Icahn School Of Medicine At Mount Sinai

NIH Research Projects · FY 2025 · 2023-07

Project Summary This proposal will explore a new axis of dopaminergic regulation–microglial expression of the dopamine receptor DRD1 and their modulation of neuronal activity and excitability in response to changing dopamine levels. Microglia, the resident immune cells of the central nervous system, exhibit a wide array of functions, some stereotypical of macrophages and some unique to the brain. Recent research from our lab and others has demonstrated that one such function is to modulate neuronal activity, but how and why they do so is still under investigation. Microglia exhibit a high degree of regional heterogeneity in form and function, perhaps to account for the diversity of local cues and demands of different brain regions. A growing body of literature suggests that microglia possess the ability to express receptor transcripts for and respond to an array of neurotransmitters and neuropeptides, and that expression of these may vary by region, activity, or disease state. Our lab has uncovered a unique subpopulation of microglia that express the dopamine receptor DRD1 (D1) in the striatum. Dopamine is a neurotransmitter involved in reward, motivation, voluntary motor behavior, and substance use disorders. How, when, and why microglial DRD1 expression emerges remains unclear, and I will confront each of these questions with my proposed experiments. I will trace the ontogeny of microglial DRD1 through development using several transgenic mouse models to investigate when microglial DRD1 expression begins, from where D1+ microglia originate, if not the striatum, and if expression/maintenance is dependent upon dopaminergic input. I will also use cutting-edge microglia transplant techniques to determine if microglia can acquire DRD1 in the striatum, which will provide important evidence for the role of local cues in microglial phenotypic determination, an open question in the field. Additionally, preliminary data from our lab have demonstrated that D1+ microglia may be able to modulate the neuronal and behavioral response to dopamine. Ablation of microglia overall and D1+ microglia specifically both amplify the locomotor response to chronic cocaine, which increases dopamine levels by blocking reuptake. Changing dopamine levels are characteristic of a number of physiological, developmental, and environmental events. In this proposal, I will explore two that are associated with an adaptation of striatal medium spiny neuron excitability: juvenile dopaminergic development and chronic cocaine. Based on our data, I hypothesize that D1+ microglia sense and respond to dopamine in order to tune neuronal excitability to changing dopamine levels throughout the lifetime. Exploring the role of D1+ microglia in dopaminergic signaling is critical to understanding the dopaminergic dysfunction that characterizes numerous neuropsychiatric and neurological disorders, including substance use disorder, Parkinson’s disease, depression, and ADHD, and could provide novel therapeutic targets for those that have thus far found few effective treatment options.

NIH Research Projects · FY 2025 · 2023-07

PROJECT SUMMARY This application addresses targeted health issues through a Cooperative Research Agreement with the World Trade Center (WTC) Health Program (UO1). The presence of carcinogens and inducers of inflammation in WTC dust have raised the possibility that those exposed to WTC dust during the 9/11 attacks could have increased cancer incidence. To date, several cohort studies indicate that total cancer rates are 6-14% above background rates with significantly greater increases for thyroid and prostate cancer (Moir, 2016; Solan, 2013; Li, 2012; Jordan, 2011; Zeig-Owens, 2011). Increased exposure based on the time of arrival for workers, their proximity to early response to the WTC and duration of exposure have been associated with increased risk of tumor progression (de la Hoz, 2008; Lioy and Georgopoulos, 2006). Recent studies in small animal models indicate that WTC dust particles or metals are undetectable or present at exceedingly low levels in prostate tissues compared to lung following WTC dust exposure by inhalation or gavage (Wang, 2022; Gong, 2019), and long-term studies of rodents have not revealed evidence of a direct carcinogenic mechanism. Instead, there is evidence from both human RNA expression and DNA methylation analyses (Yu, 2022) and animal models (Wang, 2022; Gong, 2019) that inflammation induced by this dust may be implicated in promoting prostate cancer. In the mouse, WTC dust exposure promotes systemic as well as localized prostate inflammation, increased growth in PTEN deficient prostate epithelia and promotion of genetically initiated prostate tumors (Wang, 2022). Aim 1 will investigate whether WTC associated prostate cancer is more likely to recur independent of tumor grade at diagnosis and if there are molecular signatures of aggressiveness at diagnosis in those who recur. We will utilize increased biochemical (PSA) recurrence to define responders with adverse clinical response to WTC dust following surgery or radiation therapy. We will also apply recently identified signatures by RNA expression analysis and mass spec multiplex immunostaining of primary prostate cancer tissues to test whether these immune/inflammatory markers correlate with increased tumor recurrence in WTC responders. Aim 2 will focus on correlating our human findings with those in mouse genetically engineered mouse models bearing targeted lesions to prostate that model human PC. These experiments take advantage of our strong preliminary evidence that these models support a role of WTC dust exposure in PC progression. Experiments will include testing whether WTC dust exposure promotes recurrence of genetically initiated PCs following androgen deprivation therapy and/or experimental PC metastasis. We will also compare, and contrast WTC dust associated immune/inflammatory biomarkers in the mouse with those identified in human PCs. Our overarching goal is to translate understanding gained toward improved surveillance of WTC responders most at risk for prostate cancer.

NIH Research Projects · FY 2025 · 2023-07

The US has one of the highest maternal mortality rates of high-income countries, and quality of health care may play a role. The US maternal mortality crisis has resulted in growing awareness of the need for obstetrics and gynecology (OB/GYN) professionals trained in person-centered care. Person-centered care considers patients’ goals, values, medical history, and preferences. From the provider’s viewpoint, this means engaging in supportive provider-patient communication and shared decision-making. However, courses for medical learners that take into account community-member perspectives of person-centered care are lacking. Moreover, a critical area of knowledge often left out of current curricula in obstetrics and gynecology is critically appraising research in person-centered care, specifically as it relates to quality of care and patient experience. A strong data-driven research foundation is essential to promoting quality in OB/GYN health care. Nearly half of medical schools require research in their curriculum with the understanding that research skills are essential even in a primarily clinical medical career. Furthermore, OB/GYN physicians increasingly work in Learning Health Systems where research skills are necessary to effectively integrate evidence-based practices. A course on person-centered health care targeting all medical student learners that is adaptable and uses novel reflective learning is needed to bridge research and practice. Our overall goal is to develop a curriculum for medical student learners about person-centered care in OB/GYN. The course will create new didactic modules in topics including non-medical drivers of health, patient-provider communication, shared decision-making, and patient experience. Cross-cutting themes will be best practices in research, biologic mechanisms, and interventions. The didactic training will be implemented during the OB/GYN clerkship incorporating tools from narrative and graphic medicine (e.g. use of comics to communicate healthcare concepts).

