New York University School Of Medicine

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY The overarching aim of the K12 program at the New York University (NYU) Clinical Translational Science Institute (CTSI) is to train the next generation of clinical and translational researchers to improve individual and public health through rigorous, reproducible, and solution-oriented biomedical research aligned with national research priorities. To help realize NCATS’ strategic goal to “enable all people to contribute to and benefit from translational science”, we will build on the previous three cycles of funding for our K12. The training record for previous scholars is excellent, with all 28 remaining in research or academic leadership careers and 23 out of 28 obtaining federal funding within 2 years of the program. In this proposal, the program will be led by two new, experienced program directors with a long-standing commitment to fostering the careers of early-stage investigators, Drs. Melamed and Shaukat. Both have active clinical and translational research programs, have undergone extensive mentor training, have won mentorship awards, and have led multiple institutional career development programs. They will collaborate closely to maintain the tradition of excellence of the program. The new career development program and environment will focus on fostering the seven attributes of a translational scientist and leadership development, while emphasizing rigorous study design, research transparency, and reproducibility consistent with gold-standard biomedical science. The program is composed of didactic courses, experiential learning, and individualized leadership coaching. Each scholar will have at least two science mentors, a career mentor and a mentorship advisory committee that will meet regularly to ensure adequate progress along the scholar’s independent development plan and Scholar-Mentor Compact. Our scholars will present to members of our Community Advisory Board. NYU has shown a substantial commitment to the program by increasing the number of institutionally funded positions from two to seven. We will be guided by our long-standing External Advisory Committee which meets annually and provides supervision, direction and approval of scholar appointments to the program. Our 50 faculty mentors offer a wide range of CTS expertise, from T1 to T4 funded science. Over half of the mentors have served as program directors of NIH funded training programs (T32, K12, R25, TL1, etc.) and 5 have current mid-career mentoring awards (K24 or equivalent). We will employ rigorous evaluation methods and continuous quality improvement to refine the program and equip scholars with the tools to guide their careers, accelerating the pace of CTS and preparing them to become future mentors and leaders, including training in reproducible research practices, data science approaches, and responsible use of emerging technologies such as artificial intelligence in biomedical research. By advancing their knowledge and expanding their skills, our K12 scholars will emerge as the next generation of leaders in CTS who will translate biomedical discoveries into measurable health improvements for the American public.

NIH Research Projects · FY 2026 · 2026-04

Scarring of the stroma, the central layer of the cornea, due to Injury or infection, and severe stromal thinning due to keratoconus, cause corneal blindness worldwide. Cornea transplantation is often the only cure for many of these conditions, but limited supply of donor tissue is a major concern. Cell therapy for the stroma, still under development, primarily uses limbal stem cells from donor corneas. Therefore, there is a critical need for treatment of the stroma that will be independent of donor tissues. To address this need, we recently developed human cornea organoids (HCOs) that mimic the fetal cornea. Generated from induced pluripotent stem cells (iPSC) the HCOs present a breakthrough model system of co-differentiating stromal keratocyte, epithelial and endothelial cells in a more cornea-like 3-dimensional extracellular matrix (ECM). Our single cell RNA sequence (scRNA-seq) study shows that HCOs harbor stromal progenitor and fetal corneal keratocyte-like cells which may have the desired long-lasting functionality in the cornea. In addition, we found that HCOs express ECM genes and produce a stroma rich in collagen type III, fibronectin, and other ECM components known to make up the immature corneal stroma. Additionally, as the TGF-𝛽 network is the master regulator of healthy and fibrotic ECM, this network must be specifically regulated in HCOs to maintain its regenerative ECM quality. Therefore, we hypothesize that the HCO is a novel stromal therapy resource and a corneal surrogate for identifying TGF-𝜷 signals that promote healthy but limit fibrotic ECM production. Our preliminary data shows that a mix of stem, progenitor and differentiating cells can be rapidly extracted from the HCO stroma without further monolayer culturing. Injected into decellularized donor corneas the HCO-stromal cells can integrate in the tissue. Second, the extracted ECM from HCOs promote migration in cell culture and corneal wound healing in the mouse. Importantly, as the HCO expresses all major receptors and transcription factors, it is feasible to investigate the TGF-𝛽 network in this model. Aim 1 will determine if extracted HCO-stromal cells will integrate and function in a decellularized donor cornea. Aim 2 will test whether the HCO-stromal cells or the extracted HCO-ECM promote scarless wound healing in the mouse. Aim 3 will identify specific TGF-𝛽 signals that underpin the immature ECM of HCOs. Our findings will develop the HCO as a promising donor tissue-free source of regenerative biomaterial and cells and identify regenerative TGF-𝛽 signals for future treatments of corneal scarring.

NIH Research Projects · FY 2026 · 2026-04

Polymerase chain reaction (PCR) testing for HIV viral load is a mainstay of HIV treatment monitoring, but has limitations including high costs, long turn-around times, and limited information that only reflects viral load “in the moment.” This study explores the hypothesis that low-cost rapid antibody tests can complement HIV PCR, analogously to how hemoglobin A1c testing complements “in-the-moment” glucose testing. First, we will consolidate existing quantitative antibody data across ≥13 antibody-based assays and ≥17 longitudinal HIV treatment cohorts spanning 10 countries and all major HIV subtypes. We will develop regression-based and mechanistic viral dynamics models of antibody trajectories and their determinants, hypothesizing that mechanistic models will out-perform regression. We will also explore latent trajectory models that account for unobserved heterogeneity. For example, it is known that some clients are more adherent to treatment in the days leading up to clinic visits, motivated in part by a desire for positive interactions with healthcare providers. Undetected between-visit viral rebounds can lead to HIV transmission and adverse health effects, suggesting a role for tests detecting viral rebound over a longer retrospective time window. Next, we will select several of the most promising, low-cost, widely-available antibody assays to test on ≥4 long-term treatment cohorts spanning a range of HIV acquisition modalities and viral subtypes, and which include individuals on treatment for >10 years. These newly-generated data will be used to augment the dataset, prospectively validate the trajectory models, and formally analyze performance characteristics (receiver operating characteristic curves) of the assays, alone or in combination, predicting viral rebound over different retrospective time windows. We will determine which assays best detect current and past viral rebounds. Finally, we will conduct individual- and population-level modeling of HIV treatment monitoring strategies that incorporate antibody assays. At individual levels, we will assess health impact and cost-effectiveness when antibody assays augment, replace, or partially replace PCR. We will also model hypothetical performance characteristics in order to establish target product profiles for future assays. At population levels, we will model how antibody assays could augment HIV epidemic goals such as “95-95-95” (diagnosing ≥95% of people living with HIV, providing treatment to ≥95% of those diagnosed, and achieving undetectable viral load in ≥95% of those on treatment). A potential “fourth 95” could involve maintaining long-term viral suppression. Monitoring this “fourth 95” with antibody assays could make population-level HIV studies more affordable, feasible, and useful as 95’s approach 100’s. The impact of this research is both scientific and translational. Scientifically, we will develop novel datasets and models to enhance understanding of antibody trajectories during HIV treatment. Translationally, we will pave the way for potentially game-changing diagnostics to reduce HIV care costs, improve turn-around time and convenience, and provide richer information for people living with HIV.

