Icahn School Of Medicine At Mount Sinai

NIH Research Projects · FY 2026 · 2024-12

Project Summary/Abstract Parkinson’s disease (PD) is the second leading neurodegenerative disorder in the United States with patients manifesting motor and psychiatric complications. As the global population ages, the prevalence of PD will increase accompanied by emotional and economic burden. PD is characterized by the degeneration of neuromelanin-containing dopaminergic (DA) neurons in the substantia nigra (SN). It remains poorly understood how this degeneration occurs. The use of single-cell RNA sequencing has significantly advanced our understanding of neurodegenerative disease–several studies in mouse midbrains identify the heterogeneity of DA neurons; however, limited studies have been conducted in human samples. To fill this gap, we have performed single-nucleus RNA sequencing (snRNAseq) and profiled the cells from healthy and PD human SN, which identified a novel degenerating neuronal population in PD that is highly enriched with RIT2 but lacks tyrosine hydroxylase (TH), a typical marker for DA neurons (RIT2+/TH-). It is not known whether non-DA neurons in the SN are also vulnerable in PD. Immunostaining of aged healthy and PD human and murine SN samples validated the distinct RIT2 populations (RIT2+/TH+, RIT2+/TH-). This proposal aims to characterize distinct RIT2 neuronal subpopulations in the SN to elucidate its cellular heterogeneity and to identify potential mechanisms underlying the complexity of PD symptoms. The driving hypotheses are that subpopulations of RIT2 neurons in the SN are distinct from DA neurons with unique morphology, function, and circuits (AIM 1) and that RIT2 neuronal subpopulations in the SN are vulnerable to PD-associated pathogenesis (AIM 2). Aim 1 will characterize the novel RIT2-expressing neuronal subpopulations in mouse SN. Aim 2 will assess the vulnerability of RIT2 neuronal subpopulations in both PD mouse models and human midbrain neurons. These studies will elucidate whether non-DA neurons in the SN are degenerating in PD and they will characterize distinct RIT2 subpopulations in the SN, providing mechanistic insights into the complexity of PD and identify pathways warranting further exploration for therapeutic development. This proposal is highly innovative because it will characterize a novel midbrain neuron type with vulnerability in PD that may lead to insights into resilience mechanisms. This proposal will also generate several novel model systems in both mice and hiPSC, which will be available to the research community. Completion of this proposal will provide rigorous multidisciplinary training for the candidate in assessing cell circuit innervations, transcriptomics, cell viability, and functional testing of neuronal subpopulations in transgenic mice and hiPSCs. This fellowship will enrich and accelerate the career of a promising PhD student with demonstrated dedication to research in aging-related neurodegenerative disorders and education. The training will be conducted in a highly multidisciplinary and collaborative environment in the Department of Neuroscience at Icahn School of Medicine at Mount Sinai, a leading institution with emphasis in translational and transformative discoveries.

NIH Research Projects · FY 2026 · 2024-12

Human immunodeficiency virus type 1 (HIV-1) infection can lead to both acute and chronic states of inflammation in people with HIV (PWH), even in the setting of effective viral suppression with antiretroviral therapy (ART). Dysfunctional and hyperactive inflammation in PWH is associated with an accelerated aging phenotype that results in increased risk for severe sequelae like neurocognitive impairment and atherosclerotic cardiovascular disease. Development of targeted anti-inflammatory therapies capable of synergizing with existing ART regimens to reduce the long-term burden of HIV disease is limited by a gap in knowledge of the specific molecular mechanisms underlying HIV-associated immune activation. Studies of HIV-1 infection in the lymphoid environment have revealed inflammatory signaling distinct from that in the periphery, prompting the need for methods to probe the types of immune cells directly and indirectly impacted by infection as well as the underlying inflammatory signaling pathways. We have developed a human tonsil tissue explant histoculture model of HIV- 1 infection in which intact tonsil tissue blocks preserve the full native architecture, cellular repertoire, and milieu of lymphoid tissue, and therefore many of the associated cell-cell interactions and functions. Intriguingly, unlike in peripheral blood, abortive HIV-1 infection in lymphoid tissues can cause pyroptosis, a highly inflammatory form of programmed cell death mediated by the NLRP3 inflammasome, affecting bystander cells adjacent to HIV-1 infected CD4+ T cells. This proposal seeks to test the overarching hypothesis that the architecture of intact human lymphoid tissue supports the close apposition of HIV-1 infected CD4+ T cells to activate NLRP3 inflammasome signaling and IL-1ß release in bystander myeloid cells. Aim 1 will evaluate how the presence or absence of lymphoid tissue structure affects HIV-1 infection and inflammatory signaling by comparing intact tonsil tissue with dissociated cell suspensions for differences in cell types, gene expression, and cytokine production. Aim 2 will interrogate the spatial and functional relationships within lymphoid tissue that facilitate NLRP3 activation and generate a molecular morphologic atlas of the HIV-exposed tonsil. This innovative approach, combining single-cell sequencing and spatial transcriptomics with an ex vivo human tonsil model of HIV-1 infection, can yield insights into the innate immune mechanisms driving dysfunctional inflammation in PWH. This work will take place within the Icahn School of Medicine at Mount Sinai (ISMMS) in the Mount Sinai Health System. Between the Department of Medicine Division of Infectious Diseases, Department of Immunology and Immunotherapy, and Center for Advanced Genomic Technology, I am supported by over 100,000 ft2 of research programs and an additional 4500 ft2 of institutional core facilities, in addition to over $200 million in scientific computing resources such as the Minerva supercomputer. Together, this fellowship leverages the resources of my institution and the expertise of my sponsor to support my training in four key areas: 1) scientific excellence, 2) mentorship, teaching, leadership, & advocacy, 3) professional development, and 4) clinical skills.

NIH Research Projects · FY 2026 · 2024-12

PROJECT SUMMARY/ABSTRACT Research: The post-acute sequelae of SARS-CoV-2 infection (PASC) continues to pose an unprecedented public health burden, and cognitive impairment (CI) and depression are among the most common symptoms, which profoundly impacts functioning and quality of life. The purpose of this study is to develop and pilot a novel intervention to treat post-COVID CI and depression in patients with PASC by integrating two evidence-based interventions, cognitive rehabilitation (CR) based on Goal Management Training (GMT) and cognitive behavior therapy (CBT), and adapting the intervention specifically for ethnoculturally diverse patients with PASC. The specific aims are to: 1) Develop a manualized intervention for diverse patients with post- COVID CI and depression by adapting and enhancing a GMT CR+CBT approach and 2) Determine the feasibility and preliminary efficacy of the intervention on diverse patients with post- COVID CI and depression. To accomplish these aims, we will employ a mixed methods, design. Qualitative findings from focus groups with patients with PASC will guide the development of the intervention, which will be iteratively refined through additional semi-structured individual interviews and evaluated for feasibility and preliminary impact in a pilot randomized controlled trial (RCT). Candidate: The primary objective of this application is to support Dr. Jacqueline Becker's career development into an independent investigator studying the bidirectional impact of cognitive and mental health on chronic illnesses. Dr. Becker's proposed training activities are: 1) qualitative methodology; 2) psychosocial intervention development; and 3) RCT design, implementation, and evaluation. To achieve these goals, she has assembled a multidisciplinary mentoring team. Dr. Wisnivesky, her primary mentor, is a health services researcher with expertise in PASC, health disparities research, biostatistics, and RCT design and implementation. Her co-mentors include Dr. Lin, a clinician-investigator with expertise in qualitative research and chronic disease self- management in diverse adults, Dr. Feldman, a psychologist and expert in behavioral medicine psychosocial interventions, Dr. Murrough, a world-renowned psychiatrist with expertise in clinical trials for depression, and Dr. Bagiella, an expert in biostatistics and RCT design and evaluation. Environment: The Icahn School of Medicine at Mount Sinai has a strong tradition of outstanding research and the Department of Medicine is ranked 12th nationwide in NIH funding. The Division of General Internal Medicine has a well-established research infrastructure with an exceptionally strong record of successful and well-funded, mentored and independent investigators.

