Icahn School Of Medicine At Mount Sinai

NIH Research Projects · FY 2025 · 2024-06

SUMMARY: Lynch Syndrome (LS) represents a hereditary predisposition syndrome associated with DNA mismatch repair (MMR) pathway impairment. LS-associated tumors demonstrate a high level of microsatellite instability (MSI-H), and consequently a high mutational and neoantigen burden, which results in improved response to treatment with immune checkpoint inhibitors (CPI). We previously showed that frameshift (fs) mutations encoding neoantigens in MSI-H tumors may control CPI efficacy and have quantifiably distinct characteristics from point mutations such as (i) major divergence from self, leading to differential immunogenicity; (ii) shared expression in MSI-H CRC tumors across patients; and (iii) expression of highly immunogenic epitopes that can elicit neoantigen-reactive CD8+ T cells detectable in blood, a proxy for intratumoral activity. Pre-malignant LS lesions are infiltrated with T cells expressing proinflammatory cytokines (TNF, IL-12), and CTLA-4, LAG3 and PD-L1 checkpoints suggesting early immune activation and recognition of tumor antigens. LS is therefore an ideal setting for design of cancer prevention strategies, including vaccination, and identification of antigen-specific T cell responses involved in immune surveillance and escape. We hypothesize that high quality shared neoantigen expression and a functional T cell repertoire capable of trafficking to and clearing MMRd lesions, deters progression of premalignant polyps to overt cancer in Lynch Syndrome. The goal of this application is to dissect the landscape, quality, and evolution of neoantigens expressed within pre-malignant colorectal polyps of LS patients, to track and identify immunogenic antigens that can be targets for prevention of tumor development. The UG3 aims are: 1: Identification of neoantigens expressed in premalignant colon polyps of Lynch Syndrome patients. We will map the spectrum of novel and shared neoantigen-expressing frameshift mutations in pre-cancerous colorectal polyps. 2: Identification of fs-specific TCRs capable of recognizing quality fs-neoantigens. We will confirm the immunogenicity of shared neoantigens expressed in precancerous polyps and identify fs-specific T cell receptors (TCRs), including shared TCRs, by barcoded peptide-MHC tetramers and single cell (sc)RNA/TCR sequencing from LS patient peripheral blood. The UH3 aims are to 1: Validate fs-neoantigen expression and tissue trafficking of fs-specific TCRs in a separate validation cohort. 2: Assess the influence of prior MSI-H cancer on shared fs-neoantigen repertoire and T cell recognition in subsequent colon lesions. We will determine whether prior exposure to shared MSI-H fs- neoantigens through their expression in non-colonic sites shapes new colonic lesions and T cell surveillance, as a model of “pre-vaccination”. 3: Assess fs-specific T cell exhaustion and co-localization with immunosuppressive hubs in advanced precancerous lesions. Using bulk/scRNAseq, spatial transcriptomics, and multiplexed immunohistochemistry we will determine mechanisms of immune escape in the PME to identify checkpoints for future immunoprevention strategies.

NIH Research Projects · FY 2025 · 2024-06

PROJECT SUMMARY/ABSTRACT FOR OVERALL The Icahn School of Medicine at Mount Sinai will leverage our research expertise in environmental epidemiology, analytical chemistry and clinical practice to renew our Human Health Exposure Analysis Resource (HHEAR) Laboratory Network Hub (formerly known as “CHEAR” in grant cycle 1). We will use a suite of `omic' technologies to measure environmental exposures and their response across all life stages to help NIH funded researchers determine how the environment affects human health, development and risk of disease across the life span. In the last 3 years we have expanded our laboratory resources to include liquid handlers to automate sample prep/aliquoting and worked with data scientist to automate data processing to speed the pace of our jobs. In addition we doubled the number of mass spectrometers from 7 to 14 and hired additional faculty all in preparation for this renewal application. We will leverage our substantial institutional investments, including our new $30 million Institute for Exposomics, to serve the HHEAR Lab network and its NIH researcher clients. Our Untargeted Resource will use molecular enviromics and metabolomics to measure exposure to environmental chemicals and their metabolites as well as the internal response to those exposures. We will supplement those measures with metallomics, proteomics and lipidomics. However, we are cognizant of the ever-changing landscape of health research and have included Microbiome and Viromics to prempt the NIH funded researchers' interest in including these measures to existing studies. We have state-of- the-art analytical methodologies and instrumentation that were made available to CHEAR users. While we will continue to offer these well-established methods to HHEAR clients, we are also committed to listening to the needs of HHEAR users and develop new biomarkers to meet those needs. Our Developmental core will build upon its highly successful work in creating novel methods to measure current and past chemical exposures in novel biological matrices (e.g. teeth, hair, placenta, neonatal dry blood spots) and develop new assays that arise from HHEAR's targeted and environmental resources. Our Administrative Core will coordinate planning and communication internally among all Hub components and externally with the HHEAR Coordinating Center, Data Center and the other HHEAR Network Hubs. Internally, the Administrative Core will streamline and prioritize HHEAR jobs, assess assay needs, promote and disseminate new assays as they are developed, harmonize protocols and QA/QC procedures and coordinate day-to-day operations. Our Hub will advise applicants on sample requirements, sample quality, results interpretation, sample collection, storage protocols and sample shipping specifications and guide them to the most innovative environmental health science.

NIH Research Projects · FY 2025 · 2024-06

Overall PROJECT SUMMARY/ABSTRACT The Icahn School of Medicine at Mount Sinai will leverage our research expertise in environmental epidemiology, analytical chemistry and clinical practice to renew our Human Health Exposure Analysis Resource (HHEAR) Laboratory Network Hub (formerly known as “CHEAR” in grant cycle 1). We will measure targeted chemical exposures across all life stages to help NIH funded researchers determine how the environment affects human health, development and risk of disease across the life span. In the last 3 years we have expanded our laboratory resources to include liquid handlers to automate sample prep/aliquoting and worked with data scientist to automate data processing to speed the pace of our jobs. In addition we doubled the number of mass spectrometers from 7 to 14 and hired additional faculty all in preparation for this renewal application. We will leverage our substantial institutional investments, including our new 30 million dollar Institute for Exposomics, to serve the HHEAR Lab network and its NIH researcher clients. Our targeted resource will analyze common exposure biomarkers (metals, pesticides, flame retardants, endocrine disrupting chemicals, tobacco metabolites, vitamins, nutritional status, minerals, and other organic compounds) using state-of-the-art analytical methodologies, while developing new biomarkers of chemical exposure based on the needs of our NIH clients. We will further build upon our work in CHEAR in which we created a suite of customizable panels that facilitate research in complex chemical mixtures. Our Developmental core will build upon its highly successful work in creating novel methods to measure current and past chemical exposures in novel biological matrices (e.g. teeth, hair, dried blood spots, placenta) and develop new assays that arise from hits from HHEAR's untargeted and environmental resources. This team already developed methods to objectively reconstruct past chemical exposures and identify susceptibility windows as they relate to human health in CHEAR. Our Administrative Core will coordinate planning and communication internally among all Hub components and externally with the HHEAR Coordinating Center, Data Center and the other HHEAR Network Hubs. Internally, the Administrative Core will streamline and prioritize HHEAR jobs, assess assay needs, promote and disseminate new assays as they are developed, harmonize protocols and QA/QC procedures and coordinate day to day operations. Our Hub will advise applicants on sample requirements, sample quality, results interpretation, sample collection, storage protocols and sample shipping specifications guiding them to exposures that fit the most up to date and innovative environmental health science. If necessary we will outreach to outside laboratories with analytic capabilities/expertise that do not reside in our Lab Hub. In conclusion, this proposal links highly experienced environmental health scientists with physicians, toxicologists, stress researchers, chemists, exposure scientists, epidemiologists, and computer scientists to build the infrastructure and capacity to objectively measure human environments.