NIH Research Projects · FY 2026 · 2026-04

Summary Aneuploidy—the presence of chromosome gains and losses—is very rare in normal tissues but occurs in more than 80% of human tumors, especially in solid tumors. A high level of aneuploidy in tumors correlates with higher-grade disease, tumor progression, and resistance to therapy. Whether and how aneuploidy contributes to formation and progression of human tumors is not well understood. Whereas genomic and clinical studies in cancer patients suggest that aneuploidy drives tumorigenesis, experimental studies in mouse models and in vitro systems has so far yielded conflicting data on the role of aneuploidy in tumors. Human tumors are often specifically associated with either increases or decreases in the number of specific chromosome(s). One of the main obstacles to progress has been the technical limitation of not being able to engineer the ‘right’ type of aneuploidy in the ‘right’ cell type. Our ultimate goal is to dissect whether and how aneuploidy contributes to initiation and progression or human tumors. Our first objective here is to generate cellular models that faithfully recapitulate the aneuploidy patterns found in tumors in order to study how aneuploidy affects the pathobiology of tumor cells (their ability to grow in vitro or in vivo, to evade cell death pathways, to survive cellular stress and to regulate transcription and translation). Our second objective is to uncover vulnerabilities and synthetic lethal interactions potentially associated with the aneuploid state. The outcomes of the proposed project will represent the foundation to achieve the long-term goal of our lab, which is to develop a better understanding of the causes and consequences of aneuploidy in human tumors in order to uncover aneuploidy-associated biomarkers and therapeutic targets. To accomplish this goal, we will first use a panel of newly generated human cells containing different degrees and types of aneuploidy to compare diploid and aneuploid cells for several tumor-related cellular phenotypes both in vitro and in vivo. Secondly, we will adopt a systematic approach to identify genes and pathways that when blocked, inhibit proliferation and survival of aneuploid tumor cells but not normal cells. Third, we will perform a protein and phospho-protein analysis mainly of colorectal tumor patients’ samples to dissect the consequences of aneuploidy at the level of protein stability and pathway regulation. Our results will fill an important gap of knowledge in our current understanding of how aneuploidy evolves during tumorigenesis and how we might take advantage of this knowledge to improve patient outcomes.

NIH Research Projects · FY 2026 · 2026-03

The New York University (NYU) Clinical and Translational Science Institute (CTSI) is a vibrant public–private collaboration between NYU Langone Health (NYULH), the NYU Grossman School of Medicine and NYU Grossman Long Island School of Medicine; the Family Health Centers at NYULH, our Community and Patient Advisory Boards, and all other NYU schools and colleges. Moreover, our partnerships with NYC Health and Hospitals, the nation’s largest municipal healthcare system; the Nathan Kline Institute, a psychiatric research institute; Kingsborough Community College, and >150 additional community partners allow us to reach all populations across New York City. Our focus over the next 7 years is to emphasize collaboration as a fundamental approach to advancing clinical translational science (CTS) while overcoming barriers, bridging communities, fostering a well-rounded science workforce, and continuously evaluating and improving the quality and impact of our research. We will partner with communities to bring research to where people live and promote practice and policy through five overarching aims. Aim 1: Enhance Community-Engaged Research. We will leverage our unique strengths collaborating with patient, community, and multisector partners to establish innovative research programs and practice-based learning health systems. Aim 2: Democratize Health Informatics (HI) Resources. We will foster a collaborative environment to develop, implement, and disseminate innovative HI resources that enhance the quality, safety, efficiency, and reproducibility of clinical translational research (CTR) and CTS. Aim 3: Develop a Well-Rounded Workforce to Advance CTS. We will create collaborative learning initiatives that involve research faculty, staff, clinicians, students, and community members. Aim 4: Catalyze Regional and National Collaborations to Accelerate CTS Research. We will promote and facilitate partnerships at regional and national levels to accelerate CTS research through interdisciplinary team science and knowledge sharing. Aim 5: Advance Clinical Trials through Collaborative Partnerships. We will develop and implement operational innovations to accelerate start-up and completion of clinical trials, while elevating their quality, safety, effectiveness, and impact. These goals capitalize on our major strengths, emphasizing collaborations with community and multisector partners, interdisciplinary engagement across NYU and its 11 colleges and schools, and active participation in the CTSA consortium. For the next 7 years, we envision a future in which scientific breakthroughs more swiftly transition from bench to the bedside and into our communities so every individual receives access to innovative healthcare solutions.

NIH Research Projects · FY 2026 · 2026-03

SUMMARY Profound behavioral, emotional, and cognitive changes begin in pregnancy to prepare for the transition to parenthood, underscored by plasticity in maternal brain structure and function. Translational research emphasizes evolutionarily conserved adaptation as occurring in this period, though little is known about plasticity of the human maternal brain during pregnancy. Advancing this knowledge is a public health imperative given the prevalence and severity of perinatal mood and anxiety disorders (PMADs), which frequently originate in the prenatal period. Consequences of PMADs are enduring and costly, and carry intergenerational consequences through their impact on infant development, yet very little is known about their neural bases. What is known: A small number of studies document anatomical change in the brain from pre-pregnancy to the postpartum. Associations between iron and mood are established, and maternal iron in pregnancy is a known predictor of offspring neurobehavioral development. Furthermore, brain iron is emerging as a key factor underlying neuroplastic processes across the life course. Iron deficiency affects up to 40% of women in the US, and in pregnancy iron demands are significantly heightened. PMADs also increase risk of developmental disorders and psychiatric problems in children, though mechanisms for risk transmission are poorly understood. What is unknown: Neuroimaging studies conducted during pregnancy are rare, so trajectories of brain changes during pregnancy, across multiple domains, have yet to be examined. Further, how brain plasticity relates to PMAD symptoms is also unknown, constraining potential for clinical translation in this emerging area. Brain iron changes in pregnancy and its relevance to PMADs have yet to be examined. The goal of the proposed research is to determine whether gestational neuroplasticity underlies individual differences in maternal mental health and influences offspring neural development. We will conduct multi-modal MRI in a sample of n=132 women at 2 prenatal and one postpartum time point, measuring PMAD symptoms until 6 months postpartum, and complete rigorous assessment of offspring neurodevelopment including infant fMRI. Novel eye tracking technology will be used to collect objective measures of emerging infant attentional processing. We will address 3 key aims: (1) Quantify maternal gestational neural change using an integrated multimodal imaging approach; (2) Isolate associations between gestational neuroplasticity and PMAD symptoms; and (3) Determine whether maternal neuroplasticity and brain iron, measured via novel quantitative MRI sequences, are associated with infant neurodevelopment. Expected outcomes are significant as they will advance the field beyond documentation of expected neuroplasticity and towards understanding of clinically meaningful implications of individual differences in change, significantly advancing understanding of PMAD etiology.

