Icahn School Of Medicine At Mount Sinai

NIH Research Projects · FY 2026 · 2025-04

Project Summary: The cortical plasticity during the juvenile critical period is the key impedance of recovery from neurodevelopmental disorders and brain trauma in later life. Neuromodulatory systems are abundant in the cortex and well-positioned to orchestrate experience-dependent plasticity. However, the increasingly recognized complexity of neuromodulatory circuits as well as the diversity of neuron subtypes pose a challenge to identify a specific neuromodulatory system and their cortical target to induce plasticity. The goal of this study is to identify novel molecular and circuit targets for inducing neuromodulatory changes that mediate plasticity during juvenile critical period. In our recent study, we found that only a deep cortical layer subpopulation of somatostatin- expressing interneurons with a low-threshold-spiking characteristic selectively expresses the α2 subunit containing nACh receptor (nAChRa2) and robustly responds to nicotinic ACh signaling during critical period. Using ocular dominance (OD) plasticity, a prevailing V1 critical period plasticity model, we found that enhancing nAChR signaling in this deep layer SST interneuron rapidly induced robust OD plasticity during critical period after just two days of monocular deprivation, and prolonged OD plasticity into adulthood. This study will test the hypothesis that, among various possible combinations of neuromodulatory systems and their cortical targets, nicotinic ACh modulation and deep layer SST interneurons in V1 expressing nAChRa2 are a novel combination of neuromodulatory circuit elements for inducing rapid local circuit modulation to restore juvenile-like visual cortex plasticity during critical period. We will test this hypothesis by taking full advantage of the recently developed genetically-engineered mouse lines to achieve subpopulation and cortical-layer-specific circuit-selective manipulation and measurement of gene expression or neural activity, beyond conventional cell-type level analyses, in combination with in vivo extracellular and in vitro slice electrophysiology with optogenetics, and chemogenetics. Aim1 will examine the contribution of nAChR signaling in deep layer SST interneurons on triggering OD plasticity during critical period. We will then dissect the contribution of LTS-SST to PV inhibitory circuit (Aim2) and to VIP inhibitory circuit (Aim3) to trigger OD plasticity.

NIH Research Projects · FY 2026 · 2025-04

Summary Several human diseases are caused by mutations in potassium channels (channelopathies) that are either loss- or gain-of-function. Missense mutations in KCNJ6 (GIRK2) have been linked to Keppen-Lubinsky Syndrome (KLS), a disorder characterized by lipodystrophy, severe developmental delay, intellectual disability, hypertonia, hyperreflexia and growth retardation. GIRK2 is a member of the GIRK channel family, which includes inwardly rectifying potassium (Kir) channels that are activated by G proteins. Activation of GIRK channels hyperpolarize neurons leading to reduced neuronal activity. Mutations in human GIRK2 (T152, G154S/C, L171R) have been identified in KLS, with each mutation leading to a loss of K+ selectivity and aberrant constitutive activation. However, the structural mechanisms underlying the change in ion selectivity and gating with KLS mutations in GIRK2 are poorly understood. These changes in channel properties convert GIRK2 from inhibitory to strongly excitatory (gain-of-function), contributing to the severe neuropathology and neurological changes observed in KLS patients. Currently, there are no treatments that target these channels, and current FDA approved drugs are inadequate for treating for KLS patients. We propose to elucidate the molecular mechanisms underlying the loss of K+ selectivity and G protein-independent activity with GIRK2 KLS mutations. We will then identify and characterize novel inhibitors specific for GIRK2 KLS channels using virtual docking and functional assays. In addition, little is known about the functional consequence of GIRK2 KLS channels expressed in human neurons. We will develop a human cell-based model of KLS using hiPSC-derived neurons that co-express GIRK2 KLS channels. Using these KLS neurons, we will evaluate the potential therapeutic effect of GIRK2 channel inhibitors on neuronal function. To carry out these aims, our team implements a multi-disciplinary approach, combining high-resolution channel structures (CryoEM), computational docking, drug development, and human neurons. Identification of a selective inhibitor of the KLS channels could provide the foundation for developing a novel treatment. If substantiated, our approach of identifying novel channel inhibitors would be transformative in treating neurological disorders caused by mutant potassium channels as well as other ion channels.

NIH Research Projects · FY 2026 · 2025-04

PROJECT SUMMARY/ABSTRACT Compulsivity is a transdiagnostic maladaptive behavior implicated in several psychiatric illnesses including obsessive-compulsive disorder (OCD)—the prototypical compulsive disorder that affects ~1.5% of people worldwide. OCD is highly disabling, and gold-standard treatments like exposure and response prevention (EX/RP) will result in remission for fewer than 50% of patients. Greater mechanistic understanding of compulsivity could improve clinical outcomes and lead to novel targets for treatments and early interventions. Thus, the goal of this K23 Award is to promote Dr. Rapp’s development into an independent clinical scientist who uses precision analytic methods to advance understanding of neurocognitive mechanisms underlying OCD and related anxiety disorders and translates these findings into innovative diagnostics and treatments. Specifically, Dr. Rapp’s training plan will capitalize on a multidisciplinary mentorship team and an outstanding research environment to enable her to gain expertise in: 1) methods and frameworks for studying transdiagnostic brain-behavior associations that can be applied to research on compulsivity, 2) theory-driven cognitive computational modeling, 3) trial-by-trial EEG analysis, 4) repeated-measures study design and analysis, and 5) career development toward research independence. The proposed research project will use theory-driven computational modeling together with trial-by-trial analysis of EEG to examine the neurocognitive mechanisms underlying compulsivity and will provide hands-on experience to foster these training goals. Prior theories of compulsivity purport that it is attributable to an imbalance between goal-directed and habitual behaviors, which are putatively underpinned by the “model-based” (MB) and “model-free” (MF) cognitive systems. Research in healthy individuals using computational modeling together with EEG has challenged this binary “dual-systems” theory, revealing more complex interactions of neurocognitive subcomponents. Particularly, these studies have shown that neurocognitive processes that support MB planning are combined with MF learning signals to influence reward prediction errors, which are used to adaptively guide behavior. These findings lead to a novel hypothesis that compulsivity results not from an imbalance in MB and MF learning systems, but rather an alteration in their integration. The proposed K23 project will test this hypothesis for the first time. Fifty unmedicated adults with OCD and 50 healthy controls will complete two reinforcement learning tasks while EEG is recorded at the start and end of a 10-week period during which participants with OCD will receive a standard course of EX/RP, the central mechanism of which is learning from prediction errors. The combination of theory- driven computational modeling and trial-by-trial EEG analysis will be used to reveal temporally precise neural dynamics of MB-MF integration and link this information with clinically-relevant outcomes. This K23 will provide key training and preliminary data for a future R01 grant, launching Dr. Rapp to independence.

