs are modulated by underlying features of the genome. Along the way, we will develop experimental and computational approaches that will enable regulatory RNAs and their mechanisms to be identified across biological systems. Given the centrality of gene regulation in human health and disease, we expect our work to lead to the discovery of etiologies and therapeutic opportunities in many settings.

NIH Research Projects · FY 2025 · 2024-04

PROJECT SUMMARY Objectives: To develop and integrate an innovative artificial intelligence (AI) and machine learning (ML) based intervention focused on physician variability (Aim #1) to be used in the pre- treatment peer-review process to improve RT providers’ performance during these tasks. To implement and evaluate the impact of our integrated intervention on patient safety in the real clinical environment (Aim #2). Rationale: Radiation therapy (RT) plays an important role in the curative and palliative management of many cancers; ≈ 50% of people with cancer in the US receive RT (≈ 600,000 annually). While many advances over the last two decades have improved patient safety (e.g., image guidance, conformal beam shaping), the increasing complexity (e.g., intensity-modulated Presently, up to ≈10% of patients receiving RT are affected by treatment planning errors, with more harm present in minority and underserved populations, which is unacceptable. Using cluster randomized stepped wedge design, we will evaluate RT cases in the baseline period, and after our peer-review processes are adjusted, overtime to, + the providers’ variability data. RT) has created new error pathways. Methods: ‘Optimal’ algorithms and visual summaries of these data will be determined in Aim #1. Patient safety will be quantified via the number/severity of clinically relevant errors not detected during pre-treatment peer-review and detected by downstream QA processes; expressed as the rate per 1000 RT fractions delivered. We will use advanced regression models to evaluate patient safety over time. The significance level will be set at 0.05, two-tailed.

NIH Research Projects · FY 2026 · 2024-04

SUMMARY-ABSTRACT Dynamic oscillations in protein abundance represents the most salient molecular feature of cell cycle progression. This is typified by the cyclins and cyclin kinase inhibitors (CKIs), that oscillate during cell cycle progression and determine the activation kinetics of Cyclin Dependent Kinases, which propel the cell cycle forward. Protein dynamics are not confined to kinase regulators, but rather are exhibited by hundreds of proteins, including regulators of transcription, chromatin organization, cytoskeleton, and metabolism. Defining the pathways, networks and mechanisms underlying these dynamics is essential to understanding proliferative control. Cell cycle protein dynamics are controlled, in part, by the ubiquitin proteasome system. Ubiquitin is the major regulator of protein degradation in eukaryotes and plays an essential and highly conserved role in cell cycle. A cascade of enzymes coordinates the conjugation of ubiquitin onto substrates. However, E3 ligases are the enzymes that ultimately determine when, where and who is ubiquitinated. Like other post-translational modifications, ubiquitin is reversible, and can be removed from substrates by deubiquitinases (DUBs). Thus, the countervailing activities of E3s and DUBs sculpts the proteome to regulate cell cycle progression and the maintenance of genome integrity. The goal of my research is to define enzymes in the ubiquitin pathway that control cell cycle, their cognate substrates, and how specific ubiquitination events contribute to cell cycle progression. To address this goal, the proposed project seeks to address two fundamental questions, which remain understudied. The first relates to key molecular events of G2-phase. Cells arrest in G2 in response to stress and damage and utilize this time to make key decisions about whether to proliferate. However, G2 remains the most poorly studied phase in the cell cycle. We uncovered a widespread program of protein degradation that occurs in G2 and G2/M, and which is regulated by the activity of the multi-functional kinase PLK1. The identity and timing of substrate degradation, the E3 ligases involved, and the consequences of this regulation are almost entirely unstudied. The second question relates to the role of DUBs in cell cycle, which relative to the E3s they antagonize, remain vastly understudied. Using computational and proteomic methods we identified DUBs with understudied roles in cell cycle. We are determining their enzyme kinetics and preferences, substrates, mechanisms of action, and structures when bound to E3 counterparts. We pursue these questions using a combination of cell, molecular and biochemical assays, combined with proteomics and cryo-electron microscopy. Collectively, addressing these questions will identify new regulatory pathways that control cell cycle, proliferative decision making, and the maintenance of genome integrity.