NIH Research Projects · FY 2026 · 2026-03

ABSTRACT This study will conduct a hybrid type II implementation-effectiveness trial of a peer change agent intervention designed to increase pre-exposure prophylaxis (PrEP) and medication for opioid use disorder (MOUD) uptake among people who inject drugs (PWID). The study will be conducted in partnership with a peer-led organization providing services to PWID in Los Angeles, CA. Los Angeles is an Ending the HIV Epidemic (EHE) priority jurisdiction. This project builds upon the Investigative Team’s extensive partnerships to address the persistently low uptake of PrEP and MOUD among PWID by leveraging social network diffusion strategies. Guided by the Exploration, Preparation, Implementation, and Sustainment (EPIS) framework and evaluated using the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework, the study will assess both effectiveness and implementation outcomes. A total of 372 PWID will be enrolled using peer chain referral sampling and randomized into one of two study arms: (1) LINKED (Leveraging Interpersonal Networks to Keep Engagement in PrEP & MOUD), a social network-based peer social network intervention designed to motivate network members to engage in PrEP and MOUD uptake, or (2) an equal-attention control arm focused on HIV and overdose risk assessment and prevention. Participants will complete booster sessions at 21- and 42-days post-intervention, with follow-up assessments at 6 and 12 months. The primary outcome will be a confirmed PrEP and/or MOUD uptake and persistence at the individual level and PrEP and/or MOUD uptake at the network level. All participants, regardless of study arm, will receive opioid overdose prevention education and resources as part of standard services. The study will integrate longitudinal mixed-methods research to iteratively refine implementation strategies and evaluate key implementation outcomes at both the participant and HRO levels. Strong collaborations with PWID and the staff at our partner organization will ensure the feasibility and impact of the study. If effective, this trial will provide a scalable model to expand PrEP and MOUD engagement among PWID in other EHE jurisdictions, strengthening HIV and overdose prevention efforts nationwide.

NIH Research Projects · FY 2026 · 2026-03

Project Summary The family is the canonical basis of social structure for mammalian species. Families help ensure that offspring survive, learn pivotal skills, and thrive. Adults initially find mates and have behavioral adaptations to ensure the welfare of the mother and prepare for postnatal care. After parturition, offspring require intense caregiving by one or more adults for nourishment, warmth, and protection over varying periods of postnatal development. This commonly requires a lactating mother until infants transition to other food sources. Despite millennia of neuro- behavioral adaptations, infant and adult mortality can be shockingly high, even in the seemingly ideal conditions of lab vivaria. In more natural environments, families must contend with other challenges: infection, weather, predators, and conspecific competition for scarce resources. The dynamic and unpredictable nature of such stressors means that flexible strategies are required for success and survival. This requires socially- or environmentally-induced neuroplasticity and complex decision-making in the face of life-or-death stakes. Here we propose a collaboration between behavioral neuroscientists, a theorist, and an engineer to develop and validate a new integrated system for life-long and high-resolution monitoring of mouse colony life. Technological and computational advances over the last decade, in part pioneered by our groups, now enable studies of neural circuits for social and parental behavior in complex environments in ways not formerly feasible or even possible. There have been major improvements in wireless recording, cell- and circuit-specific methods for measuring and manipulating brain activity and behavior, algorithms for neural data analysis, methods for quantifying multi-animal behavioral interactions, and capacity to store and share large data sets. This now provides an opportunity to build a theoretical and quantitative framework for understanding mouse social behavior and family life, with models constrained by continuous video synchronized with neural recordings. Our main hypothesis is that the duties and challenges of parenting define many aspects of mouse adult social behavior. Specifically, we predict that the need to provide safety and support to offspring leads to systematic engagement in territorialism, nest/burrow construction, foraging, mating, and then recruitment of co- parents initiated by the dam. In Aim 1, we will quantify behaviors in a new statistical framework of one or two colonies of 5 mice each with a litter of pups, in 3-D engineered burrows with food and water above-ground, using machine learning methods and a large data center provided by NYU. In Aim 2, we will validate and optimize a new wireless high-frequency single-cell imaging system to reveal the activity of molecularly defined cell types as animals engage in cooperative and competitive foraging and childcare, with a focus on the hypothalamus. In Aim 3, we track individuals over time, perturbing specific hypothalamic cell types and updating our model to reflect individual brain states and hormone systems on survival strategies.

NIH Research Projects · FY 2026 · 2026-03

Project Abstract In recent years, the prevalence of depression has risen, and with it, the prescribing of serotonergic antidepressants. Approximately 13.2% of adults aged 18 and over report using antidepressant in the past 30 days. Anhedonia (loss of interest or pleasure in previously rewarding activities) is a common symptom of depression. First-line antidepressants, selective serotonin reuptake inhibitors (SSRIs), can effectively lift low mood, but often come at the cost of further blunting emotion and reward-processing. In contrast, psilocybin (a 5HT-2A psychedelic) has shown promise in alleviating anhedonia and improving emotional range, even outperforming SSRIs in head-to-head trials. Emerging clinical research supports the safety and efficacy psilocybin in individuals currently taking an SSRI, offering a promising new adjunctive treatment option for those experiencing residual anhedonia. Despite this potential, the neural mechanisms underlying psilocybin's therapeutic effects on anhedonia remain poorly understood. Parallel fronto-limbic circuits—connections between the medial prefrontal cortex (mPFC) and limbic system—regulate motivation and emotional response. One crucial circuit, connecting the pregenual anterior cingulate cortex (pgACC) and the nucleus accumbens (NAcc), forms the core of the brain’s reward system and is implicated in anhedonia. In anhedonia, activity and connectivity in this pgACC-NAcc circuit is suppressed. SSRIs may further suppress this circuit, leading to residual deficits in motivation and pleasure. This study will use a clinical trial to assess the effects of a single dose of psilocybin (25 mg single dose) or control (psilocybin 1mg) in individuals experiencing SSRI-induced anhedonia. We will utilize Precision Functional Mapping (PFM), a novel fMRI technique enabling individual-specific brain mapping, to investigate how psilocybin modulates fronto-limbic circuitry in individuals with SSRI-induced anhedonia. In addition to PFM, we will use well-validated task-fMRI (emotional processing, monetary incentive delay) to probe key fronto-limbic circuits. Then we will test the ability of psilocybin to engage reward circuitry relevant to anhedonia. This work will advance our mechanistic understanding of anhedonia, identify biomarkers for targeted treatment, and potentially lead to more effective therapies.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY/ABSTRACT Dr. Andrew Michalak is an Assistant Professor of Neurology at New York University Grossman School of Medicine (NYUGSoM) with clinical expertise in epilepsy. His long-term goal is to be a physician scientist using multiscale electrophysiology to bridge the gap between the basic mechanisms of epilepsy and therapeutic options for patients. Outcomes after responsive neurostimulation (RNS) implantation for drug-resistant epilepsy vary widely, and there are currently no known biomarkers to guide lead placement or patient selection. Ictal onset patterns (IOPs) are used widely for predicting response to surgical resection, but we do not know if they are effective for guiding RNS placement. Furthermore, classifying IOPs is subjective and time-consuming. This proposal explores the basic mechanisms that give rise to ictal onset patterns using hybrid micro-/macroelectrode recordings, determines their use in predicting RNS outcomes, and uses machine learning to classify ictal patterns rapidly across the full ictal period. The specific aims are (1) identify interictal neural mechanisms that generate IOPs via multiscale recordings, (2) quantify the predictive value of IOPs for seizure reduction after RNS, and (3) determine the accuracy of neural networks to classify the full ictal period. This proposal builds on Dr. Michalak’s prior research on epilepsy surgery outcomes and microscale electrophysiology. With a mentor team of experts in the field from NYUGSoM, Dr. Michalak will gain expertise in multiscale electrophysiology methods and analysis, signal processing, and machine learning. Dr. Michalak’s mentors (Drs. Friedman, Flinker, Liu, and Devinsky) have strong track records of mentorship and will provide specific expertise in these areas. He will take advantage of the high volume of surgical epilepsy at NYUGSoM and a large retrospective dataset, as well as an existing multicenter collaboration with University of Pennsylvania and University of California – San Francisco. The data and training derived from this career development award and his strong mentorship will position Dr. Michalak as an independent clinician scientist and leader in the field of epilepsy biomarker research and therapeutic strategies.