NIH Research Projects · FY 2026 · 2025-04

Project Summary/Abstract. The goal of this project is to provide a long overdue psychometrically valid and biologically informed update of cognitive status in relapsing remitting and progressive multiple sclerosis (MS). The existing framework used to characterize cognition in MS assumes slowing of cognitive processing speed (COG SPD) is the primary cognitive disability and slowing causes impairments in other cognitive domains (e.g., memory). This framework has never been prospectively tested, does not incorporate the past two decades of advances in disease management, including treatment discoveries that slow disease progression alongside improved diagnostic sensitivity leading to ascertainment of milder cases and has not been updated in over 30 years. The speed- centric framework depends on invalid polyfactorial psychometric COG SPD assessment tools. There is no way to know if low scores indicate impaired COG SPD or impairments in other cognitive domains. Cognitive psychology and computational modeling offer strong frameworks to investigate a psychometrically valid, theoretically derived, and empirically testable model of the time-course of cognitive processing in MS. Specifically, the diffusion model (DM) is an empirically validated mathematical method that extracts 'less contaminated' dissociable components of cognitive processing. Components include rate of information accumulation (COG SPD), criteria necessary to make a cognitive decision, and stimulus encoding/motor response execution. Our preliminary psychometrically valid computational modeling research strongly supports a revised cognitive profile in MS that is likely a result of the clinical advances in disease treatment and diagnosis. In aim 1, we translate and integrate cognitive psychology and computational modelling with confirmatory factor analysis to reappraise and prospectively test the longstanding speed-centric model of MS cognition and determine whether there are domain general vs. domain specific changes in DM cognitive processes across MS phenotypes. We test the specific hypothesis that MS cognitive impairment is primarily due to changes in stimulus encoding/motor response execution with larger differences in the progressive compared to relapsing remitting disease course. We also test the hypothesis that COG SPD is impacted in more advanced progressive disease where neurodegeneration is more prominent. In aim 2, we investigate the predictive value of DM components of cognitive processing and use structural equation modeling to evaluate relationships between DM cognitive processes and brain pathology (T2 lesion and normalized brain volumes) along with patient reported outcomes (PRO: psychological/psychiatric and cognitive symptoms) and performance in other cognitive domains (derived from extensive neuropsychological battery). This will lead to a comprehensive scientific understanding of the dynamic interplay across what cognitive domains are impaired in present-day MS, at what stages of disease and pathology, and moderating effects of PROs that will allow us to closely monitor and develop treatments that specifically target those domains and/or moderating variables.

NIH Research Projects · FY 2026 · 2025-03

PROJECT SUMMARY / ABSTRACT A significant disparity in prostate cancer (PCa)-associated mortality is observed in Black men, who are twice as likely to die of prostate cancer than White men. Multiple factors contribute to Black men’s disproportionately higher cancer burden. Our group and others have demonstrated that tumor biology plays a significant role in the observed disparities, emphasizing the need for risk stratification tools for the early detection of lethal PCa phenotypes in Black men. Our long-term goal is to introduce a novel label-free Stroma Weighted Automated Gleason Grading (SWAG) system for improved risk stratification of PCa in both races and nominate molecular drives of disparity for therapeutic intervention. The overall objectives of this application are to (i) annotate H&E and Multiphoton microscopy (MPM), and second harmonic generation (SHG) images with all glandular and stromal features of PCa, developing an Artificial Intelligence (AI) enabled SWAG system for risk prediction, and (ii) to define and validate the molecular drives of racial disparity using spatial transcriptomics and multiplexed CRISPR approach in vivo. The central hypothesis is that SWAG risk prediction will accurately estimate the risk of specified prostate cancer outcomes. The rationale for this project is that the development of the SWAG system is likely to offer a strong scientific framework whereby new strategies for the early prognosis of PCa. Two specific aims will test the hypothesis: In Aim 1, we will develop a compendium of H&E and MPM/SHG images that captures all major glandular and stromal patterns of prostate cancer from 450 Black and White men’s tumors with outcome data. Next, we develop a) a machine learning (ML) tool for automated annotation of glandular and stromal features in both H&E & MPM images and develop the race-specific AI-enabled MPMSWAG system. Finally, we will test the performance of the SWAG system in risk prediction utilizing large training-validation primary cohort and secondary validation multi-institute cohorts. In Aim 2, we will perform an in-depth transcriptomic analysis of MPM-AI-identified driver (stroma-activated) regions using a spatial transcriptomics/proteomics approach and evaluate how the identified novel gene signatures contribute to adverse pathology using a multiplexed lentiviral CRISPR approach in GEM model. Our unique disparity PCa cohort and bulk gene expression data will validate the novel gene signature. The proposed research is innovative because of its focus on an AI-enabled, stroma-inclusive risk predictor tool that utilizes a label-free microscopy imaging approach. The proposed study is significant as it provides a strong scientific justification for the continued development of an MPM-SWAG inclusive, integrated model in a future iteration of these studies. Comprehensive molecular profiling and validation will provide significant functional and mechanistic insight into cancer vulnerability in Black men compared to their White counterparts. Ultimately, the combined knowledge obtained has the potential to develop innovative risk predictor tools for PCa in Black men, fostering faster adoption in routine clinical decision-making.

NIH Research Projects · FY 2026 · 2025-03

PROJECT SUMMARY: Dr. Son Duong (PI) is a clinician-scientist specializing in pediatric cardiology and advanced cardiovascular imaging at the Icahn School of Medicine at Mount Sinai (ISMMS). The primary objective of this application is to support the PI’s career development into an independent investigator of the translational application of artificial intelligence to cardiovascular imaging and patient risk prediction in patients with tetralogy of Fallot and other congenital heart disease. Patients with repaired tetralogy of Fallot (rTOF) are at risk of are at increased risk of heart failure, arrhythmia, and sudden cardiac death, but current methods of clinical risk stratification for poor outcome are inaccurate and limited in the feature set they incorporate. Accurate assessment and monitoring of right ventricular (RV) volumes and ejection fraction (EF) are critical for effective management of patients with rTOF, and thus cardiac MRI (cMRI) is recommended every 1-3 years in adulthood because traditional methods for quantitative RV assessment are limited. Frequent cMRI is a patient and system burden which may limit care. This proposal will leverage deep learning tools for the following specific aims: Develop and validate a prediction tool of RV volumes and EF from 12-lead electrocardiogram waveforms and two-dimensional echocardiographic video (Aim 1); and incorporate electrocardiogram, echocardiogram, and electronic health record data into a multimodal clinical risk stratification tool (Aim 2). The PI’s training plan focuses on coursework, tutorials, and seminars/workshops in four key areas: (1) statistical machine learning, (2) deep learning, (3) patient-oriented clinical risk prediction, and (4) career development. To meet these research and career development goals, the PI has assembled an expert cross-disciplinary mentorship team consisting of primary mentor Dr. Girish Nadkarni MD, MS (Professor of Medicine and Division Chief of Data Driven and Digital Medicine), a clinical informaticist with expertise in machine- and deep learning; co-mentors Dr. Bruce Gelb MD (Professor of Pediatrics and Genetics and Genomic Sciences and Dean of Child Health Research), a pediatric cardiologist with extensive expertise in study design and scientific career mentorship; Dr. Hayit Greenspan PhD (Professor of Diagnostic, Molecular and Interventional Radiology, and Director of Artificial Intelligence in Imaging), a computer scientist with expertise in deep learning in medical image analysis; and Dr. Brett Anderson (Associate Professor of Pediatrics), an expert of multicenter outcomes research in pediatric cardiology. The ISMMS Department of Pediatrics has a strong track-record of NIH funding and successful mentorship to scientific independence. They will provide the PI with access to cutting-edge computational power, clinical data infrastructure, and robust collaborative and educational platforms, as well as protected time to ensure the PI’s success. The results from these research aims will set the foundation for future R01 studies for multicenter validation, expansion into other congenital heart disease populations, and translation of these findings to clinical practice in a prospective fashion.