NIH Research Projects · FY 2026 · 2023-07

Project Summary/Abstract Patients with Alzheimer’s disease and Alzheimer’s disease-related dementias exhibit symptoms that include deficits in spatial navigation, and in forming/using cognitive maps of space to guide decision-making, especially in new environmental situations. These deficits are linked to disease-related perturbation of medial temporal lobe and frontal lobe brain structures, but surprisingly little is known about the underlying computations that go awry. Spatial navigation is believed to be dependent on populations of neurons in the hippocampus with “place-cell” like representations. Decision-making in novel situations is dependent on representations of latent features that are shared across examples or experiences, as observed in prefrontal cortex. Finally, the output of these computations must reach the motor cortex where neural activity is coupled to immediate behavior. However, studies to determine whether/how neural computations across these brain regions contribute to decisions based on spatial location, especially in novel situations have not been conducted. Furthermore, whether symptoms of Alzheimer’s disease and related dementias can be treated by modulating these computations is not known. To address this gap, I created an innovative new virtual reality paradigm and trained monkeys to make decisions about which objects to collect based on learned spatial rules. I will combine this with high-channel- count electrophysiology in trained monkeys to determine if/how population-level representations in the HPC- PFC-PMd support decision-making based on spatial rules. Then, I will elucidate if and how population activity in the HPC-PFC-PMd circuit supports generalization in novel situations. In my independent laboratory, I will use this model system as a platform for elucidating the neural mechanism of an emerging treatment for Alzheimer’s disease and Alzheimer’s disease-related dementias. These contributions are significant because they will provide new insights into the neural mechanisms of some of our most adaptive cognitive capacities, while also creating a new platform for discovering and testing new treatments where I systematically test the effects of neural perturbations on neural circuit function and behavior. This project will facilitate my training as an independent researcher through new experience in high-channel count, multi-area recordings, training in the etiology and treatment of Alzheimer’s disease and related dementias, and in running a monkey electrophysiology lab at the intersection of basic and translational neuroscience. This project will result in direct interactions between experimental neurophysiologists, theoretical neuroscientists, and clinician-scientists. This award will help me achieve my long-term career goal to run an independent research laboratory at an academic institution with a medical school, where I will operate a monkey electrophysiology lab at the nexus of 1) elucidating neural mechanisms of learning and decision-making, and 2) developing/testing novel therapeutics for disorders of memory and decision-making, including Alzheimer’s disease and Alzheimer’s disease related dementias.

NIH Research Projects · FY 2025 · 2023-07

Project Summary The reported two-fold excess risk of thyroid cancer in multiple World Trade Center (WTC) cohorts is not solely explained by overdiagnosis due to surveillance or physician bias. Endocrine disruptors (EDs), known to disrupt thyroid function and associated with thyroid carcinogenesis and cancer aggressiveness, have been found in WC dust samples. WTC dust-associated EDs’ exposure may potentially be associated with thyroid carcinogenesis and thyroid cancer aggressiveness via multiple pathways, in particular in children and adolescents exposed to the WTC dust during these critical developmental windows. Thyroid cancer in the WTC survivors’ population is largely unstudied and no study to date has investigated the potential impact of early life exposure to the WTC dust cloud on thyroid carcinogenesis and cancer aggressiveness. Using the WTC Environmental Health Center survivor population, including individuals who were <18 years at the time of WTC exposure, we aim to investigate the clinical, mutational, pathological, and inflammatory thyroid cancer profiles, hypothesizing that (early life) WTC exposure is associated with more aggressive thyroid cancer. First, we will perform an in-depth assessment comparing the clinical and mutational characteristics of WTC thyroid cancer to non-exposed controls (aim 1). Additionally, we will compare WTC thyroid cancer cases in the survivor population with unexposed control cancer cases to investigate the pathological features using computational modelling approaches (aim 2) and the gene expression profiles using Spatial Gene Expression (aim 3). We will perform a subgroup analysis of the individuals < 18 years at the time of WTC exposure. This study would be the first in-depth study to investigate thyroid cancer in the WTC survivor population, including an assessment of thyroid cancer in patients exposed as children or adolescents, integreting novel techniques including computational pathology modelling and Spatial Gene Expression. The proposed methods can easily be transposed to other solid cancers with increased risk in the WTC survivor population and to other environmentally exposed populations with increased cancer risk. Furthermore, identifying phenotypes and biomarkers associated with increased risk of more aggressive thyroid cancer will help identify patients needing more aggressive thyroid cancer screening and management and may lead to more effective health care delivery for this population.

NIH Research Projects · FY 2026 · 2023-07

Project Summary: The endogenous opioid system is involved in many diverse biological processes and contributes to a range of disorders that have enormous health and societal consequences such as opioid use disorder, pain, and major depressive disorder. The endogenous opioid system consists of dozens of opioid peptides derived from three distinct precursor proteins, and three cell surface receptors that are activated by these peptides as well as by opiates and synthetic drugs. Recently, ketamine has emerged as an effective treatment for both major depressive disorder and chronic pain, and may also be effective in treating opioid use disorder. While ketamine’s anesthetic actions are due to its inhibition of a subtype of glutamate receptors, the mechanisms of its other biological effects remain elusive. Studies from our laboratory and other groups have found that ketamine interacts with the endogenous opioid system, however the full scope of these interactions is not known. Moreover, a single dose of ketamine produces rapid effects within minutes/hours, as well as sustained effects that last days/weeks. The long-term effects are remarkable and unlike the anesthetic action of ketamine which correlates with plasma levels. Our central hypothesis is that ketamine interacts with the endogenous opioid system to produce both rapid and long-term effects. This hypothesis is supported by our preliminary data showing that ketamine acts as a positive allosteric modulator of opioid receptors to synergize with endogenous opioid peptides. Our central hypothesis will be tested in three Specific Aims that are highly interrelated. Aim 1A will characterize the activity of ketamine as an allosteric modulator of the endogenous opioid system using cultured cells and membrane preparations. These studies will investigate short- and long-term effects of ketamine (including racemic ketamine and the stereoisomers S- and R-ketamine) and major bioactive metabolites (norketamine and hydroxynorketamine). Using electrophysiology in brain slices, Aim 1B will measure acute effects of ketamine on opioid receptor-mediated signaling and persistent changes induced by in vivo ketamine administration. Aim 2A will test the interaction of ketamine with highly purified preparations of opioid receptors. Aim 2B will determine the cryoEM structure of the mu opioid receptor in complex with ketamine and a peptide ligand. Aim 3 will examine the effect of ketamine on the levels of endogenous opioid peptides in mouse brain. Collectively, these studies will provide a solid understanding of the interactions of ketamine with the endogenous opioid system, providing mechanisms to account for the rapid and long-term effects of this drug. Historically, understanding the molecular targets of drugs have led to insights into the pathophysiology of disease and novel therapeutics. Because little is known regarding the mechanism(s) of ketamine as an antidepressant and analgesic, and the comorbidity of these diseases with opioid use disorder, our studies to determine the interaction of ketamine and the endogenous opioid system are highly relevant to human health.