NIH Research Projects · FY 2026 · 2024-06

Project Summary/Abstract Obsessive-Compulsive Disorder (OCD) is a psychiatric disorder with a lifetime prevalence of 2-3% in the general population. It manifests in a variety of intrusive thoughts (obsessions), rigid decision-making and ritualistic behaviors (compulsions), with prolonged and disabling effects. However, the neural and computational mechanisms underlying the disorder or its differentiations remain unclear, so that misdiagnosis is frequent, and even when an appropriate treatment is established, about half the patients keep exhibiting disabling residual symptoms. In this project, we propose to use an innovative approach, relying on neurocomputational and connectivity analyses of fMRI data, jointly with multi-model-based computational analyses of choice behavior across decision-making tasks. With these analyses, the project aims to characterize OCD symptom severity and phenotype differentiation based on cortico-striatal and cortico-cortical circuit dynamics, and to establish a relation between network-based phenotypes and model-based parametrization of choice behavior across decision-making tasks. We will test the predictions of a newly published neurocomputational theory, and its leading hypothesis that rigidity in motor, planning and goal selections is caused by aberrant stability of transient dynamics in the dorsal, lateral and ventral cortico-striatal circuit, respectively. We will test this hypothesis in a population of 140 subjects, equally distributed across five categories defined on the YBOCS scale of OCD severity (subclinical, mild, moderate, severe and extreme). We will use Dynamic Causal Modeling and Dependency Network Analysis to estimate subject-specific cortico- striatal circuit dynamics (with planned redundancy to test convergence of results), and we will use computational models based on reinforcement learning and Bayesian inference algorithms for the analysis of choice behavior across decision-making tasks. OCD phenotypes are expected to show task-related motor, planning and goal selection rigidity, expressed both in terms of model-based parameters of choice behavior and effective connectivity and network measures responsible for aberrant circuit stability. If validated, this novel characterization of neurocomputational OCD phenotypes would provide a more comprehensive explanation of the heterogeneity in OCD symptomatology and treatment responses, helping the development of subject- specific treatment tools, such as, for instance, personalized neuromodulation targets in deep brain stimulation or transcranial magnetic stimulation.

NIH Research Projects · FY 2026 · 2024-06

PROJECT SUMMARY It has been shown that variation in cancer risk is influenced by mutations that may be inherited, caused by environmental factors such as smoking and ultraviolet exposure, or resulting from random DNA replication errors. Here we propose a novel factor in cancer risk, which is related to the genetic diversity of the immune system across humans and its ability to detect and eliminate early cancers. Immunosurveillance is the concept that the immune system acts as a surveillance system to detect and destroy neoplastic cells before they progress to a detectable malignant cancer. This process relies on T cells, which recognize tumor mutation-derived neoantigens presented by the human leukocyte antigen (HLA) molecules on the cell surface, resulting in tumor- killing. While HLA genes are among the most polymorphic genes in vertebrates, including humans, and are associated with several infectious diseases and can also increase the risk for autoimmunity, our preliminary analysis suggests HLA diversity influences cancer risk. The goal of this proposed research is to study the contribution of immunogenetics on the efficiency of tumor immune surveillance and its ultimate effect on cancer risk. Our preliminary analysis demonstrates an association between HLA homozygosity and increased risk of cancer in lung cancer. Using large prospective cohorts of individuals with deep genetic and phenotypic data, we will investigate the relationship of HLA diversity and lung and melanoma cancer risk and the interaction of HLA immunogenetics with environmental risk factors. A murine carcinogen induced lung cancer model will offer validation of causality as well as mechanistic insights for therapeutic targets. The insights gained from these studies will potentially improve predictive cancer risk models in germline carriers and suggest strategies for immune-mediated cancer prevention.

NIH Research Projects · FY 2025 · 2024-06

PROJECT SUMMARY Obstructive Sleep Apnea (OSA) is a common chronic condition that affects over 1 billion people worldwide. Clinically, OSA is defined using the apnea-hypopnea index (AHI) which quantifies the rate of respiratory events. Recent evidence suggests that AHI has demonstrable limitations including poor predictive ability and relationship to outcomes. To overcome the limitations of AHI, our group has recently developed “ventilatory burden”, a fully automated breath-by-breath measure of abnormal breathing overnight, which is independent of hypoxia or arousal consequences, as an alternative metric better suited in clinical management of OSA. Another pathway that several groups have attempted to overcome the limitations of AHI is to use wearable devices that are easy to use and provide surrogates of AHI (e.g., WatchPAT, Oximetry etc.). However, these devices do not characterize the underlying ventilatory burden in OSA, which first and foremost is a sleep-related “breathing” disorder. Further, the exclusion of EEG in these devices implies that the denominator for AHI, which is the total sleep time, is estimated and not accurate. In this proposal, we aim to tackle both these issues by investigating the utility of a low-profile, low-cost, non-commercial, open-source wearable sensor system (SLEEPTRONIX), with physical resemblance to adhesive bandages that can monitor the requisite signals for fully characterizing OSA pathophysiology (EEG/EOG/airflow/SpO2). Using innovative algorithms, we aim to show that the SLEEPTRONIX derives accurate estimates of not only clinically used AHI metric, but also the ventilatory burden which overcomes limitations of AHI. Using N=30 subjects newly diagnosed with OSA, and age, sex matched healthy controls our primary aim is to develop and refine the SLEEPTRONIX system for continuous assessment of multiple night’s sleep and breathing patterns. In addition, we will refine our SLEEPTRONIX system to measure circadian rhythm parameters using temperature and cortisol levels that are assessed using novel nanotechnologies. The successful completion of above aims will establish that sacrificing on the requisite measurements of characterizing an individual’s underlying OSA is avoidable, and the use of wearables coupled with innovative measurements of underlying ventilatory deficit in OSA has the potential to shift the paradigm in OSA management.

