Rutgers Biomedical And Health Sciences

NIH Research Projects · FY 2026 · 2023-07

PROJECT ABSTRACT In April 2022, the U.S. Food and Drug Administration (FDA) announced a proposed ban on menthol cigarettes and all characterizing flavors in cigars. African Americans have high rates of menthol cigarette and flavored cigar use, which likely contributes to their disproportionate experience of tobacco-related health conditions. In response to the FDA’s announcement, the tobacco industry and its sources promulgated disinformation in African American communities about the increased criminalization and police discrimination for using tobacco products when the rules are enforced. Although the FDA has stated that it cannot and will not enforce actions against individual consumers for possessing or using menthol cigarettes or flavored cigars, disinformation about the flavor ban and its harmful impacts continues spreading among African American communities. The proposed study seeks to develop and evaluate the effectiveness of multi-level, anti-disinformation messages (ADM) to disrupt the spread and mitigate the detrimental effects of disinformation about the FDA’s proposed ban on menthol cigarettes and flavored cigars. In Aim 1, we will employ community-based participatory research methods to develop and engage with an Expert Advisory Board (EAB) that will engage in shared decision-making and provide their perspectives on all study activities. In Aim 2, we will conduct formative research to a) characterize the tobacco industry and its operatives’ rhetoric about the consequences of the anticipated flavor ban and b) elicit AA/Bs’ knowledge and perceptions about the anticipated flavor ban. Aim 2 data will inform the development of the Intervention Mapping (IM) logic models that depict the behavioral and environmental risk factors and determinants of respondents’ flavor ban receptivity. In Aim 3, we will use of IM process to develop, pre-test, and refine the individual and community-level ADM and creative concepts among AA/B participants. Finally, in Aim 4, we will conduct a randomized treatment and control evaluation design to test the effectiveness of our individual and community-based ADM campaign on AA/Bs’ receptivity to the flavor ban and counter- industry beliefs. Knowledge gained from this study will inform the FDA’s Center for Tobacco Products Communication Office and state and local public health departments regarding salient messages to communicate about the flavor ban to AA/B and other vulnerable populations.

NIH Research Projects · FY 2025 · 2023-07

Project Abstract Surgery is often indicated when asymptomatic gallstone disease, with a prevalence as high as 20% in the US population, becomes symptomatic; this occurs when gallstones block the digestive drainage of the gallbladder, pancreas, liver, or intestine. Cholecystectomy, occurring in a million people in the US annually, is the surgical removal of the gallbladder to treat this diagnosed symptomatic gallstone disease (dSGD). Whether patients have a more morbid and costly emergency rather than a non-emergency cholecystectomy, may depend on many factors which are largely unknown. However, since emergency cholecystectomy has been suggested to possibly have 5 to 10x the mortality elective cholecystectomy has, if gallstone disease could be avoided completely via high-quality prevention and non-surgical therapy, or when surgery is indicated it could be elective rather than an emergency, overall mortality from this extremely common condition might be reduced. The objective of this K23 is to start population-based research on disease requiring emergency surgery, currently representing over two- thirds of healthcare delivery in US hospitals and alarmingly over half of total mortality and cost. This will begin with a study of the frequency of, and mortality from, emergency cholecystectomy, informed by the overall population experience with dSGD. The main hypothesis of this study is emergency has higher mortality than non-emergency cholecystectomy; if the natural history of dSGD were shifted from emergency to non-emergency cholecystectomy this leads to a decrease in the overall mortality rate with dSGD. The goal this program of research begins will be to provide population-based data to decrease less safe emergency surgery, moving toward safer non-emergency surgery or non-surgical care, decreasing the overall US mortality of dSGD in the process. The proposed study fits well with the candidate’s career development goals and 4-year training and mentoring program to evolve into an independent clinical epidemiologist studying digestive diseases requiring emergency surgery. The candidate is pivoting from a primarily clinical career to a research career. He has strong experience in emergency surgery and public health, and seeks training in rigorous clinical epidemiology methods, claims data research, deeper biostatistical expertise, new skills to collaborate on mixed-methods patient-oriented research, and a mentored transition to designing new etiologic studies of his own. The mentorship team consists of recognized experts in clinical epidemiology research and training, gallstone epidemiology, inferential biostatistics, prevention and qualitative methods, and emergency surgery, who will oversee the execution of the training and career development plan. Research and training will occur at Rutgers, which is a ripe environment for fostering this junior investigator through a transition to research independence. At the conclusion of this project, the candidate will have documented the natural epidemiology and the overall mortality of dSGD in the US, and how this may or may not have changed in response to increasing health insurance. This will inform the candidate’s design of future etiologic (R01) studies to understand and eventually to reduce mortality from dSGD.

NIH Research Projects · FY 2025 · 2023-07

ABSTRACT: Infections of the lung significantly impact health worldwide, with non-tuberculosis lower respiratory infections causing 2.7 million deaths annually and chronic infections significantly contributing to impaired lung function and morbidity. Pulmonary macrophages are critical, front-line mediators of host protection against helminth parasites, fungi, and viruses. Despite the well-defined role of lung macrophages as crucial initiators of immunity to diverse sets of pathogens, our understanding of the cellular and molecular events that regulate macrophage responses in the lung remain poorly defined. For example, the precise mechanisms that allow pulmonary macrophages to eliminate both intracellular and extracellular pathogens while simultaneously mitigating tissue injury and preserving lung function remain elusive. Further, an emerging body of literature has now revealed that macrophage populations in the lung are more heterogeneous than originally appreciated. Specifically, it is now understood that alveolar macrophages present in the lung can originate from embryonic precursors (tissue- derived alveolar macrophages-TD-AMs) or from blood monocytes (monocyte-derived alveolar macrophages- Mo-AMs). Despite this important advance, it is currently unclear whether these ontologically distinct pulmonary macrophage populations perform comparable or distinct functions in mediating protection (reduction in pathogen burdens and/or maintenance of tissue integrity). Also, whether these distinct macrophage populations initiate similar or unique effector functions in the context of helminth, fungal, or viral challenges remains unknown. Finally, our understanding of how a previous exposure to one pulmonary pathogen alters the responsiveness of lung macrophages to a subsequent challenge with a distinct pathogen is poorly understood. This important gap in knowledge has become extremely evident during the COVID-19 pandemic where individual outcomes vary dramatically and we have a poor understanding of how one’s infectious past may contribute to these differences. The leaders of this project will employ their combined expertise to address these critical questions. The central hypothesis of this application is that infection with diverse pathogens program TD-AMs and Mo-AMs to perform distinct functions against heterologous pathogens while mitigating tissue injury. We further hypothesize that the pathogen-induced response of TD-AMs and Mo-AMs is critically shaped by neutrophil-derived signals and type I and III interferons. In three distinct and complementary aims we will use a combination of discovery-based studies combined with targeted in vitro and in vivo approaches to define the overlapping and unique contributions of tissue-derived macrophages and recruited monocyte-derived cells to host protective responses following helminth, fungal or viral infections. This thorough and comprehensive approach will allow us to gain an unprecedented understanding of fundamental innate immune functions. This novel insight may inform therapeutic strategies to target lung macrophage populations in a manner that will allow for the fine tuning of inflammation and pulmonary infection outcomes.