NIH Research Projects · FY 2026 · 2024-12

PROJECT SUMMARY Checkpoint blockade therapy of cancer has had tremendous impact, but still only a subset of patients respond. One possible explanation is that some tumor types do not have a sufficient number of somatic mutations to produce tumor-associated-antigens (TAA) that can be targeted by the immune system, specifically CD8 T cells. Recent data from our group and others suggest an alternative explanation: there are sufficient TAA, but also suboptimal cross-presentation of these antigens by suitably activated dendritic cells. We have proposed that this central problem can be addressed using a novel in situ vaccine approach which uses 1) Flt3L to recruit DC, 2) radiotherapy to load Flt3L-mobilized DC with TAA, and 3) Toll-like Receptor agonist (TLRa) to activate TAA-loaded DC for cross-presentation. We carried out an early phase trial testing this approach and observed partial and complete systemic tumor regressions at distant (untreated) tumors, improving months after therapy, and even specific elimination of malignant B cells with sparing of healthy B cells, suggesting a systemic anti-tumor immune response. However, whether this approach actually addressed this problem of insufficient TAA cross-presentation, and whether this could potentiate subsequent checkpoint blockade therapy is unknown. In this proposal, we will investigate the mechanism of the in situ blockade therapy in a mouse model we have developed and in banked, unidentified samples from two clinical trials of in situ vaccine alone or with anti-PD1 antibody therapy. First, we will assess clinical samples from the nearly completed in situ vaccine trial to assess whether the appropriate subsets of DC were recruited and whether this results in the induction of TAA-specific CD8 T cell responses. Next, we will use several unique resources in the mouse model, including a novel GFP- collaborators, a panel of CRISPR gene-edited GFP-expressing lymphoma cell lines, and a mass cytometry (CyTOF) panel to perform deep profiling of tumor-specific T cells in each therapeutic setting. Finally, we will assess samples from our newly developed clinical trial (funded by CRI) combining the in situ vaccine with anti- PD1 antibody therapy to assess whether cross-presentation of both TAA and two surrogate antigens introduced alongside the ISV (HBsAg and CRM-197) actually occurs and correlates with clinical benefit. We are well positioned to perform the proposed studies, having generated a large set of preliminary data indicating not only therapeutic opportunity but also our ability to perform high level immune monitoring of samples from our patients treated on these novel and promising clinical studies. The proposed studies are important because they will deepen our understanding of anti-tumor T cell mechanisms and address an urgent and unmet clinical need for our patients with advanced stage lymphoma, and potentially in the future, for many cancer types.

NIH Research Projects · FY 2026 · 2024-12

Project Summary/Abstract More than half of individuals infected with COVID-19 continue to experience debilitating symptoms beyond the initial phase of their infection – a syndrome that is now known as Post-Acute Sequelae of COVID-19 (PASC). When neurological manifestations such as altered smell or taste, post-exertional malaise, “brain fog” (impaired cognition, executive function, and memory), fatigue, dizziness, abnormal movements, headache, sleep disturbances, mood disorders, and/or dysautonomia, are concerned, this syndrome is termed neuroPASC. Knowledge of the specific mechanisms by which SARS-CoV-2 causes damage to the brain and brainstem is vitally important to inform clinical treatment of patients suffering from neuroPASC, but at this point, our knowledge is severely lacking. We hypothesize that SARS-CoV-2 infection causes immune-mediated injury to the neurovascular endothelium, causing microhemorrhages, microinfarctions, and vascular leakage followed by secondary damage to the neural parenchyma due to immune-mediated inflammation in response to breakdown of the blood-brain barrier. The consequences of this tissue injury will manifest as a specific spatiotemporal distribution of neuroimaging findings on in vivo MRI, associated with neurological signs and symptoms and markers of inflammation. The results of this project will rigorously confirm the mechanisms by which SARS-CoV- 2 infection causes tissue damage that leads to neuroPASC, and by leveraging ex vivo MRI to link in vivo neuroimaging findings on a clinically translatable MRI protocol and the presence and temporal evolution of neurological signs and symptoms to a detailed histopathological explanation of the underlying mechanisms by which neural tissue is damaged in neuroPASC, this project will establish a foundation of knowledge for targeted interventions and provide protocols and biomarkers to evaluate the efficacy of those interventions. The specific aims of this project are as follows: Aim 1: we will acquire high-resolution, multi-contrast, quantitative ex vivo MRI and detailed histological datasets in hemibrains from 25 neuroPASC-positive decedents and 15 neuroPASC- negative control decedents who recovered from their acute course of COVID-19 without persistent neurological sequelae. We will compare frequencies of MRI and histological findings in neuroPASC and controls throughout the regions of the brain and brainstem implicated by prominent symptoms to confirm the aforementioned mechanistic hypothesis, and also identify additional spatial patterns of neuroPASC-related abnormalities through data-driven analyses. Aim 2: we will apply an in vivo 7 T structural, vascular, perfusion, and diffusion MRI protocol and perform neuropsychological testing and quantification of blood inflammatory markers in 60 neuroPASC-positive patients at two time points, and 60 neuroPASC-negative control subjects at a single time point. We will analyze the spatial distribution of neuroimaging findings and their evolution over time as neuroPASC symptoms abate to support a hypothesis that resolution of symptoms is closely temporally linked with resolution of specific spatial distributions of neuroimaging findings.

