Icahn School Of Medicine At Mount Sinai

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.

NIH Research Projects · FY 2026 · 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.

NIH Research Projects · FY 2026 · 2024-04

Diabetic kidney disease (DKD) is the leading cause of end-stage kidney failure in the USA and is increasing in prevalence at an alarming rate worldwide with no targeted therapy available. The pathogenesis of DKD is complex, influenced by genetics and the environment. The underlying genetic susceptibilities to DKD remain poorly understood. To investigate the genetic basis of DKD, we studied diabetes-induced podocyte depletion associated with DKD susceptibility in inbred DBA/2J mice and C57BL/6J mice, well established mouse models for DKD susceptibility and resistance, respectively. We also examined the BXD recombinant inbred panel to map genetic loci (QTL) associated with podocyte number after long-term diabetes (6 months). These studies identified a genome wide significant cis-acting regulatory region for the Xor gene encoding xanthine oxidoreductase (Xdh+XO) and an important source for ROS production in diabetes. Our data show Xor expression and activity was strongly increased by diabetes in glomeruli of DBA/2J, but not C57BL/6J resistant mice. A functional role for Xor was confirmed by a significant amelioration of albuminuria, endothelial cell mtDNA oxidative stress damage and podocyte loss in diabetic DBA/2J mice co-treated with a Xor inhibitor. We hypothesize that Xors are key contributors to phenotypic consequences in diabetes, and differential Xor regulation can predispose to DKD. We used genome editing clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 to knock in the high risk Xor promoter variants in whole animals and generated B6-Xorem1 mice to comprehensively study the effects of Xor regulation and activity in diabetes. Diabetic B6-Xorem1 mice had increased diabetic kidney injury and significant podocyte depletion compared to the parental C57BL/6J strain. B6-Xorem1 mice showed increased oxidative stress and an accumulation of mitochondrial DNA damage specifically in the glomerular endothelial cells, which was prevented by a small molecule inhibitor of Xor. Therefore, differential regulation of Xor contributed to phenotypic consequences with diabetes. We also uncovered promoter XOR orthologue variants associated with high-risk for DKD in a large human cohort. Our proposed studies will advance our understanding of DKD genetics and determine the therapeutic potential for gene editing in 2 Specific Aims: 1) To edit the high risk Xor promoter variants for DKD using gene editing. 2) To interrogate the genetics of human XOR orthologues. LONG-TERM: Our proposed studies will advance our understanding of mice and human genetics for risk of diabetic complications by investigating the role of Xor promoter risk variant, ROS, glomerular endothelial injury and cell crosstalk with podocytes. The study also proposes to edit the risk variants using gene editing with the potential for a future treatment for patients at risk of DKD.

NIH Research Projects · FY 2026 · 2024-04

Research: Colorectal (CRC) and breast cancer (BC) are leading causes of preventable cancer mortality, yet screening rates remain well below Healthy People 2030 benchmarks for many US populations. Despite the proven effectiveness of screening in reducing cancer death, uptake is low among individuals with limited understanding of screening and those who face logistical challenges. The purpose of this study is to develop and evaluate a multi-component, community-based intervention (‘CG’) by adapting the FAHS, a NCI Cancer Control Program that successfully improved CRC screening rates. Our specific aims are to: 1) Develop CG by adapting and enhancing the FAHS to simultaneously support CRC and BC screening and 2) Conduct a pilot RCT to assess the feasibility and preliminary impact of CG on CRC and BC screening on unscreened individuals. To accomplish these aims, we will employ a community-based design, and qualitative findings from focus groups and interviews across multiple screening experiences (i.e., up-to-date vs ever-screened vs never-screened) will guide the development of CG. The intervention will be iteratively refined and evaluated for feasibility and preliminary impact in a pilot RCT. Candidate: Dr. Christina Wang aims to become an independent patient-oriented investigator and leader in intervention development to improve cancer screening uptake. Dr. Wang’s proposed training activities are in four areas: 1) qualitative methodology; 2) development of community-based interventions; 3) RCT design and evaluation; and 4) career development (e.g., manuscript and grant writing, leadership skills). To achieve these goals, she has assembled a multi-disciplinary mentoring team. Dr. Lin, her primary mentor, is an accomplished clinician-investigator with qualitative expertise who has focused on disease management and illness beliefs in patients with breast cancer. Dr. Wisnivesky, her co-primary mentor, has a research focus in cancer prevention, comparative effectiveness, and RCT design and implementation. Her co-mentors include Dr. Itzkowitz, a national leader in CRC prevention, Dr. Mazumdar, expert in biostatistics, and Ms. Jandorf who has expertise in CRC and BC screening programs. Her advisor, Dr. Diefenbach, will provide expertise in cancer-related health communication. Environment: The Icahn School of Medicine at Mount Sinai has a strong tradition of outstanding research and is ranked 11th nationwide in NIH funding. The Division of Gastroenterology is consistently ranked among the top 10 divisions by US News and World Report and is nationally renowned for pioneering research and clinical care in gastrointestinal cancer. 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 · 2024-04

PROJECT ABSTRACT/SUMMARY In the past few years, several gene therapy products using adeno-associated virus (AAV) have been approved for clinical use for treatment of non-cardiac diseases. However, existing data indicate extremely low cardiac uptake of AAV in human hearts, hampering clinical translation of cardiac gene therapy. My lab has recently developed a clinically applicable approach to overcome this low AAV uptake. Our preliminary data indicate that intracoronary delivery of AAV during simultaneous occlusions of coronary artery and sinus (stop- flow delivery) results in globally increased gene expression with up to 500-fold higher expression compared to the standard antegrade delivery, even in pigs with pre-existing neutralizing antibodies against AAV. Unique to our approach, we ensure safety by supporting the systemic hemodynamics and alleviating cardiac ischemia using a catheter-based cardiac assist device. Our method will thus offer minimally invasive, safe, but efficacious gene delivery to human hearts. Although our preliminary data is strong, we still lack understanding in how and which delivery-related factor(s) contributed to improved gene expression. Defining key factor(s) that led to significant improvement will allow us to rationally design AAV gene delivery for further refinement. In this application, we propose inter-connected, but independent Aims in large animal heart failure models to: 1.Identify the key mechanical factor(s), 2. Understand uptake mechanisms and 3.Establish clinically applicable delivery protocol. Based on our preliminary data, we will focus on capillary pressure and dwell time in Aim 1 as key factors, endothelial permeability and vesicular AAV uptake in Aim 2 as potential mechanisms of improvement, and clarify remaining uncertain issues for clinical realization in Aim 3, which include optimal serotype for targeting human heart, antibody inhibition, and defining optimal patient population for stop-flow gene therapy. Our proposal is conceptually novel in focusing on various factors in delivery (mechanical, biological and pathological), in contrast to the majority of delivery-focused studies only testing methods of their interest. Additional innovative points include exploring repeat AAV dosing, mechanistic studies of cardiac AAV uptake, and treating hibernating myocardium using gene therapy. By further improving our promising AAV gene delivery method that allows efficient and safe cardiac gene expression, an obstacle currently plaguing the clinical translation of cardiac AAV gene therapy will be overcome.