NIH Research Projects · FY 2026 · 2025-03

PROJECT SUMMARY DNA methylation (5mC) is an essential epigenetic mechanism crucial for the establishment and maintenance of cell function. Dysregulation of DNA methylation leads to various diseases, such as hematological malignancies. In acute myeloid leukemia (AML), aberrations in DNA methylation patterns are a central feature, often arising from mutations in epigenetic regulators such as DNMT3A and TET2. These mutations disrupt the normal epigenetic programming of hematopoietic stem cells (HSCs), leading to aberrant gene expression and methylation patterns that are characteristic of AML. However, the intricate interplay between DNA methylation and gene regulation, especially in a cell-type-specific manner, remains largely unknown, limiting our understanding of the epigenetic mechanisms underlying cancer initiation and progression. Recent advances in single-cell technologies have been revolutionizing our understanding of tissue structure and disease progression. However, current single-cell 5mC mapping techniques are either low throughput (96 or 384 cells per assay), low data quality, or without paired scRNA-seq information, limiting their application in cancers. To bridge the gap, we seek to develop a scalable and cost-effective single-cell multi-omic profiling method (SHARE-ME-seq) that jointly captures gene expression, chromatin accessibility, and DNA methylation at the single-cell level, in a larger effort to make a substantive leap in AML treatment by identifying and targeting methylation-driven pathways. In Aim 1, we will develop and optimize SHARE-ME-seq in cell line mixture and mouse brain samples, focusing on improving the data quality and throughput of the assay. We expect SHARE-ME-seq to achieve a throughput of 1 million cells in a single assay with sensitivity rivaling current state-of-the-art methods and 100 times lower cost. In Aim 2, we will apply SHARE-ME-seq to bone marrow samples from 4 healthy donors and 8 AML donors with TET2 or DNMT3A mutations, generating ~360k high-quality multi-omic single-cell profiles. By further integrating single-cell transcriptome and chromatin accessibility data that is measured simultaneously with DNA methylation, we will ask i) how DNA methylation, chromatin accessibility, and RNA co-define hematopoietic cell type and cell state and ii) how DNA methylation contributes to lineage priming in AML with different mutations. Together, these experiments enable genome-wide unbiased identification of 5mC-associated regulatory elements, transcription factors, and candidate genes in AML providing unprecedented insights into the regulatory mechanisms underlying cancer cell plasticity and metastasis. This approach is broadly applicable to various cancers and primary tissue types, holding the promise of unveiling new therapeutic targets in malignancies and potentially formulating approaches to counteract the cancers.

NIH Research Projects · FY 2026 · 2025-03

Chronic inflammation is a key factor contributing to age-related risks of tumor occurrence and progression. Myeloid cells of the immune system, such as monocytes and macrophages, play crucial roles in maintaining homeostasis and regulating inflammation. Besides their role in initiating the immune response, tissue-resident macrophages (TRMs) are essential for resolving inflammation and repairing tissues. TRMs are established during embryonic development and can persist into adulthood. However, a gradual replacement of embryonic- derived TRMs by monocyte-derived macrophages is suspected to contribute to tissue inflammation. Our previous research has demonstrated that myelopoiesis in response to tumorigenesis is pathogenic, with tumor-infiltrating mo-macs impairing immune control of lung tumors. In aged mice, we found that the aging of the immune system, independent of stromal age, drives tumor progression, and that hematopoietic aging promotes tumor-induced myelopoiesis. Additionally, we observed that age-associated myelopoiesis correlates with the production of IL-1 alarmins in monocytes and myeloid progenitors. Blocking this pathway with the IL1R1 inhibitor anakinra normalized myelopoiesis and promoted tumor control. However, the specific molecular mechanisms and cellular players driving age-associated pro-tumoral myelopoiesis remain unknown. In this proposal, we aim to elucidate these mechanisms through several approaches. We will conduct high-dimensional profiling of tumors from an early-stage lung cancer patient cohort, perform multi-omics phenotyping of myeloid cells and progenitors from young and aged patients as well as healthy donors, and undertake complex bone marrow experiments to isolate and characterize the impact of immune aging on age-associated inflammation. Specifically, in aim 1 we will identify the cellular players involved in the response to IL-1 signaling and define their role in age-associated inflammation and tumor progression. In aim 2, we will define the central role of DNA methyltransferase 3A in age-dependent changes in the myeloid compartment. In aim 3, we will characterize the contribution of age- associated transposable element reactivation in the myeloid compartment to age-associated inflammation. This proposal is the first to propose defining the cell-specific molecular pathways contributing to age-associated pathogenic myelopoiesis. The results of this study will enable the development of new therapeutic approaches targeting pathogenic myelopoiesis and associated inflammation in aged patients.

NIH Research Projects · FY 2026 · 2025-02

PROJECT SUMMARY Henipaviruses (HNVs), including Hendra (HeV) and Nipah (NiV) viruses, are highly pathogenic agents causing severe respiratory and neurological diseases in humans and animals. With case fatality rates ranging from 40% to >75%, and classification as biosafety level 4 (BSL-4) pathogens, these viruses pose a significant public health concern. Current vaccine and monoclonal antibody (mAb) candidates are targeted against closely related NiV and HeV. While promising, these narrowly focused approaches are insufficiently broad in their effectiveness, rendering them inadequate against increasingly diverse HNV clades. This project aims to overcome this critical gap by developing human broadly neutralizing antibodies (bnAbs) against HNV fusion (F) and receptor-binding glycoproteins (RBP/G). Our primary objective is to overcome current limitations by developing bnAbs effective against a wide range of HNVs, with a secondary objective of assessing the utility of the eliciting immunogens in future vaccine development. Our approach accounts for the existing diversity among HNVs, targeting not only NiV and HeV but also Ghana virus (GhV) and Cedar virus (CedV) as representatives of the extant diversity amongst bona fide henipaviruses. Informed by structure-function data, we will design novel immunogens to elicit broadly neutralizing antibodies (bnAbs) to HNV F and G proteins. By immunizing Harbour H2L2 mice transgenic for human immunoglobulin VH-VK genes, we overcome limitations posed by the rarity of convalescent patient samples, which has commonly been used to derived human mAbs against infectious agents. Our initial characterization of potent bnAbs derived from immunized Harbour H2L2 mice provide a strong premise for this project. Our driving hypothesis is that rationally designed immunogens can induce bn Abs, and that these bnAbs can be developed as prophylactic or therapeutic agents against a broad spectrum of HNVs. We will (1) comprehensively characterize extant bnAbs already generated from Harbour H2L2 mice, (2) design and engineer immunogens expected to enhance the immunogenicity of conserved epitopes on F and G proteins, (3) assess the protective efficacy of developed bnAb candidates in animal models, and (4) develop optimized mAb cocktails for broad- spectrum HNV therapy. This project is poised to make significant advancements in the development of bnAbs as countermeasures against the wide array of HNVs. It offers a developmental pipeline that could greatly enhance our approach to managing these highly pathogenic viruses. The outcomes will not only contribute to the immediate need for effective therapies but will also have broader implications for the field of antiviral countermeasures.