NIH Research Projects · FY 2026 · 2023-07

Trauma is the leading cause of death for children and adults 46 years and younger, killing more Americans than AIDS and stroke combined. African Americans (OR 1.2, P<0.001), people living in high poverty neighborhoods (OR 1.01, P<0.001), and those enrolled in public health insurance programs (OR 1.53, P<0.001) have increased mortality after trauma when compared to their injured counterparts. Quantifying disparities in access to Emergency Medical Services (EMS) and designated/verified trauma centers (TCs), as well as the extent to which timely access to care improves health outcomes are critical first steps to address this alarming discrepancy. Expeditious availability to EMS has yet to be evaluated and timely access to TCs is understudied. In fact, no one has explored the importance of expeditious availability to emergency health care services such as EMS and timely access to emergent trauma care as key social drivers of health (SDoH). Models to evaluate the role of SDoH as major predictors of these disparities remain untested. Rapid transport to a TC is associated with a 25% reduction in mortality; however, nearly 45 million Americans lack timely access to a verified TC. When compared to majority populations, recent data show some populations have significantly less access to TC and worse outcomes following trauma. Understanding the factors that determine trauma-related socio-spatial disparities can inform interventions at both the policy and system levels to mitigate the disproportionately large numbers of deaths experienced by some populations. Thus, there is a compelling need for research in these areas to facilitate targeted interventions to eliminate socio-spatial disparities within the pre-hospital phase of the emergency trauma care system to improve patient outcomes. To evaluate socio-spatial disparities in availability and access to both EMS and to TCs among critically injured trauma patients, we will evaluate the pre-hospital phase of the emergency trauma care system (availability to EMS, EMS response time, EMS scene time, EMS transportation time, EMS decision to transport to TCs vs. non-TCs, and EMS total prehospital time) and use large national databases to develop spatiotemporal models to assess drivers of disparities in traumatic injuries. Our interdisciplinary team will use data science methods and novel analytics to address this critical public health need by identifying health disparities at the level of the pre-hospital emergency trauma care system.

NIH Research Projects · FY 2026 · 2023-07

Project Summary/Abstract Antibiotic resistance is a rapidly growing threat to human health, further exacerbated by the limited development of new antibiotics. Thus, there is a dire need for research informing the design of new therapeutic options to counter the rise of antibiotic resistance. Polymyxins are cationic antimicrobial peptides that associate with the outer membrane of Gram-negative (GN) bacteria through electrostatic interactions and are considered the last line of defense against multi-drug resistant GN bacterial infections. Yet, resistance to polymyxins develops often and with relative ease, due to modifications that bacteria have developed as defenses against antimicrobial peptides (AMPs) produced by the innate immune system or secreted by other bacterial species. Modification of Lipid A, the lipidic anchor of the bacterial lipopolysaccharide (LPS or endotoxin) decorating the outer membrane of GN bacteria, with diverse chemical moieties, is a common mechanism leading to resistance to antimicrobial agents. In E. coli, S. enterica and P. aeruginosa, “capping” of the phosphates of Lipid A with an aminoarabinose moiety (L-Ara4N) is the predominant modification leading to resistance against polymyxins and AMPs. The aminoarabinose “cap” is synthesized by GN bacteria through an enzymatic relay of eight proteins collectively called the aminoarabinose biosynthetic pathway. The mechanistic basis of function for the membrane enzymes of the pathway is poorly understood, in large part due to the technical challenges associated with studying enzymes that function at or near the membrane and utilize lipidic substrates. As part of this research program, we will use a variety of experimental techniques, including cryo-electron microscopy (cryoEM), mutagenesis, bacterial growth assays, bacterial genetics, and microscale thermophoresis (MST), to achieve the following core goals: (1) Structure determination and substrate-binding characterization for the three bona fide membrane enzymes that operate in the aminoarabinose biosynthetic pathway (the polyprenol phosphate glycosyltransferase ArnC, the deformylase ArnD and the lipid-to-lipid glycosyltransferase ArnT), and (2) Investigating the mechanistic basis of enzymatic function, metal cofactor coordination, and catalysis, in each of the three membrane enzymes under study. The research program will leverage our multidisciplinary training in membrane protein biochemistry and structural biology, and experience gained from having successfully solved several structures of the enzyme ArnT bound to different lipidic substrates. The impact of the program lies within its potential to: i) Provide detailed mechanistic insights into the structural basis of a diverse set of enzymatic functions responsible for aminoarabinose biosynthesis and polymyxin resistance in GN bacteria, ii) Advance our understanding of protein-lipid interactions with undecaprenyl phosphate, as all three enzymes under study utilize undecaprenyl phosphate as either a donor or acceptor substrate, and iii) Inform structure-based drug design of compounds capable of restoring susceptibility to polymyxins by targeting enzymes of the aminoarabinose pathway.

NIH Research Projects · FY 2025 · 2023-07

PROJECT SUMMARY In this study, I seek to understand how common and rare genetic variation influences the risk of developing obsessive-compulsive disorder (OCD). OCD is a disabling psychiatric condition with unclear pathophysiology, which has hindered the development of effective treatments and interventions. Although there is strong evidence of genetic contribution to OCD risk, decades of research have not yet produced reproducible, statistically significant findings that identify high-confidence risk genes. In contrast, other neurodevelopmental psychiatric disorders (NDDs)—including schizophrenia, attention-deficit/hyperactivity disorder (ADHD), and autism—have seen major advances through genome-wide association studies (GWAS) and whole-exome sequencing (WES) in large samples. These efforts have identified risk loci and genes, paving the way for novel therapeutic targets. Similar progress in OCD is expected as sample sizes increase and multi-omic approaches are applied. However, most existing OCD studies have focused on individuals of European ancestry (EA), limiting generalizability and our understanding of genetic risk in diverse populations. Expanding studies to include globally diverse populations is essential for comprehensive risk gene discovery. Such inclusion facilitates finemapping through differences in allele frequency, enables the investigation of recent rare and ancient functional alleles that may be absent in EA cohorts, and allows examination of complex inheritance patterns such as compound heterozygosity and digenic/oligogenic models. These approaches are vital to advancing our understanding of psychiatric disease biology. To address this gap—and with the ultimate goal of identifying the role of common and rare deleterious variants in OCD—I will analyze rare and common genetic variation in OCD samples, building on prior work during the K99 phase, during which I collected 380 Latin American ancestry (LA) OCD trios. These will be combined with 150 trios from the Rutgers Center for Genomics of Psychiatric Health, totaling 530 trios for this project. The main objectives are to: a) Identify OCD risk genes impacted by rare deleterious variants via meta-analyses with OCD case-control data from the LATINO study; b) Identify OCD risk genes impacted by common variation using ancestry-informed GWAS; and c) Contribute all data to the Psychiatric Genomics Consortium (PGC) OCD Working Group and LATINO consortium to enhance statistical power and fine-mapping of risk loci. While previous OCD studies have largely relied on broad case-control comparisons, this proposal will integrate genomic data from trios with clinical and environmental variables—such as trauma exposure, treatment history, and geolocation—to uncover gene-environment interactions and modifiers of genetic risk. These analyses will move beyond diagnostic categories, allowing for phenotype refinement and the identification of biologically meaningful dimensions of heterogeneity. Finally, we will begin exploratory work to evaluate whether OCD risk genes converge with cortical structural alterations and transcriptomic profiles, contributing to a deeper neurobiological understanding of OCD

