New York University School Of Medicine

NIH Research Projects · FY 2026 · 2026-06

SUMMARY In the United States, Native American communities face the greatest burden of chronic diseases among all ethnic groups and high rates of cardiovascular disease (CVD) incidence and mortality. Elevated disease risk may be in part attributed to arsenic in drinking water, which is a key environmental risk factor among rural households that rely on private wells. Arsenic-related CVD risk may be modified by the biomethylation of arsenic, a pathway that decreases arsenic toxicity and increases urinary excretion. Arsenic methylation efficiency varies between individuals and populations and is influenced by genetic variation. However, the role of pre- and post- transcriptional gene regulatory factors, including DNA methylation (DNAm) and microRNAs, on arsenic methylation efficiency and arsenic-induced CVD is not fully understood. This study will leverage data and biospecimens representing multiple omics layers from the Strong Heart Study (SHS) and Strong Heart Family Study (SHFS), large, prospective, well characterized cohorts of Native American adults with longitudinal data on CVD outcomes and risk biomarkers. The aims of this project are to (K00, Aim 1) determine the relationship between DNAm, arsenic methylation efficiency, and CVD to identify epigenetic biomarkers of arsenic toxicity and arsenic-related disease risk; (K99, Aim 2) determine the effect of genetic variation on DNAm associated with arsenic methylation efficiency to distinguish molecular mechanisms underlying arsenic methylation phenotypes; and (R00, Aim 3) investigate the role of microRNAs in mediating the association between arsenic exposure and methylation efficiency and CVD risk biomarkers to elucidate molecular processes underlying arsenic-related CVD. To accomplish these aims, Dr. Bozack will be receive mentorship from experts in environmental, molecular, and genetic epidemiology. In the K99 phase, Dr. Bozack will also receive training in bioinformatics and machine learning, including approaches for developing DNAm biomarkers and investigating gene-epigene interactions. In the R00 phase, she will generate circulating microRNA expression data and will further apply her training in clustering and network analyses to identify microRNA signatures linking arsenic exposure and methylation efficiency to CVD risk. The proposed training and research will enable Dr. Bozack to establish an independent research path focusing on biomarker development and applying multiple omics approaches to environmental molecular epidemiology. Furthermore, mentorship and career development activities will facilitate her transition to an independent researcher. Overall, this study will advance the understanding of gene regulatory factors involved in arsenic-related CVD risk through a multiple omics perspective, which is necessary to unravel the relationship between environmental and biological factors involved in the etiology of complex diseases. Findings will contribute the development of noninvasive biomarkers of arsenic-related CVD risk and may aid in targeting arsenic mitigation and public health interventions.

NIH Research Projects · FY 2026 · 2026-06

Project Summary Prostate cancer affects 1 out 8 men and is the second deadly cancer in the United States. Accurate detection of clinically significant disease is essential for guiding treatment decisions. Diffusion-weighted Imaging(DWI) is a key component of multiparametric MRI for prostate cancer detection and risk stratification. However, current clinical DWI protocols are limited by severe geometric distortion, coarse native spatial resolution and lengthy scan time especially when high b-value DWI is needed. These limitations impair diagnostic accuracy and hinder the clinical use of advanced diffusion models such as diffusion kurtosis imaging (DKI), which may provide direct insight into cancer tissue identification. The goal of this K99 project is to develop and validate a novel diffusion MRI framework to overcome these limitations and enable fast, high-resolution, distortion-free imaging of the prostate within clinically feasible scan times. This framework integrates spin and gradient echo acquisition with PROPELLER-based sampling, which inherently corrects for B0 inhomogeneity and motion induced phase variation. In Aim 1, we will implement and optimize the sequence and demonstrate distortion-free DWI with true high spatial resolution and true high b-value in under 5 minutes. In Aim 2, we will develop advanced reconstruction methods using low-rank subspace modeling and deep learning to enhance image quality and enable robust calculation of quantitative metrics such as ADC and DKI parameter maps from multi-b-value data. In Aim 3, we will evaluate the diagnostic performance of this technique in patient cohort undergoing clinical prostate MRI and biopsy, comparing image quality, PI-RADS scores, and correlation with Gleason grade to DWI derived quantitative metrics. This work will address several critical unmet needs in prostate MRI: reducing scan time, eliminating distortion near the rectum and bladder, improving the visualization of small or recurrent lesions with high-resolution acquisition, and enabling advanced quantitative modeling. The proposed framework not only has the potential to significantly improve prostate cancer detection, but also to support accurate lesion localization and targeted biopsy. Beyond the prostate, the techniques developed here can be adapted to other anatomies affected by distortion in the pelvic region, including the bladder and rectum. During the mentored K99 phase, the PI will receive dedicated training in sequence design, deep learning image reconstruction, cancer biology, diffusion MRI based biomarker, clinical translation, biostatistics, lab management, mentoring, teaching, and grant writing, for the transition to independence. Successful completion of this project will deliver a clinically impactful imaging solution that improves the accuracy, confidence, and efficiency of prostate cancer diagnosis, while also establishing a foundation for an independent research program focused on advancing motion-robust, quantitative MRI for improved diagnosis and precision imaging.