NIH Research Projects · FY 2025 · 2023-07

SUMMARY Psychosocial stress contributes to cardiovascular disease at several stages, including promoting coronary artery disease progression and acutely triggering cardiac events1,2. In this project, we aim to investigate both acute and chronic stress exposure and their immediate and long-term effects on the immune system and atherosclerosis. We will approach these important questions through the development and application of non- invasive imaging methods. Stress activates diverse signaling circuits in the brain, including the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS), which subsequently affect leukocyte distribution and function as well as atherosclerotic plaque inflammation. Specifically, HPA axis activation during acute stress controls lymphocyte and monocyte homing to the bone marrow, while neutrophils are rapidly mobilized from the bone marrow due to motor cortex signaling3. In parallel, SNS activation leads to the production of catecholamines, which induce a long-lasting pro-inflammatory phenotype in monocytes based on metabolic and epigenetic rewiring4,5. SNS activation due to stress has also been directly linked to enhanced atherosclerotic plaque inflammation6,7. During chronic stress exposure, direct sympathetic signaling enhances the proliferation of hematopoietic stem and progenitor cells (HSPCs) in the bone marrow (hematopoiesis), leading to higher numbers of circulating pro-inflammatory neutrophils and monocytes6,8. These cells subsequently extravasate into the arterial wall and enhance plaque inflammation. We hypothesize that stress exposure induces long-term effects on the immune system through the induction of trained immunity and changes in myeloid cell dynamics. In this highly innovative project, we will employ newly developed and established PET imaging methods to probe stress’s effects on the immune system and atherosclerotic plaque inflammation longitudinally, in vivo, and at a whole-body level. In Aim 1, we will focus on metabolic and epigenetic rewiring in hematopoietic organs over the course of stress exposure and after stress withdrawal. Aim 2 evolves around stress-induced alterations in myeloid cell dynamics (cell proliferation, migration, egress, and myeloid cell burden), probed by sophisticated imaging methods. Completing these Aims will help decipher stress’s immediate and long-term impact on the immune system though unique integration of molecular biology and immunology with state-of-the-art translational cardiovascular imaging research.

NIH Research Projects · FY 2025 · 2023-06

PROJECT SUMMARY Posttraumatic stress disorder (PTSD) is a common, debilitating disorder, triggered by exposure to a traumatic event. PTSD is often under-diagnosed and undertreated, despite early detection and treatment governing favorable outcomes. Better identification of elements of disorder susceptibility or resilience is important for prompt delivery of care to mitigate disorder burden. As PTSD has shown to be heritable, a prevailing theory of disorder susceptibility is genetic. Large-scale genome wide association studies (GWAS) have revealed an estimated single-nucleotide polymorphism (SNP)-based heritability of 5-20%. Yet, environmental factors, such as childhood trauma, have also shown to independently predict PTSD development. Genome-wide integration of PTSD-associated genetic loci with stressful exposures may elucidate gene by environment interactions that influence disorder susceptibility. In this proposal, I will investigate loci with joint genetic and environmental contributions to PTSD risk, employing an integrative multi-level approach to examine and validate brain region and cell type-specific regulation. One major issue integrating GWAS findings with environmental exposures is the largely non-coding nature of GWAS-identified loci, obscuring clear functional ramifications. To overcome this, I will associate identified variants with nearby expression changes to uncover regulation of proximal or distal gene targets. Such variants with transcriptomic regulatory activity are termed expression quantitative trait loci (eQTLs). As transcriptomic regulation is context-dependent, eQTLs capture genetically and environmentally regulated expression, making them useful for deciphering genomic regulation of PTSD. I performed a preliminary eQTL search in post-mortem brain samples from the dorsolateral pre-frontal cortex (DLPFC), demonstrating that stress-interactive eQTLs are detectable in brains of trauma-exposed cohorts. In Aim 1, I will extend this analysis beyond the DLPFC to the medial amygdala, to uncover the regulatory landscape of genetic stress response across the brain. In Aim 2, I will examine causality of these variants to demonstrate stress-dependent regulation. I have developed an in vitro model capturing PTSD-specific stress response. In this model, candidate effector variants will be interrogated for downstream effects impacting disorder biology. This will be accomplished via training in large scale CRISPR-screening methods and in computational probing of convergent downstream pathways. This work will take place within the Icahn School of Medicine at Mount Sinai (ISMMS) and Yale University, currently ranked #11 and #10 among the nation’s best medical schools for research, respectively. Between the Departments of Genetics and Neuroscience, I am supported by over 100,000 ft2 of research programs and 4500 ft2 of institutional core facilities, in addition to over $200 million in scientific computing resources. Together, this fellowship leverages the resources of my institutional and the expertise of my co- sponsors to support my training in four major areas: (1) Scientific excellence, (2) professional development and scholarship, (3) mentorship, leadership, and advocacy, (4) and clinical-research integration.

NIH Research Projects · FY 2024 · 2023-06

Project Summary: Primary immunodeficiencies (PIDs) are monogenic disorders of the immune system. PIDs affect 1 in 780 hospitalized children. Incomplete penetrance of PIDs is common and remains largely unexplained. Herein I hypothesize that incomplete penetrance in PIDs may also be explained by monoallelic expression (MAE). Traditionally, transcription of autosomal genes is thought to occur from both inherited genes. Recent studies indicate that up to 10% of autosomal genes can randomly commit to gene expression from a single allele, termed monoallelic expression. Unlike X-inactivation or imprinting, MAE is independent of other genes and leads to a diverse population of cells at the transcript level. The existence of MAE of PID genes is unknown. Families with mutations in JAK1 or PLCG2 exhibit incomplete disease penetrance. My preliminary data suggests that both JAK1 and PLCG2 can undergo MAE. Within this proposal I aim to 1) Map MAE of PID genes in primary immune cells and 2) evaluate the functional impact of monoallelic expression in JAK1 and PLCG2 ex vivo. The findings of this proposal will inform the biological study and clinical genetics of PIDs by identifying thresholds of transcript diversity which drive disease penetrance. In addition, these findings will provide a framework for similar work in other genetic diseases, while setting a foundation for mechanistic studies directed at the control of MAE as a therapeutic for monogenic disease.