NIH Research Projects · FY 2024 · 2023-07

PROJECT SUMMARY Specifically, this proposal focuses on novel new small molecules that inhibit both the blood and liver stages of malaria infection. The causative pathogen – Plasmodium spp. – was responsible for 241,000,000 cases that resulted in 627,000 deaths in 2020. Plasmodium spp. drug-resistant infections leave few good choices for physicians and put at risk the productivity and the lives of those infected. A clear case has been made for new drugs to treat these infections through the discovery and development of novel therapeutic strategies. These strategies would optimally be dual stage, targeting the blood stage for treatment and the liver stage for prophylaxis. The innovative strategy in this proposal builds on the technology of machine learning models for the prediction of novel dual-stage antimalarial small molecules with significant potential as drug discovery entities. Such a computational approach to seed the discovery of small molecule malaria parasite inhibitors with dual- stage efficacy has only been reported by us in 2022. The approach begins with preliminary data around two novel antimalarial small molecules with demonstrated in vitro efficacy versus both blood and liver stages of Plasmodium spp. infection and a lack of significant cytotoxicity to cultured liver cells. These molecules were derived from a set of hits discovered with a random forest model trained with high-throughput screening data. The molecules are representative of novel chemotypes for dual-stage antimalarials and, thus, offer a high probability of modulating new targets that are critical throughout the parasite’s lifecycle. This initial machine learning effort will be significantly expanded with a range of model types and a different and larger commercial library to predict a set of new hit compounds. Two validated hits, meeting in vitro efficacy and cytotoxicity criteria and maintaining wild type in vitro efficacy versus a set of drug-resistant parasite strains, will be profiled for key molecular properties such as mouse liver microsomal stability, aqueous solubility, and mouse pharmacokinetic profile. These data along with the existing in vitro efficacy and cytotoxicity evaluations will guide the evolution of each hit with a goal of preparing one or more analogs with a composite profile to enable downstream in vivo efficacy evaluation in infection models. A novel combination of medicinal chemistry and machine learning will be leveraged to afford such molecules.

NIH Research Projects · FY 2025 · 2023-07

Project Summary/Abstract The over-arching goal of the current program is to unify the training in substance use disorder research at Rutgers Piscataway/New Brunswick encompassing the existing strengths in basic and human imaging research. The result is the Rutgers Training Program in Addiction Research (TARP), which aims to recruit a diverse group of outstanding predoctoral and postdoctoral researchers and provide them with rigorous and comprehensive training in interdisciplinary addiction-focused research. The goal is for all trainees to gain an appreciation of addiction neuroscience research from cells to circuits to behavior. Our faculty members represent an extraordinary range of addiction research expertise, from epigenetics to human imaging. The thirteen participating mentors, who together hold over $10 million dollars in annual active research support, have decades of collective experience training dozens of students and fellows who have gone on to successful careers in academia, industry and government. More senior program mentors include Drs. Gary Aston-Jones, Danielle Dick, Zhiping Pang and David Zald. The program director, Dr. Chris Pierce, initiated and co-directed a NIDA-funded translational addiction training program (pre- and postdocs) for over nine years at the University of Pennsylvania before he moved to Rutgers in early 2020. The proposed predoctoral and postdoctoral training programs are integrated through events, programs and courses designed to foster interactions among trainees as well as the Rutgers addiction research community as a whole. These joint activities satisfy many of the goals of the program including practice communicating research findings, instruction in contemporary addiction neuroscience research, grant writing, critiquing the addiction neuroscience research literature, networking, leadership, career development, etc. All training activities also emphasize ethical conduct of research and the importance of scientific rigor and reproducibility. Although the research and didactic aspects of the Rutgers TARP are neuroscience focused (basic science and human imaging) we also strive to give our trainees a better understanding of the totality of the field including the challenges associated with developing treatments for substance use disorders. Our over-arching goal is to better equip the next generation of addiction neuroscience researchers to apply novel and innovative approaches to develop new therapies, which are needed now perhaps more than ever.

NIH Research Projects · FY 2026 · 2023-07

Abstract GABAergic cortical interneurons (cINs) play critical roles in balancing, synchronizing, and gating brain activity by inhibiting other neurons. Their malfunction, especially those of medial ganglionic eminence (MGE)-derived cINs, has been associated with various neurodevelopmental brain disorders, such as schizophrenia (SCZ) and autism spectrum disorders (ASD). Considering the fact that the divergence between human brains and rodent brains has resulted in the failure of many central nervous system (CNS) therapeutics validated in rodent models, it is critical to study human neurons to better understand the mechanisms of these cIN-associated brain disorders. Human fetal brain tissues are not accessible for mechanistic studies, but we have developed a method to efficiently generate homogeneous populations of MGE-type human cINs from pluripotent stem cells (PSCs) of healthy or diseased subjects. We have extensively characterized them and demonstrated their authenticity and functionality, making it possible to study the converging functional consequences of complex genetics in real patient neurons, which cannot be studied in mouse neurons due to a lack of conservation of non-coding regions, where most of risk loci are present. However, in vitro cultured neurons lack other critical components of the brain environment, such as astrocytes, oligodendrocytes, microglia and blood vessels, which can significantly impact their function. There have been efforts to optimize in vitro culture systems to better recapitulate in vivo physiological environments by adding other brain cellular components, but there are still limitations as to how closely they can simulate in vivo situations. To resolve this issue, in our previous study, we pioneered human neuron-mouse brain chimeras to study the function of human SCZ neurons in physiological environments. Although we were able to successfully identify SCZ cIN-intrinsic connectivity deficits in mouse brains, we were not able to analyze the impacts of grafted neurons on brain circuits and behaviors due to the presence of healthy mouse neurons in the grafted mice. Thus, in this proposed study, we will perform brain-region-specific cIN-ablation in NodScid gamma (NSG) mice, followed by the replacement of ablated host cINs with human cINs to generate region-specific humanized cIN chimeras. Based on previous studies, including ours, that show successful restoration of compromised mouse inhibition by grafted human cINs, these mice will allow us to analyze the functional impacts of grafted human cINs on the brain circuits and behaviors in physiological in vivo environments. This novel physiological model system will help us tease apart cell-type- and brain-region-specific disease mechanisms for complex brain disorders, and aid in developing novel therapeutics.