NIH Research Projects · FY 2026 · 2024-12

The advent of immunotherapies (IO) such as immune checkpoint inhibitors (ICI) heralded a significant improvement in cancer patient survival, but the mechanisms underlying treatment response are still opaque. The level of tumor-infiltrating lymphocytes (TILs) has been suggested as one potential ICI response biomarker, signaling an active anti-tumor immune response. So-called “hot” tumors, those with many TILs, are more frequent in some cancers (e.g. melanoma) than others (e.g. ovarian cancer, OC). Strategies to recruit additional TILs and thereby make cold tumors hot are in development, including the use of oncolytic viruses (OVs). Refining IO outcome predictors, for both ICI and OV therapies, is an unmet clinical need. Expanding on my previous findings of a novel germline genomic biomarker of ICI resistance in the circulating CD8+ T cells of metastatic melanoma patients (H-MAX), I hypothesize that inherited immune biomarkers can be identified in other IO-treated cancers. Whether such markers are the same for “hot” tumors like melanoma, or differ for cold tumors such as OC, remains to be seen, as does their applicability to novel IO combinations such as those including OVs. Understanding the interplay between circulating and tumor-infiltrating immune cells and charting the dynamic post-treatment changes in the immune landscape may further illuminate the anti-tumor responses induced by IO therapies. This proposal aims to answer these questions using peripheral blood and tumor samples from IO clinical trials of ICI alone (NRG-GY003; NCT02498600) or in combination with OV (ONCOS-102; NCT02963831). Sequencing these samples, I will define the inherited and acquired mutational profiles of these patients (Aim 1.1), correlating these with their treatment outcomes. I will then assess their association with known (e.g. TILs) and novel (e.g. H-MAX) IO biomarkers in both OC and other cancers. Using high-resolution spatial profiling, I will then map the pre-treatment (NRG-GY003) and pre- and post-treatment (ONCOS-102) tumor immune landscape (Aim 1.2), correlating these profiles with IO response and the genomic signatures in Aim 1.1. Sequencing both tumor and peripheral blood TCRs from NRG-GY003, I will identify the baseline tumor-resident TCR sequences and, using post-treatment blood samples, map their expansion in the periphery following ICI treatment (Aim 2). I will conduct the same analysis in ONCOS-102, for which I also have post-treatment tumor samples, allowing me to correlate the changes in circulating TCR profiles with those in the tumor. I will also use ECCITE-seq, an emerging technology for obtaining single-cell proteomic, transcriptomic, and TCR data, to profile pre/post-treatment ONCOS-102 peripheral blood mononuclear cells. With this deep profiling, I will precisely define the cellular phenotypes and TCR repertoires of the reactive T-cell clones, charting their dynamic post-treatment evolution following combined OV and ICI treatment. Collectively, the results from this work may identify novel OC response biomarkers, potentially improving treatment stratification and pointing to mechanisms of IO response and resistance.

NIH Research Projects · FY 2026 · 2024-11

PROJECT SUMMARY This MPI grant proposal is spearheaded by Drs. Lee and Lim, who bring together complementary expertise in paramyxovirus entry and reverse genetics (Lee) and advanced animal and human organ explant models of viral pathogenesis (Lim) to address a potential global health threat posed by pararubulaviruses (PRubVs), a genus of emerging bat-derived paramyxoviruses related to but distinct from human-specific orthorubulaviruses exemplified by mumps virus, and human parainfluenza virus 2 and 4. PRubVs such as Menangle virus (MenV) and Sosuga virus (SosV) cause severe disease when spilled over into humans, and MenV infection of pregnant sows has resulted in fetal demise and a myriad of fetal abnormalities. Despite their known risk, critical aspects of PRubVs' interaction with human hosts, such as cellular tropism, receptor usage, and pathogenesis mechanisms, remain elusive, hindering the development of effective medical countermeasures (MCMs). The overarching goal of this project is to elucidate these unknowns through three interrelated Specific Aims: (1) to define the cellular tropism of Menangle and Sosuga viruses in human cells, employing innovative organ explant techniques and cutting-edge molecular biology tools; (2) to characterize the receptor usage pathways of these viruses, leveraging state-of-the-art reverse genetics systems; and (3) to develop a pathogenic animal model that reflects human disease, facilitating the study of viral pathogenesis in vivo. These aims are designed not only to fill critical knowledge gaps but also to establish foundational insights that can guide the development of targeted medical countermeasures, which are lacking for this group of understudied viruses. By synergizing the distinct but complementary scientific approaches and expertise of the MPIs, this project promises to advance our understanding of PRubVs significantly. Through a combination of reverse genetics, organ explant models, and animal studies, it aims to uncover the molecular and cellular mechanisms underlying PRubV infection and pathogenesis. This research will provide critical insights into how these viruses cross species barriers and interact with human cells, laying the groundwork for novel therapeutic and preventive strategies against PRubVs and enhancing our preparedness for future zoonotic outbreaks.

NIH Research Projects · FY 2026 · 2024-11

PROJECT SUMMARY Viruses extensively remodel the cells that they infect. Ubiquitination networks are frequent targets of viral manipulation, but compared to other modifications such as phosphorylation, our general understanding of functional ubiquitination events is limited. In this project, we will apply CRISPR-Cas9 base-editing approaches to assess ubiquitination site function in a systematic, unbiased manner in the context of flavivirus infection. We have previously quantified ubiquitination responses to West Nile virus (WNV) infection, identifying hundreds of modulated ubiquitination targets with unknown functions. In Specific Aim 1, we will systematically introduce mutations at these ubiquitinated residues and assess the impact on WNV infection in a pooled base-editing screening format. In Specific Aim 2, we will apply base editing to perturb ubiquitination enzyme active sites for enzymes that physically interact with flavivirus NS5 proteins. Successful completion of these aims will discover novel pathways that promote flavivirus infection and will provide CRISPR-Cas9 base-editing resources tailored towards research questions in virology and ubiqutination functions.

NIH Research Projects · FY 2026 · 2024-11

PROJECT SUMMARY Stress is a major risk factor for neuropsychiatric disorders including anxiety and depression. Stress increases the propensity of lateral habenula (LHb) neurons to emit high-frequency bursts of action potentials. This cellular adaptation contributes to stress-related behavioral abnormalities, including deficits in reward processing and cognition. Mechanisms by which stress increases the burst-firing of LHb neurons are poorly understood. Microglia play critical roles in maintaining homeostatic levels of neuronal activity. Preliminary single-cell RNA sequencing and in situ hybridization data collected in support of this application suggest that microglia but not neurons in the LHb express β2 adrenergic receptors (β2ARs). Stressors that increase burst-firing of LHb neurons enhanced norepinephrine (NE) signaling in the LHb of freely moving mice. NE acted directly on LHb microglia via β2ARs to attenuate ATP-evoked calcium signaling in these cells, which is known to promote homeostatic interactions between microglia and activated neurons. Finally, lesioning microglia precipitated a stress-like increase in burst-firing of LHb neurons. These exciting preliminary data suggest that stress enhances NE signaling in the LHb, which acts via β2ARs to disrupt microglial surveillance of local neuronal activity, thereby promoting burst-firing of LHb neurons. Here, I will investigate the role of β2AR-mediated NE signaling in microglia in regulating stress-induced cellular adaptations in the LHb and associated behavioral abnormalities. In Aim 1, I will use high-resolution spatial transcriptomics to characterize the effects of stress on gene programs in microglia and other cell types in the LHb of wild-type (WT) mice and mice in which β2ARs have been conditionally knocked out from microglia (microgliaβ2AR-cKO mice). I predict that stress will shift gene programs in LHb microglia from homeostatic to pro-inflammatory mode in WT but not microgliaβ2AR-cKO mice. In Aim 2, I will use miniscope- based single-cell fluorescence imaging to characterize the effects of stress on calcium signaling in LHb microglia from WT and microgliaβ2AR-cKO mice. I predict that stress will attenuate calcium signaling in LHb microglia in WT but not microgliaβ2AR-cKO mice. Whole-cell recordings will also be used to characterize the effects of stress on burst-firing of LHb neurons in WT and microgliaβ2AR-cKO mice. I further predict that stress will increase burst- firing of LHb neurons in WT but not microgliaβ2AR-cKO mice. In Aim 3, I will characterize stress-induced behavioral abnormalities in WT and brain-wide microgliaβ2AR-cKO mice. To restrict β2AR deletion to microglia in the LHb, I will administer tamoxifen directly into the LHb of our inducible microgliaβ2AR-cKO mice. I predict that stress will precipitate deficits in reward processing and cognition in WT mice and that these behavioral deficits will be attenuated in brain-wide microgliaβ2AR-cKO, and also in LHb-restricted microgliaβ2AR-cKO mice. This highly innovative proposal will reveal new insights into the role of NE-sensing microglia in regulating cellular and behavioral adaptations to stress. The proposed training and career development plan will position me to submit a competitive K99/R00 Pathway to Independence Award.