NIH Research Projects · FY 2026 · 2024-04

PROJECT SUMMARY The ability of the heart to contract continuously is vital to the organism and is dictated in part by the sarcomeres, the functional units of the contractile apparatus. Consequently, any errors in the formation, composition or homeostasis of the sarcomere structure lead to congenital heart defects (CHD) or various forms of cardiomyopathy. While the highly complex structure of the cardiac sarcomere and its function have been studied extensively for decades, comparatively little remains known about how the sarcomere structure is established in the first place, during de novo sarcomerogenesis. Current knowledge is largely qualitative as in depth mechanistic studies are challenging at such early stages of development. Here we will use human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) to interrogate our hypothesis that de novo sarcomerogenesis occurs via a mode of assembly that involves formation of membrane-less organelles (MLOs) with distinct biophysical properties. In Aim 1 we will interrogate the biophysical properties of Z-bodies and Z-discs during early heart development and identify individual candidates and biological processes that dictate Z-body formation. We will use super-resolution and time-lapse microscopy, FRAP analysis and transmission electron microscopy. To identify drivers of Z-body formation we will use CRISPRi for candidates identified in the ACTN2 interactome and likely to be involved in formation of MLOs. Lastly, we will assess if Z-bodies possess distinct biochemical functions, including the presence of specific mRNA transcrips and/or local translational activity. In Aim 2 we will determine the mechanisms that underlie Z-body initiation at the onset of de novo sarcomerogenesis. We have described a role for WNT and RHO signaling in Z-body formation and we will identify additional mechanisms using small molecule screening. The successful completion of this comprehensive and detailed mechanistic study of Z-bodies holds the promise of delivering an unprecedented level of characterization of this critical stage of de novo sarcomerogenesis. It will encompass a thorough understanding of the formation and function of Z- bodies as a biomolecular condensates, as well as the identification of novel candidates involved in this process and their role in cardiac function.

NIH Research Projects · FY 2026 · 2024-04

SUMMARY Mount Sinai's Training Program in Social Neuroscience Research will offer late-stage predoctoral (PhD) students and early-stage postdoctoral fellows an integrated program of training in social behavior research that builds on vast expertise in translational neuroscience, neurology, psychiatry, and genomic sciences. The overarching goal of the program is to provide rigorous, broad-based, individualized, and multidisciplinary training with enhanced opportunities for mentoring, collaboration, and career development designed to prepare the next generation of independent investigators in social behavior research, particularly as it relates to neuropsychiatric syndromes. At the heart of this new Training Program will be a superb training faculty representing remarkable diversity in basic and clinically-relevant topics, including social behavior disturbances in psychiatric and neurological diseases; molecular and synaptic mechanisms of social behavior; and developmental disorders of social function. The training program comprises seven inter-related components: academic coursework, laboratory training, non-curricular training activities (seminars, retreats, etc.), testing/evaluation, teaching opportunities, mentoring, and career development activities. Varied laboratory opportunities at Mount Sinai take advantage of strengths in translational neuroscience, computational neuroscience, neuropsychiatric genomics, neuroimaging, epigenetics, and synaptic and behavioral plasticity and provide opportunities for the study of diverse model systems. The Training Program includes more than a dozen opportunities either newly created or building on existing opportunities to create sharp focus on training in social neuroscience relevant to neuropsychiatric disease, to emphasize multidisciplinary collaborations, and to foster and promote exceptional rigor and creativity. Pre-and-postdoctoral trainees will participate in a range of required and optional training activities to ensure strong grounding in basic neuroscience and opportunities to learn from and with peers and faculty from across the Icahn School of Medicine at Mount Sinai (the Graduate School of Biomedical Sciences, the medical school, interdisciplinary Centers and Institutes, central among them the Friedman Brain Institute), as well as from other institutions. Creating a structure for, and culture of, mentoring across the continuum of the Training Program is a key component of the program; formal and informal advising and mentoring will be integrated into training across roles and levels, including mentoring opportunities for training faculty and sponsors (preceptors). Integrating predoctoral and postdoctoral training through formal mechanisms will provide greater continuity in the overall training experience, enhanced opportunities for collaboration among trainees interested in pursuing careers in mental health research, and will benefit the neuroscience research effort at Mount Sinai. The Training Program in Social Neuroscience will prepare the most promising trainees for productive, independent careers in social neuroscience research through a training program that both promotes rigor and nurtures innovation.

NIH Research Projects · FY 2025 · 2024-04

PROJECT SUMMARY The addiction and overdose crisis in the United States has reached a record high, with almost 109,000 overdose deaths in 2021, the majority of which are due to opioid overdoses, according to the Centers for Disease Control and Prevention. Medications exist for treating brain Expanding the range of effective therapeutics for substance disorders caused by drug abuse, but use disorders, particularly opioid use disorders they have limitations. (OUDs), is necessary and urgent. T he National Institute on Drug Abuse's Division of Therapeutics and Medical Consequences has identified a number of G protein-coupled receptors (GPCRs) modulated by functionally distinct ligands as key targets for developing novel therapeutics to treat opioid overdose and opioid use disorders. Identifying specific and selective small-molecule ligands for these receptors is crucial for understanding their function and developing effective treatments. However, this is a challenging task due to the functional complexity of GPCRs and the difficulty in customizing ligands for them, despite advances in GPCR functional and structural biology. With the increasing availability of functional data from sophisticated bioactivity assays, billion-scale electronic chemical libraries, and ever-growing high-resolution structural information on GPCRs, it is important to develop quantitative and analytical approaches to leverage knowledge and information towards the development of effective medications for OUDs. The proposed research aims to develop Artificial Intelligence (AI)-driven strategies to design customized GPCR ligands and efficiently screen ultra-large electronic chemical libraries to speed up the discovery of novel chemical compounds with distinct pharmacological profiles targeting GPCRs linked to drug abuse. Specifically, the study will investigate the performance of deep neural network classifiers trained on large datasets of key structural and physicochemical properties of ligands and targets from receptor subfamilies and compare it with the performance of classifiers trained on features from a single GPCR of those subfamilies in distinguishing between ligands with varying efficacy at that receptor. The goal is to create a scalable platform that can add value to current rational drug design approaches for GPCRs associated with drugs of abuse by identifying lead compounds that can be developed into successful drugs for clinical applications.