NIH Research Projects · FY 2026 · 2026-02

In 2023, about 4750 Americans died while awaiting a kidney transplant (KT), but over 8,500 kidneys were recovered and not transplanted. The National Academies of Sciences, Engineering, and Medicine (NASEM) declared kidney non-utilization a critical problem that mandates immediate attention and remedy. Highly prioritized candidates receive many offers for superior kidneys, but also receive offers for many non-ideal kidneys that they refuse sequentially while the clock counts down to kidney non-use. Many candidates with low priority would benefit from receiving a non-ideal kidney quickly but rarely get these offers. Stratified kidney allocation is a proposed system under which patients would make an obligatory but modifiable choice between receiving a superior kidney after a longer wait or a non-ideal kidney sooner. Stratified kidney allocation might increase organ utilization while shortening wait times and improving transplant outcomes for selected patients. Prior work has shown that patients have misperceptions about the dimensions of kidney quality, underestimate the survival benefit of transplant with non-ideal kidneys, and alarmingly, are given a very limited role in decisions about offer quality. While stratified allocation might expedite and increase the use of non-ideal kidneys, impacts are unknown because myriad and sundry details such as which deceased donor kidneys would be categorized as non-ideal, which candidates would select which quality category, etc., have never been specified, nor have patient perceptions about acceptability been investigated. We will build expert consensus on the design of stratified kidney allocation, estimate the impact of stratified allocation to assist policymakers, and investigate attitudes and perceptions of patients, care partners, and providers on shared decision making about kidney offer acceptance, and on making a choice to receive either superior or non-ideal kidneys. Our aims are (1) To understand patient and care partner attitudes, perceptions, and preferences about stratified allocation, shared decision-making, and needs for transparency around organ offers and declines, (2) to assess transplant provider attitudes, perceptions, and preferences about a stratified allocation system, and (3) to estimate the impact of stratified allocation on kidney utilization, and to estimate waiting time for KT candidates choosing either to receive either superior or non-ideal offers. This research will take stratified allocation from a speculative proposal to a concrete policy design that supports deliberation and possible adoption, informed by the judgements of transplant experts, by patient and caregiver perceptions, and by numerical estimates of its impacts. Whether or not stratified allocation succeeds, we will, as advocated in NASEM’s 2022 report, investigate approaches for increasing transparency around offer declines, and involving patients in shared decision making about the kidney quality vs. wait time tradeoff.

NIH Research Projects · FY 2026 · 2026-02

Abstract The Complement-ARIE program aims to develop and implement New Approach Methodologies (NAMs) to reduce animal experimentation. Sage Bionetworks and NYU Grossman School of Medicine propose establishing the NYU-Sage NAMs Data Hub and Coordinating Center (NDHCC) to create an interoperable NAMs data ecosystem that accelerates NAMs adoption. The NYU-Sage NDHCC is organized to support four critical objectives: (1) The development of a new, adaptive framework called FUSION (FAIR, Unified Schema for Interoperability of Ontologies in NAMs) to harmonize NAMs standards and ontologies into a NAMs Common Data Model (CDM); (2) The implementation of a FAIR- compliant repository supporting both centralized and federated data access, data sharing, data analytics, training, and dissemination of NAMs information; (3) The deployment of a battery of analytical and visualization methods applicable across our centralized and federated data network; and (4) The cultivation of a collaborative research community which contributes to the development of standards, analytics, and insights and ensures sustainability of the NAMs ecosystem though their continuous engagement. To attain these objectives the NYU-Sage NDHCC is organized into five cores. The Vision and Management Core provides scientific vision and oversees the internal operations of the NDHCC and engages with the Complement-ARIE Consortium. The Data Hub Infrastructure Core builds a scalable, secure, and FAIR- compliant repository that facilitates data ingestion, integration, and sharing using a hybrid centralized/federated cloud architecture. The Data Standardization and Harmonization Core creates FUSION CDM—an evolving knowledge graph integrating diverse biomedical ontologies to harmonize terminologies in the NAMs world. This core also develops model credibility metrics aligned with regulatory requirements, creating a strong framework for NAMs validation and qualification. The Analytical Tools and Software Development Core provides standardized pipelines enabling researchers to rapidly generate analysis-ready data from diverse NAM sources and developing predictive models using AI methodologies. The Consortium Coordination and Outreach Core fosters collaboration through participatory activities. These activities include interactive workshops within the Complement-ARIE Consortium, benchmarking competitions for an extended community of researchers, and engagement with constituencies vested in the advances of NAMs technologies. By fostering a NAMs data ecosystem that actively contributes to and engages in NAMs advancements, aligning standards with regulatory needs, enabling validation of experimental results, and providing accessible analytical tools, the NYU-Sage NDHCC will contribute to accelerating NAMs adoption, reducing animal testing, and speeding biomedical discovery.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY In the healthy intestine, the microbiota and intestinal immune system are intimately linked. One of the major regulators of the microbiome is the mucosal antibody, IgA, produced by intestinal B cells, which exerts unique immunomodulatory functions on bacterial communities. Failures in bacterial regulation by IgA has serious health implications, impacting the progression of a wide range of diseases like inflammatory bowel disease (IBD), obesity, cancer, and depression. However, whilst many studies have identified roles for IgA in bacterial regulation, how the presence of the microbiota directs differential programming of local B cell responses towards production of regulatory IgA is poorly understood. Most homeostatic IgA is produced via gut-associated germinal centers (gGCs), microanatomical niches which are essential for B cell and antibody evolution. Although we have previously shown that gGCs support effective selection of microbiota-specific B cell clones, accumulating evidence indicates that fundamentally altered signaling networks govern the dynamics of steady-state gGCs. In our preliminary data we identify composition of the microbiota as a significant modulator of several aspects of gGC responses, suggesting a crosstalk that is established between the intestine, B cells, and the microbiota. We therefore hypothesize that ‘education’ in the intestinal microenvironment by the microbiome fundamentally alters how B cells to evolve in gGCs. We show evidence that the responsiveness of several immunoreceptors is modified following exposure to the microbiome, suggesting that chronic bacterial stimulation broadly desensitizes receptor function and sets lowered activation thresholds. Commensals are perceived by cells specifically through the B cell receptor (BCR) and via generic sensing through Toll-like receptors (TLRs). We present new evidence supporting that sustained stimulation by TLR ligands acts as a signal rheostat, tuning inherent responsiveness of B cell receptor and CD40 signaling networks to regulate permissive entry to chronic gGCs. Consequentially, TLR deficient animals host enlarged gGCs, in direct opposition to inflammation-driven GCs, which are severely compromised in the absence of TLR activation. We propose a model whereby continuous low-level TLR signaling in combination with weak BCR binding could be sufficient to initiate gGCs towards the microbiome, facilitating the selection of a regulatory pool of IgA with broad binding specificity. We will test our hypotheses through use of two specialized imaging approaches, a novel commensal-specific transgenic BCR mouse model, and restricted-diversity microbiomes, to address how exposure to microbial signals tunes the magnitude and specificity of intestinal B cell responses. Our studies will further our understanding of the mechanisms driving dysregulation of the microbiome, important for autoimmunity, cancer, and metabolic disorders. Results from our proposal will also generate valuable insights into the rules governing tissue-specific antibody responses and IgA memory, a rapidly emerging interest area in mucosal infectious disease research.