NIH Research Projects · FY 2026 · 2026-06

Project Summary Metastasis is the leading cause of cancer-related death yet its molecular mechanisms, especially at the level of mRNA translational regulation and reprogramming still remain poorly understood. Our recent work has identified DAP5, a novel translation initiation factor, as a key player in selective mRNA translational reprogramming that is essential for metastasis. We recently showed that DAP5 along with novel cap-binding protein eIF3d, directs the selective translation of mRNAs involved in metastasis, the epithelial-to- mesenchymal transition (EMT) and cancer cell survival, but is not essential for primary tumor growth. Our unpublished data herein demonstrates that DAP5 is a novel dual m6A-specific mRNA translation initiation factor and a novel component of the m6A mRNA methyltransferase “MACOM” complex, directing 3’ untranslated region m6A modification of EMT, survival and metastasis promoting mRNAs in the nucleus which DAP5 then directs the translation of in the cytoplasm with m6A writer/reader METTL3. Our findings are highly significant and novel because we have discovered an exciting new mechanism by which selective m6A mRNA modification and translation occurs to drive breast cancer metastasis and metastatic cancer cell survival. We will test the hypothesis that in the metastatic setting, DAP5 plays a dual role, regulating both nuclear selective m6A mRNA modification as a unique metastasis mRNA-specific component of the m6A modification MACOM complex, and in the cytoplasm as a key decoder of m6A-dependent mRNA translation that is essential for EMT, and metastasis and survival of established metastases, but not for primary tumor growth. Our data suggest that in the nucleus, DAP5 replaces METTL14 in the MACOM complex, creating a "metastasis methyltransferase complex" that selectively m6A methylates mRNAs involved in metastatic progression that are then translated by DAP5 in concert with eIF3d and m6A reader METTL3 in the cytoplasm. Three Specific Aims were developed to investigate how DAP5 orchestrates selective m6A modification and translation required for metastasis, and to explore in animal models its metastasis translation functions. In Aim1 we will fully characterize the cytoplasmic and nuclear m6A methyltransferase protein complexes of DAP5 and its binding partners. In Aim 2, we will characterize the functional role of DAP5 in regulating m6A mRNA modification and translation. In Aim 3 we will characterize how blocking DAP5 interactions with the m6A methyltransferase complex or altering its nuclear/cytoplasmic localization inhibits selective m6A mRNA modification and mRNA translation and metastasis. Animal (murine) experimental models are currently still the gold standard with no realistic alternatives. For metastasis studies that test tumor cell EMT, invasion, vascular intra and extravasation, and recolonization at distant tissue sites, organoid culture development in this area is nascent and not yet representative of the natural process. Consequently, this proposal must still use (limited) animal metastatsis models.