NIH Research Projects · FY 2026 · 2025-02

Project Summary I am an environmental epidemiologist and exposure scientist by training with a primary research interest in the impact of environmental exposures on immune function and vaccine response – a critical public health issue highlighted by COVID-19. The goal of this proposal is to obtain training and acquire the skills necessary to become an independent investigator at the air pollution-immunology-infectious disease nexus. I have assembled a world-class mentoring team with interdisciplinary expertise in immunology, toxicology, biostatistics, data science, exposure science, exposomics, and epidemiology. The proposed training plan includes formal coursework, field work, clinical observations, laboratory rotations, academic meetings and conferences, and a variety of activities designed for leadership and professional development. I am confident that by the end of the K99 phase of this proposal, my existing expertise combined with the training proposed in this project will allow me to establish myself as an independent investigator in a tenure-track faculty position, with the skillset to build my future independent research program integrating exposure science, epidemiology, and infectious diseases. For this proposal, I will leverage the Programming Research in Growth, Environment and Social Stress (PROGRESS) cohort, an ongoing longitudinal pregnancy/birth cohort based in Mexico City to investigate the impact of ambient environmental pollutants on the antibody response to routine vaccinations. Specifically, I will: 1) build a daily ozone model for Mexico City, which will be integrated with our existing models for fine particulate matter, nitrogen dioxide, and temperature that already exists for the area; 2) assess the association between these ambient environmental pollutants with vaccine antibody levels to routine vaccinations; 3) assess the association between the same pollutants and levels of several specific cell types involved in vaccine response; and 4) explore whether the associations between ambient environmental pollutants and vaccine antibody levels are partially or fully mediated through the immune cell population subsets assessed in #3). This research proposal has several innovations, including the generation of new exposure data (the first of its kind in Mexico City), the use of cutting-edge statistical approaches, and its leverage of both extant data and new measurements that addresses a unique research question while maximizing cost effectiveness. If successful, this work will be able to significantly foster interdisciplinary research and advance our understanding of a critical and urgent public health issue.

NSF Awards · FY 2025 · 2025-02

The broader impact of this I-Corps project is based on the development of a wearable, wireless temperature sensor designed for laboratory animals, aiming to improve temperature monitoring in biomedical research and clinical applications. By providing a non-invasive, continuous, and stress-free method for monitoring body temperature, this device enhances animal welfare and improves the quality of research data. Accurate and reliable temperature data from laboratory animals leads to better results in drug testing and biomedical studies, ultimately accelerating the development of effective therapies and medical interventions. By minimizing physiological alterations caused by invasive methods or sedation, the sensor ensures that outcomes are more reflective of true biological responses. The device's wireless charging capability increases operational efficiency and reduces maintenance costs. Beyond animal research, the technology holds potential for human healthcare applications, such as non-invasive patient monitoring in intensive care units. The broader commercial potential includes advancing biomedical research practices, improving the drug development process, enhancing patient care, and setting new standards for temperature monitoring technologies across various industries. This I-Corps project utilizes experiential learning coupled with a first-hand investigation of the industry ecosystem to assess the translation potential of the technology. The solution is based on the prior development of a wearable, wireless temperature sensor utilizing advanced microfabrication techniques and Micro-Electro-Mechanical Systems (MEMS) technology. MEMS thermocouples leverage micromachining techniques to produce very small-scale thermocouples for precise and continuous temperature monitoring. The sensor features a minimally invasive microneedle design, enabling rapid and accurate detection of temperature changes in biological environments. This innovation addresses critical gaps in existing temperature monitoring methods by providing a non-invasive, continuous monitoring solution that preserves the physiological integrity of subjects. By improving the accuracy and reliability of physiological data from laboratory animals, the technology enhances the validity of experimental results, particularly in drug testing and biomedical research, thereby advancing scientific understanding and supporting the development of new therapies. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2026 · 2025-02

PROJECT SUMMARY The approval of two fecal-based products for the treatment of recurrent Clostridioides difficile infection (rCDI) demonstrates the potential of microbial therapeutics to treat human disease. However, fecal-based products have a poorly defined safety profile that varies by fecal donor. In addition, fecal-based products are inherently not scalable as increasing drug production requires increasing stool donations provided by individual humans. Defined live biotherapeutic products (LBP) comprised of in vitro manufactured bacterial strains provide a scalable alternative to fecal products and ideally contain only the necessary active ingredients (i.e., bacterial strains) that are sufficient for the desired therapeutic benefit. The transition of the microbiome field from fecal products to defined consortium has been slow as the former requires a stool sample, a blending device and a crude filter, while the latter requires knowledge of in vitro manufacturing of anaerobic bacteria on animal-free media at scales sufficient to dose humans. We developed and manufactured the defined LBP MTC01, comprised of the 15 best engrafting bacterial strains isolated from a frequently successful fecal transplant donor. MTC01 is currently being tested in a phase 1b clinical trial comparing this defined consortium with fecal transplant with stool from the donor from which the MTC01 strains were isolated. Building on this successful transition from fecal based products to defined LBPs, we now propose to increase the scale and throughput of defined LBP generation to bringing new bacterial consortia to the clinic while sharing know-how to expand the number of translational studies in the microbiome field. We will develop a solid-state fermentation platform for manufacturing defined LBPs in parallel to decrease manufacturing times from months to weeks (Aim 1). We will develop strain characterization pipelines to estimate the feasibility of manufacturing each strain on animal- free media and to identify safety concerns related antibiotic resistance and the feasibility of standard microbial enumeration assays for non-sterile products (USP61/USP62) that are required for human defined LBPs. We will use these advances to develop multiple drug products for the treatment of UC, and we will seek regulatory feedback through preIND and IND submissions to the FDA (Aim 2). Finally, we will explore genetic engineering strategies to add new functions to stably-colonizing high abundance anaerobes for use in future defined LBPs (Aim 3). Collectively, these studies will advance defined LBP manufacturing technologies and concepts to streamline the generation of live microbial therapeutics, and they will advance multiple defined LBPs manufactured in this proposal through the regulatory steps necessary for at least two additional human trials of defined LBPs in rCDI and ulcerative colitis.