NIH Research Projects · FY 2026 · 2026-02

Summary Central Nervous system (CNS) perivascular macrophages are part of a group of macrophages names border- associated macrophages (BAM). Most BAM are generated during embryogenesis and maintained by self- division. We developed a genetic system in which the main type of BAM (CD206H) is ablated in the brain. When experimental autoimmune encephalomyelitis (EAE) is induced in these BAM-ablated mice, the disease is much more severe, indicating that healthy BAM are generally protective from neuroinflammatory diseases such as EAE. Given that in the CNS perivascular BAM are located in the perivascular space formed between the endothelium and the astrocyte feet that delimit the blood-brain barrier (BBB), we hypothesize that this unique location endows BAM with the capacity to reinforce the BBB thereby limiting the flow of inflammatory cells into the CNS. In contrast to BAM, monocyte-derived macrophages are not resident of the CNS but swiftly enter into the CNS in diseases such as EAE and multiple sclerosis (MS), together with a large number of other inflammatory myeloid and lymphoid cells. In contrast to what we hypothesize is the function of BAM, monocyte-derived macrophages are known to be part of the pathogenesis of EAE and MS, being considered the main executioners of demyelination through phagocytosis of pieces of myelin. In this R21 application, we propose to test the hypothesis that healthy perivascular BAM contribute to the barrier function of the BBB. We will also determine whether BAM, a subgroup of which express MHC class II, can affect the activation profile of T cells. We propose two specific aims. In Aim 1, we will induce EAE in mice that lack BAM and mice with normal BAM and will monitor daily the inflow of inflammatory cells (myeloid and lymphoid) into the spinal cord of mice. We will inject monocytes labeled at the Ccr2 locus to follow the fate of monocyte-derived CCR2+ macrophages inside the inflamed CNS, and monitor the permeability of the BBB under unstimulated conditions or EAE in mice. In Aim 2, we will focus on the differences that BAM presence or absence would make on the T cell activation state and cytokines produced, We will also bypass the priming in lymph nodes by using the adoptive transfer model of activated T cells and monitor the fate of these T cells in mice with normal BAM versus ablated BAM. Finally, in collaboration with Dr Gabriel Victora, we will use a novel mouse strain, named uLipstic, to label T cells and identify what are the CNS cells that first interact with myelin-reactive T cells. At the end of the proposed studies, we will deliver a clear picture of whether perivascular CNS-resident BAM are an important player in EAE, thus suggesting that reinforcing the BAM compartment could have a beneficial impact in neuroinflammatory diseases.

NIH Research Projects · FY 2026 · 2026-02

Project Summary T lymphocytes are critical for many aspects of immunity to infection and cancer, and they play important roles in autoimmune and allergic diseases where they promote inflammation and help B cells produce antibodies. Given the importance of both CD4+ and CD8+ T cells for many aspects of immune responses in health and disease, it is essential to understand the mechanisms that control their function both from a basic science and translational perspective. T cell function depends on ion channels in the cell membrane which transport charged ions such as calcium in and out of cells. While several ion channel types are known to be required for T cell function, only a small fraction of the hundreds of ion channels and related proteins have been studied in T cells. To address this knowledge gap and to identify potential new drug targets we conducted two forward genetics screens for ion channels in CD4+ T cells using animal models of brain and intestinal inflammation. We identified a putative channel protein called CLNS1A, whose deletion prevents the expansion of antigen-specific CD4+ T cells in mice and thus, their ability to induce inflammation. We had included CLNS1A in our screens because it was initially reported to be a chloride channel or a regulator of such channels. We did not, however, find evidence that CLNS1A affects chloride channel function in CD4+ T cells. Neither does it seem to regulate spliceosome maturation and thus, the splicing of pre-mRNA into mature messenger RNAs in T cells. Instead, our data show that CLNS1A controls DNA repair in activated and rapidly expanding T cells. Moreover, CLNS1A regulates several cell cycle checkpoints, thus allowing T cells to proliferate. CLNS1A controls these functions in CD4+ T cells by regulating the expression of hundreds of genes which are involved in cell cycle regulation and DNA repair. The function of CLNS1A is dependent on the enzyme PRMT5, a protein methyltransferase. Both CLNS1A and PRMT5 bind to the promoters of many genes, thereby regulating their expression. The goals of this proposal are to 1) investigate the effects of CLNS1A on DNA repair and cell cycle regulation in CD4+ and CD8+ T cells, 2) elucidate the molecular mechanisms by which CLNS1A regulates gene expression in T cells that includes the identification of additional CLNS1A binding proteins besides PRMT5, and 3) determine the role of CLNS1A in CD4+ and CD8+ T cell-mediated immune responses to infection and inflammation. Our study will shed new light on the hitherto unknown role of CLNS1A in T cells, determine the molecular mechanisms underlying CLNS1A function and reveal the involvement of CLNS1A in T cell mediated immune responses in health and disease.

NIH Research Projects · FY 2026 · 2026-02

Project Summary Brain motor circuitry is influenced by neurohormonal regulators that underlie energy homeostasis through regulation of food intake (satiety) and physical activity. Leptin is a key player in these incompletely understood interactions. We have shown that leptin boosts striatal dopamine release by increasing the excitability of striatal cholinergic interneurons (ChIs) that regulate dopamine release via activation of nicotinic acetylcholine (ACh) receptors on dopamine axons. We also find that leptin directly excites dopamine neurons of the substantia nigra pars compacta (SNc). Moreover, systemic leptin enhances locomotor behavior in open-field testing. Given the role of the nigrostriatal pathway in motor regulation, highlighted by the motor deficits of Parkinson’s disease, which is characterized by loss of SNc dopamine neurons, our findings suggest that nigrostriatal dopamine is the neural substrate for leptin’s motor enhancing effect. Key aspects of this regulatory process are missing, including how leptin activates ChIs and SNc dopamine neurons, and whether motor activation by leptin is mediated at the level of the striatum or SNc, or both. In Aim 1, we will focus on the cellular level by identifying ion channels involved in ChI and SNc DA neuron activity. Experiments will test possible closure of two different K+ channels (Kv1.3 and TASK-3) as the mechanism by which leptin excites these cells using current-clamp recording in ex vivo striatal and midbrain slices. We will also examine the influence of these channels on evoked dopamine release in slices, monitored using fast-scan cyclic voltammetry. In Aim 2, we will move to the circuit level and determine the extent of dopamine and ACh release in dorsolateral striatum in vivo after leptin administration, with dopamine and ACh detection using genetically encoded sensors (GRAB-DA and GRAB-ACh) with fiber photometry. A key experiment will be to determine whether the motor-enhancing effect of leptin is absent in mice lacking ACh synthesis in striatum. Overall, the cellular mechanisms and circuits examined in this project highlight the role of leptin as a novel regulator of motor output, which may have implications for alternative therapies in Parkinson’s disease, while leptin’s DA-enhancing effects may also be relevant for depression and other neuropsychiatric disorders that are linked to dopamine dysregulation.