NIH Research Projects · FY 2025 · 2024-06

PROJECT SUMMARY: CCR5 is a chemokine receptor that holds significant importance in public health due to the following factors: 1) CCR5 is the primary co-receptor for HIV infection; 2) approximately 1% of individuals with European ancestry worldwide possess a natural deficiency in CCR5; 3) an FDA-approved CCR5 antagonist exists for HIV treatment and is currently undergoing clinical trials for potential use in various chronic diseases. Our research has revealed that the absence of CCR5 leads to heightened vulnerability to West Nile virus (WNV), a neurotropic flavivirus, in both human subjects and mouse models. Additionally, we and other researchers have observed a similar susceptibility to other neurotropic pathogens, such as Japanese encephalitis virus, tick-borne encephalitis, cerebral malaria, and toxoplasma gondii. While these studies have been conducted using mice deficient in Ccr5, further in-depth investigations have been limited by the lack of appropriate tools for mouse experimentation. Through this proposal, our aim is to create a floxed Ccr5 reporter mouse and develop a collection of specific antibodies targeting Ccr5. These resources will facilitate research on CCR5's function, expression patterns, and its involvement in various inflammatory conditions and diseases.

NIH Research Projects · FY 2025 · 2024-06

Since 2016, the All of Us Research Program (AoURP) has striven to build the foundation for major advancements in precision medicine. Mount Sinai will continue to maintain regulatory requirements, continue its engagement and retention efforts, and achieve EHR milestones to contribute to All of Us’ national dataset.

NIH Research Projects · FY 2026 · 2024-05

PROJECT SUMMARY Black individuals have for decades been disproportionately impacted by kidney failure and rapid progression of kidney disease when compared to their White counterparts. Black individuals with APOL1 high-risk alleles are particularly vulnerable to accelerated chronic kidney disease (CKD) progression and kidney failure. However, these high-risk genotypes only occur in about 12-14% of Black individuals, and they do not guarantee CKD progression or kidney failure. Other risk factors, such as hypertension, HIV, and COVID-19, are thought to confer additional second-hit risks. Structural racism (SR)—defined as discriminatory policies and practices promoted through reinforcing systems (e.g., housing, wealth, health care) –– is also widely understood to be a contributor to racial disparities in kidney health. I hypothesize that SR acts as a “third hit” which contributes to excess risk of adverse kidney health outcomes among Black individuals with APOL1 risk alleles. Through four complementary aims, I will characterize the effects of structural racism on kidney health among Black individuals with high-risk APOL1 alleles and design and test a patient-centered intervention to mitigate effects of SR on health outcomes. In Aim 1, I will engage a multidisciplinary stakeholder board to collaborate in the analysis and interpretation of mixed-methods studies in Aims 2 and 3, and in the design and evaluation of a patient-centered pilot intervention in Aim 4. In Aim 2, I will quantify the longitudinal effects of SR with poor kidney health leveraging 3 large APOL1-enriched cohort studies. In Aim 3, I will characterize the experiences of structural racism of Black patients with APOL1 who have CKD and their clinicians with SR in health settings and their communities using qualitative analyses (photovoice, focus groups, semi-structured interviews). In Aim 4, in collaboration with the stakeholder board, I will pilot a patient-centered, navigator-led intervention designed to mitigate the effects of structural racism on kidney health. Throughout the award period, I will pursue training in advanced epidemiologic and statistical science, including longitudinal analysis and multilevel modeling, and develop skills in patient-centered clinical trial design and execution. Training goals and research aims are aligned and integrated to support a holistic experience. The robust training and world-class mentorship supported by this award, and Mount Sinai's enriched training environment and extensive resources, will prepare me for a career as an independent investigator dedicated to mitigating the devastating impact of structural racism on kidney health and eliminating kidney health disparities.

NIH Research Projects · FY 2026 · 2024-05

Despite recent progress in the identification of mediators of podocyte injury, mechanisms underlying podocyte loss remain poorly understood, and cell-specific therapy is lacking. Our long-term goal is to elucidate critical signaling pathways that disrupt podocyte cytoarchitecture in order to identify targets for therapeutic intervention for glomerular diseases. Our work has identified KIBRA (encoded by WWC1) as a key regulator of glomerular disease progression, podocyte cytostructure, and podocyte injury via downstream LATS kinase activation and YAP inhibition in the canonical Hippo signaling pathway. However, little is known about the regulation of WWC1/KIBRA expression, and therapeutic implications for KIBRA upregulation in FSGS and diabetic nephropathy remain unclear. Additionally, our preliminary data support non-canonical direct KIBRA downstream regulation of transcription factors TEAD 1-4. The overall objectives of this application are to define the regulators of WWC1/KIBRA expression and function in podocytes, test non-canonical KIBRA-TEAD signaling, and to target LATS and TEAD as novel therapeutic strategies for KIBRA-mediated and diabetic podocyte injury. Based on our preliminary RNA-seq analysis, our central hypothesis is that WWC1/KIBRA function in podocytes is repressed by the micro-RNA 200 family and regulated by transcription factors such as SOX4. In addition to canonical KIBRA regulation of LATS/YAP, KIBRA non-canonically directly suppresses TEAD 1-4 expression. Together, these downstream signaling events disrupt podocyte structural integrity and podocyte-glomerular basement membrane (GBM) adhesion, thereby promoting glomerular disease progression. The rationale for the proposed research is that testing novel regulators of KIBRA, non-canonical KIBRA signaling, and both novel canonical and non- canonical therapeutic approaches will significantly increase understanding of the mechanisms underlying glomerular disease progression and advance the quest for new selective treatments. Our hypothesis will be tested by pursuing three specific aims: Aim 1 will test novel micro-RNA and transcriptional regulation of WWC1/KIBRA expression and function and will define the biomechanical sequelae of KIBRA-mediated podocyte structural disruption. Aim 2 will test downstream KIBRA non-canonical regulation of TEAD 1-4 and the effects of LATS kinase depletion and inhibition in vitro and in vivo. Aim 3 will test the therapeutic efficacy of pharmacologic TEAD agonists and LATS inhibitors individually and combined as multi-targeted therapy for KIBRA-mediated and diabetic disease models in vitro and in vivo. The work proposed here is expected to define disease relevant regulators of podocyte KIBRA expression and elucidate novel targets and treatment strategies for glomerular diseases.