NIH Research Projects · FY 2026 · 2024-11

Abstract The purpose of this training and research application is to identify novel noncoding mechanisms of disease associated with developmental disorders (DDs) using a suite of statistical and functional genomics strategies. Approximately 30-40% of DDs can be explained by a rare de novo protein-truncating variant or structural variant (SV; genomic alterations larger than 50 base pairs) in genes that are under strong evolutionary constraint. What is currently unknown, and represents a major void in genetic architecture studies, is the contribution of rare noncoding genetic variation to DDs. There have been a handful of examples of pathogenic long-range positional effects (LRPEs) caused by noncoding SVs that result in DDs, and preliminary work by our group and others have suggested that disruption of three-dimensional (3D) genome structures called topologically associated domains (TADs) may be responsible for the strong regulatory effects observed at these loci. To systematically assess the relationship between SVs, TAD disruption, and risk for DDs we will: (1) define novel candidate LRPE loci via the identification of TADs intolerant to disruption and build models to predict the pathogenicity of noncoding SVs; (2) determine the impact of TAD disruption on gene expression; and (3) elucidate the added diagnostic value of identifying pathogenic LRPEs in DDs. The proposed application will also develop an extensive research program for Dr. Chelsea Lowther whose goal it is to become an independent investigator. Dr. Lowther is a computational genomicist trained in the identification and interpretation of SVs from chromosomal microarray and whole genome sequencing data who now seeks to obtain new expertise in advanced statistical modeling and functional genomics to examine the impact of 3D chromatin disruption as a mechanism of disease. Dr. Michael Talkowski is the Director of the Center for Genomic Medicine at Massachusetts General Hospital, with appointments at Harvard Medical School and the Broad Institute, and will serve as the primary mentor, while Dr. Erez Lieberman- Aiden, an Associate Professor in Molecular and Human Genetics and the Director of the Center for Genome Architecture at Baylor College of Medicine, will serve as the co-mentor and close collaborator. Drs. Talkowski and Lieberman-Aiden are world-leaders in statistical, computational, and functional genomics as well as in genome organization and nuclear function. The mentorship team also consists of diverse expertise in genome diagnostics and variant interpretation (Dr. Heidi Rehm), genome evolution and regulation (Dr. Katie Pollard), the functional annotation of SVs associated with neurodevelopmental and neuropsychiatric conditions (Dr. Douglas Ruderfer), and in noncoding mechanisms of disease associated with human malformations (Dr. Stefan Mundlos). This outstanding mentorship team and training program will facilitate Dr. Lowther’s transition to independence and will strongly support her trajectory towards becoming a leader in the field of genomic medicine.

NIH Research Projects · FY 2024 · 2024-09

Project Summary Chronic intestinal failure (CIF) is a devastating condition where individuals are unable to eat and drink enough to meet basic survival needs. Patients with CIF are dependent on parenteral nutrition (PN) delivered intravenously by a pump via an indwelling central venous catheter. While PN is lifesaving, life-threatening complications can cause considerable morbidity, impair quality of life (QOL) and carry significant mortality risk. Care of patients with CIF is highly complex and best delivered by experienced multi-disciplinary (multi-D) teams working in intestinal rehabilitation programs (IRP). Our recent work has shown a critical lack of expertise in CIF among US gastroenterologists and over half the states in the US do not offer IRP. This lack of widely available expertise results in significant healthcare disparities for patients with CIF. Our recent work has shown that use of technology to disseminate knowledge through the LIFT-ECHO Project, based on the well- established ECHO Model can fill a critical gap in CIF care. However, getting non-specialist primary car doctors and community gastroenterologists to engage in LIFT-ECHO has been challenging, because each community doctor likely manages no more than one to two patients at most and participation in LIFT_ECHO is time- consuming. With the following specific aims, we will test the hypothesis that provision of multi-D education and support directly to CIF patients and their family care providers through a live, virtual learning model – the Patient Intestinal Failure-ECHO Project (PIF-ECHO) – will enhance knowledge, increase confidence in self- care, and foster a virtual support group system, for patients to learn from each other's lived experiences. AIM 1a: Demonstrate that the ECHO™ Model can be successfully adapted to allow patients with CIF and their family care givers direct access to case-based education and tele-mentoring though a virtual multi-D team. Aim 1b: Demonstrate safety, acceptability, and value of the PIF-ECHO Model for patients with rare diseases like CIF, using a pilot evaluation framework. Aim 1c: Evaluate effectiveness of PIF-ECHO and disseminate results widely. There are only very rare instances of applying the ECHO Model, directly to patients and family caregivers, and none has been systematically evaluated. Our novel patient-centric approach directly aligns with AHRQ priorities by supporting disadvantaged populations living with disabilities [SEN NOT-HS- 24-004]. Our study will help improve healthcare safety and indirectly increase access to expert healthcare for patients with CIF, while providing a 360-degree view of CIF patients in the communities in which they live.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY Sudden cardiac arrest (SCA) is a leading cause of cardiovascular deaths in the United States. Despite its prevalence, predicting risk of SCA is challenging due to limited methods for early detection. It has been known that risk of SCA is mediated by genetic contributions, which can be inherited as monogenic and polygenic factors. Although there exist techniques for assessing clinical risk, there is currently no viable approach to deduce genetic risk unless through direct genotyping or genetic sequencing. Furthermore, current clinical genomic testing is constrained in terms of accessibility, cost, and expert interpretation requirements, leading to a lack of scalable methods for early determination of SCA genetic risk. The electrocardiogram (ECG) is a non-invasive, widely used tool for measuring cardiac electrical activity. As biological mechanisms influence waveform patterns that define certain arrhythmias, the ECG has potential to reveal the genetic underpinnings of the electrical function of the heart. While subtle waveform morphology may escape human observation, ECG interpretation has been greatly augmented by deep learning (DL) techniques, allowing for the discernment of subtle waveform patterns of even subclinical disease for which diagnostic guidelines are lacking. DL has already been leveraged on ECG to identify various cardiac pathologies, such as hypertrophic cardiomyopathy, low left ventricular ejection fraction, ST elevated myocardial infarction, and valvular disease, but has yet to be applied to genetic predisposition to SCA. As such, the applications of DL to ECG waveform promise to provide insight into genotypic foundations of SCA to enable prevention and prophylactic strategies in cardiac electrophysiology and personalized medicine. This proposal seeks to develop DL models that bridge the gap between phenotypic ECG patterns and disease genotypes. To improve the identification of monogenic inherited syndromes, a DL model will be leveraged on electronic health record (EHR) and ECG data to classify those with risk genotypes (Aim 1). To facilitate identification of those at high polygenic risk for SCA, a separate DL algorithm using EHR and ECG data will be developed for classification of individuals with high polygenic risk score (PRS) for coronary artery disease and SCA (Aim 2). For Aims 1 and 2, by integrating data from large repositories of genetic data such as the Mount Sinai Million Health Discoveries Program, All of Us Research Program, the United Kingdom Biobank, we hypothesize that DL has potential to enable identification of monogenic and polygenic risk of SCA. Supported by resources and renowned faculty from the Charles Bronfman Institute for Personalized Medicine at the Icahn School of Medicine at Mount Sinai, this multimodal study will provide data-driven insight into preventing SCA and establishing a clinical and research foundation for an MD/PhD candidate.