NIH Research Projects · FY 2026 · 2026-02

SUMMARY: The physical properties of the cell interior are crucial for the organization and efficiency of biochemical reactions. The highly crowded and non-thermodynamically equilibrated cellular environment can both enhance binding, and impede particle motion, thereby altering the efficiency of biochemical reactions. These effects are particularly pronounced at the mesoscale (10 - 1000 nm), where metabolic and mechanical perturbations can lead to dramatic changes, including transitions to a glassy, solid-like state. These mesoscale biophysical properties also change during normal development, cancer progression, and aging; therefore, it is increasingly imperative to uncover both the mechanisms that control these properties, and physiological consequences of perturbations to them. It is also of great interest to define these properties in organelles including the nucleus, cytoplasm, endoplasmic reticulum and mitochondria. However, this understanding has been hampered by a lack of reliable and high-throughput tools. Our approach to solving this issue involves the use of microrheology, which is the inference of the physical properties of the cell interior from the motion of probe particles. The previous gold-standards were inorganic particles like Q - dots. However, introducing these particles into cells is low-throughput, damaging, and largely ineffective in organisms with cell walls. To overcome this problem, we have developed self-assembling, Genetically Encoded Multimeric particles (GEMs) that massively increase the efficiency and reproducibility of microrheology experiments. We benchmarked GEMs against gold-standard Q- dots and confirmed that they are better, more passive probes for the cytoplasm and nucleoplasm. GEMs are permanently present in cells after inserting the encoding gene, and transform microrheology into a reliable, high-throughput approach. We have developed and validated an initial set of GEMs with diameters of 20 and 40 nm, and targeted them to the cytoplasm and nucleus. This project comprises three aims: 1. Expanding GEM technology (size, color, and surface properties) to enhance versatility and applicability. 2. Targeting GEMs to previously inaccessible organelles, such as the endoplasmic reticulum and mitochondria. 3. Applying GEM technologies to diverse tissues and cell types in animal models of aging. Additionally, we are committed to advancing software tools for data analysis and GEM detection, incorporating machine learning techniques for enhanced efficiency. By investigating an almost entirely unexplored parameter in animal models of aging, this project seeks to discover mechanisms controlling cellular biophysical properties and the consequences of age-related biophysical perturbations. Ultimately, these findings may enable discovery of mechanisms to correct biophysical perturbations, thereby providing a new avenue towards therapeutics that address age-related diseases.

NIH Research Projects · FY 2026 · 2026-02

Maternal immune activation (MIA) is a significant prenatal insult associated with increased risks of preterm birth and neurodevelopmental disorders in offspring. However, it remains unclear how MIA alters fetal and infant brain development during the critical birth transition period, and how these changes influence later neurodevelopmental outcomes. This study will establish a unique cohort of 90 high-risk pregnancies, leveraging advanced neuroimaging techniques, maternal inflammatory biomarkers, and objective infant behavioral assessments to address two specific aims. Aim 1 will identify brain regions sensitive to MIA and characterize how brain development trajectories are disrupted across the birth transition, focusing on attention, salience, and limbic networks. Aim 2 will investigate whether MIA-related brain disruptions mediate the relationship between maternal inflammation and developmental outcomes. By integrating neural, biochemical, and behavioral data, this work will uncover the mechanisms by which maternal inflammation shapes neurodevelopment, identify early biomarkers of child risk, and inform interventions to improve outcomes for high-risk pregnancies.

NIH Research Projects · FY 2026 · 2026-02

SUMMARY The prevalence of Alzheimer’s disease (AD), the most common form of dementia, is expected to triple and reach 13 million in the United States by the year 2050. Despite the public health burden of dementia on an aging population, the etiology of AD is still not well-understood. The interplay between the human virome—the total collection of viruses in and on the human body—and host immunity is linked to complex diseases, including AD. Evidence suggests that viral infectious pathogens, such as certain herpesviruses, promote the development of AD. However, methodological limitations of the relevant epidemiologic studies include: 1) reverse causality due to cross-sectional or retrospective case-control study design or consideration of viral infections in elderly participants; 2) underdiagnoses of infections due to detection of clinically apparent infections only; 3) confounding due to unmeasured infections; 4) lack of consideration of joint or interacting effects of multiple infections; and 5) lack of consideration of potential intermediate phenotypes, such as changes in brain and cognitive health, AD-related biomarkers, and DNA methylation patterns related to accelerated aging. The limitations of these studies render interpretation of their findings difficult, presenting an important research gap we propose to address. Recently developed high-throughput methods enable detection of immune responses to all human viruses. However, no studies conducted comprehensive analysis of antiviral antibodies in human sera for AD-related outcomes. We propose a prospective study that uses three prospective cohorts to identify viral infections associated with brain health, cognition declines, and the risk of AD later in life. We will use VirScan, a revolutionary new technology that uses bacteriophage immunoprecipitation sequencing (PhIP-Seq) for comprehensive serologic profiling of exposure history to all known human viruses. Our pilot work shows viral signatures are stable over time, supporting one-time measurement for long-term analysis. Our prospective case- control study of AD nested in the NYU Women’s Health Study (NYUWHS), a prospective cohort of 14,273 women (ages 35–65) who were enrolled between 1985–1991 and donated blood samples at baseline, will assess both: 1) responses to viral infections in relation to AD risk, and 2) whether viral infections are associated with epigenetic age acceleration and AD-related biomarkers. We will use the Cognitive Reserve (CR) study and the Reference Ability Neural Network (RANN) study, which share 529 healthy participants recruited since 2011 across the adult lifespan, to assess responses to viral infections in relation to longitudinal averages and changes in AD biomarkers, as well as brain and cognitive health measured using magnetic resonance imaging and neuropsychological tests. Our findings promise to discover emerging risk factors for AD, improve risk stratification, direct earlier intervention, and open new areas for prevention.