NIH Research Projects · FY 2025 · 2023-07

PROJECT SUMMARY Poor sleep quality is a very common symptom in the WTC General responder cohort (WTCGRC). Comorbid conditions including obstructive sleep apnea (OSA) can contribute to poor sleep quality and daytime sleepiness and may affect cardiovascular health similar to the general population. The consequences of untreated OSA include disturbed sleep, excessive daytime sleepiness, and an increased risk for major adverse cardiovascular events (MACE). In OSA patients, plasma biomarkers associated with MACE such as highly sensitive C-reactive protein (hs-CRP) are elevated. We have previously shown in the WTC-CHEST study (NCT01466218) that presence or high risk of OSA is associated with elevated levels of hs-CRP. In the current proposal, we will evaluate whether CV risk in these WTC-CHEST OSA subjects is similar to the general population, and if hs-CRP is a predictor of MACE. Three distinct clinical phenotypes of OSA have been described: 1) a sleepy phenotype (2) a disturbed sleep phenotype and 3) a minimally symptomatic phenotype. WTCGRC with OSA has almost a 50% prevalence of the disturbed sleep phenotype in contrast to other populations with OSA, where the sleepy phenotype is predominant. The pathophysiology of OSA is complex and multifactorial and has been described using polysomnographically (PSG) determined endotypic traits: impaired upper airway anatomy, low arousal threshold, high ventilatory loop gain and altered neuro-muscular control of upper airway muscles. Our preliminary data shows that unlike in other populations, low arousal threshold endotype is the primary physiological endotype that leads to OSA. However, the relationship between endotypes and clinical phenotypes are unknown. In this proposal, we will determine whether the low arousal threshold physiological endotype is associated with the “Disturbed Sleep” clinical phenotype. We will also examine the association between a recently developed PSG index, the odds ratio product (ORP-9) that measures excessive overnight wakefulness and physiological endotypes and clinical phenotypes as a biomarker of disturbed sleep. There have been no studies determining the association of clinical phenotypes of OSA and plasma hs- CRP. Therefore, the third aim of this proposal will determine whether the “Disturbed Sleep” clinical phenotype of OSA in the WTCGRC is associated with increases in plasma hs-CRP. Finally, we will determine the relationship of hs-CRP with poor sleep quality in subjects without OSA but with other comorbidities in the WTCGRC. The studies proposed in this project will significantly advance our understanding of the consequences of poor sleep in the WTCGRC and will inform future screening recommendations for these participants.

NIH Research Projects · FY 2026 · 2023-07

Abstract Schizophrenia (SCZ) is a highly heritable and complex neurodevelopmental disorder. Remarkable advances have been made recently in SCZ genetic studies with an increasing number of risk loci reaching genome-wide significance; however, gleaning biological insight from these loci has been challenging. The majority of SCZ risk loci are located in non-coding regions. As such, it is hypothesized that they function by regulating distal gene expression via 3D chromatin interactions. However, it has yet to be determined which loci are operational in which cells, at what time points, and with what impact. Recent genomic analyses showed enriched SCZ heritability in human fetal brains rather than adult brains, suggesting the role of SCZ risk loci in modulating fetal development for increased SCZ risks. Thus, unraveling SCZ risk loci function during development will be critical for understanding genetic influences on SCZ risks. Genetic influences on gene expression (e.g. expression quantitative trait loci (eQTLs)) are cell-type-specific, and sometimes confer opposing effects depending on the cell type, underscoring the importance of cell-type-specific studies using homogeneous cell populations for a clear mechanistic understanding. Parvalbumin (PV)- or somatostatin (SST)-expressing medial ganglionic eminence (MGE)-derived cortical interneurons (cINs) are consistently affected in SCZ brains. More importantly, SCZ heritability is shown to be enriched in MGE cells in human fetal brains, necessitating the study of these cells to understand the mechanisms of SCZ risk loci. Although there are no postmortem fetal SCZ tissues for mechanistic study, in vitro differentiation of iPSC—which well recapitulates early embryonic development— provides developmental SCZ brain cells with the same genetic makeup as patient brains. We established methods for the efficient generation of homogeneous populations of MGE-derived cINs from healthy control (HC) and SCZ iPSCs. We also extensively validated their functionality and authenticity both in vitro and in vivo, including robust migration and synaptic integration into host brains that results in efficient inhibitory regulation of host circuitry in transplanted mice. Using an unprecedentedly large number of iPSCs to provide homogeneous populations of HC vs SCZ fetal cINs for mechanistic studies, we will address our hypothesis that SCZ risk loci active in developmental MGE-type cINs regulate distal gene expression via 3D chromatin interactions. Employing transcriptome analysis, PrediXcan analysis, and Micro-C analysis, we will map SCZ risk loci with unknown functions to the risk genes they regulate in these vulnerable cell populations during development. Developmental cIN-specific genetic influences on gene expression, identified based on multiple lines of corroborating evidence, will be functionally validated using CRISPRi/CRISPRa approaches. This unbiased genome-wide comprehensive data set from developmental MGE-type cINs with functional validation will provide a road map for unravelling the genetic basis of developmental SCZ risks and help us identify mechanism-based novel therapeutic targets.

NIH Research Projects · FY 2025 · 2023-07

Project Summary/Abstract Childhood cancers require lifelong risk-based follow-up care tailored to their treatment exposures, including routine medical appointments, monitoring for late effects, and regular cancer screenings. Unfortunately, less than 1 in 5 adult survivors of childhood cancer obtain such risk-based follow-up care. The transition from pediatric to adult follow-up care for adolescent and young adult (AYA) survivors is a critical period when many survivors are lost to follow-up, particularly AYA survivors who identify as Hispanic or have low self-efficacy to manage their care. While the barriers to care are well-characterized, there are no efficacious interventions to help improve this transition for AYA survivors of childhood cancer. To address this gap, we developed Managing Your Health, a digital self-management and peer mentoring intervention to improve survivorship care self-management. It consists of six 1:1 virtual sessions with a peer mentor, another young adult survivor who independently manages their own care. Each session involves discussion of a complementary web-based self-management educational module. Peer mentors act as supportive accountability agents, providing specialized support based on shared experience and facilitating engagement with the modules. Our preliminary two-arm randomized feasibility trial showed that survivors found the intervention useful, were highly engaged, and reported significant improvements in self-management. Per participant feedback, we translated the web-based modules into a mobile app for easier accessibility. The goal of this project is to evaluate the efficacy of Managing Your Health (app + peer mentoring) compared with educational control in a two-arm randomized trial with 300 young adult survivors of childhood cancer currently aged 18-25 years. We will oversample for AYA survivors who identify as Hispanic given evidence of low self- efficacy and follow-up care in this group. Participants will complete outcome measures at baseline, 3 months, and 12 months post-randomization, with medical record abstraction for guideline-concordant care at 12 months. Specific aims will evaluate the efficacy of the intervention on self-management behaviors, quality of life, and adherence to guideline-concordant follow-up care, as well as mediators and moderators of treatment effects. The proposed research aligns with priorities detailed in the notice of special interest “Navigating Pediatric to Adult Health Care: Lost in Translation,” and seeks to address gaps in the long-term health care of childhood cancer survivors by evaluating an innovative theory-based intervention to facilitate the transition from pediatric to adult self-management of care.