NIH Research Projects · FY 2026 · 2024-05

PROJECT SUMMARY/ABSTRACT Alopecia areata (AA) is a T cell–mediated, hair-specific disorder with a 2.1% lifetime risk, that recently has been also associated with Type 2 polarization and atopic comorbidities. 14%-25% of AA patients progress to alopecia totalis (AT) or even whole-body hair loss [alopecia universalis (AU)]. A large unmet need exists for efficacious and safer therapeutics for extensive AA patients (≥50% scalp loss), such as targeted therapeutic strategies that are now in use for other immune-mediated skin diseases such as atopic dermatitis (AD). This is particularly important in children, where treatments suitable for long-term use are not available. In a well-characterized clinical trial with 60 adult AA patients, we have recently showed that dupilumab, a monoclonal antibody that inhibits IL-4/IL-13 signaling by blocking the IL-4Rα subunit, induced significant hair regrowth, and significantly modulated the molecular AA phenotype in scalp tissues, particularly in patients with high IgE and/or atopic comorbidities, opening the door for targeted treatments for younger subjects with extensive AA. These data established a solid rationale for the potential of dupilumab to induce hair regrowth in pediatric AA patients with an atopic background. We hypothesize that the Th2 cytokines IL-4 and IL-13 are “drivers” in AA and their inhibition with dupilumab in pediatric AA subjects with an atopic background and/or high levels of IgE will shed light on the role of Type 2 inflammation in AA and the immune and regulatory pathways underlying suppression and/or induction of hair-associated keratins. We will test our hypothesis in a double-blinded clinical trial in 76 children (6-17 years old) with extensive AA (>/=50% scalp), randomized 2:1 to dupilumab or placebo, respectively, for 48 weeks, followed by another 48 weeks of open label dupilumab, and 16 weeks of follow-up (for a total of 112 weeks). We will test our hypothesis with the following specific aims (Aim 1 is related to clinical effects, while Aims 2 and 3 are translational aims): 1. To assess the safety, tolerability clinical efficacy, and durability of response with subcutaneous administration of dupilumab in pediatric subjects with severe (?50% scalp) AA and high IgE and/or atopic background; 2. To evaluate the ability of specific Th2 antagonism with dupilumab to modulate Th2 and other immune and regulatory pathways, as well as hair keratins, and stem cell biomarkers in scalp of children and adolescents with extensive AA; and 3. To characterize the ability of dupilumab to modulate inflammatory, regulatory, and tolerogenic immune pathways in blood of pediatric AA patients during and after treatment. By closely coupling biomarkers with clinical response, this trial will permit the maximal translational advantage. This study will expand our mechanistic understanding of AA in children and if successful, it may change the treatment paradigm for pediatric AA, enabling the use and further development of targeted therapeutics.

NIH Research Projects · FY 2026 · 2024-05

PROJECT SUMMARY Human immunodeficiency virus type 1 (HIV-1) infection remains incurable, with over 38 million people affected worldwide. While HIV-1 is known to enter the brain within the first two weeks of infection, it is estimated that 20- 50% of people with HIV-1 will develop HIV-associated neurocognitive disorder (HAND). Neuroinflammation is thought to play a key role in HIV-1 persistence, and substance use disorders, including smoking, may further contribute to inflammation and cognitive decline. In this study, we aim to investigate the impact of nicotine, a key component of tobacco smoking, on NLRP3 inflammasome activation in the central nervous system of people with HIV-1 and substance use disorders. Our research addresses a critical gap in understanding how inflammation contributes to HIV-1 persistence and cognitive decline in smokers with HIV-1. We will investigate how HIV-1 infection and nicotine exposure interact to activate the inflammasome and increase inflammation in human tonsil explants and iPSC-derived microglia to achieve our goals. We will use a newly developed xenograft humanized mouse model to track inflammasome differential expression and activation in brain regions, specifically in latent and productively infected and bystander cells. Finally, we will analyze post-mortem brain samples from individuals with HIV-1 and compare the expression of markers associated with NLRP3 inflammasome activation in smokers versus non-smokers. The proposed research will provide crucial insights into the mechanisms underlying neuroinflammation and cognitive decline in people with HIV-1 and substance use disorders. Our work will elucidate the role of NLRP3 inflammasome activation in HIV-1-associated inflammation and identify potential therapeutic targets to address this issue. By advancing our understanding of inflammation and the immune response to HIV-1 in smokers, we hope to develop novel treatments for this population's cognitive decline and immune dysregulation.

NIH Research Projects · FY 2026 · 2024-05

Mount Sinai’s Institute for Exposomic Research requests support for an annually held international series of 5 symposia focused on Exposomics, Aging, and Alzheimer’s Disease Across the Life Course. The exposome is the study of all the health relevant environmental factors encountered across life. Exposomics is a complex “big data” science with branches that include untargeted chemical assays, satellite remote sensing, wearable devices, and social media mining among other measures. Mount Sinai has been hosting Exposome symposia annually since 2018 and our team has successfully hosted meetings internationally in Europe and Latin America already. Our goals are to advance exposomic science globally in order to accelerate such research in Alzheimer’s Disease and Related Dementias (ADRD). These symposia will foster new research collaborations and catalyze a critical mass of researchers working in Aging and Exposomics. Many of the attendees, including junior faculty, are or will become, future leaders in the exposomics of aging. These conferences will also target important health issues around ADRD, such as promoting policy and research initiatives designed to address solutions. Our R13 proposal has multiple highly committed partners already. Our meetings will be held in 5 locations-Japan, Mexico, France, Rwanda and Nashville TN. Our program will promote international research in ADRD Exposomic Research and to address the role of environment in aging processes globally. By doing so, we maximize its impact. Each symposium is preceded by a ½ day workshop. We will invite prominent speakers from major research institutions. For example, several NIH Institute directors as well as the NIH ECHO director have been past presenters. Local experts from the host countries will be prioritized as presenters, and we will include U.S. leaders in exposomic science and leaders in ADRD research from across America based solely on merit. Our poster sessions will bring together junior scientists with established researchers, and we will use R13 funding for travel awards targeting junior scientists, such as junior faculty and trainees from within the U.S. Each Symposium is evaluated by attendees, and evaluation data will be used to improve each subsequent symposium. We will track our ability to attract participants from different disciplines. We also track attendees and employ a Kirkpatrick Model-based survey to measure knowledge and use of exposomics in attendee research.