NIH Research Projects · FY 2026 · 2026-06

PROJECT SUMMARY There is a fundamental gap in our ability to monitor and modify vocal behaviors that lead to phonotrauma in real-world settings, creating a critical barrier to effective voice disorder treatment. While voice therapy can effectively treat these disorders when patients consistently follow therapeutic guidelines, success is limited by the inability to objectively measure and modify vocal behaviors outside the clinic. Current voice dosimetry technologies, though valuable for research, remain impractical for clinical use due to being cumbersome, visibly obtrusive, and prohibitively expensive. This project will transform clinical voice assessment and treatment by validating a novel wireless ambulatory voice evaluator (WAVE) that integrates miniaturized sensors to capture voice and respiratory data in a discrete design about the size and weight of a U.S. quarter. The goal is to move voice dosimetry from the research lab to the clinic, enabling accurate real-world monitoring that provides actionable insights to clinicians and patients. This contribution will revolutionize the treatment of dysphonia by enabling, for the first time, widespread objective monitoring of vocal behaviors outside the clinic, shifting the paradigm of clinical management of voice disorders. Guided by strong preliminary data, this research will pursue three specific aims: 1) Optimize the WAVE wearable's real-time algorithms for accurate on-device vocal dose calculations, 2) Validate the novel WAVE device to enable accurate and scalable measurement of the Lombard effect in both laboratory and real-world environments, and 3) Validate respiratory monitoring capabilities of the WAVE for identifying disordered vocal behaviors. The approach is innovative because it represents the first wireless, multimodal system for voice dosimetry that integrates voice, environmental sound level, and respiratory monitoring in an unobtrusive wearable device suitable for extended use during daily activities. The successful completion of this work will provide voice clinicians with an evidence- based tool that enables objective documentation of patients' voice use patterns, allowing more informed clinical decision-making and targeted therapeutic interventions. Ultimately, this research pathway will improve therapeutic outcomes and reduce the substantial public health burden of voice disorders through improved monitoring of vocal behaviors and proactive prevention in at-risk populations.

NIH Research Projects · FY 2026 · 2026-06

PROJECT SUMMARY/ABSTRACT The discovery of the mutations that commonly drive cancer has revolutionized cancer research and spurred the development of novel treatments. However, current genetic testing methods physically take hours to perform and clinically often take days to weeks to return results. Consequently, information about cancer- driving mutations is rarely available during cancer surgeries whose time must be minimized for safety. Thus, the past two decades of genetic discoveries have had little impact on cancer resection surgeries that are a primary treatment for many types of cancer. This project aims to bring the era of molecular-genetic information into the operating room, not just at one timepoint, but in a manner that is rapid and cost- effective to repeat across many tissue samples throughout a cancer resection surgery. Specifically, we will develop a method for ultra-rapid droplet digital PCR (ddPCR) that can repeatedly and accurately quantify cancer-driving mutations in tissue samples to both provide surgeons with a molecular profile guiding overall resection strategy (for example, distinguishing low- versus high-grade tumors), and to aid surgeons in maximally resecting tumor tissue while minimizing resection of healthy tissue. ddPCR is an established technology for targeted quantification of mutation burdens with high sensitivity, but standard ddPCR takes 3 hours to perform. We previously developed an ultra-rapid ddPCR method that combines ultra-rapid DNA extraction in 4 minutes with ultra-rapid ddPCR thermal cycling in only 3 minutes while achieving the same performance as standard ddPCR to detect tumor cell percentages as low as 0.1% and < 10 tumor cells/mm3. However, our current method is not scalabe as it requires many manual steps. In this project, we will: 1) develop a microfluidic device that performs all steps of ultra-rapid ddPCR in one chip to profile 8 tissue samples in parallel in only < 15 minutes; 2) create multiplex ddPCR assays spanning most common cancer hotspot mutations; 3) implement the device and assays in the operating room for low-grade glioma brain tumors, followed by comparison of results to clinical-grade assays and high-fidelity sequencing. We have assembled an interdisciplinary engineering and clinical academic team that will work closely with our industrial partner Wainamics, a company with extensive experience designing commercial microfluidic devices and biosensors. This academic-industrial partnership will ensure that our device is designed for scalable and cost- effective manufacturing, and that it meets industry-standard testing metrics for future regulatory requirements. As such, the device we develop will be ready for advancement to commercialization immediately after completion of this project. Our development of a “commercialization-ready” microfluidic device for unprecedented speed and scale in quantifying mutation burdens in tissue samples will unlock a new dimension in how cancer resection surgeries are performed. Our technology will likely also find utility in many other areas of medicine that benefit from point-of-care diagnostics.