NIH Research Projects · FY 2024 · 2024-09

PROJECT SUMMARY Obesity, the most common medical condition among women of reproductive age, increases maternal-fetal risks that may prompt specialized obstetric intervention. A key decision is whether and when to initiate delivery, often by inducing labor before its spontaneous onset (i.e., induction of labor, IOL). While IOL planning should follow principles of shared decision-making (SDM) – centering women's values and preferences for different birth outcomes in choices for delivery mode and timing – multiple evidentiary gaps impede SDM for IOL with obesity. Perinatal risks of obesity compound the complexity of IOL counseling and decision-making and, in addition to biological risks, weight stigma and bias challenge quality of care and birth experience. Moreover, Black women have higher rates of maternal obesity than White women, and Black women with obesity have the highest rates of IOL. Given the maternal health crisis among Black women in the US, a patient-centered approach is essential. Growing literature suggests that weight bias may contribute to the overuse of interventions including IOL. Further, women with obesity often describe obstetric care as depersonalized and overly focused on weight. Experts urge shifting away from weight-centric care paradigms and toward the AHRQ-stated goal of whole-person, 360- degree care. The proposed project will address critical research and practice gaps by discovering new approaches to obesity phenotyping tied to individualized care models for racially and ethnically diverse patients. Aim 1 will empirically derive maternal obesity phenotypes using latent class analysis and evaluate subtype associations with pregnancy outcomes in data from 9000 racially, ethnically, and geographically diverse nulliparous women. Aim 3 will use these phenotypes in Aim 2 interviews with clinicians to elicit contextual barriers and facilitators to SDM with diverse patient profiles and organize themes along AHRQ's SHARE SDM framework. Aim 3 will adapt an existing IOL patient decision aid (PDA) to the obesity context and pair the PDA with implementation strategies, informed by Aim 2 interviews, to overcome barriers to use. The mentor/advisor team will function as an “Implementation Team” to incorporate findings into a SDM toolkit through iterative workshops. Building on the applicant's background in perinatal epidemiology, qualitative research methods, and health care quality and equity, the proposed training program of formal coursework, mentoring, and professional development will build expertise in (1) latent class and cluster analysis, 2) shared decision-making, and (3) implementation science. The collective research and training will generate preliminary data and culminate in the submission of an R01 proposal for an equity-focused implementation-effectiveness trial on SDM adherence, decision quality, patient experience, and perinatal outcomes. The proposed K01 Mentored Research Scientist Career Development Award will establish the applicant as a leading independent investigator in the design and implementation of decision tools and practice guidelines for person-centered obstetric care of perinatal women with obesity, with the long-term goal of advancing equitable, evidence-based, and values-aligned obstetric care.

NIH Research Projects · FY 2024 · 2024-09

PROJECT SUMMARY Nurses play a vital role in optimizing safety, quality, accessibility, equity, and affordability across healthcare settings. The nursing profession has invested in expanding clinical and comparative effectiveness research to explore best practices, and translational research and implementation science to integrate evidence into practice. Clinically based nurse researchers (CBNR) emerged as part of this effort with the goal of bridging the gap between nursing research and nursing practice. Distinct from nurse researchers who work in traditional academic roles and spaces, CBNR are nurse researchers who have permanent positions within the structure of clinical practice settings, such as hospitals and health systems. CBNR are uniquely and intentionally positioned to conduct research that is timely and responsive to emerging needs, and to expedite the integration of findings into practice. However, multiple barriers limit the scale, scope, speed, and rigor of this critically needed work. Currently, there are no dedicated professional organizations or scientific meetings to connect the growing number of CBNR across the country. Thus, there are few opportunities to collectively examine and strategically address shared challenges, identify common research priorities, or forge tactical partnerships to facilitate rigorous large-scale multisite research. This two-day research development conference, scheduled tentatively for June 5-6, 2025, will address the long-term goal of accelerating the scale, scope, speed, and rigor of research to optimize patient outcomes through nursing care. The conference will unite CBNR and other key stakeholders, including executive hospital leaders, interdisciplinary research collaborators, and academic partners from across the United States to accomplish the following specific aims: (1) Identify barriers, potential solutions, and facilitators to conducting large-scale, comprehensive, timely, and rigorous research in CBNR roles to optimize patient outcomes through nursing care. (2) Develop a strategic framework to guide CBNR in generating and translating evidence to improve safety, quality, accessibility, equity, and affordability of care through nursing practice. (3) Establish and sustain a national consortium of CBNR to facilitate dissemination, implementation, and evaluation of the strategic framework. A conference planning committee consisting of six CBNR and one executive nurse leader will offer diverse perspectives, experiences, methodological expertise, programs of research, and professional networks to support the conference aims. The primary outcome of the conference will be a five-year strategic framework outlining the mission, vision, goals, strategic priorities, and cross-cutting strategies for CBNR.

NIH Research Projects · FY 2026 · 2024-09

Primary open-angle glaucoma (POAG) produces chronic, progressive, and irreversible optic nerve degeneration, leading to visual disability and blindness. We propose to analyze preclinical proteomic and metabolomic markers and their interactions with glaucoma genetic predisposition to better understand POAG pathophysiology. We will use plasma samples from a matched case-control group (500 cases and 500 controls) nested within ongoing prospective cohorts (Nurses' Health Study (NHS), NHS2, and Health Professionals Follow-up Study) as well as genetic data and prospectively collected biennial questionnaire data and clinical data on incident glaucoma cases. For incident POAG cases, we have used an artificial intelligence algorithm to define POAG subtypes by visual field loss patterns; the POAG subtype with paracentral visual field is of particular interest, as this subtype is more strongly associated with considerable functional disability. This study will employ a cutting-edge platform that uses slow off-rate modified aptamer reagents, which bind proteins like antibodies to quantify 5,000 proteins (Aim 1). In addition to an untargeted approach, we will test a priori hypotheses in targeted approaches to investigate the relation to POAG for proteins related to nitric oxide signaling, lipid metabolism, and immune response. We will then test the hypothesis that dysregulation of lipid metabolism is important in POAG etiology by using a commercial NMR metabolomics platform assaying 168 metabolites that quantify metabolites in 3 categories: a) low molecular weight molecules like ketone bodies; b) lipoproteins like high-density lipoproteins of specified particle size; and c) plasma lipids (Aim 2). We will use preclinical plasma collected ~10 years before diagnosis in 600 cases and 600 controls who previously underwent high throughput genotyping and LC/MS metabolomics. For Aims 1 and 2, we will explore whether associations vary by visual field loss patterns in POAG. Lastly, in NHS, NHS2, and HPFS, participants with the top 10% of the POAG polygenic risk score (PRS) had a 10+ fold higher risk of POAG; yet ≥70% of those in the highest PRS did not develop POAG and are “resilient to high POAG polygenic risk”. We will evaluate the biomarker signature and ophthalmic features associated with this resilience in those with the highest POAG PRS scores (Aim 3). We will seek nominal replications for all aims in the UK Biobank. The aims will expand the repository of multiple `omics data available for preclinical glaucoma. The proposed aims are significant and innovative, as analyses of prospective proteomic and metabolomic markers, in combination with genetic and clinical phenotype data to subclassify POAG, will advance our understanding of POAG etiology.