NIH Research Projects · FY 2026 · 2024-04

SUMMARY/ABSTRACT Schizophrenia is a devastating and burdensome illness that afflicts ~1% of the global population. Cognitive symptoms are a hallmark of the disease, affecting most individuals with schizophrenia, and being responsible for the greatest reduction in quality of life. Despite their significant impact, the biological mechanisms of cognitive deficits remain elusive, in part due to limitations of the experimental approaches typically used to study them in humans. To overcome these limitations, we propose a novel approach using biophysical modeling as an explanatory theoretical framework for bridging the translational gap between previous preclinical work in mouse models of schizophrenia-relevant risk and the proposed work in patients with schizophrenia. We propose translation of the findings of reduced neuronal ensemble reliability (n-ER) in the primary visual cortex (V1) as a window into a brain-wide circuit-level alteration in schizophrenia and its relationship to cognitive deficits. To achieve this, we will use a combined sample of 1,760 individuals, including healthy individuals, patients with schizophrenia or bipolar disorder and their first-degree relatives, from the HCP Young Adult, HCP Psychosis, and HCP Early Psychosis projects. Specifically, we will measure voxel ensemble reliability (v-ER) in humans using resting-state and visual-stimulation fMRI data—akin to calcium imaging studies in mice— as a theoretically grounded and translational index of excitation-inhibition balance (E/I) in cortical circuits. First, we aim to develop a biophysical model of V1 constrained by preclinical and basic neuroscience experiments, and test model predications of neuroimaging measures related to E/I. Second, we will test for reduced v-ER in patients with schizophrenia—directly translating preclinical findings—and use biophysical model simulations to identify potential biological mechanisms. Third, we will use the unique sample characteristics of the HCP Psychosis project (patients and first-degree relatives) to investigate the relationship between genetic burden for schizophrenia and v-ER. Fourth, given the convergence of cognitive deficits in the preclinical mouse models, we will examine the relationship between v-ER and cognitive performance. We will further seek to establish reduced v-ER as a brain-wide mechanism of cognitive deficits by testing for relationships in cognition across disparate sensory domains. Throughout, we will use well-powered, rigorous, state-of-the-art fMRI and statistical data-driven methods suitable for large-scale studies and HCP-like fMRI sequences, including cross-validation and independent confirmation. Together with a strong theoretical foundation and using biophysical modeling to complement fMRI analyses, this approach will begin to elucidate the biological mechanisms of cognitive deficits in schizophrenia. In doing so, this project will establish v-ER as a fully translational neuroimaging measure with the potential to be used as a biomarker for treatment selection and target engagement and will generate predictions that can be directly tested in preclinical studies.

NIH Research Projects · FY 2026 · 2024-04

Project Summary Cannabis is the most popular drug used amongst adolescents with many teens using more frequently than ever. Although perceived as relatively harmless, adolescent consumption of ∆-9-tetrahydrocannabinol (THC), the main psychoactive constituent in cannabis, is associated with vulnerability to a variety of psychiatric conditions including addiction. Parallel to increased use in teens, THC content in cannabis is now at unprecedented levels, and emerging data shows use of high potency cannabis is specifically linked to the development of cannabis use disorder (CUD). Unfortunately, research determining how adolescent high-dose THC (HD-THC) exposure affects neurobiological circuits underlying psychiatric-like behaviors is still lacking. I therefore completed a battery of experiments to disentangle the long-term effects of high dose THC on reward responsivity and stress reactivity in rats. I observed that adolescent HD-THC (but not low dose) uniquely increased stress reactivity in adulthood, a phenotype implicated in addiction risk. In stressed HD-THC rats, RNAseq of the basolateral amygdala (BLA), a region implicated in stress reactivity and cognition, revealed distinct downregulation of astrocyte-specific genes concomitant to upregulation in excitatory- and inhibitory-related genes. HD-THC animals also exhibited decreased astrocyte process length and branching, indicating HD-THC-related stress reactivity is associated with perturbations in astrocytes both on a transcriptomic and morphological level. HD-THC rats also exhibited increased risky decision making and impulsivity after re-exposure to THC in adulthood, cognitive facets tightly linked to multiple psychopathologies including substance use disorders. THC-induced cognitive deficits correlated with BLA Gfap mRNA expression. These results indicate that astrocytes, and their interactions with neurons, likely play a significant role in THC-induced behaviors in adulthood relevant to psychiatric risk. The effect of adolescent HD-THC experience on the transcriptome and function of neuronal and astrocyte populations has yet to be explained. Under the guidance of my mentor, Dr. Yasmin Hurd, and mentorship committee, Drs. Anne Schaefer, Bin Zhang, Joseph Cheer, Eric Nestler, and Xiaosi Gu, I will use single-cell sequencing and fiber photometry to determine how adolescent HD-THC exposure affects astrocyte transcriptomic diversity and maturation (aim 1) and calcium activity (aim 2). I will then causally assess the role of astrocyte activity on THC- related phenotypes (aim 3). After modulating astrocytes using chemogenetics, I will examine the effect on neuronal transcriptomic landscape, as well as calcium activity during decision-making and after THC re-exposure in adulthood. This research program will provide novel mechanistic insights into the protracted effect of high-dose adolescent THC on astrocyte maturation, calcium activity and function in cognitive behavior while providing me key skills to help my transition toward becoming an independent investigator.

NIH Research Projects · FY 2026 · 2024-04

Summary All major forms of diabetes result from a deficit of functional β-cells. Thus, it is critically important to develop therapies to preserve and expand β-cell mass. We have demonstrated that Nrf2, the master transcriptional regulator of antioxidant enzymes, plays a significant role in modulating β-cell mass. Nrf2 protects -cells from oxidative stress, but the mechanisms, external cues, and signaling pathways that regulate Nrf2 are incompletely understood. We recently found that Nrf2 activation expands cell mass, preserves -cell identity and insulin content, and improves glucose tolerance after a high caloric diet. Treatments that increase cAMP through G protein-coupled receptors (GPCRs; for example, agonism of Gs-linked EP4 prostaglandin E2 (PGE2) receptors or the GLP-1 receptor (GLP-1R), or antagonism of Gi-linked EP3 PGE2 receptors), also lead to increased β-cell proliferation, retention of β-cell identity and protection of β-cell mass after challenge with cytokines or glucose toxicity. Importantly for this proposal, our published and preliminary data suggest that Nrf2 is activated by and necessary for the effects of PGE2 receptor modulation and for the effects mediated by GLP-1 receptor agonists. In this proposal our assembled team is uniquely positioned to explore the relationship between Nrf2 activation and other pathways known to protect β-cells from oxidative stress, retain β-cell identity, and promote adaptive β-cell expansion. We hypothesize that the Nrf2 pathway is a common junction between eicosanoid and incretin signaling and thus is a critical nexus of β-cell preservation, identity, adaptation, and function; therefore, Nrf2 is crucial for these agents to improve functional β-cell mass in diabetes. Specific Aim 1 will test the hypothesis that activation of Nrf2 and EP3 antagonism and/or GLP-1R or EP4 agonism work together to enhance β-cell proliferation and β-cell protection from oxidative stress. Specific Aim 2 Identify β-cell-specific Nrf2 targets and characterize the transcriptome and chromatin landscape of Nrf2 activation, EP3 antagonism, and/or GLP-1R or EP4 agonism as these treatments preserve β-cell mass. Specific Aim 3 Explore the in vivo therapeutic potential of combined Nrf2 activation with EP receptor modulation and/or GLP-1R agonism. These studies will provide key mechanistic information, identify new β-cell-specific gene targets, and test the therapeutic potential of three attractive and inter-related pathways that will be of great value to the field for the therapeutic preservation and expansion of functional β-cell mass highly needed in diabetes.