NIH Research Projects · FY 2026 · 2026-06

PROJECT SUMMARY/ABSTRACT Effective immune responses to infection with influenza and many other viruses require the production of neutralizing antibodies. Besides protection from viruses and other infectious pathogens, antibodies mediate disease in the context of allergies, including allergic asthma and food allergies, and many autoimmune diseases. Neutralizing antibodies are produced by plasma cells that develop from B cells in draining lymph nodes of infected organs such as the lung. Antibody production by B cells requires help from a specific subset of T cells called T follicular helper (Tfh) cells. The development of Tfh cells is regulated by transcription factors such as Bcl6 that drive the expression of genes required for Tfh cell functions. We previously reported that Tfh cell development is dependent on the influx of calcium ions through calcium release-activated calcium (CRAC) channels. CRAC channels are formed by ORAI1 and ORAI2 proteins and activated by STIM1 and STIM2 molecules. Deletion of these proteins in T cells abolishes calcium influx and suppresses the expression of transcription factors, costimulatory molecules and chemokine receptors required for Tfh cell development and function. The mechanisms by which calcium signals regulate Tfh cell development, however, are not well understood. In experiments leading up to this proposal, we discovered that abolishing CRAC channel function strongly affects chromatin accessibility in T cells during Tfh cell development and thus, the ability of transcription factors to regulate gene expression. Closed chromatin regions in CRAC channel-deficient Tfh cells were strongly enriched for binding sites of transcription factors belonging to the Ets family. The role of these factors in Tfh cells is largely unknown. Genetic deletion of one Ets family member whose binding sites are located in chromatin regions opened and closed in a calcium dependent manner resulted in impaired Tfh cell development, B cell maturation and antibody production after influenza infection. The goals of this proposal are to determine how calcium signals control the activation of this Ets family transcription factor and how this factor regulates the process of Tfh cell development. Moreover, we will investigate the role this factor in different aspects of humoral (that is antibody-mediated) immune responses to infection using animal models and protocols to study human Tfh cell function. Our project is both innovative and significant because the role of Ets family transcription factors in Tfh cells is poorly understood. The effects of deleting the Ets family transcription factor we identified on Tfh cell development are very strong, suggesting that it plays an important role in humoral immune responses. A better understanding of Tfh cell development is essential to devise strategies to improve antibody responses to vaccination, and potentially also to limit the production of pathological antibodies in the context of autoimmune diseases.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY Embryonic development culminates with an astonishing number of terminal differentiation cellular states. Transcription factors (TFs) bind to specific DNA sequences in the genome and are key regulators of gene transcription responsible for generating cell diversity. TFs are grouped in families with similar DNA binding preferences and sometimes similar activation or repression domains, yet they perform different functions during cell differentiation. Consequently, how different TFs of the same family bind and regulate gene expression is poorly understood. Hox genes code for homeodomain (HD) TFs, the second largest TF family in the mammalian genome. Vertebrate HOX TFs are divided into anterior (HOX1-5), central (HOX6-8), and posterior (HOX9-13) paralog groups. In vertebrates, Hox genes pattern various developing tissues. Notably, spinal cord neuronal diversity requires Hox gene activity along its rostro-caudal axis. The role of Hox genes in organizing the spinal cord presents an interesting conundrum. The limb-innervating expression program is controlled by central (HOX6 & HOX8) HOX TFs at the brachial level and posterior (HOX10) HOX TFs at the lumbar spinal cord. Thus, HOX TFs with different DNA sequence preferences induce a similar motor neuron fate. Meanwhile, the posterior HOXC9 induces thoracic fate. Thus, two posterior group genes, Hoxc9 and Hoxc10, induce different spinal cord fates. In agreement with their genomic cluster position, Hox13 paralogs are expressed late during development, distally, and in posterior regions. This application aims to understand how the mammalian posterior group Hox TFs diversify their function to pattern the spinal cord. Aim 1 will dwell more on the protein domain and specific HOX amino acids in Hoxc9 and Hoxc13 that mediate their ability to bind to inaccessible chromatin and DNA residence time. Aim 2 will take a complementary machine learning approach using ChIP-exo data coupled with chromatin features to distinguish individual pioneer Hox binding sites from non-pioneer sites. Aim 3 will investigate how the very variable N-terminus controls the transcriptional output.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY/ABSTRACT Myeloid sarcoma (MS) is a subtype of acute myeloid leukemia (AML) found in ~5-10% of patients. In MS, myeloid blasts form solid tumor-like, invasive masses in multiple extramedullary sites, including the skin, the lymph nodes, and the gastrointestinal tract. MS is a heterogeneous disease that is clinically unified by its poor survival outcomes, with almost inevitable relapse if treated with standard cytotoxic chemotherapy. Survival rates for MS patients are dismal, with a 5-year overall survival rate below 20%. Such patients are excluded from AML clinical trials, making the introduction of novel therapies in MS a clinical emergency. In the last several years, we have initiated an extensive transcriptomic (bulk and single cell RNA sequencing), genomic (whole genome and mutant panel sequencing) and spatial mapping of human MS. Our analysis included samples at diagnosis, matched bone marrow (BM) and extramedullary site collections, and, in some cases MS samples from a number of extra- medullar sites from the body of the same patient. Our data reveal: a) site-specific extramedullary clonal tumor evolution, including the presence of site-specific, “solid tumor-like” mutations (APC, MITF, MTOR), b) the over- representation of RAS pathway mutations (NRAS, KRAS, PTPN11, CBL), c) RAS/ERK pathway activation (by phospho-ERK1/2 activation in AML blasts), and, d) changes in the cellular and transcriptional landscape suggestive of a gradual transition to a solid tumor environment (by upregulation of EMT-like, adhesion, apical junction genes), and, e) genetic and pharmacological targeting of the RAS/ERK pathway leads to a significant reduction in tumor burden. These findings introduce the hypothesis that myeloid sarcoma is characterized by unique mutational signatures, aberrant gene expression, and immunological adaptations leading to immune escape and the eventual emergence of a “solid-tumor”-like myeloid blast that has the ability to expand outside of the bone marrow (BM). To address this hypothesis, we will initially focus on mapping myeloid sarcoma ultra- structure and understanding the molecular mechanisms of the adaptation to a solid microenvironment. Also, we focus on the RAS/MEK/ERK pathway that is activated in the majority of MS patients and test whether its inhibition constitutes an “Achilles heel” of this treatment-refractory AML subtype, with a future goal to provide data-driven support for the design of the first frontline trial for MS patients. This is the first large-scale study in myeloid sarcoma, combining genomic, transcriptomic, and spatial mapping of the extramedullary disease. It is also the first study that proposes spatial imaging, generation of novel MS animal models, establishment of PDX models, and pre-clinical testing of new therapy protocols in this devastating disease.