NIH Research Projects · FY 2026 · 2024-05

Project Summary Obsessive-compulsive disorder (OCD) is a life-long, serious psychiatric disorder that affects 2-3% of the population and is associated with high personal and societal costs. Genetic factors are undoubtedly important in the etiology in OCD, and associated loci and genes are just beginning to be discovered. Studies by us and by others have shown that rare and ultra-rare variation, the latter including recent variation, plays an important role in risk for OCD. In ongoing sequencing studies, we are identifying genes impacted by such variation, using samples collected by the investigators in this application. In this proposal, we take an important new direction to address a critical gap in OCD research by recruiting subjects of self-reported African ancestry (African-American; AA), a group poorly represented in OCD research and not previously represented in OCD genetic research. In fact, AA individuals with OCD are vastly underrepresented, or altogether absent, from treatment centers and research studies, in spite of the evidence for 1) disparities in access to treatment, 2) persistent OCD due to lack of treatment, and, 3) differences in OCD subtypes in AA populations, as well as, 4) Covid-19 pandemic amplified mental-health disparities (including OCD and anxiety disorders). In this proposal, we will systematically investigate the phenotypes of OCD in AA populations, and use high-throughput sequencing to identify rare single nucleotide variation (SNV), insertions/deletions (indels), and structural variation (SV) contributing to OCD susceptibility in this population. To further our understanding of OCD in AA populations we propose the following Specific Aims: 1) To recruit at least 1,250 African American OCD participants and compare phenotypic findings and genetic architecture across ancestries; and, 2) to carry out genetic association studies for ultra-rare variants in the African American cohort and across ancestries. With this new research we will accelerate our overall objective, which is the identification of OCD genes across diverse populations, thereby facilitating our long-term goal of building the foundation from which therapeutic targets for OCD emerge. Our rationale is that the identification of genes conferring significant risk to OCD and associated disorders can form the basis of studies to understand pathogenesis, as well as the basis for novel therapies. Our central hypothesis – formulated based on recent results – is that rare genetic variation contributes significantly to risk of OCD, with certain rare variants conferring substantial risk. The research proposed is innovative, in our opinion, because it uses groundbreaking and novel statistical methods for identifying risk variants for OCD in AA populations, involving a systematic effort to investigate OCD genetic architecture across populations. The research will increase the number of known OCD genes, expand our knowledge of networks and pathways that are disrupted in subjects with OCD, and determine whether recent deleterious variation differs across ancestry. These outcomes are expected to have important positive impact, leading to a molecular understanding of OCD, identifying targets for novel therapeutics, and aiding in gene and locus discovery across ancestries.

NIH Research Projects · FY 2025 · 2024-05

PROJECT SUMMARY The overarching aim of this research and career development plan is for Dr. Solnick, the Principal Investigator (PI), to establish herself as an independent physician-investigator whose research focuses on advancing HIV prevention care for individuals diagnosed with sexually transmitted infections (STIs) in emergency departments (EDs). EDs have great potential as underutilized allies in the effort to end the HIV/AIDS epidemic. EDs especially could be useful in increasing the initiation of HIV pre-exposure prophylaxis (PrEP) – a key component of the National HIV/AIDS Strategy. EDs could be used as an access point where higher HIV-risk individuals, particularly those with STIs, can be initiated on PrEP and referred for further outpatient maintenance on PrEP. Dr. Solnick's K23 research project aims to improve ED-based HIV prevention in STI-diagnosed patients by developing and evaluating a protocol for Telephone Initiated PrEP Post-ED Discharge (TIPPED). The specific aims of her K23 research project are to (1) Develop a stakeholder-engaged TIPPED protocol and implementation strategy; (2) Adapt a tailored counseling message, a Persuasive Health Communication Intervention (PHCI), to encourage PrEP uptake during post-ED “callback” sessions as conducted by the ED clinician as part of their regular callback procedure to inform patients of the STI diagnoses; and (3) Implement and evaluate TIPPED, including a nested pilot randomized controlled trial of PHCI's impact on PrEP initiation and adherence. This research will incorporate both evaluations of implementation science-focused processes outcomes–feasibility, fidelity, acceptability–and clinical outcomes of PrEP initiation, linkage to care, and medication adherence. Advanced statistical methods, such as interrupted time-series methods, will be used to assess clinical outcomes. This career development plan will enable Dr. Solnick to build upon her experience as an emergency medicine physician and healthcare researcher to gain new expertise in (1) Implementation science approaches towards protocol development, deployment, and analysis; (2) Behavioral interventions in randomized controlled trial design; and (3) Advanced statistical methods in time-series data from electronic health records. She will receive in-depth mentorship from a multi-disciplinary research team of experts in the domains of implementation science, the HIV care continuum, clinical trial design, behavioral interventions, and statistical analysis. The results of this K23 will guide improvements to TIPPED and form the basis for Dr. Solnick’s subsequent R01 study. Her future R01 study will evaluate process and clinical outcomes relevant to implementing TIPPED in multiple EDs. The public health importance of this work is that it will contribute to expanded HIV prevention delivery and improved outcomes for individuals at risk of HIV infection, namely those with an STI receiving care in the ED.

NIH Research Projects · FY 2026 · 2024-05

PROJECT SUMMARY The initiating genetic alterations leading to blood malignancy occur as early as during fetal development. This is also true in children with Down syndrome (trisomy 21, T21), who have a significantly increased risk of developing preleukemia and leukemia during early childhood. The vision of our project is to identify and characterize fundamental mechanisms that contribute towards the initiation of preleukemia in Down syndrome children and to establish early therapeutic interventions. Children with Down syndrome have a 150-fold increased risk of developing myeloid leukemia during childhood compared to children without Down syndrome. In 30% of newborns with Down syndrome, a transient abnormal myelopoiesis (TAM) occurs, which is characterized by a clonal proliferation of immature megakaryoblasts that carry somatic mutations in the transcription factor GATA1. The preleukemic state resolves spontaneously in most newborns but can lead to liver fibrosis and in some cases liver failure. Recently, we utilized CRISPR/Cas9 editing in human primary fetal liver derived T21 and disomic hematopoietic stem cells (HSCs) to generate an in vivo model of Down syndrome preleukemia and identified the cellular origin of TAM. However, it remains unclear how an extra copy of chromosome 21 predisposes HSCs to blood malignancy, why somatic mutations are acquired with high frequency and what factors cooperate with GATA1 to initiate TAM. Because the liver is the primary site of hematopoiesis during fetal development, we hypothesize that a combination of intrinsic and extrinsic factors related to T21 and the fetal liver microenvironment contributes to the higher susceptibility towards preleukemia development. The overall objective of our project is to define specific mechanisms that explain the underlying predisposition of T21 fetal liver HSCs towards initiating preleukemia. In Aim 1, we are proposing to characterize intrinsic factors in T21 HSCs from fetal liver through mapping the gene expression and mutational burden at single cell resolution. We will assess transcriptional differences in the development and lineages of T21 HSCs compared to disomic fetal liver. In addition, we will quantify the rate of somatic mutations in each subpopulation. In Aim 2, we plan to characterize extrinsic factors in the T21 fetal liver microenvironment through transcriptional and spatial profiling of the fetal liver. We will carry out functional studies to assess the interaction of stromal components with T21 HSCs. Finally, in Aim 3, we are proposing to functionally evaluate the roles of candidate pathways in preleukemia initiation using our previously established model and primary TAM patient samples. Our goal is to identify and characterize therapeutic targets for preleukemia and associated liver fibrosis. The proposed research has the potential to change our basic understanding of why Down syndrome children are susceptible to preleukemia and our results could provide a strong rational for subsequent translation into the clinic.