NIH Research Projects · FY 2026 · 2024-04

Project Summary Epilepsy is a debilitating neurological disorder characterized not only by spontaneous recurrent seizures, but also severe cognitive deficits that present a significant detriment to quality of life. Changes in synchrony within and across brain regions have been implicated in temporal lobe epilepsy (TLE), but it is unclear how these changes contribute to memory deficits. Electrophysiological recordings from the Shuman lab have shown that coherence between the hippocampus and medial entorhinal cortex (MEC) is disrupted in a mouse model of TLE. This synchronization between hippocampus and MEC has been theorized to be important for spatial memory by allowing efficient information transfer at distinct phases of theta. However, there have been few causal studies on the impact of synchronization due in part to limited technical methods to manipulate the timing of inputs in behaving mice. Thus, investigating the causal nature of altered synchrony in cognitive dysfunction requires the application of novel tools to precisely manipulate the timing neural activity. To address this gap, I have developed a closed-loop optogenetic system that can stimulate neural populations at distinct phases of endogenous theta oscillations. In this proposal, I will use this system to test the hypothesis that the timing of MECII and MECIII inputs relative to endogenous theta oscillations controls memory performance in both healthy and epileptic mice. I will employ a head-fixed virtual reality task to test the effect of altered input timing on spatial memory performance and will investigate the role of this timing on other measures of synchrony including interregional coherence. I hypothesize that mistiming MEC inputs in healthy mice will impair memory performance and disrupt coherence, while restoring proper timing in epileptic mice will improve performance and increase coherence. Furthermore, I will use a layer specific viral approach to restrict optogenetic stimulation to afferents arriving to the hippocampus from MEC layer II or layer III and determine the distinct role of each of these inputs into hippocampus. Together, the results of these experiments will determine how the timing of inputs into the hippocampus impacts spatial processing in both health and disease and will pave the way for future therapeutic targets in epilepsy.

NIH Research Projects · FY 2026 · 2024-04

Project Summary The epidermis is a vital tissue that protects our bodies against infection and environmental insults. Upon wounding, epidermal basal cells undergo a transient transcriptional switch to increase proliferation and migrate into the wounded area to re-epithelize the epidermis. Regulation of this wound-activated transcriptional switch is unknown, but research has suggested that chromatin remodelers may be responsible. My analysis revealed that a key chromatin repressor, Polycomb repressive complex 1 (PRC1), occupies more than half of wound-related genes during homeostasis, suggesting a potential role of PRC1 as a regulator of the transient switch in epidermal basal cells upon wound induction. By generating and analyzing mice lacking PRC1 function in epidermal basal cells, I observed arrested wound repair as PRC1-null epidermal basal cells failed to migrate during the re- epithelialization stage of wound healing. Cell migration during wound repair is mediated by epithelial- mesenchymal plasticity (EMP), a biological process in which cells undergo molecular and functional changes to interconvert between an epithelial phenotype to a migratory mesenchymal phenotype. The regulation of EMP processes during wound healing is unknown. E-cadherin is an epithelial protein that is transcriptionally downregulated in migrating epidermal basal cells and a key marker of the EMP process. Interestingly, E-cadherin expression was retained in PRC1-null epidermal basal cells upon wound induction. Given these data, I hypothesize that PRC1 mediates the ability of epidermal basal cells to migrate by repressing E-cadherin and reprogramming the transcriptional landscape upon wound induction to undergo EMP processes. To test this hypothesis, in Aim 1, I will investigate the significance of E-cadherin repression in migrating epidermal basal cells by overexpressing E-cadherin in cultured primary epidermal basal cells and ex vivo wound explants. Additionally, I will perform CUT&Tag to investigate if E-cadherin is a direct target of PRC1 regulation, as well as use genetically engineered mice and shRNA technology to repress or ablate E-cadherin expression in PRC1- null mice and PRC1-null epidermal basal cell lines, respectively. In Aim 2, I will determine EMP genes that are most affected by the loss of PRC1 in epidermal basal cells during wound repair and examine the functionality of the identified genes for epidermal basal cell migration. I will also perform immunostaining to assess if PRC1- regulated EMP genes are misexpressed in samples of human chronic wounds. Altogether, these data will uncover a novel role for PRC1 regulation in reprogramming the transcriptional landscape needed for epidermal basal cell migration during wound healing, as well as define the role of PRC1 in controlling EMP during wound healing.

NIH Research Projects · FY 2026 · 2024-04

Nucleoside modified RNA-based drugs (modRNA) are a powerful new class of medicine. One type of modRNA, RNA vaccines, has been pivotal in immunization to SARS-CoV-2. modRNA is delivered via lipid nanoparticles (LNP), and antigen presented by whichever cells take up and expresses the modRNA. The identity and phenotypic state of cells presenting antigen directs how T cells become activated and differentiate. FDA-approved LNPs for modRNA delivery are not cell specific, resulting in expression in pAPCs, hepatocytes, myocytes, and other cells. The contributions of different transfected cell types to the immune response to modRNA-encoded proteins is not known. This is an important question because antigen presentation by some cell types may work against therapeutic goals. While there are efforts to alter LNP organ distribution, precisely tailored cell specificity is still not feasible. We previously developed a technology that enables highly effective cell type specific silencing of vector-expressed RNA. We showed target sites for miRNA (miRT) could be incorporated into the 3’UTR of a transgene, and when the transgene is expressed in cell types that encodes the cognate miRNA, transgene expression is suppressed. Work by numerous labs, including ours, has demonstrated miRT can de-target vector expression from many cell types, including hepatocytes, hematopoietic cells, pAPC, stem cells, and neurons. Preliminary and published data indicate that adding target sites for miR-142 (142T) or miR-122 (122T) to modRNA silences modRNA expression in hematopoietic cells or hepatocytes, respectively, demonstrating the technology can be used to control modRNA expression. Our objective is to use miRT to generate modRNA with tailored cell expression patterns and apply miRT to determine how modRNA expression in specific cell types directs immunity to modRNA-encoded protein. We hypothesize modRNA expression in non-pAPCs, such as hepatocytes, reduces immunity to modRNA-encoded proteins by presenting antigen in a tolerogenic context, and this lowers vaccine efficacy but can be exploited for tolerance. We will generate and test miRT for silencing modRNA in different cell types, including endothelium & myocytes, and determine how modRNA expression in different transfected cells, such as hepatocytes, influences immunity to modRNA antigen. The outcome of this project will establish novel modRNA configurations that tailor expression of proteins to specific cell types and determine how expression in specific cell types directs immunity to modRNA-encoded protein.