NIH Research Projects · FY 2026 · 2025-02

Project Summary/Abstract Age-related macular degeneration (AMD) is a leading cause of vision loss after 50 years of age. While genetic studies have identified various polymorphisms associated with AMD, there still is no clear picture of the mechanisms leading to disease initiation and progression. The main pathological hallmark of AMD is the accumulation of lipid-rich deposits, namely drusen, between the retinal pigmented epithelium (RPE) and the choroid, leading to retina degeneration. Several risk variants for AMD occur in lipid-related genes, including the apolipoprotein E (APOE) gene, but their role in AMD is unknown. We hypothesize that differences in lipid transport between APOE variants contribute to or inhibit AMD phenotypes. Unfortunately, there are currently no model systems for a rigorous assessment of the interplay between genetic factors and AMD pathology. Using induced pluripotent stem cell technology we developed an in vitro human outer blood-retina barrier (oBRB) that includes RPE and a choriocapillaris-like compartment and spontaneously forms sub-RPE deposits. Here, we propose to leverage these technologies and generate genetically modifiable retina tissue to investigate interactions between AMD phenotypes, lipid metabolism and APOE variants. In Aim 1, we will optimize the oBRB to study AMD phenotypes in a robust system that can also be assembled from cryopreserved cells. We will manipulate intrinsic and extrinsic factors to induce drusen in this system and correlate with human postmortem eyes. Next, we will generate isogenic oBRBs with different APOE variants to determine the mechanisms by which the APOE genotype influences AMD pathology by comparing their transcriptomic, lipidomic and functional profiles. Since the contribution of choriocapillaris hypoperfusion and function to the initiation of AMD is not well understood, in Aim 2, we will integrate microvascular perfusion into our system to investigate how genetically driven abnormalities affect AMD phenotypes. We will optimize a microfluidic approach with microvascular perfusion, generating a perfused oBRB (poBRB). Next, we will use a panel of live assays to investigate the contribution of APOE variants to poBRB vascular phenotypes and correlate that with the spatial distribution of drusen-like deposits. Collectively, we will unravel how APOE variants contribute to drusen formation, RPE and microvascular dysfunctional phenotypes and pinpoint cellular subtypes responsible for APOE effect. We will also determine the contribution of specific types of lipids to drusen formation. This work will establish a multimodal retina modeling approach to study AMD phenotypes. We anticipate that our work will reveal AMD therapeutic targets associated to lipid metabolism.

NIH Research Projects · FY 2025 · 2025-02

Project Summary Cardiovascular-related complications are a leading contributor of U.S. maternal morbidity, of which women of color bear the disproportionate burden. Current approaches to intervene on perinatal cardiovascular health emphasize prenatal lifestyle and pharmacological interventions. Given the considerable time needed to achieve optimal health, these approaches have been characterized as “too little, too late” to meaningfully reduce maternal morbidity such as gestational diabetes, pre-eclampsia, macrosomia, and preterm birth. Adolescence is a crucial period to establish optimal health trajectories to avert later life health risks. One in five adolescent girls in the U.S. is obese and nearly one in three have prediabetes, which suggests escalation of the maternal health crisis. Schools are arguably one of the most important levers available to policymakers to influence adolescent cardiovascular health. Prior research on schools has documented associations between aspects of the built, food, social and learning environments on adolescent obesity. Yet disparities in the `healthfulness' of school environments have also been documented by school-level socioeconomic and racial/ethnic composition, with lower income schools typically equipped with fewer physical activity and extracurricular resources. Rarely, has research considered the influence of school attributes on cardiovascular risk trajectories outside of obesity, examined the implications for later maternal morbidity or applied a health equity implementation framework to school policy development. We propose a mixed-method study to construct a school-based adolescent preconception cohort through innovative data linkages, engage adolescents and local stakeholders to develop acceptable school-based policy solutions to achieve health equity, and utilizes an innovative approach to capture school system dynamics using agent-based modeling. Our overall goal is to identify school policy interventions to avert excess cardiovascular and maternal health risk and to narrow racial/ethnic inequities. In Aim 1, we will assess the association between school attributes, adolescent cardiovascular risk and maternal morbidity at first birth by creating a school- based adolescent preconception cohort that leverages existing data on school environments, adolescent health and fitness records, and Medicaid birth claims data between 2008 and 2024. In Aim 2, we will engage adolescents and local stakeholders to co-design school-based solutions to improve adolescent and perinatal cardiovascular health using a participatory systems dynamic method, group model building. In Aim 3, we will test promising school-based solutions using agent-based modeling to inform later life health outcomes. Findings will inform actionable policies to transform school environments with the goal of disrupting lifecourse trajectories that lead to racial/ethnic disparities in maternal health and beyond.

NIH Research Projects · FY 2026 · 2025-02

The exposome, defined as “every exposure to which an individual is subjected from conception to death” underlies critical issues such as health disparities and gene–environment interactions. Two key concepts that allow us to holistically conduct robust exposomic studies are continuous measurement of all environment exposures and measuring the environment from conception to death, which invariably means reconstructing the past environmental exposures as nearly all human research studies start post-conception. The exposome's complexity is both temporal and spatial in nature. With new recent advancement, we can robustly reconstruct environmental exposures decades back at an ultra-fine residence level resolution. Geospatial core datasets can vary by their exposures, estimate errors, primary source, underlying models, populations and health outcome associations. The heterogeneity and volume of the core datasets require that selected information that is relevant to exposomics is extracted and curated from these datasets. Lack of this resource is a critical research gap that can lead to missed hypotheses on strengthening the evidence for linking human health to environmental exposures. To address this critical research gap we propose to develop an integrated biomedical knowledgebase and geospatial data science ecosystem, the GeoSpatial Knowledgebase for Exposomics-GEOSPACE. We will start by developing a geospatial database of curated exposure datasets (GSEDB, aim 1). We will index multiple data streams which will be readily explored, interpreted, and integrated with other chemical and biological information, resulting in a one-of-a-kind curated knowledgebase. In the early stage of GEOSPACE knowledgebase, we will focus on the high priority environmental exposures (PM2.5, Air Temperature and Greenness). We will then develop the Geospatial Data interpretation Resource (GSDIR, aim2). The GSDIR to link our curated environmental exposures with biological endpoints that may suggest the toxic effect of the environmental exposures on human body. Selected primary literature and omics datasets will be curated to cover the biological pathways and health outcomes related to the prioritized environmental exposures. Finally, we will develop the GEOSPACE Exposome Workspace (GES, aim 3). The GES and its sub-modules will allow exposomics researchers to query both the GSEDB and GSDIR in a fast and intuitive way. To facilitate that we will include a geospatial mapping and visualization tool as well as conduct a literature exploration to allow exposomics researchers to retrieve publications with extracted sentences that may suggest a link between the high priority exposures, biological pathways and the health outcomes. The GEOSPACE knowledgebase will be a curated and authoritative database of high-confidence external exposures that are observed in multiple core datasets. GEOSPACE will be a key resource in the exposomics field to assess curated information on ambient environmental exposures and their health effects. This curated information may promote new hypothesis-driven research using one or more core datasets.

NIH Research Projects · FY 2026 · 2025-01

Project summary In low- and middle-income countries ~2.8 billion people are exposed daily to smoke from cooking fires, termed household air pollution (HAP), resulting in an estimated 2.3M deaths and 91.4M disability adjusted life years in 2019. A large proportion of HAP-attributable deaths are due to respiratory disease over the life course. Establishment of lung health in childhood is critical to reduce risk for future respiratory disease. We propose to build on an existing pregnancy cohort in Ghana – the Ghana Randomized Air Pollution and Health Study, or GRAPHS – to assess how randomized early life air pollution exposure programs subsequent microbiome and virome over childhood, and how these changes are further associated with lung function and lung function growth. We will use well-established, validated methods to assess these outcomes. In the long run, our research will help build the evidence base for public health interventions to reduce HAP exposure-associated respiratory disease.