NIH Research Projects · FY 2026 · 2023-06

PROJECT SUMMARY: Asthma is characterized by chronic inflammation and bronchial obstruction due to human airway smooth muscle (HASM) shortening. However, the underlying basis for an enhanced shortening or the hyper-contractile state of HASM in asthma is not known. Further, our incomplete understanding of type 2 (T2) inflammation- regulated excitation-contraction (E-C) coupling in HASM shortening has hindered the development of new HASM bronchodilators with a novel mechanism of action for over 60 years. This application seeks to gain a foundational knowledge on the mechanical endotypes of HASM shortening in asthma (inflammation-dependent and -independent) and identify improved bronchodilators that are less susceptible to tolerance and less affected by immune inflammatory responses in asthma, focusing on previously unrecognized mechanisms evoked by bitter taste receptors (TAS2Rs) expressed on HASM. Our preliminary data, in pre-clinical models, support a premise that the immunologic and/or pathogenic mechanisms associated with a sustained mechanical reinforcement of HASM shortening, and the loss of β2-adrenoceptor (β2AR)-mediated bronchodilation, involve a transcriptional repressor function of the polycomb group (PcG) protein EZH2 (enhancer of zeste homolog 2). Further, our preliminary studies find a mechanistic role for microRNA-214 (miR-214) in TAS2R-evoked translational inhibition of EZH2. Based on these results, we hypothesize that TAS2Rs on HASM inhibit T2 cytokine-regulated E-C coupling in HASM shortening and the physiological loss of β2AR function in EZH2- and miR-214-dependent manners. Our goals are, first, to characterize T2- and non-T2- mediated molecular kinetics and mechanics of E-C coupling in HASM shortening and, second, determine miR- epigenetic nexus (i.e., non-genetic mechanisms) by which TAS2R activation promotes the functional efficacy of β2ARs and inhibits the mechanical endotypes of HASM shortening in asthma. Toward this end, we will leverage our unique technological innovations of single-molecule and single-cell micromechanical methods and integrative genetics and genomics approaches in clinically relevant human precision cut lung slices (hPCLS) and primary HASM cells derived from donor lungs of patients with and without severe asthma. When successful, the knowledge gained from these experimental and computational studies will: 1) shed new light on inflammation-dependent and -independent regulation of E-C coupling in HASM shortening; 2) uncover previously unidentified TAS2R paradigms to mitigate the physiological loss of β2AR function; and 3) establish new druggable targets and agents to treat β2-agonist-insenstivity in a large cohort of patients with difficult-to- control and severe asthma. This line of research is underappreciated in asthma and represents a clear shift in the asthma treatment paradigm.

NIH Research Projects · FY 2025 · 2023-06

There is a central problem in biological learning known as the “credit assignment problem”: how does information about the outcome of a decision or behavior modify the right synapses in the right neurons across multiple brain regions to improve future performance? The standard solution to this problem in artificial neural networks is to perform direct gradient descent, which minimizes error in the output of a network by precisely adjusting the strengths of every connection in proportion to that error. However, it is unlikely that the brain is able to compute the impact of each synapse on performance error and “backpropagate” fine-grained error signals across multiple layers of neuronal circuitry to every synapse. Recent work identified a new candidate biological mechanism for supervised learning in the brain. In addition to “bottom-up” connections that process sensory inputs, neurons also send “top-down” connections to the dendrites of neurons in lower layers. This feedback drives special events called “dendritic calcium spikes” that induce a potent form of synaptic plasticity and cause neurons to become selective for stimulus features in as few as a single trial, a phenomenon called “one-shot learning.” This project aims to develop new learning theory inspired by these experimental observations, and to experimentally test predictions of this theory in awake, behaving mice to better understand how top-down instructive signals in the brain coordinate learning across multiple layers of neuronal circuitry by regulating dendritic calcium spiking and associated plasticity. The team synergizes expertise in neuronal cellular and synaptic physiology, systems and computational neuroscience, and machine learning to better understand an important cognitive function - memory formation during goal-directed learning. A major objective is to develop and critically test a new theory of learning based on the regulation of dendritic calcium spikes and associated synaptic plasticity. Computational modeling will directly inform the proposed experiments, which entail imaging and manipulating neuronal population activity in vivo during spatial foraging behavior in mice. Preliminary results suggest that incorporation of these insights from biology into artificial neural networks leads to enhanced performance compared to standard techniques, highlighting the transformative potential of the proposed approach.

NIH Research Projects · FY 2026 · 2023-06

Project Abstract: Rhinoviruses (RV) have been impugned in the development of asthma and are the leading cause of acute asthma exacerbations. RV exposure evokes inflammation of the airways, but how RV modulates human airway smooth muscle cell (HASM) function to alter bronchomotor tone is unclear. HASM is the pivotal cell modulating airway tone, shortening in response to contractile agonist stimulation through increases in intracellular calcium, through activation of Rho kinase, and through modulation of actin dynamics. We previously showed that RV exposure evokes AHR in human precision cut lung slices (hPCLS), increases [Ca2+]i in HASM, and increases agonist-induced phosphorylation of myosin light chain in HASM from human airway epithelial cell (HAEC)/HASM co-cultures stimulated with RV-C15. We also demonstrate that RVC exposure attenuates β2 agonist-induced bronchodilation in hPCLS, cAMP production in HASM, and attenuates bronchodilator-induced reversal of HASM contraction. Our preliminary data shows that TFF3, and other inflammatory mediators, are released from HAEC and hPCLS following exposure to RVC, and that TFF3 attenuates bronchodilation of human small airways and production cAMP in HASM in response to bronchodilators. Furthermore, our data demonstrates that inhibition of TFF3 and putative TFF3 receptors can reverse RV-C15-induced attenuation of bronchodilation. Therefore, we posit RV-C15 modifies signaling mechanisms modulating bronchomotor tone in HASM through a TFF3- dependent mechanism, thereby altering responsiveness of the airways to bronchodilators. We also show that signaling downstream of Gαs-coupled receptors is attenuated in HASM following exposure to RV-C15- conditioned HAEC media. We propose a central hypothesis that RVC exposure of HAEC attenuates β2 agonist-induced bronchodilation via modulation of Gαs-coupled receptor function via TFF3-dependent mechanisms. We will utilize HASM cells, air-liquid interface-differentiated HAEC, and hPCLS to examine the aims of this proposal. In Aim 1, we will determine how RV exposure modulates Gαs-coupled receptor-induced signaling to attenuate bronchodilator-induced airway/HASM relaxation and how asthma alters these mechanisms. Aim 2 will examine how RV-C15-induced TFF3 release attenuates agonist-induced bronchodilation/relaxation of HASM and how asthma alters these mechanisms. Utilizing primary HAEC/HASM co-cultures and an ex vivo system of human small airways, we will delineate signaling pathway alterations regulating bronchomotor tone that can be targeted in the treatment of RV-induced exacerbations of asthma to restore bronchodilator responsiveness.