NIH Research Projects · FY 2026 · 2024-09

ABSTRACT - Overall The overall goal of the University of Washington Translational center for kidney microphysiological systems to improve drug safety and efficacy is to expand upon kidney tissue chip developmental work our team has accomplished over the past decade, in order to qualify these microphysiological systems as drug development tools for specific Contexts of Use. Despite marked recent advances in our understanding of the physiology and pathophysiology of the human kidney in health and in disease, there are relatively few drugs that are proven to be safe and effective therapies for kidney diseases. Historically, the structural, functional and physiological complexity of the kidney has contributed significantly to the high rate of failures in therapeutic drug development. The complex multicellular architecture and unusual triad of physiological processes characterized by glomerular filtration, tubular secretion and tubular reabsorption, have limited the ability of animal models to recapitulate the diversity of etiologies, mechanisms, and heterogeneous clinical manifestations of most human kidney diseases. The limitations resulting from extrapolating animal model data to human kidney diseases constitutes a major barrier to developing new therapies. Until recently there has been a lack of human in vitro models that recapitulate critical aspects of kidney function or assess reparative mechanisms in response to injury. This is in part because microfluidic flow is so essential to kidney structure and cellular function. In response to this critical unmet need, our group has pioneered the development of ‘human kidney-on-a-chip’ microphysiological systems. Our in vitro on chip models recapitulate critical aspects of kidney physiology, assess the mechanisms and response to injury, and can test reparative mechanisms, all of which can substantially enhance successful drug development that is needed to improve the lives of people living with kidney diseases

NIH Research Projects · FY 2024 · 2024-09

PROJECT SUMMARY Neurometabolic diseases encompass a wide range of more than 1600 genetic conditions caused by a metabolic defect that results in significant neurological deficits. The incidence is estimated to be 1 in 800 births and the number of reported cases is increasing every year largely due to the advancements in genetic diagnostics. The natural course of these conditions is primarily progressive, and without effective interventions, patients experience a decline in neurological function, frequently resulting in premature mortality. Despite the magnitude of the problem, available information about these diseases is scattered (often a list of facts or long tables), is not publicly accessible for meta-analysis or integration with third-party sites, and it is unavailable for quantification of underlying annotation. This lack of accessible and structured information exacerbates the challenge faced by physicians, including neurologists, psychiatrists, and general practitioners, who often do not receive formal training in neurometabolism. Consequently, patients often find themselves taking multiple medications to address a single deficit, thereby accumulating side effects, perpetuating unresolved symptoms, and increasing suffering. Basic science research in this field has also suffered from neglect due mostly to the lack of validated databases and epidemiological information on these conditions. There is, therefore, a need to create a smart online platform for all neurometabolic diseases that is accessible to anyone, easy to use, and user friendly. We will focus the first version of the platform on physicians and scientists. There are three reasons for it: firstly, the platform will fulfil an area of unmet need in terms of understanding, patient management, and research in these conditions. Secondly, doctors and scientists will be able to contribute to the development, curation, and expansion of the database. And thirdly, targeting this user group is feasible within the time and financial support of the R03. To develop this platform, we propose two aims: (1) the development of a comprehensive database that includes clinical, biochemical, radiological, and therapeutic data on all known neurometabolic diseases; and (2) the creation of an intuitive, clinically oriented web application. Our multidisciplinary team comprises experts in clinical neurometabolism, chemical analysis, bioinformatics, and software engineering, who have already developed a suite of 16 web applications for neurometabolic and clinical data analysis. These tools are part of our Neurometabolomics & Neuroinformatics Core at the Icahn School of Medicine at Mount Sinai. This initiative is poised to significantly enhance understanding, clinical management, and mechanistic insight into neurometabolic diseases. Its innovative nature lies in its status as the first comprehensive, open-source, and intuitive online infrastructure dedicated exclusively to these conditions. The platform's value is expected to translate into tangible benefits for this underserved patient population, improving both care and outcomes.

NIH Research Projects · FY 2026 · 2024-09

PROJECT SUMMARY/ABSTRACT Health disparities science has advanced significantly over the last two decades, yet complex challenges remain. Improving the health and health care of populations, and by extension the health of all communities, will require a robust, transdisciplinary minority health and health disparities (MH/HD) research workforce with expertise in health equity research methods and approaches, and experience engaging with communities and multi-sector stakeholders. Emerging MH/HD researchers will need to become adept at designing multi-level, multi-domain studies to address the many intersecting factors and sources that contribute to health disparities and should be committed to engaging communities across all phases of research, from the development of research questions to dissemination of findings to scientific and non-scientific audiences. We propose to establish the Institute for Health Equity Research Catalyst Center at the Icahn School of Medicine at Mount Sinai, guided by an Appreciative Inquiry framework. The Center will provide scientific training and funding support to promote the engagement, advancement, and retention of investigators across Mount Sinai in community-informed research focused on understanding and eliminating health disparities. A key priority will be bi-directional capacity building in MH/HD research (investigators  community partners), and we will engage community partners across Center programs and activities. The Center’s aims are to: (1) Build on existing strengths, expertise, and resources to develop the Center’s governance, programmatic, and evaluation components (Administrative Core); (2) Catalyze efforts to conduct MH/HD research to support trainees/faculty at all levels and across all disciplines through education and training; and implement the Catalyst Scholars Pilot Project Program for early-stage investigators planning to submit NIH K or R applications (Investigator Development Core (IDC)). Pilot projects will be required to: focus on disparities populations, incorporate domains from the NIMHD framework, and include community- engaged approaches; (3) Leverage our existing, expansive academic-community partnerships to convene a Catalyst Community Board (CCB) to collaborate with the IDC on all aspects of the Center’s work (Community Engagement and Dissemination Core/CEDC) and link Scholars to community consultants, and research and dissemination partners. Catalyst activities for all faculty and trainees include Health Equity Research Methods and Approaches Workshops & Seminars, a health disparities consultation service, multi-sector summits. Catalyst Scholars will be paired with health equity mentors, have access to experts in MH/HD research approaches and methods, and participate in research methods workshops, health equity seminars and career development activities; they will present their work to the CCB for input at project start-up and upon completion to co-develop novel dissemination strategies. We will evaluate all programs/activities and the Center’s overall performance to create and share a blueprint for others to build similar centers. Catalyst will become a dynamic transdisciplinary Center producing MH/HD research designed for rapid translation to policy, practice, and measurable impact.

NIH Research Projects · FY 2025 · 2024-09

Modified Project Summary/Abstract Section Adolescent pregnancies remain an area of marked health disparities. What there has been significant effort put into the initial development and testing of evidence-based teen pregnancy prevention programs (EBPs), little data exist to guide replication and adaptation to local contexts or for different populations. Yet most EBPs require some type of adaptation. This project combines mixed methods data from nine large-scale federal- and state-funded replication projects with over 17,000 participants from various locations and populations across the state of Indiana. The project seeks to advance our understanding of adaptation in EBPs focused on four key areas: system involvement, rural communities, use with different populations, and virtual approaches. Using the Framework for Reporting Adaptations and Modifications-Expanded (FRAME) as a guide, the specific aims of this proposal are: (1) to describe the frequency, characteristics and type of adaptations made when implementing EBPs with a focus on the above four areas; (2) to quantitatively examine the effect of adaptations in these four areas on key EBP targets, including skills, knowledge, attitudes, intentions and behaviors, using youth surveys; (3) to describe stakeholder’s approaches for determining the need for adaptations in these four areas; and (4) to create an adaptation toolkit using a Delphi process involving expert and community stakeholders. This project will inform EBP adaptation and replication.