NSF Awards · FY 2025 · 2025-01

This CAREER project aims to develop a miniature sensor capable of measuring how heat flow within living cells is affected by variations in thermal conductivity. Thermal conductivity – the ability of a material to conduct heat – is a fundamental material property, and variations in thermal conductivity inside a cell can provide valuable insights into biological processes such as metabolism, enzyme activity, and cell communication. This project will create a microdevice specifically designed to detect variations in thermal conductivity within single cells. The knowledge gained from this research has the potential to significantly enhance medical diagnostics and treatments. Understanding the thermal properties could lead to improved therapeutic techniques. Furthermore, insights from this work could benefit studies on disorders and diseases by elucidating how heat flow dynamics influence cellular health and disease progression. This project also includes initiatives to advance education in science, technology, engineering, and mathematics (STEM) and to promote diversity. Research findings will be incorporated into workshops and curriculum development, inspiring students and engaging the public. By tackling fundamental scientific questions and fostering educational growth, this project supports the national interest by advancing scientific knowledge and delivering societal benefits through technological innovation and improved health outcomes. This CAREER project aims to develop an innovative microelectromechanical systems biosensor to measure thermal conductivity at the subcellular level using the 3-omega method. Thermal conductivity is a key biophysical property that governs how heat is transferred. This project seeks to investigate localized thermal conductivity and its correlation with cellular functions such as metabolic activity, enzyme dynamics, and signal transduction pathways. The research involves the design, fabrication, and calibration of a biosensor, which will achieve precise measurements of thermal conductivity. Experimental studies will focus on various cell models. The findings are expected to advance understanding in cellular thermodynamics and contribute to the development of diagnostic tools and therapeutic interventions. In cancer therapy, for example, precise thermal conductivity data could optimize techniques such as hyperthermia treatments, thermal ablation, and cryotherapy. Additionally, this work may benefit research on metabolic disorders and neurodegenerative diseases by uncovering how heat transfer properties affect cellular function and disease progression. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2026 · 2025-01

ABSTRACT Acute graft vs. host disease (GVHD), attacks the skin, liver, and/or GI tract, is treated with high doses of steroids, and is the primary cause of non-relapse mortality (NRM) in patients undergoing allogeneic hematopoietic cell transplantation. The overall response rate (ORR) to treatment that combines complete (CR) and partial response (PR) at day 28 (D28) was accepted by the FDA as evidence of therapeutic benefit in a clinical trial based on both accuracy and timeliness: it was the earliest time point that stratified patients for NRM (and survival) among several evaluated. Disadvantages to D28 ORR as the primary endpoint for clinical trials include: (1) lack of inclusion of severity at onset in calculating response; (2) all target organ responses are weighted equally despite the fact that NRM is driven by GI GVHD; (3) symptom severity often reflects the presence of confounding factors; and (4) CR and PR response groups have the same long-term outcomes and thus cannot support different approaches to GVHD of differing severity. This application proposes to validate a new model that overcomes these disadvantages. The Mount Sinai Acute GVHD International Consortium (MAGIC) algorithm probability (MAP) uses serum biomarkers to calculate a risk score that predicts long-term outcomes after treatment. Our preliminary “real world” data show that (1) a D14 MAGIC clinical model that accounts for symptom severity both at onset and D14 is as accurate a surrogate for long-term outcome as D28 ORR; and (2) a new MAGIC integrated response that adds the D14 MAP to the new D14 MAGIC clinical response more accurately predicts long-term outcomes than D28 ORR. The D14 MAGIC integrated response also creates three response groups with distinctly different outcomes. These findings require confirmation in patients who were treated in the context of clinical trials. We propose to use existing clinical and laboratory data from five multicenter GVHD treatment trials (n=682 patients) to test the hypothesis that novel D14 clinical trial endpoints are accurate surrogates for one-year NRM. In Specific Aim (SA) 1, we will validate the D14 MAGIC clinical response an accurate surrogate for 1 year NRM if both sensitivity and specificity are non-inferior to D28 ORR. Other performance measures such as balanced accuracy (average of sensitivity and specificity), PPV, NPV, and AUC for NRM will provide a comprehensive comparison between the two clinical endpoints. In SA2, we will validate the D14 MAGIC integrated response as the best surrogate for 1y NRM if its balanced accuracy is significantly better than D28 ORR. We will also analyze the performance of different definitions of treatment response when there are three, rather than two, distinct response categories. If successfully validated these novel endpoints will be the first advance in GVHD clinical trial design in 15 years and provide the ability to tailor trial endpoints to different treatment goals as conceived when CR and PR groups were defined.

NIH Research Projects · FY 2025 · 2025-01

PROJECT SUMMARY Alzheimer's disease (AD) is an age-related neurodegenerative disease characterized by progressive cognitive decline and dementia. Genetic studies of AD have identified 75 loci associated with susceptibility. Accumulating evidence indicates that AD risk loci (both common and rare variants) are enriched for myeloid cell (monocytes and microglia) expressed genes. We have previously demonstrated that AD susceptibility alleles affect myeloid function by altering gene expression, splicing or chromatin. These AD-associated noncoding variants are highly enriched in myeloid cell enhancers, but whether they affect enhancer function and binding of myeloid transcription factors—and if so, how—remains largely unknown. The overall objective of this study is therefore to identify the AD-associated common genetic variants that alters the binding of AD-relevant TFs in myeloid cells. In Aim 1, we will perform Chromatin immunoprecipitation followed by sequencing (ChIP-Seq) by pooling microglia samples to generate genome-wide profiles of PU.1, CEBPβ, MEF2C, BCL11A, BHLHE41, and CTCF, and histone H3 lysine 27 acetylation (H3K27ac) (TFs prioritized by AD genetics and functional genomics studies). In aim 2, we will use a pooling-based approach to map transcription factor binding quantitative trait loci (bQTL). TF binding profiles combined with RNA-seq (eQTL) and ATAC-seq (caQTL) data being generated from the same samples will allow us to identify genetic effects on chromatin that propagate to gene expression. We will perform colocalization analysis to identify AD susceptibility alleles that affect binding of TFs. The combined analyses of data on multiple types of regulatory mechanisms will allow us to understand the basis for concerted changes in regulatory outputs, and prioritize functional variants among statistically equivalent genetic associations. Finally, in aim 3, we will validate the regulatory effect of binding-disrupting functional variants using massively parallel reporter assays (MPRA) in human induced pluripotent stem cells (iPSCs) into induced microglia-like cells (iMGL). Together these studies will not only further our understanding how AD risk variants affect disease process but also provide key information bridging AD genetics to molecular mechanisms in microglia, setting the stage for future mechanistic studies.