NIH Research Projects · FY 2026 · 2026-02

Project Summary/Abstract Most children with neurofibromatosis type 1 (NF1), one of the most common inherited neurological disorders in the United States, experience difficulties with large muscle movements. Current methods of measuring gross motor impairment in young children with NF1 are time- and resource-intensive, reliant on coarse scoring from a proxy typically based on the presence or absence of abilities without regard to the quality of function. These limitations hamper counseling in the clinic on the severity of gross motor difficulties, prediction of future function, and guidance on treatment planning. The objective of this K23 proposal is to develop office-based tools to quantify gait in young children with NF1 that reflect overall gross motor impairment and predict future gross motor difficulties. In this prospective observational study of ambulatory children less than six years old with NF1, we will evaluate gait speed as the fastest time to walk 10 meters and interlimb coordination derived from artificial intelligence-based pose estimates from video. We will conduct office-based gait assessments with video, clinical exams, and neurodevelopmental evaluations during routine medical visits at baseline, 12 months, and 24 months at one of the largest NF1 centers in the U.S., the NYU Comprehensive Neurofibromatosis Center. Using this design, our specific aims are to: (1) evaluate how well gait speed and interlimb coordination reflect gross motor impairment compared to currently available neurodevelopmental assessments; (2) determine the test-retest reliability of gait speed and interlimb coordination; and (3) investigate the prognostic ability of gait speed and interlimb coordination to predict gross motor impairment up to two years later. We expect these findings will result in improved developmental surveillance in clinic and inform clinical trial design with the addition of performance-based endpoints. This proposal aligns with the NINDS strategic plan of “seeing more precisely – develop and validate biomarkers and outcome measures that stimulate therapy development and improve patient care.” During this five-year award, Dr. Abreu will complete the following training goals: (1) gain fluency in advanced statistical methodologies for outcome measure development and predictive analyses; (2) deepen knowledge of clinical gait analysis; and (3) grow his skillset in pediatric NF1 clinical trial readiness. Dr. Abreu is ideally positioned to accomplish this work based upon his unique background and a stellar mentorship team, including primary mentor, Dr. Heidi Schambra (leader in quantitative motor assessment in neurological disorders), and co-mentors, Drs. Kaleb Yohay (leader in NF1) and Moriah Thomason (leader in early childhood neurodevelopment). His training program will be enriched by a scientific advisory committee with complementary expertise. This K23 award will advance Dr. Abreu towards his goal of becoming an independent physician-scientist studying quantitative motor assessment in NF1 and other pediatric neurogenetic disorders, including an R01-level submission treating gross motor impairment in early NF1.

NIH Research Projects · FY 2026 · 2026-01

Resident memory T cells (TRM) remain at a site of infection long after disease has been resolved. TRM form a critical first line of defense against re-infection, but TRM can be pathogenic in the context of recurrent autoimmune inflammation. The canonical protein used to identify TRM is the membrane-bound C-type lectin CD69. Naïve T cells up-regulate CD69 within hours of stimulation by type I interferons or antigen recognition, and hence CD69 has long been used as an “early activation marker.” However, TRM are memory cells, and by definition have not been recently activated. It remains unknown why established TRM express high levels of surface CD69. Early after a naïve T cell has been activated, CD69 performs several key functions. First, CD69 retains the T cell in the lymph node by antagonizing sphingosine 1-phosphate receptor 1 (S1PR1), a G-protein-coupled receptor that guides T cell exit from lymph nodes. This causes a T cell activated by cytokines to reside longer in the lymph node to search for its cognate antigen, and a T cell activated by antigen to reside longer in the lymph node to complete its activation. Second, CD69 may amplify signals through cytokine receptors or the T cell receptor. CD69 cross-linking induces elevation of intracellular calcium, and our preliminary data implicate CD69 signaling in activation of Akt and Erk. Our central hypothesis is that there is an inverse relationship between the speed of T cell activation and the ability of a T cell to circulate, mediated by the antagonism between CD69 and S1PR1. Thus CD69+ resident memory T cells stay at likely sites of pathogen re-entry and respond very quickly upon re-infection, while S1PR1+ circulating T cells arrive more slowly but contribute to a sustained response. Consistent with this hypothesis, our preliminary data suggest that early after re-challenge, Cd69-/- TRM fail to recruit inflammatory monocytes efficiently to the skin. Furthermore, we have developed Cd69f/f mice in order to interrogate the role of CD69 specifically in TRM, avoiding confounding effects of CD69 expression in T cell development and initial activation. We will test our hypothesis in two aims. We will define the role of CD69 in skin-resident CD8 TRM at steady-state, asking whether CD69 expression on TRM regulates their numbers, localization, or transcriptional profile at baseline. We will then define the role of CD69 in skin-resident CD8 TRM after re-challenge, assessing changes in leukocyte recruitment and vascular permeability; whether any change reflects changes in chemokine secretion or endothelial adhesion molecules; and whether this in turn reflects altered cytokine secretion or other key properties of TRM.

NIH Research Projects · FY 2026 · 2026-01

Project Summary Sarcopenia is a leading cause of disability and mortality the aging population worldwide, and poses a societal burden, resulting in $18 billion in annual costs in the United States alone. The management of patients with sarcopenia remains challenging, given that diagnosis often occurs at late stages of the disease, when the treatment strategy available are mostly ineffective. Thus, there is a pressing need for non-invasive biomarkers capable of distinguishing normal aging from early-stage sarcopenia, and correlating to functional outcomes such as muscle strength. To address this need we propose the development of innovative tools for the analysis of Magnetic Resonance Imaging (MRI) data. This project aims to explore the feasibility of using MRI, in combination with novel data analysis and modeling technique, to study key features of muscle tissue affected by aging, and that might play a role in the age-related loss of muscle strength. Our specific aims are to (1) investigate the impact of age on shape and structure in thigh muscles, and their contribution to muscle strength, and to (2) develop a novel diffusion MRI framework with heightened sensitivity and specificity to cellular atrophy. This framework can increase the predictive values of muscle strength from diffusion MRI data. The innovation of this project lies in the development of analysis tools that make use of shape information to predict strength. This approach can facilitate the retrospective analysis of existing data and “opportunistic screening” of sarcopenia. Additionally, we propose the development of an innovative framework for the analysis of diffusion MRI data, capable of non-invasive quantification of muscle atrophy. The outcome of this proposal is a set of quantitative MRI tool to investigate muscle quality and structure, and its connection to patient strength and functional status. These tools will be openly shared with the research community, maximizing their impact, and allowing for the detection of early signs of sarcopenia. This, in turn, will facilitate the implementation of targeted and timely interventions that can halt or slow the progression of sarcopenia.