NIH Research Projects · FY 2025 · 2023-06

Project Summary This proposal addresses a novel way in which microglia functional states are regulated by the transcription factor PU.1 in the context of amyloid pathology and its potential contribution to neuroprotection against Alzheimer’s disease (AD). The expression level of PU.1 is crucial for instructing commitment to myeloid versus lymphoid lineages and is enriched in microglia. PU.1 also determines the inflammatory activation state of macrophages by priming cis-regulatory regions to elicit appropriate gene expression upon stimulation. Recently, genome wide association studies (GWAS) have identified a variant in Spi1 (encoding PU.1) that modulates AD risk. Unlike other variants, the Spi1 variant is unique in that it leads to a reduction in PU.1 expression and has a protective effect against AD risk. In a 5xFAD amyloid mouse model of AD, I observed heterogeneous protein expression of PU.1 in microglia. Recent work supports the idea that specific microglia activation states have unique impacts on AD pathogenesis. The Disease Associated Microglia (DAMs) are thought to serve a protective role in AD by robustly responding to amyloid plaques whereas inflammatory populations potentially play a harmful role in disease. I hypothesize that low PU.1 expression in microglia induces neuroprotective functional states in microglia against AD. We generated genetic mouse models that increase (Spi1cOE) or decrease (Spi1cKD) PU.1 expression specifically in microglia and crossed them to the 5xFAD amyloid disease model. Ribosomal profiling of these microglia revealed significant bulk transcriptional changes. To understand how PU.1 expression level regulates microglia activation states during amyloid pathology, I performed single nuclei RNA-sequencing. These new data reveal that Spi1cKD in 5xFAD favors microglia states associated with neuroprotection (DAM) while attenuating the proportion of cells in toxic states (inflammatory). Knowing the location of these microglia in relation to amyloid plaques will enhance our understanding of where engagement of such states occur and where these microglia may be exerting protective or harmful effects. In my first aim, I will use multiplexed error-robust in situ hybridization (MERFISH) to spatially identify microglia in DAM and inflammatory activation states with Spi1cKD or Spi1cOE in 5xFAD. In addition to these transcriptional changes, we showed a reduction in the complement protein C1qa in Spi1cKD 5xFAD animals. We further found that Spi1cKD microglia prevented synapse loss that is characteristic in human AD and recapitulated in the 5xFAD model. It has been shown that pathological activation of complement occurs with inflammatory activation and contributes to synapse loss in AD. Therefore, I propose to assess the production of C1qa by microglia with differential PU.1 expression level in vitro and synaptic co-localization of C1qa in 5xFAD mice with Spi1cKD and Spi1cOE microglia.

NIH Research Projects · FY 2026 · 2023-06

PROJECT SUMMARY CD4+ T helper (Th) cells of different Th1, Th2, Th17 and Treg subtypes, developed in thymus, have important functions in adaptive immunity. Their dysregulation has also been implicated in diseases such as Th2- associated inflammatory and allergic diseases including asthma, Crohn’s disease and atopic dermatitis. Th2 lineage-specific differentiation from naïve CD4+ T cells is tightly controlled by cytokines (IL-4, 5, 13) through highly ordered subtype-specific gene transcription directed by a set of transcription factors and regulators with opposing activities to promote (YY1, Gata3, Stat6) or inhibit (Foxp3) Th2 cell differentiation. However, the underlying molecular mechanism remains elusive. BRD4, a key member of the bromodomain and extra- terminal (BET) protein family, is well known for its role in gene transcriptional activation, but whether and how it functions in gene transcriptional repression in a cell-type specific manner has remained elusive. Recently, we discovered that Brd4 works with Polycomb repressive complex 2 (PRC2) to repress transcriptional expression of Th2-negative regulators Foxp3 and E3-ubiqutin ligase Fbxw7 in lineage-specific differentiation of Th2 cells from mouse primary naïve CD4+ T cells. Brd4 through its second bromodomain (BD2) binds to lysine- acetylated-EED subunit of the PRC2 complex to control target gene repression through histone H3 lysine 27 trimethylation (H3K27me3). We found that Foxp3 represses transcription of Th2-specific transcription factor Gata3, while Fbxw7 controls Gata3 protein stability via ubiquitination-mediated protein degradation, which in turn ensures Gata3-mediated transcriptional activation of Th2 cytokines including Il4, Il5 and Il13. Chemical inhibition of BRD4 BD2 induces transcriptional de-repression of Foxp3 and Fbxw7, and transcriptional down- regulation of Il4, Il5 and Il13, resulting in inhibition of Th2 cell differentiation. Our study uncovers previously unappreciated BRD4 functions in directing Th2-specific gene transcriptional repression to safeguard Th2 cell lineage differentiation. Building on our promising findings, in this study, we seek to define the mechanistic details of BRD4’s transcriptional repression function in the temporal regulation of Th2 cells, develop and use new BRD4-BD2 selective inhibitors to study the transcriptional regulation of Th2 cell differentiation, and investigate the therapeutic potential of BRD4-BD2 inhibition as new Th2 immunomodulation to block Th2- associated allergic inflammation in mouse models of asthma.

NIH Research Projects · FY 2026 · 2023-06

SUMMARY – OVERVIEW Transplantation has revolutionized the lives of patients suffering from organ failure. The design of modern immunosuppression has employed a time-honored focus on controlling T cell-mediated responses. However, current immunosuppressive therapies have suboptimal success rates and induce significant side effects, including increased susceptibility to infections, metabolic toxicity, and cancer risk. Given the growing body of evidence showing that innate immunity is also critical to alloresponse initiation and allograft survival, it is not surprising that current immunosuppressive regimens do not achieve satisfactory long-term graft and patient survival. Recent work by this P01’s investigators has shown that trained immunity plays a vital role in allograft survival. Trained immunity is a long-term increase in the functional responsiveness of innate immune cells, which is maintained by epigenetic modifications and can be considered de facto innate immune memory. On a systems level, we demonstrated that trained immunity is regulated and maintained by epigenetic modifications in bone marrow hematopoietic progenitors, which consequently release trained innate immune cells with augmented inflammatory and antimicrobial function. Our preclinical and clinical preliminary data revealed a discrete causative connection between allograft transplantation, the induction of trained immunity, systemic inflammatory response, and activated or amplified T cell-mediated alloimmunity. Furthermore, we identified trained immunity as a compelling therapeutic target in mouse and non-human primate heart allograft models. Based on these results, our central hypothesis is that trained immunity is a critical mechanism that amplifies and sustains both innate and adaptive rejection responses and is therefore a compelling clinical therapeutic target for achieving long-term allograft survival without requiring chronic immunosuppression. In this P01, we will address our central hypothesis by drawing on the expertise of authorities in the fields of immunology and bioengineering. This multidisciplinary team of scientists and clinicians will work together to i) understand trained immunity’s clinical relevance in kidney transplantation, ii) elucidate the mechanisms by which trained immunity is induced and leads to organ rejection, and iii) develop bioengineering solutions for diagnosing and therapeutically regulating trained immunity in transplantation. We anticipate that, together, these highly interactive Projects will generate innovative new therapeutic strategies to more effectively prevent rejection and potentially achieve immune tolerance. If successful, these studies could impact the entire field of transplantation and provide insights that could also be highly relevant for bone marrow transplantation and autoimmune disease.