NIH Research Projects · FY 2026 · 2025-01

PROJECT SUMMARY/ABSTRACT People with HIV (PWH) often experience chronic systemic inflammation and are at risk for cognitive impairment due to neuroinflammation and blood-brain barrier (BBB) breakdown. Tobacco use exacerbates neuroinflammation and is associated with poor outcomes, such as increased risk of virologic rebound, poorer response to ART, and increased mortality. NLRP3 inflammasome activation, a key feature of neuroinflammation and BBB dysregulation, is influenced by both HIV and nicotine. Nicotine and HIV-1 have been shown to promote activation of the NLRP3 inflammasome in the periphery, leading to chronic inflammation, inflammatory cytokine release (including IL-1β), and pyroptosis. Periodic reactivation of dormant provirus within microglia is thought to be associated with inflammatory signaling, including NLRP3-induced IL- 1β secretion. However, specific mechanisms underlying the combined effect of HIV and nicotine on NLRP3- driven inflammation in the CNS remain largely undefined. Previous work in the Swartz laboratory demonstrated that HIV-1 infection activates the NLRP3 inflammasome in myeloid cells in a human tonsil explant model, and recent data suggest that this is potentiated by nicotine. The Swartz lab and collaborators recently reported on a novel humanized mouse model incorporating HIV infection of engrafted induced pluripotent stem cell (iPSC)- derived microglia to study HIV infection and latency in the CNS at a single-cell level. My underlying hypothesis is that the combined effect of HIV and nicotine drives NLRP3 activation, which promotes proinflammatory signaling in HIV-infected microglia, compromises BBB integrity and incites viral reactivation in latently infected cells. The Chen laboratory’s enhanced HIV-induced lineage tracing system (E-HILT) will allow me to test nicotine’s impact on latency establishment and maintenance by tracking productively and latently infected cells in both in vivo and in vitro. By probing the role of nicotine interactions with the BBB and its influence on inflammatory pathways using in vitro BBB models and a humanized mouse model, I aim to characterize its role in modulating neuroinflammation (Aim 1), BBB functionality (Aim 2), and viral latency (Aim 3). My findings will provide novel insights into the mechanism of nicotine’s impact on the pathogenesis of HIV-1-associated neurodegeneration, informing possibilities for future therapeutic development. This work will uncover novel connections between HIV and nicotine-associated inflammatory pathways, leading to an improved understanding of the complex effects of substance use on the BBB in PWH. This training at the Icahn School of Medicine at Mount Sinai will support my development as a scientist and prepare me to become a well-rounded principal investigator in the fields of neuroimmunology, virology, and substance use.

NIH Research Projects · FY 2026 · 2025-01

Summary Cell-cell communication in the early embryo specifies cell fates and orchestrates collective cell movements. One of the main drivers of collective cell behaviors in vertebrates is the core planar cell polarity (PCP) pathway. Genetic studies demonstrated the requirement for vertebrate PCP proteins in many morphogenetic processes including neural tube closure. Our preliminary data revealed the anteroposterior and the mediolateral axes of PCP in the Xenopus neuroectoderm that are marked, respectively, by Vangl2 and Diversin protein clusters. The proposed study will test a hypothesis that the two orthogonal PCP axes are mediated by distinct signaling pathways. This will be achieved using a combination of cell biological, proteomic and live imaging approaches in Xenopus, a powerful experimental model allowing rapid functional analysis in vivo. The medially-enriched PCP clusters will be studied by identifying Diversin- interacting proteins and correlating the dynamics of their assembly and localization with Myosin II-dependent cell behaviors in the neural plate and epidermal ectoderm. The regulation of the anteriorly-enriched PCP clusters and neural tube folding by fibroblast growth factor (FGF) signaling will be investigated and the relevant structural motifs and intracellular pathways will be defined. Wild-type Vangl2 will be compared to mutated Vangl2 constructs that are not sensitive to FGF signaling. The proposed study will reveal the relative contributions of secreted growth factors and actomyosin contractility to morphogenesis in early vertebrate embryos. These experiments will expand the knowledge of morphogenetic mechanisms that are critical for normal development and often disrupted in disease.

NIH Research Projects · FY 2026 · 2025-01

PROJECT SUMMARY/ABSTRACT Maladaptive adolescent risk-taking behaviors are a public health concern associated with a variety of adverse health outcomes. Although studies have explored neurobiological mechanisms underlying adolescent risk-taking, few have examined the potential role of early-life environmental exposures. To address this knowledge gap, this proposal utilizes a Developmental Origins of Health and Disease (DOHaD) framework to elucidate early-life environmental influences of adolescent-risk taking, focusing on the unique vulnerability of the perinatal period (prenatal to 1 year postnatal). Throughout the perinatal period, the brain undergoes significant structural and functional maturation, making exposures at any point a risk for abnormal neurodevelopment. Converging epidemiological data suggest that individual metal exposures (e.g., lead, manganese) during this period may contribute to adolescent-risk taking by disrupting the development of subserving brain regions within the reward and/or cognitive control systems (e.g., striatum, prefrontal cortex). However, although metals commonly co-occur in the environment, no epidemiological study to date has assessed the impact of perinatal metal mixture exposure in relation to adolescent risk-taking. Furthermore, evidence suggests prenatal maternal stress (PMS) may enhance metal neurotoxicity, suggesting that combined exposure to PMS and metals may increase risk for maladaptive adolescent risk-taking. Yet, the modifying effect of PMS on metal-associated outcomes has not been studied in the context of adolescent risk-taking. This study proposes to examine associations between perinatal metal mixture exposure on cognitive (Aim 1) and neural (Aim 2) constructs underlying adolescent risk-taking, and to evaluate the modifying role of PMS on these associations (Aim 3). Using state-of-the-art statistical methods, I will analyze existing data (dentine metal biomarkers, maternal stress measures, gambling task fMRI) collected from adolescents enrolled in the Programming Research in Obesity, GRowth, Environment, and Social Stress (PROGRESS) study. My analyses will focus on brain regions associated with reward, risk, and/or cognitive control (e.g., ventral striatum, insula, dorsolateral prefrontal cortex), and the following constructs derived from a computational model of risky decision-making: risk-taking tendency, risk sensitivity, reward sensitivity. I hypothesize that perinatal metal mixture exposure will be significantly associated with alterations in these constructs, and that these associations will be enhanced in offspring exposed to higher PMS. The proposed project is supported by the Icahn School of Medicine at Mount Sinai’s Department of Environmental Medicine and Public Health, which provides a highly cross-disciplinary research environment. By integrating environmental epidemiology, biostatistics, and developmental cognitive neuroscience, the proposed research presents a unique training opportunity in the growing field of environmental developmental neuroscience and will prepare the applicant for an interdisciplinary academic research career. Importantly, the proposed research will also inform public health interventions aimed at improving adolescent health.