NIH Research Projects · FY 2026 · 2024-04

Modified Project Summary/Abstract Section Obesity-induced liver injury is a significant health concern. In obesity, levels of circulating free fatty acids increase, which are taken up by the liver. Moreover, obesity-induced hyperinsulinemia causes pathway-selective insulin resistance, leading to reduced glucose uptake and increased gluconeogenesis and lipogenesis in the liver. Chronic alterations of these pathways contribute to lipotoxic stress, steatohepatitis, and hepatocellular injury. The resulting accumulation of excess fatty acids and cholesterol as lipid-droplets in hepatocytes is termed non-alcoholic fatty liver disease (NAFLD). With the progression of obesity, the injury and the associated activated macrophages together stimulate hepatic stellate cells (HSCs) into a fibrogenic phenotype, observed in non-alcoholic steatohepatitis (NASH). Sustained fibrogenesis can progress to cirrhosis, and a subset of cirrhosis patients develop hepatocellular carcinoma. Although no FDA-approved drugs are available to treat NASH yet, pathways that reduce body fat, insulin resistance, inflammation and fibrosis are being targeted. Inositol hexakisphosphate kinase-1 (IP6K1) generates the signaling inositol pyrophosphate molecule, 5-InsP7, which is a critical regulator of diverse metabolic functions including insulin secretion and signaling and energy metabolism. Our published studies demonstrated that IP6K1 promotes development and progression of obesity, insulin resistance and NAFLD/NASH. Furthermore, hepatic IP6K1 expression directly correlates with NASH and cirrhosis in humans. These data suggest that pharmacologic inhibition of IP6K1 could be a novel strategy to treat NAFLD/NASH. Here, we propose to utilize a well-established and productive team of researchers along with ligand-based drug design and enzymatic and cell-based assays to develop novel and potent IP6K1 inhibitors and validate their biochemical and functional activities in a mouse model of NAFLD/NASH. At the completion of this work, we expect to deliver a selective and orally available IP6K1 inhibitor suitable for in vivo efficacy studies and a viable method for large-scale synthesis of the compound.

NIH Research Projects · FY 2025 · 2024-04

Knee osteoarthritis (OA) is a leading cause of pain and disability. Exercise is a first-line component of care for knee OA. However, the majority of individuals with knee OA are inactive, and exercise-based physical therapy (PT) is underutilized across health care systems. There are no established processes or pathways for systematically integrating exercise-based therapies into clinical care for knee OA; this is a major contributor to underutilization. We recently developed and tested a STepped Exercise Program for Knee OA (STEP-KOA) as a systematic approach to delivering exercise-based therapies. STEP-KOA begins with a home-based exercise program, supported by evidence-based and behaviorally informed tools (Step 1). After 3 months, patients are evaluated for clinically meaningful improvement in pain and function; patients not meeting criteria for improvement “step up” to telephone-based coaching (Step 2). After an additional 3 months, patients still not meeting criteria for clinically relevant improvement progress to PT visits (Step 3). Patient-centeredness and efficiency are hallmarks of STEP-KOA, as the interventions are based on patient needs and improvement, and the more resource-intensive interventions (particularly PT) are reserved for later stages. In our randomized controlled trial conducted within the Department of Veterans Affairs Healthcare System, STEP-KOA resulted in significant improvements in self-reported pain and function compared with an Arthritis Education control group. We are preparing to conduct a multi-site hybrid type 1 effectiveness-implementation randomized controlled trial (RCT) that will take important steps toward enhancing and implementing STEP-KOA in different health systems. We will add physical activity monitoring, behavioral messaging and tailored exercise prescriptions (that emphasize progression to ensure a sufficient training response) to STEP-KOA. We specifically plan for a 2-site RCT in which individuals with symptomatic knee OA are randomized to STEP-KOA or a usual care / wait list control group., with outcomes collected at baseline, 9 months (end of intervention period) and 15 months (6-month maintenance period). In this planning period, we will: 1) Finalize the scientific details and intervention tools for the multi-site STEP-KOA RCT; this will include enhancing the STEP-KOA patient tools to incorporate the new components, refining tools for STEP-KOA coaches and physical therapists, finalizing training materials and fidelity assessment plans, establishing procedures for telehealth delivery of PT visits, finalizing assessment plans, and establishing the randomization scheme and statistical analysis plan. 2) Finalize the logistical and practical aspects of the multi-site STEP-KOA RCT; this will include identifying referring clinics and PT clinics, addressing regulatory and logistical details, building the study database and developing data management plans, finalizing recruitment and enrollment processes, finalizing the trial budget and preparing the protocol, manual of operating procedures and study timeline. The proposed planning period will ensure our team is prepared to conduct a rigorous and efficient multi-site RCT of STEP-KOA.