NIH Research Projects · FY 2026 · 2023-06

Project Summary/Abstract Antipsychotics are a class of commonly used medications that are used for multiple indications within psychiatry, including psychosis, mood stabilization, and augmentation for depression. The use of antipsychotics among pregnant and lactating women has increased in frequency in recent years. However, their efficacy has not been directly tested in this population, and many unanswered questions remain about the potential effects of antipsychotics on the development of the fetus, neonate, and infant. We propose to conduct a prospective observational study of maternal psychiatric course and infant development among women with severe mental illness, comparing women treated with antipsychotics to women treated with other medications or without medication. The primary study outcomes will be psychiatric relapse in the mother, neonatal health at delivery, and infant developmental outcomes at 6 months. We minimize confounding by recruiting participants matched for psychiatric illness severity and by including two separate control groups (non-AP medication and no medication). We further address confounding in our analyses by collecting detailed information about participants’ home environments, partner relationships, medical comorbidities, and other important potential confounding factors for planned sensitivity analyses. We hope to determine whether antipsychotics are effective for pregnant women with severe mental illness and whether they have any measurable effects on infant development. This information will help women with severe mental illness make informed decisions about their care in pregnancy.

NIH Research Projects · FY 2024 · 2023-06

Summary: Every year, 15 million babies are born premature. Over 75% of preterm births (PTBs) are termed spontaneous (sPTB) resulting in parturition at early gestational time points without clear causes. Our lack of understanding of the mechanisms and overall pathogenesis that promotes sPTB results in limited successful interventions. While uterine contractility and cervical remodeling appear to be obligatory processes in parturition, premature triggers of these processes remain poorly elucidated. Recent studies reveal close associations between cervicovaginal (CV) microbial communities and the occurrence of sPTB. In particular, we recently studied a cohort of 2000 pregnant women and assessed the CV microbial communities, metabolic and immune responses early in pregnancy, providing strong evidence that colonization with specific bacterial taxa, specific metabolic profiles, and local immune responses were strongly associated with sPTB. However, to develop preventive or therapeutic strategies, understanding the cause of sPTB is essential. We speculate that interplay between the CV microbial communities, local immune response and the cervical and vaginal epithelial barriers induce premature cervical remodeling and initiate sPTB. The overall goal of this study is to define how specific CV bacteria interact with vaginal and epithelial cells in clinically relevant in vitro and in vivo models and to understand how those interactions modify tissue remodeling and biomechanics of the pregnant cervix, driving sPTB. We propose a process whereby bacterial taxa that are highly associated with sPTB in humans provoke exfoliation of the vaginal epithelium. This process promotes epithelial-mesenchymal transition (EMT) from both vaginal and cervical epithelial cells. While activation of EMT prevents the ascension of these bacteria, a tradeoff is that EMT fosters breakdown of the extracellular matrix in the cervical tissue, triggering premature cervical remodeling and sPTB. Therefore, our central hypothesis is that specific bacteria, such as Gardnerella vaginalis (G.vaginalis), promote EMT of the vaginal and cervical epithelial barrier which alters the structure and function of the pregnant cervix, leading to sPTB, even in the absence of ascending infection (above the cervix). This paradigm-shifting hypothesis will be tested through a series of in vitro and in vivo experiments. This proposal will first address whether ascension of bacteria into the uterus is actually necessary for PTB to occur; these studies have the potential to reframe our scientific and therapeutic approach to PTB. We will then demonstrate how bacteria induce EMT in CV epithelial barriers and how EMT might promote premature cervical remodeling. Unique to this proposal, we will provide quantitative assessment of the pregnant cervix, in terms of structure and function, in a mouse model of PTB. A multidisciplinary team adds rigor to our work by applying novel concepts and techniques to the study of sPTB. These studies will provide insight as to new and focused therapeutic targets to limit or prevent sPTB and will significantly advance this field.

NIH Research Projects · FY 2025 · 2023-06

PROJECT SUMMARY Lung diseases are among the leading causes of death worldwide. Genetic mutations underlie many lung diseases. For instance, mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene can directly cause cystic fibrosis (CF) or increase the risk of other non-CF lung diseases, like chronic obstructive pulmonary disease and asthma. To date, over 2,000 mutations have been identified in the CFTR gene, classified as CF-causing or non-CF-causing polymorphisms. Correcting CF-causing mutations and exploring the function of non-CF-causing polymorphisms could help treat a wide range of lung diseases. CRISPR-associated base editing mediates the irreversible conversion of A>G (Adenine Base Editor, ABE) or C>T (Cytidine Base Editor, CBE). The goal of this proposal is to use base editing to correct CF-causing CFTR mutations in CF primary cells and mouse models, and to investigate whether non-CF-causing polymorphisms affect CFTR activity and lung cell function. Preliminary data show that ABE can correct a CF-causing nonsense mutation (W1282X) to restore CFTR expression and function in immortalized human lung epithelial cells. In the K99 phase, ABE will be delivered to a clinically-relevant cell model, CF patient-derived primary bronchial epithelial cell line, to correct W1282X, and rigorous off-target analysis will be performed to study the efficiency and specificity of ABE (Aim 1). Moreover, an in vivo delivery method targeting lung airways will be developed by packaging an intein-split ABE system into AAV5 (Aim 2). The delivery efficiency will be tested in wild type C57BL/6 mice. GFP-CFTR reporter cell lines will also be established using CRISPR-mediated homology directed repair method to integrate a GFP sequence to CFTR genomic locus (Aim 3). Research in the mentored phase will be performed under the guidance of an esteemed mentor committee, whose expertise range from CRISPR engineering and application to pulmonary biology. By the R00 phase, the PI will be ready to establish an independent laboratory focused on using base editing techniques to study point mutations in lung disease. During the R00 phase, AAV5-ABE will be delivered to W1282X CF mice to determine its potential as a novel gene therapy method to correct an “untreatable” CFTR mutation in CF (Aim 2). Furthermore, non-CF-causing mutations will be introduced by CBE in lung airway epithelial cells to understand how they affect CFTR expression, localization, and function, and how they respond to known CFTR modulator drugs – e.g. ivacaftor (Aim 3). These studies will reveal if and how non-CF-causing mutations contribute to lung disease, and suggest potential treatment approaches for lung diseases associated with non-CF-causing mutations. Collectively, the proposed studies will shed light on diagnosis and treatment of lung diseases that are associated with CFTR polymorphisms. This project will foster the PI’s continued scientific and professional training and facilitate her transition to independence.