NIH Research Projects · FY 2025 · 2024-12

TITLE: Incorporating mobile technology into postoperative care: a shift in paradigm toward ambulatory surgery in LMIC. PROJECT SUMMARY In many low- and middle-income countries (LMICs), low-acuity surgeries require postoperative hospitalization for several days, partly due to concerns of inadequate follow-up after discharge and partly to cultural norms. This not only poses increased risks of hospital acquired complications, but also increases the total surgical costs for both patients and facilities. Consequently, this inefficient practice contributes to the barriers to access safe and affordable surgical care. We propose an alternate approach of mHealth Ambulatory Surgery with Follow-up Nurse (mAS-FUN), which does not require patient hospitalization after surgery. Since 2020, we have implemented mAS-FUN at the Kyabirwa Surgical Center (KSC), the first ambulatory surgery center in rural Uganda. The current proposal aims to show mAS-FUN is safe, effective, and markedly reduces costs when patient follow-ups can be reliably performed at home via a cloud-based mobile app and visiting nurse. Based on our robust preliminary data, our central hypothesis is that implementation of mAS-FUN reduces hospital and patient costs, improves patient follow-up, and reduces recovery time, without increasing complications, compared to the current inpatient practice in other surgical facilities across Uganda. In our preliminary work, we have established the framework for mAS-FUN at KSC, including hiring key personnel and testing study protocols. In the R21 phase, we will perform a prospective, observational clinical study aimed at validating the safety, feasibility, acceptability of mAS-FUN for the primary outcomes of costs for both patients and facilities, whether patients can be assessed after discharged home, and total duration of postoperative medical care received; and the secondary outcomes of postoperative complications, time to functional recovery and ability to return to work, and acceptability of mAS-FUN by patients, healthcare personnel, and the community, as compared to historical controls. Armed with strong partnerships and adequate preparation during the R21 phase, we will then perform a stratified cluster randomized, controlled clinical trial during the R33 phase, comparing the novel mAS-FUN versus traditional approaches at three surgical centers in Uganda. Demonstrating the feasibility, acceptability, and effectiveness of this novel approach for surgical care – and its ability to improve outcomes – is necessary for wide-spread adoption. We expect our findings will ultimately shift the paradigm of how surgery for low-acuity procedures is practiced in Uganda and serve as a model for other LMICs.

NIH Research Projects · FY 2026 · 2024-12

PROJECT SUMMARY Lung cancer is the leading cause of cancer related deaths in the U.S. and worldwide. Large-scale genetic studies of lung cancer samples have discovered a number of important genetic changes that can be targeted as a treatment for lung cancer patients and led to significant improvement in outcome for patients with non-small cell lung cancers (NSCLC). In contrast, diagnosis, treatment and prognosis for patients with small cell lung cancer (SCLC), a more aggressive and widely metastatic subtype of lung cancer accounting for 15% of all lung cancer cases, have made little progress over the last decades with 5-year survival rate at a dismal 6-7%. Molecular understanding of SCLC pathogenesis also lags behind those of NSCLC. The current clinical classification of lung cancer still recognizes SCLC as a single disease. Recently, distinct molecular subtypes of SCLC have been identified that may explain diverse biological behaviors of SCLC and Achilles’ heel for development of new therapeutic potentials. SCLC is characterized by unique histological features of neuroendocrine differentiation and factors controlling this neuroendocrine state are now drawing attention for their roles in SCLC pathogenesis. Our group has been in the forefront of studying factors controlling differentiation in NSCLC through epigenetic analyses. Thus, to expand upon the current classification of SCLCs, we have employed our expertise to develop a new framework analyzing epigenetic profiles of SCLCs and we have identified two novel clusters within the major ASCL1- subtype that represent distinct identities. One of these clusters is signified by the presence of NKX2-1 super- enhancer and its expression is essential for evolving into this SCLC subtype. We hypothesize that this newly identified SCLC cluster, a sizable proportion of human SCLCs, defined by a dual pulmonary and neural lineage factor NKX2-1, represents a biological state potentially evolved through a distinct path. Thus, we aim to elucidate the mechanistic roles of lineage factors in distinct lineage subtypes of SCLCs using our expertise on transcriptional regulation and epigenomics by 1) determining how cell-of-origin and NKX2-1 impact evolution and maintenance of epigenomic SCLC states, 2) determining the mechanisms for pulmonary to neuronal adaptation in this SCLC subtype, and 3) determining the full spectrum of SCLC heterogeneity in human SCLCs and histological characteristics leveraging our access to a large collection of human SCLC specimens as well as patient-derived models.

NIH Research Projects · FY 2025 · 2024-12

SUMMARY Neuroendocrine (NE) transformation in lung adenocarcinoma (LUAD) is a lethal mechanism of resistance that is without effective treatment or prevention options. Due to a lack of cell-level resolution, preclinical models, and the limited availability of matched clinical specimens, factors underlying this lineage plasticity (LP) from LUAD to more aggressive small cell lung cancer (SCLC) are largely unknown. Our preliminary studies showed that several hallmarks of SCLC appear critical to initiating the process of NE transformation, including RB1 and TP53 loss and downregulation of NOTCH signaling. We further demonstrate the role of NOTCH-driven upregulation of lineage-determining transcription factors (LDTFs) in NE transformation in lung cancer clinical samples. Our objective is to systematically uncover core mechanisms facilitating LP in EGFR-mutant lung cancer. The long- term goal of this application is to develop therapeutic strategies to reverse or prevent LP as a mechanism of acquired resistance. Our overarching hypothesis is that in EGFR-mut LUAD, RB1, and TP53 loss, specific molecular alterations (e.g., EZH2 induction) drive LP through reprogramming of NOTCH signaling and upregulation of LDTFs (such as POU3F2, FOXN4, ONECUT2). In Aim 1, we will assess the epigenetic and transcriptional changes in EGFR-mutant LUAD before, during, and after SCLC transformation in clinical samples. We will assess genetic, transcriptomic, and epigenomic changes in pre-transformed LUAD and transformed SCLC clinical samples (matched and unmatched) at single-cell resolution (scRNAseq, snRNAseq, ATACseq). Furthermore, we will assess the dynamic changes of NOTCH pathway regulators, and LDTFs in EGFR-mutant lung cancer. In Aim 2, we will determine the role of NOTCH signaling and key transcriptional regulators in promoting LP and acquired resistance to EGFR-TKIs in preclinical models. We will establish the functional interplay of NOTCH signaling and LDTFs (POU3F2, FOXN4, ONECUT2) in LP from LUAD to T-SCLC. We will (1) comprehensively assess the genetic, transcriptomic, epigenomic, and proteomic changes driving LP in multiple preclinical models of pre-T LUAD and post-T SCLC at single-cell resolution; (2) model LP in PDX models to investigate the consequences of NOTCH inhibition on TF upregulation and vice versa, and (3) assess the effect on resistance to EGFR-TKIs. In Aim 3, we will establish the therapeutic potential of targeting EZH2 in LUAD to T-SCLC transition. In this aim, we will leverage our established transformation models to assess the role of EZH2 in (1) promoting LP and therapy resistance in EGFR-mutant pre-transformation models; (2) establishing the therapeutic strategy of targeting EZH2 to delay or reverse LP, suppressing neuroendocrine differentiation and therapy resistance in therapy-resistant post transformation models. This proposal will be conducted by a multidisciplinary team and will enhance our understanding of tumor evolution, and cell identity, and identify new therapeutic approaches to target LP. These are critical steps towards improving the detection, treatment, and mortality of patients with lung cancer developing treatment resistance.