NIH Research Projects · FY 2026 · 2024-04

ABSTRACT Endoscopy plays a vital role in the diagnosis and treatment of various medical conditions and is regularly performed millions of times every year. However, endoscopy is challenging in the context of narrow and winding pathways within the body, resulting in incomplete surveys with several ‘blind spots’, and patient discomfort. Researchers have explored various techniques that can assist physicians to perform more efficient endoscopies by enabling better visualization, guidance back to unsurveyed regions, and semi-autonomous procedures. However, these techniques are still clinically infeasible since the required 3D organ reconstructions and endoscope localization is still far from solved. Post-procedure analysis of endoscopic videos to extract and detect meaningful geometric properties, e.g. time-varying measurement of upper-airway cross-sectional area, is also challenging and time-consuming for physicians to perform, and can be automated with 3D reconstruction. Existing approaches for 3D reconstruction from endoscopy videos are primarily based on Simultaneous Localization and Mapping (SLAM) techniques, which are unreliable when faced with typical characteristics of internal organs, such as lack of geometric features, mucus layer reflections, and deformable surfaces. Existing approaches have success rates as low as 40-50% for static shapes. Even these low success rates mostly only apply to easy axial frames and 3D reconstructions may completely fail for deformable surfaces. The goal of the proposed project is to develop a novel 3D reconstruction and localization system that can effectively handle axial and non-axial frames for static and dynamic organs. We propose to develop deep neural network-based computer vision algorithms that can generate 3D meshes from endoscopy videos and determine the position and orientation of the endoscope in near-real time. Our proposed methodology leverages the reflection of the endoscope's light to help recover an organ's shape, along with camera motion (Aim 1), and models time-varying organ deformations (Aim 2). Our focus will be on reconstructing the respiratory tract and colons. However, our approach is entirely general and will apply to other endoscopy reconstructions. We will evaluate our approach on synthetic and real data, validating the results by working with clinical collaborators. In summary, our proposed next-generation 3D modeling system aims to revolutionize endoscopy by providing accurate 3D reconstructions and localization of both static and deformable organs. This advancement has the potential to enhance patient comfort, improve diagnosis accuracy, and enable a wide range of downstream applications in the field of endoscopy, e.g. semi-autonomous maneuvering, guidance to unsurveyed regions, accurate geometric measurements, and better visualization.

NIH Research Projects · FY 2025 · 2024-04

Pancreatic ductal adenocarcinoma (PDAC) is notoriously resistant to therapy and has a dismal 5-year survival rate. Development of PDAC is accompanied by changes in stromal responses and immune surveillance programs, which are now recognized as major drivers of PDAC tumor evolution and contribute to therapeutic resistance. We have recently demonstrated that B cells expressing the immunomodulatory cytokine IL35 are necessary to support the growth of PDAC in murine models. The overarching goals of this proposal are to elucidate mechanisms underlying the tumor-promoting effect of IL35 expression in B cells, and to investigate the translational potential of targeting the IL35 pathway as a novel means to augment immunotherapy for this disease. In Aim 1, we will define essential role for IL35 expressing B cells in establishing an immunosuppressive microenvironment in PDAC using B cell specific knockout of IL35 and chimeric bone marrow reconstitution. In Aim 2, we will clarify how B cell receptor (BCR) and CD40 signaling contribute to induction of IL35 expression in tumor-reactive B cells. To accomplish this task, we will analyze mouse models expressing a fixed BCR with or without antigen exposure, as well as mouse models lacking CD40 signaling in B cells. We will also perform signaling pathway analysis in primary B cells and B cell lines. In Aim 3, we will assess the translational potential of targeting pathogenic B cells in PDAC. Specifically, we will quantify, functionally characterize and study gene expression signature of IL35+ B cell subset in blood and surgically resected tissues from patients with PDAC. Additionally, we will evaluate anti-IL35 therapy in combination with immune checkpoint blockade as a novel therapeutic strategy in syngeneic murine PDAC models. Our proposed research will provide an understanding of a previously uncharacterized facet of B cell-mediated function in PDAC, use state-of-the-art PDAC murine models to test strategies that block immune suppressive pathways in TME to enhance the impact of T cell- reinvigorating therapies, and provide a quantitative and qualitative assessment of IL35+ B cells in human PDAC. This project will expand our understanding of how IL35 shapes the immunosuppressive tumor microenvironment and may inform the optimal design of B cell-directed immunotherapy strategies against pancreatic cancer.