NIH Research Projects · FY 2026 · 2024-03

SUMMARY As clinical trials have high failure rates, in part due to reliance on animal testing that can produce inaccurate results, accurate in vitro models of human physiology and disease are needed to bridge this gap. Recent progress in organoid and organ-on-chip systems demonstrates promising potential to do this; however, in vitro models have their own limitations. Stem cell derived models tend to have immature phenotypes, primary cell derived models may be difficult to keep functioning for long periods of time, and in vitro models in general do not recapitulate the full functionality of human organs. In an effort to increase the physiological relevance of these systems, we have developed a cardiovascular microfluidic organoid chip, the µCV chip, which develops according to biomimetic morphogen gradients, and can self-assemble into elongated tube-like structures when the cells are seeded in specific starting geometries with a robotic seeding machine. These pumping tube-like structures can generate flow autonomously in our microfluidic chips. Although this preliminary data is compelling, it remains to be tested whether these tube-like structures have cellular spatial organization or heart-like functionality that is more physiologically accurate than simpler cardiac spheroids. In this proposal, we aim to systematically compare cardiovascular spheroids and cardiovascular tube-shaped microfluidic organoids in depth, in order to further understand how the organization and functionality of organoids change when seeded with different starting geometries and exposed to different flow conditions, and test the hypothesis that tube-shaped flow-generating cardiovascular organoids have microphysiology more similar to a simplified human heart. We will further expand the repertoire of our microfluidic organoid chip by teaming up with colleagues in the Division of Liver Diseases to create hepatic organoids, both iPSC derived and primary cell derived, in order to similarly evaluate differences in hepatic function when the organoids are created with spheroid versus tubular geometries and exposed to different flow conditions. Finally, we will combine these two microfluidic organoid systems into a single microfluidic heart-liver microphysiologic system, the µCV-MPS, and characterize the two organoids as they co-develop and function within a single circulatory system. As the liver is responds to flow and beat rate, and the heart responds to factors secreted by the liver, we hypothesize that we will observe improvements in functionality, viability, and microphysiology by studying heart and liver organoids while they are connected via paracrine signaling and homeostatic regulatory mechanisms. We will additionally use the µCV-MPS as a model of Nonalcoholic Fatty Liver Disease, which is known to lead to cardiovascular disease including left ventricular hypertrophy and diastolic disfunction, pathologies which we hypothesize to be observable inthe µCV-MPS. Validation of this model system would represent a significant step forward in the sophistication and capabilities of human MPS models, helping to provide more predictive alternatives to animal models for next-generation therapeutic development and regulatory approval.

NIH Research Projects · FY 2026 · 2024-03

PROJECT SUMMARY Machine learning-based pathogenicity predictors, trained on known disease and non-disease-implicated variants, predict whether a variant is pathogenic or benign. They have become a key component of genetic variant discovery and clinical genetic testing. However, their use in individual-level genetic and genomic disease risk prediction has been limited by their incompatibility with typically reported measures of risk, and terminology associated with clinical decision-making. Variant pathogenicity predictors generally serve as a key interpretation tool for rare variants in the absence of large enough cohorts to achieve statistical power. As the clinical deployment of genetic and genomic risk prediction models becomes more widespread, it is essential that rare variants be readily incorporated into these models and the risk conferred by such variants be correctly accounted for. To address these gaps, the proposed study will develop methods for the systematic integration and calibration of variant pathogenicity predictors into genetic and genomic disease risk prediction and will test the hypothesis that these methods lead to more accurate and clinically interpretable predictions of disease risk. This work will be carried out through three specific aims: (1) we will adapt and calibrate existing predictors for gene-specific prediction of pathogenic variants, (2) we will develop variant pathogenicity predictor-based exomic disease risk scores, and (3) we will integrate pathogenicity predictors into genome-wide polygenic risk score (PRS) development. The principal investigator (PI) will bring deep expertise in variant pathogenicity predictor development and model calibration to this project, and build a team with complementary expertise in statistical genetics and polygenic risk score development to carry out the work. Additionally, the PI has formulated a plan for his scientific and professional development, and will assemble an external advisory committee with further complementarity of expertise (e.g., in population genetics and clinical genetics). This project will leverage multiple large genome-phenotype data sets that are available publicly (UK Biobank, dbGaP) and through the world-class infrastructure at the Icahn School of Medicine at Mount Sinai (BioMe). This work is expected to have positive impact on multiple fronts. First, there are currently no systematic integration and calibration frameworks for variant pathogenicity predictors that can be generalized for risk prediction across different types of variants, genes and/or diseases. Second, open-source software to calibrate the output of variant pathogenicity predictors in specific contexts (genes, diseases, among others) will be developed and shared with the broader community. Finally, computationally derived estimates of prevalence of pathogenic variants and risk models will be made available through Mount Sinai and NIH resources.