NIH Research Projects · FY 2026 · 2023-06

Project Summary Conventional dendritic cells (cDCs) are crucial for both innate and adaptive immunity. In general, cDCs can be categorized roughly into two functionally and developmentally distinct subsets, cDC1 and cDC2, which preferentially activate CD8T cells and CD4T cells, respectively. cDC2s are phenotypically and functionally more heterogeneous compared to cDC1s, but how different cDC2 subsets acquire distinct phenotype and function remains poorly understood. We previously showed that a mouse cDC2 subset expressing CD301b (Mgl2) is functionally distinct and plays critical role in type 2 immune responses to allergens and helminth parasites. CD301b+ DCs are present in nearly all peripheral organs and expand during type 2 inflammation, but their differentiation mechanism is unknown. Our long-term goal is to understand the mechanism of CD301b+ DC differentiation at the cellular and molecular levels and explore its potential as a therapeutic targets for diseases with type 2 inflammation such as allergies. In general, cDC2s are thought to originate from the pre- cDC, a cDC-committed circulating precursor, through the action of the transcription factor IRF4. However, it remains unclear whether the heterogeneity in cDC2s originates in their precursors, or is acquired later during terminal differentiation. Likewise, while IRF4 seems to play a significant role in cDC2 development in general, its role in diversification of cDC2 subsets remains elusive and additional factors may be responsible for their heterogeneity. We hypothesize that pre-cDCs and/or monocytes acquire the CD301b+ DCs phenotype in a context-dependent manner with context-dependent requirement of IRF4. Our specific aims in this proposal are (1) to identify the precursor cell populations that give rise to CD301b+ DCs in peripheral organs, and (2) to elucidate the role of IRF4 and CD301b+ DC-specific transcription factors in their differentiation, under both naive and infected conditions. Understanding the mechanism of cDC2 differentiation might give us clues to understand the etiology and to identify potential therapeutic targets in allergies and other diseases with type 2 inflammation.

NIH Research Projects · FY 2026 · 2023-06

ABSTRACT The SWI/SNF chromatin remodeling complexes impart epigenetic regulation and control accessibility of chromatin to transcriptional machineries. Chromatin remodeling plays important roles in normal physiology and diseases, particularly cancer. ARID1A is a component of the BAF SWI/SNF complex and a major tumor suppressor. ARID1A is inactivated by somatic mutations in a wide spectrum of cancer types. Despite the apparent importance of SWI/SNF chromatin remodelers in cancer, their regulation by growth and oncogenic signals remains not well understood. mTOR complex 1 (mTORC1) is a conserved protein kinase and a central growth controller. mTORC1 is an oncogenic driver and the target of US FDA-approved oncology drugs rapamycin and rapamycin analogs. Our preliminary data revealed that mTORC1 promotes proteasomal degradation of ARID1A protein. Moreover, ARID1A plays an important role in therapeutic response and resistance to mTORC1 inhibitors. Because mTOR pathway is estimated to be activated in nearly half of all human tumors, mTOR-dependent degradation represents a common mechanism to inactivate the ARID1A tumor suppressor in cancer. Therefore, it is important to understand the underlying regulatory mechanisms and its role in cancer biology and therapy. There are two specific aims in this application: Aim 1 will dissect the molecular mechanism by which mTORC1 regulates ARID1A and oncogenic chromatin remodeling. Aim 2 will investigate the significance of mTORC1-dependent ARID1A regulation in tumorigenesis and anticancer drug response. Our studies are anticipated to fill a knowledge gap in the regulation of the ARID1A tumor suppressor in tumorigenesis and anticancer drug response/resistance. If successful, this project could lead to better strategies to target mTOR pathway, improving clinical outcomes for cancer patients.

NIH Research Projects · FY 2025 · 2023-06

PROJECT SUMMARY Maternal inflammation during pregnancy, as defined by elevated levels of circulating pro-inflammatory cytokines, can have adverse effects on offspring neurodevelopment. However, mechanisms remain elusive. Accelerated biological aging has been proposed as an underlying mechanism by which prenatal exposures influence future health. This process can be evaluated through epigenetic clocks, which estimate epigenetic age based on DNA methylation levels, and are widely used as clinically relevant biomarkers that measure epigenetic age acceleration. To date, pediatric epigenetic studies have been limited by: (1) use of adult-specific or all-age clocks; and (2) scant longitudinal epigenetic data due to challenges of pediatric blood collection. Here, we use a newly developed pediatric-specific clock [the pediatric buccal epigenetic (PedBE) clock] that can be evaluated using non-invasive buccal swabs, facilitating repeat measures across childhood. Our long-term goal is to identify easy- to-measure biomarkers in infants and young children that reflect exposure to maternal inflammation during pregnancy and predict subsequent risk for morbidity in offspring. This innovative and cost-effective longitudinal study will leverage the infrastructure, biorepository, and extant data of a rigorously phenotyped cohort of healthy pregnant women and their offspring followed from the first trimester through age 4 (R01HD083369, UH3OD023349). The Understanding Pregnancy Signals and Infant Development (UPSIDE-ECHO) cohort includes comprehensive assessments of inflammation across pregnancy, repeated measures of neurodevelopment across childhood, detailed psychological, sociodemographic, clinical, and life history data, and a rich repository of biospecimens collected from 2015 – 2024 (age 3-4 visits in progress). Our central hypothesis is that maternal inflammation during pregnancy accelerates the offspring’s epigenetic age, adversely influencing neurodevelopment. Our interdisciplinary research team is comprised of experts in maternal and child health, epigenomics, immunology, cognitive science, perinatal epidemiology, and biostatistics. In Aim 1, we will establish trajectories of longitudinal changes in offspring epigenetic age from birth through 4 years of age and identify factors associated with offspring epigenetic age acceleration. In Aim 2, we will study associations between maternal inflammation during pregnancy and offspring epigenetic age acceleration. In Aim 3, we will examine associations between offspring epigenetic age and neurocognition through age 4, and explore if epigenetic age mediates the association between maternal inflammation during pregnancy and neurocognitive outcomes. The research proposed in this R01 is significant because it will generate new insights into the link between maternal inflammation during pregnancy and genomic biomarkers of accelerated aging, with a focus on how accelerated epigenetic age can impact offspring neurocognition. This formative work will advance our understanding of how epigenetic age trajectories change across a critical developmental period and identify opportunities for maternal/offspring interventions to improve neurocognitive outcomes across the entire lifespan.