NIH Research Projects · FY 2025 · 2024-05

ABSTRACT RASopathies, pleiomorphic genetic disorders altering RAS/mitogen-activated protein kinase (MAPK) signaling, are treated symptomatically. Recent data suggest that the MAPK pathway inhibitor trametinib can reverse severe heart and lymphatic involvement in some patients; not all patients respond to MEKis, and powerful inhibition of RAS/MAPK signaling has toxic side effects. Thus, development of alternative RASopathy drugs with favorable side effect profiles is an unmet medical need. To achieve that goal, we developed a RASopathy drug development platform using transgenic Drosophila, human induced pluripotent stem cell (iPSC), and mouse models. We identified the RAS binding domain (RBD) mimetic rigosertib as highly efficacious. From chemical screening, we identified a novel compound, M1, with modest activity and then improved its efficacy substantially. The two lead M1-logs are almost certainly not kinase inhibitors. The bona fide targets for rigosertib and the M1-logs in the RASopathies are unknown. Identifying their targets represents an exciting opportunity for advancing therapies for RASopathies and may have relevance for other disorders with altered RAS signaling. In Aim 1, we will take three complementary approaches to identify rigosertib's protein targets in RASopathies. Using Drosophila genetics, we will determine functional targets of rigosertib and assess if perturbation of microtubule biology contributes to rigosertib's RASopathy efficacy. Using targets identified that way, we will look for physical proximity of rigosertib with putative targets in iPSC-derived RASopathy cardiomyocytes (CMs) using bioluminescence resonance energy transfer with nanoluciferase (NanoBRET). Finally, we will determine the impact of knock-down of the best target genes on the CM phenotype using CRISPR interference. In Aim 2, we will assess existing rigosertib analogs (rigo-logs) against our RASopathy fly models. Analogs with improved efficacy will be tested for rescue of hypertrophy in RAF1-mutant CMs. The best rigo-log will be tested head-to-head with rigosertib and trametinib in the Raf1 mouse model, looking at hypertrophic cardiomyopathy regression. In Aim 3, we will take two complementary strategies to identify the targets of our lead M1-logs. First, we will use a photoaffinity strategy, derivatizing M1-logs with a minimalist tag and then using those to tag putative targets. Isolated proteins will be identified using mass spectrometry. Second, we will use un-derivatized M1-logs for a physicochemical approach to target identification called proteome integral solubility alteration (PISA). For both approaches, we will confirm target validity using Drosophila genetic approaches and NanoBRET. The proposed research will provide new insights into the therapeutic mechanisms of rigosertib and M1-logs for the RASopathies. This may include discovery of rigosertib analogs with efficacy exceeding rigosertib itself. As the M1-logs are novel and not kinase inhibitors, their targets are expected to provide new approaches for targeting RASopathies and other disorders with RAS- MAPK gain of function, including many cancers.

NIH Research Projects · FY 2026 · 2024-05

PROJECT SUMMARY/ABSTRACT The NIDA K23 Award proposes innovative research in opioid use disorder (OUD) treatment linkage after release from incarceration. Recently incarcerated individuals are at significantly increased risk for overdose death. Despite the clear benefits of medications for opioid use disorder (MOUD), uptake is low among individuals with criminal-legal involvement (CLI). A critical knowledge gap that remains is how to overcome the gaps in post-release treatment engagement that lead to overdose-related morbidity and mortality for this population. Telehealth-delivered buprenorphine may address gaps in provider availability, competing priorities, and access gaps related to buprenorphine treatment. Interventions utilizing telehealth must be targeted to the specific needs of individuals with CLI and engage those with a vested interest across correctional and relevant population settings. The objective of this application is to develop a tele-buprenorphine clinical protocol to improve post-release treatment engagement. Specific aims include:1) Identify rates and predictors of postrelease buprenorphine treatment linkage among individuals with OUD after jail incarceration; 2) Examine the perspectives of individuals with OUD and CLI, clinicians, and administrators to inform the development of a tele-buprenorphine protocol for low-threshold treatment linkage among jail-released adults; and 3) Conduct a pilot randomized-controlled trial utilizing tele-buprenorphine for post-release treatment linkage among adults with OUD upon release from jail. An Intervention Mapping protocol incorporating input from those groups with a vested interest will be utilized to develop the intervention. These aims will identify the target population and assess the needs and objectives of these groups, support the development and testing of study measures, and assess the feasibility, acceptability, and preliminary efficacy of the intervention. The proposed research will lead to an R01 randomized controlled trial to test the impact of tele-buprenorphine on post-incarceration OUD treatment linkage, retention, and CLI outcomes. The mentorship team brings together experts in health care innovations, health services research, clinical trials, addiction medicine, substance use epidemiology, and correctional health care, as well as relevant advisors from correctional health and reentry settings. This award will allow Dr. Utsha Khatri to develop as a clinician-investigator through the pursuance of four training goals: 1) Develop advanced knowledge of correctional health care and addiction treatment care transitions during reentry 2) Acquire advanced quantitative skills for clinical outcome assessment using linked, administrative datasets 3) Design and conduct clinical trials on care delivery interventions to address the needs of high-risk patient groups and 4) Attain grant writing and project management skills to transition to independence. With the successful completion of this project, training activities, and mentorship from a team of experienced investigators, Dr. Khatri will be exceptionally well prepared to lead an independent research agenda designed to improve care and outcomes for individuals with CLI and addiction.

NIH Research Projects · FY 2025 · 2024-05

PROJECT SUMMARY / ABSTRACT Hematopoietic stem cells (HSCs) are stem cells that replenish the entire suite of blood cells needed throughout adult life, and are an important source for cell replacement therapies and disease modeling studies. The overall goal of our research is to understand how to derive these important cells, in a petri dish, from human pluripotent stem cells (hPSCs). While the signal requirements for this remain unclear, we have recently uncovered a novel differentiation approach, yielding CD34+ progenitors that harbor both transcriptional and functional properties that are similar to nascent HSCs. This methodology employs stage-specific retinoic acid (RA) signaling, and yields a population of cells capable of homing to recipient bone marrow, and give rise to differentiated progeny. We hypothesize that this population is unique, and a precursor to the HSC that requires additional signals during its specification, to confer self-renewal capacity. We will test this hypothesis across 2 Specific Aims. In Aim 1, we will characterize the transcriptional and signal dependencies for the development of these cells, and understand the role of differential splicing in a critical transcription factor. In Aim 2, we will define the translational potential of the lymphoid cells that can be obtained from hPSCs, via RA-dependent and RA-independent mechanisms. The objective of these studies is to understand the development and regulation of HSCs from hPSCs, and whether HSC-independent lymphoid cells may be a viable alternative source for adoptive immunotherapeutics. This is of fundamental importance to both basic and translational biology, and the insights generated from these studies will have clinical implications. Our unique cellular and molecular tools, combined with our expertise in hematopoiesis, stem cell biology and bioinformatics puts us in an ideal position to make a significant impact in this field.