NIH Research Projects · FY 2026 · 2026-01

Project Summary: Alzheimer’s disease (AD) patients, even in the mild cognitive impairment stage, show pronounced memory impairment that correlates with AD pathology in the entorhinal cortex (EC) - hippocampus circuit. Within the EC-hippocampal network, the lateral EC (LEC) and hippocampal area CA1 are most susceptible. Yet, there is a gap in our knowledge of potential cellular targets and pathway-specific neuromodulatory mechanisms for devising effective and translatable early- stage therapeutic strategies in humans. Our study aims to fill this gap by examining the GABAergic microcircuits within CA1, specifically those driven by vasoactive intestinal peptide (VIP+) and cholecystokinin (CCK+) inhibitory neurons (INs) that gate activity from LEC, with a hypothesis that modulating activity in these two circuits can improve LEC-CA1 dynamics and related memory-guided behavior. This hypothesis is bolstered by exciting preliminary data establishing a framework that delineates strong excitation of CA1 pyramidal neurons (PN) dendrites by LEC that is modulated by opposing impacts disinhibition by VIP+ INs and inhibition by CCK+ INs, which in turn may be tuned by cholinergic and cannabinoid modulation, respectively. In this ground-breaking collaboration between a neuroscientist (Basu) specializing in cortico-hippocampal circuit function and a physician-scientist (Masurkar) with expertise in early Alzheimer’s disease- related circuit dysfunction, we will perform a cross-species comparison of GABAergic circuits in area CA1 of AD mouse models and human patients to assess their pathological resilience and vulnerability across disease stages. To achieve our goal of developing translatable and effective targeted therapeutics, we will use a multifaceted approach leveraging our (i) recently acquired in-depth knowhow of LEC-CA1 circuitry, (ii) experience in assessing neural circuit dynamics using slice electrophysiology and in vivo two-photon imaging during behavior, and (iii) expertise in proteomic analysis in post- mortem human patient tissue. Our pilot experiments show that aged AD model mice show smaller LEC-evoked responses and cortico-hippocampal plasticity. In vivo 2P imaging in younger APP-KI shows place cell remapping deficits, and lag in spatial context-dependent memory behavior. Using this groundwork, our study will link AD-related changes in LEC-CA1 excitatory-inhibitory-disinhibitory circuit dynamics with deficits in plasticity, place coding, and associational memory behavior in the recently developed APP-KI AD and more established 5xFAD mouse models. In Aim 1, we will use in vitro opto-electrophysiology in the 2 AD models to evaluate altered LEC-driven excitatory-inhibitory dynamics in CA1 PNs and their rescue efficacy using cholinergic and cannabinoid neuromodulation of VIP+ IN and CCK+ IN activity. In Aim 2, we will apply in vivo 2P microscopy in awake-behaving mice to test that context and odor-cued spatial memory behavior and place cell activity are impaired in AD mice and can be rescued by retuning CA1 activity through chronic neuromodulation of VIP + and CCK+ INs. In Aim 3, we use immunohistology and localized proteomics in human post- mortem brain tissue to test that CA1 VIP+ and CCK+ INs have integrity relative to PNs to be engaged in early human AD. Together, our study will reveal specific neuron types and modulatory mechanisms that warrant future investigation as circuit targets and strategies for more effective early-stage AD therapeutics.

NIH Research Projects · FY 2026 · 2026-01

SUMMARY Schwannomatosis is a rare neurogenetic disorder characterized by the development of Schwann cell tumors, known as schwannomas, which grow along different nerves, causing significant morbidity and pain. There are at least three different types of this condition, based on their genetic etiology and clinical presentation: NF2, LZTR1, and SMARCB1-related schwannomatosis. Recently, LZTR1-related schwannomatosis has emerged as a novel form of this group of disorders, caused by a complex 3-step, 4-hit genetic mechanism involving the concomitant bi-allelic loss of LZTR1 and NF2 somatically. The treatment for LZTR1-related schwannomatosis has been limited to neurosurgery and/or radiotherapy to remove the schwannomas. However, the efficacy of these procedures is hampered by tumor numbers, location, recurrence, and the appearance of new lesions. Pharmacological strategies to treat or prevent schwannoma formation have not yet been discovered, likely due to the lack of preclinical models that allow for the study of the pathophysiology of the disorder and can be used to test experimental therapies. Our laboratory and others have discovered that LZTR1 is a substrate adaptor for the E3 RING Ubiquitin ligase Cullin-3, which binds and promotes the ubiquitination and degradation of the RAS GTPase proteins RIT1 and MRAS. Bi-allelic inactivation of LZTR1 leads to the accumulation of RIT1 and MRAS, promoting the activation of downstream signaling pathways such as RAS/MAPK. In this application, we propose to study the molecular and cellular mechanisms underlying LZTR1-related schwannomatosis by developing a series of cellular and animal models of this rare disease and identifying potential therapeutic strategies. Specifically, in aim 1 we will study the consequences of LZTR1 loss in Schwann cells and progenitors using human and rodent cellular models. We will assess changes in signaling, gene expression, and cellular functions, including their ability to myelinate axons. In aim 2, we will analyze the mechanisms underlying the epistatic genetic interaction between LZTR1 and NF2 loss in Schwann cells. We will conduct single-cell studies to assess changes in the cellular landscape caused by this genetic interaction and determine the schwannoma-forming capacity of LZTR1/NF2 double knockout Schwann cells. Finally, in aim 3 we will assess potential therapeutic interventions for LZTR1-related schwannomatosis by leveraging novel preclinical models of this disorder. Overall, our application aims to bridge a critical knowledge gap in the field by discovering the molecular mechanisms underlying LZTR1-related schwannomatosis, developing unique preclinical models, and testing novel therapeutic interventions in such models. In the long term, our work will provide the experimental groundwork to initiate clinical trials aimed at treating and preventing schwannomas in patients suffering from this condition.

NIH Research Projects · FY 2025 · 2026-01

PROJECT SUMMARY Atherosclerosis, the leading cause of cardiovascular disease related death, is a chronic inflammatory condition incited by the accumulation of low-density lipoproteins (LDL) and recruitment of macrophages in the arterial intima. A better understanding of the role ribonucleoprotein (RNP) granules play in regulating the innate immune system, may reveal important mechanisms underlying this maladaptive inflammatory response in atherosclerosis. We hypothesize that macrophage transformation into a foam cell state, a process that requires transcriptional rewiring, is facilitated by stress granules (SGs). SG formation is increased in plaque macrophages of atherosclerotic mice and can be induced in vitro during cellular cholesterol loading. To test our hypothesis, we using immunohistochemistry observed that the SG protein, G3BP1, is significantly increased in progressing plaques compared to regressing. Using centrifugation, we isolated SGs from bone marrow derived macrophages treated with atherogenic stimuli, and found enrichment of cholesterol efflux transcripts within the SG, suggesting that SGs play a role in cholesterol homeostasis. Using imaging and RNA-seq of macrophages treated with siG3bp1 and Dil-oxLDL, we found that G3bp1 knockdown reduced lipid binding, uptake, macrophage phagocytic capacity, and efflux. Altogether, these data support a role for SGs in dysregulating cholesterol pathways in plaque macrophages during atherosclerosis progression. In this proposal, I aim to characterize stress granule formation in macrophages exposed to atherogenic stimuli in vitro and identify the RNA transcripts and RNA-binding proteins sequestered. By investigating post-transcriptional modifications, I will uncover the mechanism by which transcripts are marked for sequestration or escape from SGs. Additionally, I will use in vivo mouse models of atherosclerosis to determine the temporal kinetics, cellular localization, and quantity of SGs per cell over disease course. I aim to test the therapeutic potential of targeting SGs by perturbing SG formation using (1) G3BP1fl/fl iLysMcre (genetic) and (2) Ldlr–/– with a small molecule inhibitor of SG formation, ISRIB (therapeutic), in atherosclerotic mice and characterize plaque burden. Collectively, the proposed investigation into RNP granules in atherosclerosis, will reveal novel mechanisms of post-transcriptional and innate immune regulation, and provide foundational studies for new therapeutic strategies.