NIH Research Projects · FY 2026 · 2024-03

MOUNT SINAI’S CoFAR CLINICAL RESEARCH CENTER Food allergy is estimated to affect approximately 8% of children and 10% of adults; in the US this translates to 32 million people. Food allergy is potentially life-threatening, significantly impacts quality of life and nutrition, and carries a high economic burden. Although significant advances have been made for prevention and therapy, prevalence rates remain high and therapeutic options are few. The long-term goals of CoFAR are to develop effective strategies to prevent and treat food allergies, and to elucidate underlying mechanisms. As the leadership center (LC) for CoFAR from 2005 to 2015, and as a CoFAR Clinical Research Center (CRC) for 17 years, we are the only CRC to have contributed to every CoFAR study, trial, and supplemental projects, with leadership roles in 9 projects, including the current SUNBEAM birth cohort study. The objectives of CoFAR CRCs is to conduct network-wide studies and trials and center-specific projects to advance knowledge, management and treatment across a range of food-allergic diseases, and to elucidate underlying mechanisms. The Mount Sinai CRC team has been successfully and safely conducting food allergy research since 1997. The CRC PI, Scott Sicherer, MD, brings broad experience having been site PI for all of the past CoFAR interventional trials, as well as being Protocol Chair of the CoFAR observational study and Co-Chair of SUNBEAM. Co-Investigators Drs. Wang and Bunyavanich (who serves as chair for the SUNBEAM biosampling program) have served as successful PIs on clinical trials. Early stage investigators on the team will benefit from their involvement to become the next generation of leaders in food allergy research. Our CRC laboratories have been the central biomarker facility for CoFAR and easily manage biological samples at the direction of the LC. The CRC is located in Manhattan, with access to an extensive base of potential participants; it has safely conducted >30,000 oral food challenges and has a superb record of study recruitment and retention. To increase opportunities to contribute to CoFAR’s goals, a Network-wide clinical trial is proposed to improve safety and allow dietary incorporation of common allergens; preliminary data suggest that potentially half of people living with IgE-mediated food allergy may benefit. Two site-specific studies will inform achieving better engagement of participants in food allergy research, and inform pathogenesis and course of food allergy through a novel, non-invasive approach. In summary, the Mount Sinai CoFAR CRC brings extensive resources and experience to ensure that the goals of CoFAR, at the direction of the LC, Steering Committee and NIAID, are met.

NIH Research Projects · FY 2026 · 2024-03

SUMMARY We previously reported that the viability of some breast cancers depends on histone deacetylase 6 (HDAC6). We also developed a biomarker (HDAC6-score, validated with a NY CLIA certified test) to identify cancers that depend on HDAC6 function. By analyzing over 3,000 primary breast cancers, we have recently found that ~30% of all breast cancers can benefit from targeted therapy against HDAC6. Thus, we designed a clinical trial in partnership with Acetylon/Celgene to investigate the leading HDAC6 inhibitor (HDAC6i, Ricolinostat) plus nab-paclitaxel as breast cancer therapy (NCT02632071). Notably, we have observed that this regimen is well tolerated, and that clinical activity is identified in patients with metastatic disease. Molecularly, we have found that HDAC6 de- acetylates cMyc and that inhibition of HDAC6 promotes hyperacetylation of cMyc and its degradation by the proteasome. Furthermore, we linked the reduction of Myc expression due to HDAC6 inhibition to the anticancer activity of HDAC6i (manuscript accepted in Nature Cancer).Objective: In this grant proposal, our ultimate goal is to understand the molecular mechanism that mediates the anticancer activity of HDAC6i/s and to use this information to improve HDAC6-based breast cancer regimens. In this grant proposal, we will pursue these objectives by two independent but complementary aims. Aim 1. Define the clinical space for HDAC6 inhibitors in breast cancer treatment we hypothesize that including HDAC6i/s in therapeutic regiments for HR+ and HER2+ patients with high HDAC6 scores will have a superior therapeutic impact. - Aim 1a. Evaluate the response of high and low HDAC6-score HR+/HER2- cancer cells to a combination of HDAC6i/s and the standard of care systemic therapy. - Aim 1b. -Aim 1b. Evaluate the response of HDAC6-score high and low HER2+ cancer cells to a combination of HDAC6i/s and standard-of-care systemic therapy. -Aim 1c. Molecular characterization of tumor response at a tumor-tumor microenvironment (TME) level using sc- RNAseq and spatial transcriptomics. Aim 2. Investigate the mechanisms of resistance to HDAC6i/s in breast cancer cells. Despite the success of targeted therapies, resistance to treatment can emerge. Here, we will perform both, candidate- driven and unbiased comprehensive analysis of tissue samples from patients in our trial plus cell lines and PDOs to catalog and functionally test the molecular differences between sensitive and resistance cancers. - Aim 2a. Profile the post-translational modifications (PTMs) of c-MYC in HDAC6i-resistant and sensitive BCs. - Aim 2b. Evaluate the steady-state levels of proteasomal activity in HDAC6i-resistant and sensitive BCs. - Aim 2c. Network analysis of HDAC6i/s sensitive and resistant BC cells. - Aim 2d. Increase the specificity of the HDAC6 score with resistance data.

NIH Research Projects · FY 2026 · 2024-03

PROJECT SUMMARY Telomere attrition starts in early life, tracks into adulthood, and is associated with increased risk for aging-related chronic diseases, such as cardiovascular disease. Because genetic factors explain only a small proportion of telomere length variability, it is critical to determine prenatal environmental exposures that affect telomere length dynamics in early life. Recent evidence shows that prenatal exposures to endocrine-disrupting chemicals (EDCs) may promote telomere attrition in young children. However, existing data are limited, and the potential interplay of EDC mixtures with other environmental stressors and the implicated mechanisms remain unknown. For example, dietary factors and obesity also have been associated with shorter telomere length, potentially by altering oxidative stress, inflammation, and metabolic pathways that are also disrupted by EDCs. Thus, EDC exposures may act synergistically with diet and obesity to influence telomere length dynamics in childhood and beyond. However, no previous study has examined the potential impacts and interactions of prenatal EDC exposures with other factors on telomere lenght dynamics during the sensitive period of accelerated growth in the transition from childhood to adolescence. Therefore, we propose the first and largest longitudinal investigation on the prenatal exposome and telomere attrition, with extended follow-up through adolescence. We will use an innovative multi-omics analytical framework to advance the knowledge about the joint impacts of prenatal EDC exposures and their interplay with diet, obesity, and inflammatory and metabolic pathways on telomere lenght dynamics and adolescent health. Our central hypothesis, supported by strong preliminary results, is that prenatal exposures to EDC mixtures and their interactions promote telomere attrition in childhood and through adolescence by dysregulating inflammatory and metabolism-regulating pathways. To test this hypothesis, we will leverage the unique existing resources of the population-based Human Early Life Exposome (HELIX) project. HELIX provides an unparalleled early-life exposome characterization (>200 environmental exposures) with completely harmonized biomonitoring data on ~80 known EDCs and repeated telomere lenght measurements in 700 mothers and their children followed longitudinally from pregnancy to age ~16 years in six European countries. We will measure high-throughput proteomics covering >700 inflammation and metabolic proteins in archived plasma from children collected at age ~8 years to comprehensively characterize biological pathways promoting telomere attrition due to early-life EDC exposures, as well as their interplay with telomere lenght tracking from childhood to adolescence. Findings will advance our understanding of the impacts of early-life exposures to exogenous chemicals and their interplay with diet, obesity, and inflammatory and metabolic pathways on telomere attrition during sensitive periods of development. This knowledge will critically inform environmental public health policies and personalized interventions for early prevention of cardiovascular disease as well as other highly prevalent aging-related chronic diseases.