NIH Research Projects · FY 2024 · 2024-09

PROJECT SUMMARY False information can fuel distrust, hinder health literacy, and negatively impact public health responses, as demonstrated during the pandemic. Yet health misinformation is epidemic, augmented by use of artificial intelligence and social media. Misinformation increases health disparities and erodes trust in science, especially in marginalized communities. To address this misinformation epidemic, we will use a strategy is to leverage community-based networks to promote health, as trusted local influencers can disseminate accurate health information that not only reaches its target audience but also is accepted by community members. Thus, we hypothesize that trusted community influencers can promote scientifically sound, specifically tailored health information in marginalized communities, and that involving students will make this effort sustainable. Accordingly, Mount Sinai researchers partnered with the Arthur Ashe Institute for Urban Health (AAIUH) to create the Community Health Information and Education Forum (CHIEF), a collective of researchers, community leaders, and students who use community-based participatory research to address health disparities in Brooklyn in New York City. Through pilot funding, CHIEF has generated preliminary data and assessed key needs in this target community. To respond to these needs, CHIEF will create a technology platform to help community influencers spread scientifically sound information to Brooklyn residents, most of whom are of African American and Afro-Caribbean descent. The technology platform will have two components: a Message Mapping Dashboard, which will provide a cockpit for members of community-based organizations to create, deploy, and measure health information campaigns; and a Mobile Health Bulletin Board, a smartphone app especially designed for barbers and stylists, who are known influencers in communities of color. The app will give these community influencers easy access to understandable, reliable, and timely health infographics they can share with clients. Health messages for the dashboard and the mobile app will be created by MPH and MD/MPH students taking graduate courses in health literacy and vetted by faculty experts. Students participating in these programs will receive mentorship and training in health communication and will have the opportunity to leverage CHIEF for research projects. Students also will present at the Health Sciences Academy, an enrichment program for underrepresented minority high school students, to expose these students to relevant issues as well as potential careers in public health research. By applying principles of implementation science, CHIEF will be sustainable beyond the life of this grant by creating an enduring technology platform that can be adapted by other marginalized communities. We expect that this project will have measurable impact by focusing on trusted community resources to reach disadvantaged populations, helping prevent spread of health misinformation in at-risk communities, promoting equitable health, and enhance diversity and inclusion in public health professions.

NIH Research Projects · FY 2025 · 2024-09

Summary Patients with diabetic kidney disease (DKD) frequently develop cardiovascular disease (CVD), and vascular complications and endothelial cell injury is a common pathological event for both DKD and CVD. Therefore, the development of novel treatments with dual cardio-renal protection is urgently needed. Krüppel-like factors (KLFs) are a subfamily of 17 DNA-binding transcriptional regulators. Through unbiased screening, we identified KLF2 as a highly regulated gene in the diabetic kidney. KLF2 is known to mediate flow-dependent phenotype in endothelial cells, and confers endoprotective effects by inhibition of pro-inflammatory pathways, thrombotic activation, and uncontrolled angiogenesis. Due to these endo-protective effects, KLF2 has been shown to be protective in CVD. Over the last several years, we have generated interesting data to support the critical role of KLF2 in protecting GEC injury in DKD. We find: 1) KLF2 expression is regulated by many factors in GECs such as glomerular hyperfiltration, high glucose, TGF-α, sex hormone, and SGLT2i. 2) KLF2 expression is reduced in GECs of human diabetic kidneys and reduction of KLF2 expression is associated with the progression of human DKD. Two missense mutations of hKLF2 gene were found to be associated with ESKD. 3) KLF2 has anti-inflammatory effects and regulates eNOS expression in GECs. 4) Endothelial cell-specific KLF2 KO mice with diabetes develop more severe GEC injury and DKD, while endothelial cell-specific overexpression of KLF2 has protective effects in DKD mice. 5) KO of KLF2 in endothelial cells also aggravates proteinuria and renal dysfunction in the mice with unilateral nephrectomy. Based on these preliminary data, we hypothesized that KLF2 has a major protective role against GEC injury in DKD and KLF2 could be an attractive drug target for treatment of DKD. To further test this hypothesis, we propose the following three aims: Aim 1: Determine how KLF2 is regulated in diabetic conditions. Aim 2: Determine how KLF2 protects against GEC injury and progression of DKD. Aim 3: Determine whether KLF2 agonists could be developed as a novel drug for the treatment of DKD. These studies will help us to further explore the mechanisms of the endo-protective role of KLF2, validate KLF2 as a potential drug target, and develop KLF2 agonists as a potential treatment for DKD. We believe that KLF2 agonists could be eventually developed as a novel drug for cardio-renal protection in diabetic patients with CKD/CVD.

NIH Research Projects · FY 2025 · 2024-09

Project Summary In May 2023, the Surgeon General declared a public health epidemic of social isolation and loneliness in the United States. Loneliness—the subjective experience of distress at one's perceived lack of social connection—has reached an all-time high in the United States, with roughly half of U.S. adults reporting sometimes or always feeling lonely. It is a key transdiagnostic symptom across psychopathology and serious risk for many deleterious outcomes, including depression, anxiety, dementia, stroke, inflammation, cardiovascular disease, cancer, suicide, and premature death. The premature mortality rate associated with social isolation and loneliness is greater than that caused by smoking 15 cigarettes per day and nearly three times that of obesity. With the enormous economic burden—more than $6.7 billion in healthcare spending annually among older adults alone—addressing this problem is a public health emergency. Despite this, the neural, cognitive, and behavioral mechanisms that underlie forming and maintaining interpersonal relationships at the individual-level are still poorly characterized—which is crucial for generating new policies, health care, and preventative interventions. This proposal aims to characterize how and when computations along a cognitive hierarchy of social information processing (e.g., perception, learning, inference, decision-making) impact social connection, and consequently, loneliness. Because loneliness can emerge via disrupted computations at multiple points along this hierarchy, the proposed project will utilize state-of-the-art computational, behavioral, and neural methods and apply theory-based as well as data-driven models of brain and behavior to identify computational phenotypes of loneliness. Aim 1 is to assess how loneliness impacts the motivation to seek social connections via the perception of social cues. Aim 2 is to examine how loneliness affects learning from social information, a key ability in forming social connections via. Aim 3 is to characterize how loneliness impacts the ability to infer others' beliefs and act accordingly, which is key for maintaining social connections. This work expands a new direction of interpersonal computational psychiatry: integrating theory with computational methods to understand the interplay between mental health outcomes and computations underlying interpersonal relationships, which is critical for identifying risk factors of chronic loneliness and designing more personalized interventions to prevent future epidemics.