NIH Research Projects · FY 2025 · 2023-06

ABSTRACT The 2009 Tobacco Control Act (TCA) gave the FDA authority to regulate tobacco products to protect public health but initially extended only to cigarettes. By the time other products were deemed under FDA authority in 2016, the tobacco landscape had changed dramatically, making modern tobacco surveillance increasingly complex. Unfortunately, the cigarette-centric tobacco surveillance systems in the US have been slow to respond to these changes. Even after formal calls for improvements in smokeless tobacco and cigar measurement more than 20 years ago, standardized measures of these products remain sparse and insufficient. Moreover, despite numerous early warning signals, questions about JUUL did not appear on major national surveys such as National Youth Tobacco Survey until 2019, two full years after it became the top- selling ENDS brand on the market and ENDS use among youth had reached concerning levels. Indeed, rapid assessment and response to changes in the tobacco market are essential to informing and evaluating FDA’s current and pending regulatory actions, including proposed product standards (e.g., banning menthol), pending marketing authorizations for e-cigarettes, and the modified risk tobacco products (MRTPs) pathway. Therefore, informed by a conceptual framework which draws upon a traditional public health surveillance perspective as well as FDA’s Sentinel Initiative, this U01 proposal assembles a large collaborative network, which includes a network of six sentinel states that triangulates multiple data sources to establish the Center for Rapid Surveillance of Tobacco (CRST). The CRST aims to perform rapid surveillance of: 1) tobacco product marketing, to generate signals of interest; 2) the tobacco product marketplace, to generate and refine signals of interest; and 3) changes in tobacco product use behaviors, to generate, refine, and evaluate signals of interest. We will implement an optimal rapid surveillance system of tobacco that will enhance FDA’s regulation of tobacco products using a range of methods and subject matter experts to rapidly assess meaningful changes in tobacco marketing, the tobacco marketplace, and tobacco use. The team assembled has deep experience with tobacco regulatory science, surveillance and analyses of these data. We also have extensive experience overseeing multi-site projects in collaboration with federal partners that support our ability to carry out the administrative aspects of CRST. Our ongoing engagement with FDA CTP, federal partners, and CASEL and deep knowledge of FDA’s regulatory authority and processes ensure that we will not only conduct rapid surveillance, but anticipate changes in the market via early signal detection, and deliver meaningful data to inform FDA’s activities and support a substantial public health impact. In doing so, we will establish a new paradigm of tobacco surveillance, serve as a resource on surveillance methods and measures, support evolutions in traditional surveillance measures, and meaningfully advance the field of tobacco regulatory science.

NIH Research Projects · FY 2025 · 2023-06

Project Summary Results of epidemiological studies and meta-analyses indicate that treatments for destructive behavior based on functional analyses, like functional communication training (FCT), typically reduce destructive behavior by 90% or more and are much more effective than other treatments. However, these treatments involve extinction, which can produce extinction-induced adverse side effects. The most common side effect of extinction involves an increase in the frequency or intensity of the target response at the start of treatment, called an "extinction burst," which can place the patient and others at significant risk of harm. Prior theories on extinction bursts fail to account for the dynamic nature of these phenomena, and the basic behavioral processes that control bursts remain poorly understood. Our clinical and animal pilot data strongly suggest that our novel refinement of the generalized matching law, called the temporally weighted matching law (TWML), which incorporates reinforcement time and reinforcement history into the quantitative model, (a) fits our pilot data quite well, (b) resolves prior discrepancies between basic and clinical studies on bursts, and (c) identifies novel clinical procedures for preventing extinction bursts. The long-term goals of the project are to test our quantitative model of extinction bursts under typical clinical conditions to demonstrate its potential for improving treatment of destructive behavior and in the lab under a wider range of highly controlled conditions to provide a formal quantitative assessment of the predictions of the theory, evaluate its boundary conditions, and identify potential future clinical refinements. The specific aims are to demonstrate that large, discriminable drops in the rate (Spec. Aim 1), magnitude (Spec. Aim 2), and quality (Spec. Aim 3) of reinforcement when extinction or FCT are introduced increase the prevalence and magnitude of extinction bursts and that preventing such drops in the rate, magnitude, and quality of reinforcement will prevent or mitigate extinction bursts for both applied and basic research participants (i.e., humans referred for destructive behavior and rats, respectively). Specific Aim 4 will examine potential interactions between the variables of rate, magnitude, and quality of reinforcement predicted by the TWML to test current and inform future clinical refinements. The effects of reinforcement rate, magnitude, and quality will be manipulated and evaluated using a within-subjects design with the human clinical participants and using a randomized group design with lab rats, and the rate of destructive behavior (humans) and lever pressing (rats) will be the primary dependent variables.

NIH Research Projects · FY 2026 · 2023-05

Project Summary/Abstract In the past decade, the scientific community has witnessed accelerated genetic discoveries for neurodevelopmental and psychiatric disorders (NPD) such as schizophrenia (SZ), autism spectrum disorder (ASD), bipolar disorder, and major depression. Genome-wide association studies (GWAS) and whole-exome sequencing (WES) have identified a mounting number of NPD risk genes. However, translating these exciting genetic discoveries into clinically actionable biology has been impeded by our limited knowledge of gene function and related disease mechanisms. A bottleneck in the field is that most biological characterization has focused on very few NPD genes, which have not necessarily been selected for study based on pathophysiological importance. Furthermore, genes are often studied one at a time, hindering the pace of our understanding of disease mechanisms. We propose an alternative strategy: large-scale, unbiased, parallel study of NPD genes in disease-relevant model systems, in response to the RFA-MH-22-111 (Scalable and Systematic Neurobiology of Psychiatric and Neurodevelopmental Disorder Risk Genes-SSPsyGene). We propose to establish the Assay and Data Generation Center (ADGC) for the Model of induced pluripotent stem cell (iPSC)-derived Neurons for NPD (MiNND), where we will implement and optimize novel scalable and systematic assays for interrogating the molecular and neurobiological functions of up to 200 NPD risk genes. Teaming up with the SSPsyGene Consortium and leveraging our team’s respective expertise in stem cell biology, functional genomics, neuroscience, and functional analysis, our MiNND-ADGC will generate loss-of-function (LoF) iPSC human neural models, and perform high-content morphometric and single-cell transcriptomic (scRNA-seq) analyses of NPD LoF alleles. We will also assay synaptic functions using optical sensors in a high-throughput fashion and carry out multimodal PatchSeq analyses and modeling to predict neuronal properties from scRNA-seq data. Finally, working with the SSPsyGene Consortium, we will conduct data integration, curation, and dissemination to the research community and public for further analysis. Our MiNND-ADGC will build a valuable resource and integrated knowledge base that will provide a fertile foundation for future studies of disease mechanisms. The data from studying the selected NPD risk genes on multiple genetic backgrounds, including the understudied African American iPSC lines, will enable robust inferences of potential cross-disorder and cross-population biological convergence and divergence relevant to NPD.

NIH Research Projects · FY 2026 · 2023-05

Project Summary/Abstract The United States is experiencing a maternal health crisis, with high rates of severe maternal morbidity (SMM) and other pregnancy-related health problems and rising rates of pre-pregnancy health conditions. Furthermore, a legacy of structural racism and discrimination has led to substantial and persistent racial disparities in SMM and other adverse maternal health outcomes. In addition to the health impact on women, maternal morbidity imposes substantial cost burdens on families and society. Social determinants of health play a significant role in maternal health, with economically disadvantaged women having lower access to care, increased exposure to health risks, and poorer health outcomes before and during pregnancy. Yet there is very limited understanding of whether economic policies aimed at increasing incomes of families can be part of an effective strategy for improving maternal health and reducing disparities. Researchers have estimated that implementing a $15 federal minimum wage (MW) by 2025, as is currently being debated in Congress, would increase the earnings of 32 million workers and lift nearly four million people out of poverty. Because they are overrepresented among lower wage workers, women and people of color could disproportionately benefit. This study examines the role of the MW as a potentially powerful tool for addressing the maternal health crisis in the U.S. In lieu of any federal MW changes since 2009, many states have taken the lead in implementing their own MW increases, with 30 states having higher MW rates than the 2019 federal rate, compared to only 10 in 2010. Although these changes are likely consequential for lower-income and minority women, there is scant evidence on how the MW affects their reproductive and maternal health. Moreover, as the labor market impacts of MW are not uniform across populations, assessing potential heterogeneity is critical for quantifying effects on maternal health disparities. The overall objective of this project is to assess how state MW policies affect maternal health, as well potentially important intermediate outcomes that may lie on the causal pathway. Our multidisciplinary team will leverage recent methodological advances in the quasi-experimental evaluation of staggered policy interventions to estimate causal effects of MW increases on SMM and other pregnancy- related outcomes. We will also explore important outcomes that represent potential intermediary mechanisms linking MW to maternal morbidity outcomes, including changes in household income and employment, health care coverage, health care utilization, health behaviors, and pre-pregnancy health outcomes. Finally, we will examine how the MW affects health care costs associated with pregnancy and delivery. Throughout, we will explore potential heterogeneous effects to better understand how MWs affect health disparities. This research addresses a critically important and potentially very impactful policy-relevant question that has significant implications for mothers, their children, and their families.