NIH Research Projects · FY 2026 · 2024-05

PROJECT SUMMARY Post-transcriptional modifications through adenosine-to-inosine (A-to-I) editing are critical for maintaining the diverse repertoire of RNA transcripts in the human brain. These modifications occur at isolated adenosines and across multiple consecutive adenosines within an extended region along the same RNA molecule. A-to-I editing influences gene function, alternative splicing, protein sequences, miRNA binding, and RNA structures. Recent work by us and others show that A-to-I editing is abundant during normal aging and changes in editing levels are tied to etiology of Alzheimer’s disease and related dementias (AD/RD). Nevertheless, substantial gaps persist regarding the precise roles and implications of A-to-I editing in AD/RD. For instance, the majority of A-to- I sites are expected to undergo dynamic regulation within a common double-stranded (ds)RNA structure throughout the progression of normal aging and dementia severity. However, our understanding of this context- dependent regulation of RNA editing is currently limited. Moreover, the role of common genetic variation on the regulation of A-to-I editing levels (editing quantitative trait loci [edQTLs]), as well as their impact on A-to-I sites en masse along a shared dsRNA structure, has been significantly understudied. There has also been a dearth of experimental tools that precisely probe the function of candidate A-to-I sites. We will bridge the existing knowledge gaps through a comprehensive approach that will: Aim 1) Address the unmet need for basic neuroscientific research that can capture fundamental regulation of RNA editing across brain development, normal aging and in AD/RD; Aim 2) Integrate individual genetic information to construct robust maps of edQTLs and identify AD/RD risk loci that modulate A-to-I editing levels and dsRNA structures across ancestries and cell types; Aim 3) Establish a systematic and biologically validated prioritization of AD/RD-associated A-to-I sites, using an integrative computational approach together with a site-directed RNA editing molecular toolbox. Capitalizing on the significant progress made by large-scale consortia initiatives, we will investigate the functional and regulatory roles of A-to-I editing in AD/RD with unprecedented scale and depth. Results from this proposal will reveal more nuanced and accurate insights into the molecular and genetic underpinnings of AD/RD pathobiology, paving the way for the identification of novel therapeutic targets for these devastating neurodegenerative diseases.

NIH Research Projects · FY 2023 · 2024-04

OVERALL-PROJECT SUMMARY/ABSTRACT Genetically defined in the 1990s, congenital disorders of glycosylation (CDG) consist of 130+ different inborn metabolism errors with overall incidence of ~>1:100,000. Thirty years later: there is no disease natural history data, no comprehensive patient registry, and no reliable screening for many CDG types. Furthermore, almost no therapy is available. We do have a strong patient association, committed clinicians, and a growing scientist group forming a virtual consortium, which closely collaborates to improve patient outcomes. We need prospective natural history data on health concerns to impact quality of life, validate disease biomarkers, and develop reliable diagnostics to increase clinical trial readiness. Our preliminary findings include retrospective natural history data, as well as data on novel biochemical biomarkers and techniques containing glycomics, which were established and validated in pilot trials for screening and diagnostics in CDG. The first clinical trials in specific CDG types started with dietary intervention, as is the most common approach in CDG therapy. Our collaborating group pioneered in these trials, most importantly in D- galactose therapy in PGM1-CDG. We also initiated the first (limited) PMM2-CDG natural history study, in parallel with the NIH single center CDG natural history study. Our nation-wide network of regional centers will further collaborate on diagnosis, follow up, treatment and clinical research in CDG. Our overreaching aims are a) establishing early reliable diagnosis b) increase diagnostic success and sensitivity, c) improve our knowledge on the natural history, d) find new biomarkers and e) develop therapies in congenital disorders of glycosylation. We will include all types of CDGs, focusing on three major biochemical disorder groups within multifaceted CDG: a) the most common form of CDG; PMM2-CDG, b) the group of potentially treatable disorders affecting protein galactosylation, and c) a defect from the new glycosylation disorder group (disorders of de-glycosylation)--NGLY1 deficiency. To achieve these milestones, we will apply cross-disciplinary, team-based clinical research to 1) define natural history, validate patient reported outcome and share knowledge on congenital disorders of glycosylation; 2) develop and validate new biochemical diagnostic techniques and therapeutic biomarkers for clinical trials; and 3) restore appropriate glycosylation to improve clinical symptoms and quality of life in disorders of glycosylation. Partners in our consortium have collaborated for more than a decade in finding solutions to complex problems in CDG biology, sharing knowledge, individualizing therapy, organizing patient conferences, and supporting physicians caring for CDG patients. We have improved patient care in this rare disease, but it is not enough. Leveraging on a nation-wide network, this proposal's aims begin to relieve decades of unresolved questions, address lack of knowledge, develop treatment and meet currently unmet patient need.

NIH Research Projects · FY 2025 · 2024-04

SUMMARY Glioblastoma (GBM), the most common and lethal brain cancer is notorious for wide dissemination in the brain. Understanding cellular and molecular underpinnings of GBM invasion is thus critical. While earlier research has made progress on intrinsic drivers of cell motility, how GBM cells meet the challenge of extrinsic factors such as physical constraints to negotiate narrow paths through the brain parenchyma remains unclear. Our preliminary studies have revealed that endocytosis at the front of migrating cells is a critical process for membrane dynamics during confined migration. Furthermore, our new data have also implicated alteration of the negative electric charge at the inner membrane surface as a key organizer of cytoskeletal activity of migrating GBM cells in confined space. These novel preliminary findings were made possible by applying new microchannel devices coupled with live-cell imaging and advanced fluorescent probes to study GBM confined migration. In this exploratory R21 proposal, we will conduct mechanistic studies to test the hypothesis that membrane dynamics and membrane surface charge via mechanoelectric coupling are key drivers of confined GBM migration. In Aim 1, we will investigate how membrane dynamics mediated by endocytosis facilitates GBM confined migration. We will conduct functional assays to assess how specific endocytosis inhibitors impact membrane dynamics and migratory capacity of invading GBM cells through microchannels. In parallel, we will perform in vivo GBM transplants for proof-of-principle efficacy studies of limiting endocytosis to curb invasive spread of GBM. In Aim 2, we will explore the emerging concept of surface membrane charge and mechanoelectrical coupling for confined GBM migration. We will test the hypothesis that change of electrical charge at the inner leaflet of plasma membrane (by anionic lipids or membrane-associated proteins) bestows GBM cells with increased migratory capacity through organization of cytoskeletal activity. We will first generate novel molecular reagents to either increase or decrease surface charge in an inducible manner and test the impact on GBM confined migration. We will apply the microchannel devices for high-resolution live-cell imaging to monitor the effects of altering membrane charges on actin network, calcium flux, and endocytosis-mediated plasma membrane dynamics. We will then conduct proof-of concept in vivo GBM transplant studies to examine the efficacy of these novel molecular agents to impede GBM invasion. Together, our studies will provide mechanistic insight and conceptual advance on membrane plasticity and mechanoelectrical membrane dynamics for confined migration of GBM cells and their impact on GBM invasiveness in vivo. It will open translational opportunities to impede GBM spread and recurrence. We will also make the innovative microchannel devices available for the wider research community, thus accelerating the research of cancer mechanobiology and tumor invasion.