NIH Research Projects · FY 2026 · 2024-03

PROJECT SUMMARY Pulmonary arterial hypertension (PAH is a rare, progressive, incurable, and fatal cardiopulmonary vascular disease leading to right ventricle failure and ultimately to death. Despite the available treatments and ongoing research efforts, there is currently no curative treatment against PAH or pathological vascular remodeling. Changes in chromatin that can influence the epigenetic regulation of many genes and their functional consequences on vascular remodeling in PAH are poorly understood. The SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complexes control the accessibility of chromatin to transcriptional and coregulatory machinery. The AT-rich interactive domain-containing protein 1a (ARID1a), a subunit of the SWI/SNF chromatin-remodeling complex, plays key roles in normal physiology and diseases. The functional implications of ARID1a deficiency are dependent on its downstream transcriptional consequences, which can be altered by other epigenetic transcriptional regulators in the specific cellular context. Homeostasis requires balanced action of ARID1a and the Enhancer of Zeste Homolog2 (EZH2), a histone methyltransferase, through chromatin-mediated gene expression. Yet, the role of ARID1a in PAH remains understudied. Given the various studies implicating ARID1a as a critical tumor suppressor, the objective of this proposal is to investigate the expression level of ARID1a and the link between ARID1A and EZH2 in pulmonary vascular smooth muscle cells (PASMCs) growth and dysfunction. The central hypothesis is that ARID1a loss impairs enhancer-mediated gene regulation and drives aberrant growth of PASMCs in PAH through altered chromatin accessibility and/or DNA methylation via EZH2. The hypothesis is supported by preliminary data of a significant reduction of ARID1a expression level in PAH human and animal models of PAH. Importantly, ARID1a depletion increases PASMC proliferation and increases EZH2 expression. Hence, the hypothesis will be tested by pursuing the following three specific aims: 1) Investigate the function of ARID1A in PASMC phenotype, and the central role of ARID1a in the chromatin dynamics and the regulation of gene expression in PASMCs; 2) Evaluate the impact of SMC conditional ARID1a ablation in the pathogenesis of PAH; and 3) Assess the effectiveness of the combination therapy of AAV2.5/ARID1a with EZH2 inhibitors in the context of severe rat models of PAH. The data generated from this proposal will advance our knowledge about the role of ARID1a in the phenotype of PASMC-driven pulmonary vascular disease with implications for potential therapeutic interventions in PAH.

NIH Research Projects · FY 2025 · 2024-03

Abstract Type 1 Diabetes mellitus (T1D) is an autoimmune disease targeting pancreatic β-cells that affects over 8 million people worldwide. Standard treatment for T1D is limited to administration of exogenous insulin, which can result in hypoglycemic episodes, and fails to fully prevent micro- and macro- vascular complications. Thus, deriving glucose-responsive insulin-producing β-cells from renewable sources is an index goal of regenerative medicine. Yet, current human stem cell-derived β-cells produce insulin at lower levels than native β-cells and fail to recapitulate regulated insulin secretion typical of mature adult islet β-cells. This limits their therapeutic potential and reflects a significant gap in our knowledge regarding mechanisms regulating human islet maturation. Exciting recent studies identified human-specific age-dependent gene expression changes, including novel transcription factors, such as RXRG, not expressed in mouse or immature human β-like cells, that might control functional maturation of human islet cells. My Preliminary Data shows that RXRG loss in human adult β-cells results in impaired glucose-stimulated insulin secretion. Recent studies also showed that gradual turnover of enhancers drives lineage progression and maturation. I have found a presumptive enhancer regulatory element of RXRG that becomes differentially accessible with age in adult β-cells compared to immature β-cells and a-cells, as measured by H3K27Ac occupancy. My objective here is to discover mechanisms that induce maturation of human β-cells, using two approaches. In Aim 1, I will investigate the regulatory roles of the novel transcriptional regulator of β-cell maturation RXRG. This will involve knock down of RXRG, and then β-cell specific RNA-seq and CUT&RUN to identify RXRG downstream targets. In addition, I will activate RXRG endogenous promoter using the CRISPRa system and evaluate chromatin accessibility changes induced by activation of this maturation-required transcription factor. In Aim 2, I will study the non-coding regulatory mechanisms activating RXRG expression to induce β-cell maturation. Since these mechanisms do not occur in mouse or stem cell-derived human β-cells, and are specific to adult β-cells, the studies I proposed will be performed in adult human islets using the pseudoislet-genetics platform I developed during my postdoctoral studies. Here, I will use novel technological advancements, including CRISPR-Cas9 ribonucleoprotein (RNP) editing of human islet cells, to delete the presumptive enhancer element of RXRG and evaluate its role in regulating RXRG expression. Finally, I will activate RXRG expression in juvenile islets using CRISPRa to activate RXRG promoter, enhancer or both, and evaluate if RXRG expression enhances coordinated glucose-dependent insulin secretion in adulthood. Altogether, findings from this proposal will uncover novel pathways leading to β- cell maturation, that could be exploited towards efforts with β-cells from renewable sources. Equally importantly, these studies provide a novel toolkit for genetically manipulating previously “unstudiable” or inaccessible non- replicating mature and immature β-cells.

NIH Research Projects · FY 2026 · 2024-03

Project Summary/Abstract Temporal lobe epilepsy (TLE) is a debilitating disorder that includes chronic seizures and pervasive memory impairments that significantly impact quality of life. In rodent models of TLE, my lab and others have found dramatic changes in brain synchronization with specific changes in the theta phase locking of individual interneurons of the dentate gyrus. However, it remains unclear whether this abnormal phase locking is a causal mediator of seizures and cognitive deficits in epilepsy. In order to test whether the timing of interneuron activity is directly controlling epileptic phenotypes, we have developed a novel closed-loop optogenetic system to control the timing of interneuron activity during behavior. In this proposal, we will use our closed-loop optogenetic system to shift the phase locking of parvalbumin- or somatostatin-expressing interneurons and determine how the timing of these interneurons alters seizure susceptibility and cognitive performance. In control mice, we will force an abnormal firing pattern onto the interneurons and determine whether this can drive increased seizure susceptibility and impair cognition. In epileptic mice, we will use optogenetics to normalize the timing of interneuron activity and determine whether this can reduce seizure susceptibility and rescue memory impairments. Together, these experiments will determine how the timing of interneuron activity mediates seizures and cognitive deficits in epilepsy.