NIH Research Projects · FY 2025 · 2023-06

Psychiatry is a fertile medical specialty for translational research and physician-scientists bring a unique perspective to research through the blend of clinical and research experiences. Physician scientists are uniquely poised to bridge the gap between basic neurobiology and clinical disease and excel as leaders in translational research in psychiatry. However, the pipeline of physician scientists in psychiatry is in danger. The number and proportion of clinically trained physicians (MD or MD/PhD) who remain involved in research after residency has decreased substantially. Residency training is a critical period that can “make or break” a research career. Years of clinical training without adequate protected research time between pre-residency research training and residency graduation often result in a decline in research skills and psychiatry residency graduates often need to retrain in research skills, delaying the transition to independent research. Together with high indebtedness and low funding rates, this results in few psychiatrists applying for K or R01 Awards after residency training. Our proposed R25 program aims to train the next generation of psychiatrists-scientists during the critical period of psychiatry residency, to equip them to conduct translational research in psychiatry and accelerate the launch of independent research careers. Our program will help trainees acquire research skills and pilot data to obtain a career development (K) award. We will provide ample research protected time and coursework organized based on an Individual Development Plan. This training, coupled with outstanding mentoring and networking opportunities, grant writing seminars and an internal K award review process, will prepare promising physician scientists and help accelerate the launch of productive, independent careers in translational psychiatry research. Mount Sinai is the ideal place for this R25 program because of the strength of our Departments of Psychiatry, Neuroscience and Genetics/Genomics, which have been among the top departments nationwide in NIH funding over the past years, and have a wealth of potential mentors, including 123 NIH- funded PIs. Our exponential success in research accomplishments and funding is the result of a focused institutional effort to support physician-scientists and translational research. As an example of our commitment to recruitment, training and retention of physician-scientists, we have retained or recruited back over 50% of the graduates from our pilot physician-scientist training program.

NIH Research Projects · FY 2026 · 2023-05

Whole-genome sequencing (WGS) is revolutionizing the diagnosis of rare diseases. However, at present, even the most powerful approaches to etiological discovery typically fail to find a genetic cause in a majority of partici- pants (Turro et al., Nature 2020). There are a number of reasons for this. Firstly, rare disease studies are typically composed of small sets of unresolved cases, each sharing a different genetic etiology, which constrains statistical power when only WGS and clinical phenotype data are available on participants. Secondly, the unknown causal variants may have molecular consequences that are challenging to predict computationally, such as disruptions to the regulatory elements (REs) of a gene or the introduction of a cryptic splice site. Thirdly, some types of causal mutations, such as structural variants, are prone to being missed by WGS. Systematic, transcriptomic profiling of homogeneous cell populations taken from rare disease patients has the potential to overcome these limitations. We have access to a collection of ⇠1,000 comprehensively phenotyped rare disease study participants with WGS and RNA-seq of platelets, neutrophils, monocytes and CD4+ T-cells. Here, we present a research program of statistical, computational and experimental approaches to uncover novel etiologies of rare diseases that exploits the high dimensionality and the hierarchical nature of these data. We will concentrate on the etiologies under- lying ⇠300 cases with a rare platelet disorder (RPD), exploiting our expertise in blood genomics. In Aim 1, we will develop a Bayesian method for identifying rare disease-causing rare variants in REs, treating expression as a molecular mediator of genetic etiology. Our approach models the causal path between rare variants that overlap cell type-specific REs, the corresponding cell type-specific changes in expression, and the consequent alteration in rare disease risk. To include a recently discovered class of enhancer marked by H3K122ac but not H3K27ac in our hypothesis search space, we will generate H3K122ac data on the relevant cell types from healthy donors. In Aim 2, we will apply several approaches for identifying pathogenic changes in transcript sequences. For ex- ample, we will apply recently developed methodology for identifying splicing outliers within the cohort. To ensure these outliers are extreme in the wider population, we will compute splicing frequency spectra in large RNA-seq datasets such as GTEx. These spectra will capture the population distribution of the within-individual proportion of RNA-seq reads for a gene that include a given splice junction. We will also exploit the joint availability of WGS and RNA-seq in patients to identify extreme allelic imbalances at WGS-called heterozygote sites. The candidate variants that we identify will be validated in cell lines and primary samples. Rare diseases collectively affect one in 20 people but current etiological knowledge cannot resolve half of patients by WGS alone. The modeling and analysis of large-scale, patient-derived RNA-seq data on multiple cell types as molecular mediators of disease risk can fill this gap. The methodological and etiological output of our research program will ultimately boost the diagnostic power of WGS and broaden the scope of precision medicine.

NIH Research Projects · FY 2026 · 2023-05

PROJECT SUMMARY Recent progress has been made on understanding the role of the innate immune system in the pathogenesis of Alzheimer’s disease (AD); however, the role of adaptive immunity in the periphery and the central nervous system in AD remains largely unexplored. Therefore, a critical next step is to understand the interaction between innate and adaptive immunity, and its impact on brain aging and neurodegeneration. Previous work has shown that clonally expanded CD8+ T cells are present in the peripheral blood and the cerebrospinal fluid of patients with AD. In our ongoing work, utilizing single cell profiling of human brain immune cells, we expanded this observation and identified cell type changes of the adaptive and innate immune system in the brain parenchyma of AD derived samples. In addition, published and ongoing work from our group provides evidence in humans and mice that astrocyte and adaptive immune cell-sourced interleukin-3 (IL-3) programs microglia to ameliorate the pathology of AD. Further analysis of the interaction between innate and adaptive immunity in humans and mice is needed to mechanistically understand its role in AD at different stages of the disease. Studying the interaction between innate and adaptive immunity in AD in humans is challenging due to limited availability of fresh tissue specimens. Over the last 5 years, our team has established a pipeline to isolate immune cells from fresh brain tissue to generate multiscale single cell data. Building on our expertise and existing resources, here we propose to perform multi-tissue single cell multiomics and spatial transcriptomics of immune cells from AD cases and healthy controls. To gain additional mechanistic insights into the interactions between adaptive and innate immunity, we will perform parallel studies in AD mouse models. In Aim 1, we will examine the diversity, abundance and spatial location of adaptive and innate immune cells across the brain-barrier-blood axis (brain, meninges, choroid plexus, and peripheral blood) to identify differences in the composition, phenotype, and antigen specificity of adaptive immunity (T and B cells) in AD that are shared or distinct across tissues. In Aim 2, we will explore the interactome of adaptive and innate immune systems in the brain-barrier-blood axis to identify differential cell-to-cell interaction networks in AD, pointing to gain or loss of ligand-receptor relationships among immune cell subpopulations. In Aim 3, we will mechanistically delineate intercellular crosstalk between adaptive immune cells and central innate immune cells in murine models of AD. Collectively, these studies will enable us, at unprecedented resolution, to explore the adaptive and innate immune response in AD cases and provide a putative mechanistic explanation for our observations by utilizing mouse models. Importantly, our work will provide the scientific community with an urgently needed resource for adaptive and innate immunity in the central nervous system that can be utilized in future studies.