NIH Research Projects · FY 2025 · 2023-05

PROJECT SUMMARY/ABSTRACT Epithelial cancers are common malignancies that account for 80 to 90 percent of human cancers. Despite breakthroughs in chemotherapy, targeted therapy, and immunotherapy, they generally are incurable in advanced stages. Cell therapy has shown remarkable efficacy in certain advanced stage hematologic cancers, but application of the approach to epithelial cancers has been more difficult. The short-term goal of this project is to elucidate principles of cell therapy in epithelial cancers using human papillomavirus (HPV)-associated cancers as a disease model. The long-term goal of this project is to discover and develop cellular therapy for HPV-associated cancers and other common malignancies. Research in the Si2 phase demonstrated that tumor- infiltrating lymphocytes can cause durable, complete tumor responses in HPV-associated cancers; genetically engineered T cells targeting an HPV oncoprotein can induce robust tumor regression in HPV-associated cancers – including immune checkpoint blockade resistant tumors; and tumor-intrinsic genetic defects in antigen processing machinery (APM) and interferon (IFN) response pathways control resistance to engineered TCR-T cell therapy. Research in the R00 phase will build on the Si2 findings with the goals to 1) elucidate in HPV- associated cancers a multidimensional picture of tumor-intrinsic immune related genetic resistance (IRGR) and 2) investigate the impact of cell therapy and immune pressure on IRGR and of IRGR on tumor response to cell therapy. HPV-associated cancers will be profiled for alterations in genes with defined function in tumor recognition and killing by T cells. In addition, exploratory analyses will be conducted to identify candidate immune evasion genes that are altered at frequencies greater than expected or that drive clonal evolution based on spatial clonal architecture mapping. The impact of cell therapy on IRGR and vice versa will be investigated by study of HPV-associated cancers from patients treated with tumor-infiltrating lymphocyte therapy and engineered TCR-T cell therapy. The longitudinal impact of immune pressure on IRGR will be investigated by comparing primary versus metastatic tumors and by analyzing serial intra-patient, metachronous tumor resections. This research will provide an integrated understanding of the reciprocal effects of immune response and IRGR in HPV-associated cancers. The work is critical to understanding immune editing and tumor resistance in the context of cell therapy and is necessary to guide the discovery of predictive biomarkers and the rational design of next- generation treatment strategies.

NIH Research Projects · FY 2025 · 2023-04

Per year, globally an estimated one million children develop tuberculosis (TB) and more than 15 million children are estimated to be exposed to Mycobacterium tuberculosis (Mtb). The case fatality rate is high in children < 5 years of age. Current approaches to diagnosis and management of young children that are close contacts to a TB case are inadequate. Those that are symptomatic may undergo sputum-based diagnostics that are not well tolerated (eg gastric aspirates), require access to a reference laboratory, and are not sensitive because TB may be paucibacillary or extrapulmonary. For that reason empirical multidrug anti-TB treatment predominates in many locales. Management of the asymptomatics is sub-optimal as well. Given the poor performance of IGRAs and TST in this age group, most are treated with isoniazid preventive therapy (IPT). In adults, asymptomatic (subclinical TB) is at least as common as active TB and will not be detected by current symptom-based screening. We do not know how often this is the case in exposed children, however, IPT, would be inadequate in them. Further, about 19% of children in this age group with latent TB infection (LTBI) will progress to active TB, usually within the next 3-6 in the absence of IPT (and IPT is only 63% effective). The need therefore is to discover a biomarker or biomarkers that identify those children < 5 years of age with subclinical TB (likely to progress despite IPT); and those without subclinical TB that are likely to progress. These biomarkers would allow appropriate targeting of IPT and ATT to those likely to benefit. This consortium of investigators have on-going diagnostic and cohort studies of child (< 5 years of age) close contacts of TB cases in Uganda that include a rigorous bacteriologic reference standard applied to asymptomatic as well as symptomatics and evaluation of novel diagnostics and discovery of non-sputum- based approaches. We propose now to evaluate in children < 5years old that are close contacts of a TB case a diverse and complementary panel of bacterial, host-based and imaging non-sputum biomarkers that have shown promise as predictors of progression in adults. Further, we will discover relevant biomarkers in this population through an unbiased multi-omics approach using proteomics, single-cell omics, T-cell activation markers, antigen-specific antibody profiling, Mtb exosomal assays, computer-aided detection (CAD) for chest X-ray interpretation and point-of-care ultrasound (POCUS). Our goal is to characterize a biomarker or group of biomarkers that meet a minimal target performance profile to identify children with subclinical TB and/or at high risk of progression. We will apply advanced machine learning and integrative multiomics to identify combinations of these biomarker signatures alongside TB risk variables to improve precision of predicting progression. These results will provide novel approaches to risk-stratify children <5 years of age for targeting the administration of preventive therapy and ATT.

NIH Research Projects · FY 2026 · 2023-04

Project Summary/Abstract The goal of this project is to understand the development and function of aging-associate lymphocytes. This proposal focuses on group 2 innate lymphoid cells (ILC2) that accumulate in the choroid plexus (CP) with aging. Aging is a complicated process associated with profound changes in the immune system, characterized by both a deterioration of adaptive immune function (immunosenescence) and also increased inflammation (inflammaging). Suprisingly, some immune cell subsets with anti-inflammatory and reparative function also accumulate with aging, which might represent a protective negative feedback mechanism to counter inflammaging. Our recent work discovers that group-2 innate lymphoid cells (ILC2), a type of tissue-resident innate lymphocytes, accumulate in the CP of aged mice and humans. The goal of this proposal is to understand the development and function of these aging-associated innate lymphoid cells in the CP. We will use lineage tracking mice, precursor homing assay, and adoptive transfer to examine the developmental origins of these cells and to explore the factors that lead to their accumulation with aging. We will use ILC2 deficient and ILC2 inducible-deletion mice to examine the specific role of these cells in physiological aging. Finally, we will test whether enhancing ILC2 function can alleviate neuroinflammation and cognitive impairment in aged mice with Alzheimer’s disease associated pathologies. We expect that the data generated will provide significant insights into the mechanisms of immune cell aging, and will inform strategies to combat geriatric diseases.