NIH Research Projects · FY 2026 · 2024-03

Project Summary Obstructive sleep apnea (OSA) affects over one billion adults and is an independent risk factor for cardiovascular disease (CVD). Yet, in randomized clinical trials (RCT), treatment of OSA has failed to demonstrate a beneficial impact of continuous positive airway pressure (CPAP) on cardiovascular (CVD) event rates in this population. In this proposal, we hypothesize that the non-significant RCTs are not due to lack of continuous positive airway pressure (CPAP) effectiveness but instead due to suboptimal CPAP adherence, variability in the clinical presentation of OSA as well as the heterogeneity of treatment effect with CPAP. Notably, no study has applied machine learning (ML) to multimodal data that extends beyond polysomnography to identify individuals at enhanced risk for atherosclerosis progression or experiencing CVD events. The 2021 NIH Sleep Research Plan identified critical and high-priority areas for further research, including leveraging ML analytic approaches for big data to advance our understanding of sleep disorders and assist in the personalization of treatment. The overall goal of this proposal is to apply ML to well-characterized datasets with multimodal data to develop separate prediction tools for predicting incident CVD events (Aim 1), and heterogeneity of treatment effect with CPAP in OSA patients (Aim 2). We will then validate the models using real-world electronic health records to ensure their generalizability and clinical relevance (Aim 3). This groundbreaking proposal aims to revolutionize the management of OSA patients by developing prediction tools using multimodal data and cutting-edge ML techniques, resulting in a more personalized approach to care that can improve patient outcomes and reduce the burden of OSA-related CVD events. These decision tools will be readily integrated into the clinical environment, guiding treatment decisions and assisting sleep physicians in determining which patients should avoid CPAP use and which OSA patients should be prioritized for CPAP treatment, optimizing treatment plans and reducing healthcare costs.

NIH Research Projects · FY 2026 · 2024-02

PROJECT SUMMARY Americans commonly consume excess amounts of dietary fructose. Added fructose has been shown to have an adverse impact on metabolic health, including increased insulin resistance and type 2 diabetes (T2D) risk. However, the mechanisms that link dietary fructose and metabolic health are poorly understood. Malabsorption or incomplete metabolism of fructose in the small intestine is common in the population. Excess fructose reaches the colon where it may change the structure and function of the gut microbiome, alter bacterial metabolites and trigger inflammatory responses impacting T2D risk. To elucidate whether commonly consumed levels of dietary fructose influence metabolic outcomes through altering the gut microbiome, we will randomize 30 participants to a controlled cross-over dietary intervention, in which they will consume 12-day isocaloric, added fructose or glucose diets (25% of total calories) separated by a 10 day controlled diet washout period. We aim to: 1: Determine the relationships between high fructose consumption, the gut microbiome and metabolic risk. 2: Characterize the causal role(s) that fructose-induced alterations to the gut microbiome have on metabolic risk using a germ-free mouse model. We will measure 1) microbiota community structure and function via metagenomic sequencing of stool, 2) fecal metabolites via targeted and untargeted metabolomics, 3) anthropometrics, 4) insulin resistance, serum markers of T2D risk and inflammatory cytokines, 5) fecal microbial carbohydrate oxidation capacity and 6) liver fat via MRI elastography. We will use novel statistical approaches, including Distributed Lag Modeling, to understand the complex relationships between diet, the microbiome, metabolites and health outcomes. We will then conduct controlled dietary interventions and fecal microbiome transplantation studies in germ-free mice. Donor fecal samples from human participants in both the glucose and fructose arms of the clinical intervention will be transplanted into germ-free and colonized mice to establish a causal relationship between fructose-induced changes to the gut microbiome, liver fat and metabolic and inflammatory changes known to increase risk for T2D. We aim to comprehensively assess the structural and functional changes to the gut microbiome brought about by a high fructose diet. Determining the impact of excess fructose on the microbiome will help identify novel means by which fructose contributes to metabolic disease risk. In addition to identifying strategies to improve metabolic health in adults, data from this proposal could help inform targeted approaches to mitigate future disease risk in vulnerable populations that consume high levels of fructose, such as children.

NIH Research Projects · FY 2025 · 2024-02

PROJECT SUMMARY Internalizing problems, most prominently anxiety and depressive disorders affect > 400 million people globally. Rooted in early development starting in utero, there is a steep rise in these disorders in the transition to adolescence. Identifying those at risk as early in life as possible is critical in order to ensure optimal development and prevention. There has been growing interest in studying the role of nutritional factors in modifying effects of chemical environmental exposures, as nutrition is amenable to intervention. Our group was recently funded to examine the role of prenatal exposure to metals and their mixtures on early life neurobehavioral domains linked to a greater risk of developing anxiety and depressive disorders later in childhood (R01 ES033436, RJ Wright PI). In addition, we demonstrated that several nutrients, particularly those with antioxidant potential (e.g., vitamin A) can mitigate the impacts of metals on fetal growth, providing proof of concept for this proposal. The joint associations between maternal prenatal nutrition and in utero metal exposures in influencing offspring’s internalizing disorders remain poorly understood, particularly beginning in the prenatal period. To overcome existing knowledge gaps, we will examine the joint associations of prenatal exposure to maternal nutrition and heavy metals on young children’s internalizing problems and related prefrontal cortex (PFC) functions in the PRogramming of Intergenerational Stress Mechanisms (PRISM) cohort. PRISM is a racially and ethnically diverse urban sample with extant data on prenatal urinary metal exposure and children’s neurobehavioral outcomes measured at ages 6 months and 3-5 years. We will leverage available data on maternal prenatal nutrition assessed two ways - (i) using a food frequency questionnaire (FFQ) and (ii) measurement of additional micronutrient biomarkers in maternal blood and urine obtained in pregnancy. This will enable us to determine how maternal nutrition affects internalizing behaviors in early childhood as well as to examine the modifying effects of optimal or inadequate intake of key micronutrients on associations between metals and neurobehavioral outcomes. We hypothesize that increased intake or higher measured levels of antioxidant micronutrients (e.g., retinol, carotenoids, tocohperhols) will mitigate associations between prenatal metal exposures and internalizing problems whereas lower intake or levels of iodine will interact with metals to enhance risk of neurobehavioral problems. Novel advanced statistical modeling will consider interactions between metal and micronutrient mixtures allowing examination of non-linear relationships between mixtures and internalizing problems. Applying mixture analysis and agonistic selection of nutrients has the potential to characterize modifiers that have not been identified in studies focused on a single nutrient or a specific diet pattern. Sex-specific effects will also be explored. Understanding the independent and modifying effects of key micronutrients in the relationship between prenatal metal exposures and early indicators of psychiatric risk is arguably critical to informing future interventions.