NIH Research Projects · FY 2026 · 2023-05

Fear learning allows animals to detect and defend themselves from dangerous situations by forming a memory that links stimuli encountered during trauma with the experience of physical or psychological harm. Conversely, the primary mechanism through which these behaviors are constrained is through extinction, in which repeated re-exposure to conditioned stimuli without aversive consequences attenuates fear. Research suggests that extinction forms a new memory of safety that competes with the original fear association during memory recall. However, while deficits at the recall stage are a major factor in pathological fear, the circuit mechanisms underlying extinction recall and how they might differentiate between competing fear and extinction memories remain largely enigmatic. This is a fundamental knowledge gap that limits insight into extinction and the potential reasons for its failure in psychiatric disorders. In this project we hypothesize that an important mechanism in context fear extinction is recruitment of somatostatin interneurons in the ventral hippocampus, and that these cells control switching between competing context representations, one signaling threat and the other safety. In support of this hypothesis, we find that somatostatin interneurons are preferentially activated by an extinguished context and their manipulation modulates fear expression in this context but not others. Using a combination of intersectional genetics, electrophysiology, optogenetics and calcium imaging, we will investigate the properties and function of discrete populations of somatostatin interneurons underlying context-dependent behavior. In particular, we will examine whether these cells control transitions between high and low fear states and elucidate the mechanisms underlying this switch at the level of excitatory neuronal populations involved in fear and extinction memory. Successful completion of these aims will shed light on how the brain governs conflicting internal models of an ambiguous environment as well as provide a detailed account of circuit dynamics that promote the loss of fear and prevent it from reemerging.

NIH Research Projects · FY 2026 · 2023-05

PROJECT SUMMARY The HIV-1 Vif protein is expressed late during infection and has a well-described function to ubiquitinate and degrade proteins in the APOBEC3 family, thus neutralizing their antiviral activities. More recently, an additional function of HIV-1 Vif was described by us and others to ubiquitinate and degrade protein phosphatase 2A holoenzymes containing B56 family regulatory subunits (PP2A-B56). The conservation of Vif-mediated PP2A- B56 degradation throughout globally circulating HIV-1 subtypes suggests that it is functionally important. However, there remains a gap in understanding the mechanisms by which PP2A-B56 degradation confers a fitness advantage to HIV-1. Furthermore, in contrast to APOBEC3 degradation, the host cellular determinants required for Vif-mediated ubiquitination and degradation of PP2A-B56 are undefined. In this project, we aim to address these gaps in understanding by defining the cellular determinants and functional effects of PP2A-B56 degradation by HIV-1 Vif. In Aim 1, we will apply unbiased protein interaction technologies to determine proteins interacting with PP2A-B56 while it is degraded by Vif. In Aim 2, we will carry out a genome- wide CRISPR/Cas9 genetic screen to identify genes regulating APOBEC3 and PP2A-B56 degradation. In Aim 3, will test the impact of individual phosphorylation sites regulated by PP2A-B56 in HIV-1 replication in primary CD4+ T cells. Successful completion of this project will advance understanding of the Vif-PP2A-B56 signaling axis, potentially leading towards the development of novel classes of antiretroviral therapies that target late processes of HIV-1 infection.

NIH Research Projects · FY 2026 · 2023-05

Project Summary Artificial turf fields and playgrounds have become common playing surfaces. It is estimated that there are over 13,00 fields, and up to 1,500 new artificial fields are installed each year. Most of these fields and playgrounds utilize infill generated from recycled tire crumb. Communities have consistently reported chemical smells in fields, playgrounds, and surrounding areas. Despite the widespread usage of artificial turf fields and playgrounds, uncertainty remains about safety and the potential for exposure to toxic chemicals, heat exposure, impacts resulting in injury, and environmental impacts in the community. Many studies have identified the presence of toxic chemicals, known to be neurotoxic and carcinogenic in tire crumb infill. Parents and communities are concerned because young children and athletes could be exposed and could potentially experience health effects in the future from playing on these surfaces. Laboratories have identified toxic chemicals in tire crumb, but results of exposure assessment information generated under realistic playing conditions in children and adults are very limited. Exposure assessment studies are underway at a state and federal level. Despite that, an increasing number of communities are opting to use alternative infills made from plastics, virgin rubber, silica sand, cork, and waste shoe materials. However, as with tire crumb infill, safety information is also lacking. As such, communities in general struggle to make informed decisions about safe playing surfaces. The proposed community-engaged project will employ a citizen science approach to collect samples from alternative infill fields, identify chemicals in alternative infills materials, and characterize exposure in such fields under real-life conditions. This project is well-positioned to achieve our goal to address concerns from the community and inform policymakers in their communities to incorporate environmental health research into consideration during the decision making for the procurement, installation, use, and disposal of playing surfaces. This project embraces the involvement of community member participation in the project’s research activities. Active community involvement will allow community members to gain first-hand knowledge of the chemicals in their fields and heat during playing conditions. Most importantly, it will enable them to assist other communities regarding better practices and effective policies to protect concerned communities.