NIH Research Projects · FY 2026 · 2024-04

Project Summary Developing an effective HIV vaccine to curb HIV infections is a global urgency. Env is the sole target for broadly neutralizing antibodies (bNAbs), and is the focus of vaccination strategies. One barrier to a protective HIV vaccine is the dense array of glycans that covers the surface of the Env spike restricting the immunogenicity of Env proteins. There are ~90 individual glycan sites per trimer and each site can be decorated with high-mannose, hybrid or complex-type glycans. These glycans are crucial for various Env functions including its conformation, antigenicity, immunogenicity and the ability of HIV to evade humoral responses. The presence/absence and type of glycans on Env-based vaccine candidates can influence both antigenicity and immunogenicity of the protein. Most bNAbs include Env glycans as part of their binding epitope, making the glycosylation of Env a key aspect of HIV-1 vaccine design. These bNAbs has been isolated from chronically HIV-1 infected individuals but induction of such bNAbs by vaccination has not been successful yet. Thus, Env immunogens that display glycan and antigenic profile matching those present on the virus may have a better prospect at inducing a cross-neutralizing Ab response. However, a clear understanding of what comprise the site-specific glycan make-up of virus- associated Env is missing, particularly for clinically relevant isolates being pursued for human vaccine trials. The mechanisms/factors that regulate the Env glycan pattern and composition are not understood. This information is critical for improving Env as immunogens and for understanding the optimal epitopes of glycan-dependent bNAbs. The proposed study aims to fill this gap in knowledge by investigating Env biogenesis and glycosylation that starts in the endoplasmic reticulum (ER) compartment of the host cells and continues to be modified in Golgi. A better understanding of the processes that are involved in the ER and Golgi will provide us with the tools that can be used to generate Env immunogens with native antigenic and glycosylation profiles. The overarching goal of the proposed study is to 1) characterize the site-specific glycosylation of native Env on virus, 2) investigate the processes in the ER and Golgi that regulate and imprint the type of glycans on HIV Env, 3) identify ways to express Env with glycans that match virus-associated Env, 4) characterize how native glycans impact the structural and conformational flexibility of Env, and, 5) evaluate the immunogenicity of these Env in animal models for their capacity to elicit cross-neutralizing antibodies. This study will take advantage of several innovative technologies such as LC-MS/MS, HDX-MS along with the complementary expertise of the investigator team to accomplish the goals. Successful completion of the study will reveal several new and unknown aspects of protein synthesis and mechanisms that can be applied towards the development of improved Env immunogens for HIV vaccines.

NIH Research Projects · FY 2026 · 2024-04

Alzheimer's Disease and Related Dementias (AD/ADRD) progressively impair essential cognitive and mental functions, resulting in significant emotional, physical, and financial burdens. Genome-wide association studies have identified thousands of loci contributing to the risk of more than a hundred serious mental and neurological disorders (SMND), including AD/ADRD and others such as schizophrenia, Parkinson’s disease and multiple sclerosis. Integrating risk loci with quantitative trait loci (QTLs) for molecular traits, such as gene expression and epigenome regulation, in human brain tissue, has been widely adopted as an analytical strategy to nominate causal mechanisms for AD/ADRD and SMNDs. So far, large-scale integrative analyses using this approach have utilized homogenate brain tissue, which is composed of multiple cell types, and therefore cell-type-specific QTLs are not fully captured. This is an important limitation given that risk variants for AD/ADRD and SMNDs act through cell-type-specific biological mechanisms. Initial efforts have included cell-type-specific QTL analysis in the human brain by utilizing single-cell data, but the sample size of such studies is hindered by the increased experimental costs. To overcome these limitations, we propose to establish the brain single-cell xQTL (BrainCellQTL) Consortium that brings together existing resources of more than 10,000 single-cell libraries from more than 3,000 unique brain donors, as well as expertise in single-cell biology, neuroscience, statistical genetics and machine learning, to facilitate the harmonization of brain single-cell data, QTL generation and data sharing with the scientific community. Activities will be organized around the Synapse Data Platform by Sage Bionetworks, an NIH-Designated Generalist Repository that supports dozens of research consortia, focused on neurodegeneration, neuropsychiatric disease, cancer, rare disease, and other research areas. The Synapse Data Platform will be utilized to receive data, validate it against metadata and data standards, and harmonize them for downstream analysis. To increase the reproducibility and transparency of BrainCellQTL consortium research, we will use CAVATICA by Seven Bridges for data processing and analysis. CAVATICA is a secure, scalable, and extendable data commons platform that empowers collaboration and scientific analysis. Upon successful completion of the proposed research, we expect to construct a cell type-specific QTL atlas for the human brain, which we will use to derive genetically driven gene dysregulation in AD/ADRD and SMNDs, thus, enabling us to: (1) increase our mechanistic understanding of dysfunction in AD/ADRD and SMNDs; (2) better prioritize significant genes and molecular pathways for future mechanistic studies; (3) provide a valuable resource that can be applied in ongoing and future genome-wide association studies; (4) provide preprocessed and harmonized single-nucleus brain omics data that can be utilized by the research community to address other biologically-driven questions; and (5) establish a mechanism for data sharing and harmonization across consortia and projects, which can be utilized in future studies to perform single-cell mega-analyses and meta-analyses.

NIH Research Projects · FY 2025 · 2024-04

Household air pollution (HAP) results in an estimated 2.3M deaths every year. A large proportion of HAP-attributable deaths are due to respiratory disease over the life course. Establishment of optimal health in childhood is critical to reduce risk for future chronic disease. To realize the maximum scientific potential of the GRAPHS cohort, we will improve data management to enable broad data sharing.