NIH Research Projects · FY 2024 · 2024-09

ABSTRACT Clonal hematopoiesis (CH) has been linked to an increased risk of cancer and cardiovascular diseases. However, its potential implications in various age-related conditions, particularly neurodegenerative diseases, remain insufficiently explored. Recent research has highlighted the protective effect of clonal hematopoiesis of indeterminate potential (CHIP) against Alzheimer's disease (AD), emphasizing the need for further investigation into CH's role across a spectrum of neurodegenerative diseases. Yet, the involvement of CH in other neurodegenerative diseases, such as Parkinson's disease (PD), dementia with Lewy bodies (DLB), and amyotrophic lateral sclerosis/frontotemporal lobar degeneration (ALS/FTD), has not been comprehensively investigated. Additionally, the distinct implications of other types of CH, including autosomal mosaic chromosomal alteration (mCA) and loss of the Y chromosome (LOY), on these diseases have yet to be thoroughly examined. To fill this knowledge gap, this project will unravel the disentanglement of commonalities and disparities in associations between different CH types and neurodegenerative diseases by leverage a large amount of high-throughput sequencing data of AD, PD, DLB, and ALT/FTD. Moreover, this project will gain insight into the underlying mechanisms of its potential varying effects of CH across the diseases by utilizing extensive functional genomics data. To this end, this project has three specific aims. In aim 1, we will uncover the associations of different CH types with neurodegenerative diseases by leveraging whole-genome sequencing data from multiple cohorts. We will also perform Mendelian randomization to support causal associations between CH and neurodegenerative diseases. In aim 2, we will characterize inter-individual transcriptomic variability in individuals with and without CH across central nervous system tissues and myeloid cells by leveraging previously published data, including bulk, sorted, and single-nuclei RNA-seq (snRNA-seq), as well as assay for transposase-accessible chromatin using sequencing (ATAC-seq), from disease cohorts. We will also perform cell type-specific transcriptome and chromatin accessibility characterization by detecting cells with autosomal mCA and LOY from snRNA-seq/ ATAC-seq. In aim 3, we will employ two innovative experimental approaches: (1) snRNA-seq paired with genotyping of transcriptome (GoT) and (2) iPSC-derived human microglia-like cells (iMGL) to delve into the cell type-specific functional impacts of CHIP. Aim 3 will significantly complement Aim2 since cell type-specific characterization of CHIP is challenging unlike autosomal mCA and LOY. Our preliminary results suggest varying effects of CHIP and LOY on the risk of different neurodegenerative diseases and functional impact of LOY, especially highlighted in microglia. These findings validate and motivate our work plan, driving us to pursue further studies in this project. The comprehensive understanding of CH's role in neurodegenerative diseases achieved through this project will make significant contributions to the discovery of novel treatment options and the discovery of biomarkers for predicting the risk or progression of these diseases.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY Down syndrome (DS) is the most common form of autosomal aneuploidy in humans, with an incidence of ~1 in 700 live births, and is characterized by physical growth delays, skeletal abnormalities, neurological deficits and cognitive impairments. Although the genetic cause of DS is full or partial triplication of chromosome 21 (HSA21), triplicated genes on HSA21 do not fully account for the widespread transcriptional dysregulation observed in DS. Given the tremendous amount of variability in the severity and clinical presentation of DS, it has long been believed that epigenetic processes may also contribute importantly to global patterns of transcriptional dysregulation, both during neurodevelopment and in adulthood. However, until recently, our understanding of how chromatin-based mechanisms may contribute to DS-related phenotypes remained limited. During the previous funding periods of this R01, we found that the HSA21-encoded chromatin effector protein, BRWD1, is upregulated in neurons from individuals with DS and in brain of both male and female trisomic mice. We demonstrated that selective copy number restoration of Brwd1 in trisomic animals robustly rescues deficits in hippocampal LTP, gene expression and cognition. We observed that Brwd1 binds tightly to the mammalian BAF chromatin remodeling complex – both neural progenitor (np) BAF during development and neuronal (n) BAF in adulthood – and that increased Brwd1 expression promotes BAF genomic mistargeting. Importantly, Brwd1 renormalization rescues aberrant BAF localization, along with associated changes in chromatin accessibility and gene expression. These findings established BRWD1 as a key epigenomic mediator of normal neurodevelopment and an important contributor to DS-related phenotypes. Although Brwd1 is clearly important for BAF genomic targeting and neural gene expression, the molecular mechanisms through which this targeting is achieved remains unclear, and the primary neural cell-types affected by Brwd1 triplication in DS-like brain have yet to be explored. Also, while DS has largely been assumed to be untreatable due to disrupted in utero development, our recent data suggest that restoring Brwd1 gene activity in early postnatal brain may be sufficient to ameliorate cognitive deficits in adult trisomic mice, yet the molecular underpinnings and/or importance of neurodevelopmental timing of this rescue have yet to be explored. Using a unique combination of biochemical, single-cell omics, genetic and behavioral analyses, we will comprehensively explore: (Aim 1) the biochemical basis through which Brwd1 recruits the BAF complex to neural chromatin via its histone ‘reader’ functions and protein-protein interactions; (Aim 2) the longitudinal and cell-type specific contributions of Brwd1 triplication to BAF genomic targeting, chromatin accessibility and gene expression across multiple brain regions known to be affected in DS; and (Aim 3) the molecular, physiological and behavioral impact of Brwd1 copy number restoration during postnatal periods. These studies will provide valuable insights into the molecular mechanisms of Brwd1 dysregulation in DS-like brain and inform on the possibility of postnatal treatments for this disorder.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY Psychiatric disorders remain a leading cause of disability in the US and are associated with increased morbidity and mortality. Early detection and treatment is essential to improving long-term outcomes, yet a substantial proportion of patients with psychiatric complaints experience long diagnostic odysseys before receiving an appropriate diagnosis and initiating effective treatment. “Learning health care systems” aim to short-circuit this slow process by leveraging the diagnostic, treatment, and utilization patterns left behind in “big data” (e.g., clinical, genomic, and social determinants of health) to more efficiently and accurately match the right patient with the right diagnosis/treatment, at the right time. Furthermore, over the past several years, a new paradigm– precision medicine–has moved to the forefront of biomedical research and clinical practice. Precision medicine has been defined as “an approach to disease treatment and prevention that seeks to maximize effectiveness by taking into account individual variability in genes, environment, and lifestyle.” Since its inception in 2018, the mission of the PsycheMERGE network has been to advance precision psychiatry in a learning health care system framework. This application, which was developed collaboratively by PsycheMERGE Network members, represents an opportunity for profound advancement of both basic and translational research in precision psychiatry. We propose extending our foundational efforts to now address barriers to scalability, utility of genomic data, clinical application, and translation to clinical practice in a precision psychiatry paradigm. Specifically, Aim 1 creates a nation-wide federated transfer-learning platform for the development of generalizable and bias-aware algorithms. Aim 2 integrates state-of-the-art methods to perform inclusive trans-ancestry genomic analysis of biobank samples and further innovates by leveraging the breadth and depth of medical record data to discover novel biology that can further inform precision psychiatry paradigms. Aim 3 addresses the application of algorithms by focusing on two use cases including (a) differential diagnosis between bipolar disorder 1 and other mood disorders, as well as (b) probabilistic treatment response to antidepressants for acute depressive episodes. Lastly, Aim 4 uses mixed methods to assess the feasibility, utility, and attitudes towards precision psychiatry tools. Our combined sample of clinical EHR data exceeds 29 million individuals and of those, nearly 2 million also have genetic data already available for analysis across the twelve sites included in this application. A cross-cutting theme throughout the application is the intentional focus on equitable performance of algorithms, innovative integration of social determinants of health, and inclusive methods for genomic analyses. The sites included are also representative of many diverse communities across the United States including the East and West Coasts, the South, and the Midwest. This application represents a major step towards equitable precision psychiatry and brings the field closer to the goals outlined in the updated NIMH Strategic plan.