NIH Research Projects · FY 2026 · 2023-05

Type 2 immune responses are classically associated with parasite infections at barrier surfaces, and evolved in part to repair the massive tissue damage that these maladies induce. However, the role of Type 2 immunity in cancer progression is understudied, despite the fact that many cancers occur at mucosal surfaces that are primed to engage such responses upon tissue insult. Non-small cell lung carcinoma (NSCLC) is the leading cause of cancer-related death worldwide. PD-(L)1 immunotherapy has revolutionized care for NSCLC patients, but its efficacy is limited by the immunosuppressive tumor microenvironment (TME) which is predominantly populated by various myeloid cell subsets. Using single cell RNA-sequencing (scRNA-seq), we recently mapped the immune landscape of the human and murine NSCLC TME. We identified several newfound populations of myeloid cells that exhibited high transcriptional concordance across species. In both instances, we found that myeloid cells within the TME specifically upregulated a transcriptional program driven by IL-4, a prototypical Type 2 cytokine. Blockade of IL-4 strongly protected mice against orthotopic lung tumors. Surprisingly, we found that IL-4-producing Th2 cells were essentially absent from the lung TME in mice and humans. Instead, IL-4 was almost exclusively produced by basophils. Accordingly, antibody-mediated depletion of basophils in vivo strongly reduced lung tumor development. Using mice with cell type-specific deletion of the IL-4R we found that granulocyte-monocyte progenitor (GMP)-derived cells were the dominant immune cells responding to IL-4 to enhance tumor burden. Within the tumor, the overwhelming majority of these cells are macrophages and neutrophils. Surprisingly, we also discovered that myeloid progenitors in BM directly sense IL-4/IL-13 signaling during lung tumor development. Furthermore, GMP-specific deletion of IL-4R enhanced myeloid cell differentiation in response to lung tumors, preventing the so-called “emergency myelopoiesis” known to fuel tumor growth. Our central hypothesis is that basophil-derived IL-4 promotes NSCLC by controlling the development and function of immunosuppressive myeloid cells. To address this, we first will identify signals from neoplastic cells that activate basophils to produce IL-4 (Aim 1). Then, we will define how myeloid-intrinsic IL-4R signaling controls the immune response to NSCLC, both at the level of the TME and at the level of myeloid differentiation in BM, and how these two arms synergize during PD-1 immunotherapy (Aim 2). Finally, we will integrate our findings from murine systems into the first human clinical trial of dupilumab, an FDA-approved IL-4R blocking antibody, in metastatic NSCLC patients who have not responded to immunotherapy and evaluate relevant immunologic alterations. Collectively, our work will (i) define a novel axis controlling lung tumor development, (ii) identify targets for therapeutic intervention, and (iii) reinforce a growing paradigm in which tumor signals instruct the fates of developing myeloid cells to affect cancer outcome.

NIH Research Projects · FY 2025 · 2023-05

PROJECT SUMMARY/ABSTRACT This new T32 application entitled Research Training in Systems Skin Biology is a combined pre- and post- doctoral training program (MPIs Kim and Millar Co-PDs). The rationale for this proposal is that Icahn School of Medicine at Mount Sinai (ISMMS) has a track record of success in dermatology, skin immunology, and epithelial biology such that it can leverage additional institutional strengths (e.g., neuroscience, translational medicine, etc.) to build an interdisciplinary training program in Systems Skin Biology. The central hypothesis is that such intersectional science is critically important for the training of future scientists within single organ systems like the skin. Finally, there is a major gap in our ability to train physician-scientist in a formalized manner which this T32 would provide a platform to do successfully. The overall objective of this program is to attract and train talented MD/PhD and PhD students and postdocs over 2 year periods, for successful, independent careers in Systems Skin Biology relevant to human disease. We have a diverse, well-funded faculty with broad interests in Systems Skin Biology in immunology and a strong pool of pre- and post-doc trainees that includes significant numbers of underrepresented in science (UiS) minorities. The program is designed to provide training by individual mentors performing research in all aspects of Systems Skin Biology relevant to human disease. The program is supported with strong oversight and administrative structure, significant didactic training in Systems Skin Biology, scientific writing and career development, and contains newly added state of the art evaluation approaches with defined goals and benchmarks for success so as to optimize the development of independent academic researchers in the field. The long-term goal of this program is to produce 1 MD/PhD or PhD scientist in investigative dermatology/skin biology research every 2 years who become independently funded via a K or R mechanism.

NIH Research Projects · FY 2025 · 2023-05

The burden of digestive diseases in the United States is staggering, with annual costs exceeding $140 billion, based on National Institutes of Health (NIH) estimates. To meet this challenge, a key mission of the National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK) is to support the training of a talented, diverse pool of young investigators who will attack scientific unmet needs to improve the lives of patients with gastrointestinal and liver diseases. The Icahn School of Medicine at Mount Sinai (ISMMS) has been a center of excellence for care in gastrointestinal and liver diseases for decades, with clinical fellowship programs in these disciplines consistently ranked among the best in the country. Moreover, ISMMS offers a fertile environment from which a cadre of outstanding candidates have launched successful careers in academic gastroenterology and hepatology. The overarching goal of this Training Program proposal is to leverage this outstanding environment to support the training of M.D., M.D./Ph.D or Ph.D. postdoctoral fellows by providing exceptional research opportunities and mentorship in three broad areas: A) Gastrointestinal inflammation and the microbiome; B) Non-alcoholic steatohepatitis (NASH), hepatic inflammation and fibrosis; and C) Genetics of gastrointestinal and liver diseases. The highly structured training program provides a tailored curriculum that integrates clinico-epidemiologic-, genetic-, environmental- and cellular/molecular research excellence. The program is built upon a foundation of world class research faculty who have outstanding track records of academic achievement and successful mentorship. The curriculum focuses on cross-disciplinary training in order to prepare trainees for the current and future challenges of gastrointestinal and liver disease research, which now requires integration of complementary research skill sets. To address this need, a highly selected pool of mentors has been chosen not only from within the Divisions of GI and Liver Diseases and other clinical disciplines, but who also represent outstanding multi-disciplinary institutes at the ISMMS. Each year this program will support 3 trainees (PGY 4 - PGY 6), with 15 candidates entering the program over 5 years. Each trainee will pursue an individualized research project and tailored curriculum formulated together with their primary and secondary mentors, curriculum committee and the Program Directors. Trainees will dedicate at least 90% effort in either the laboratory or clinical setting, and their progress will be monitored through quarterly meetings with their advisory committee and program directors. Overall quality and adaptability of the program will be ensured through oversight by internal and external advisory boards, based on compliance with defined metrics of success for both individual trainees and the overall program. This rigorously structured and closely monitored program, committed to excellence and built upon a rich scientific environment and outstanding faculty, will yield superbly trained future leaders in investigative gastroenterology and hepatology.

NIH Research Projects · FY 2026 · 2023-05

Project Summary Almost all living cells use specific non-enzymatic carbohydrate binding proteins (e.g. lectins) to recognize carbohydrate ligands for cellular trafficking, signaling and defense. The systematic study of lectins and their carbohydrate ligands has improved our understanding of human health and the high specificity of lectins for certain cellular interactions has made them a valuable resource for therapeutic discovery. In previous research, my laboratory suggested that human commensal microbiota utilize lectins (e.g. human-microbial-lectins) to regulate a complex network of host-microbe interactions beyond those mediated by simple pattern recognition receptors and conserved microbial metabolites. Furthermore, our characterization of a highly prevalent human- microbial-lectin Cbeg5 suggests this specific lectin may regulate fundamental human myeloid cell interactions integral to normal microbiome homeostasis. As such, the central hypothesis of this proposal is that the study of Cbeg5 and other human-microbial-lectins will elucidate microbiome functions relevant to human health and which can be developed therapeutically. We will advance this hypothesis through three aims to define (1) how Cbeg5 regulates distinct myeloid cell populations, (2) the potential to develop Cbeg5 as a therapeutic for inflammatory bowel disease, and (3) to explore the larger network of microbiome interactions regulated by human-microbial lectins.