NIH Research Projects · FY 2026 · 2026-05

Abstract. Oxidative stress is a key factor in many inflammatory airway diseases, driven by redox dysregulation. Cigarette smoke, a major contributor, induces reactive oxygen species (ROS) accumulation, disrupting redoex homeostasis and upregulating pro-inflammatory pathways. While the gut microbiome’s influence on host redox status and antioxidant capacity is well documented, the role of the lung microbiome in oxidative stress has been less clear, despite observed lower airway dysbiosis in many inflammatory diseases. Recent research, including data from us, indicates that the lung microbiome is functionally active and can directly influence the metabolic landscape of the lower airways. Enrichment of anaerobic bacteria such as Veillonella and Actinobacteria, along with metabolites like glutathione disulfide, is associated with worsening pulmonary function and symptoms in inflammatory lung diseases, such as chronic obstructive pulmonary disease (COPD). This suggests that microbial metabolites contribute to disease pathophysiology. Many oral commensal bacteria utilize sulfur-containing compounds, and their enrichment in the lower airways, observed in early-stage COPD patients, may impact the local sulfur pool. This can alter crucial sulfur compounds, including sulfur-containing amino acids, reactive sulfur species, and thiol antioxidants, which are vital for redox signaling and oxidative stress modulation. Our central hypothesis is that the aspiration of oral commensals alters sulfur metabolism and shifts sulfur compound abundance in the lungs, contributing to redox dysregulation and increased susceptibility to oxidative stress, leading to inflammation. To investigate this, we propose two specific aims: 1.) Assess if altered sulfur metabolism is associated with the enrichment of oral commensals and increased oxidative stress in the lower airways, using samples already collected from a human cohort; and 2.) Evaluate the microbial contribution to lower airway sulfur compounds and oxidative stress in a preclinical mouse model. We hypothesize that introducing these bacteria will decrease lower airway abundance of sulfate, increase total sulfide, and cause heightened oxidative stress and subsequent inflammation. This research aims to provide proof of concept for the role of the lower airway microbiome in oxidative stress injury, potentially present in early inflammatory airway diseases. Our findings will support larger prospective and longitudinal studies, which will be key to proving that these microbial metabolic pathways are active in the lower airways and amenable to targeted interventions.

NIH Research Projects · FY 2026 · 2026-05

SUMMARY Monoclonal antibody therapy for severe COVID-19 and for prophylaxis in immunocompromised individuals was initially of great value but was sidelined by the rapid emergence of virus variants with mutations in the spike gene that rendered the antibodies ineffective. Receptor decoys offer a means to overcome this problem. Because the viral spike protein needs to conserve its high affinity for ACE2, there is a high genetic barrier for the virus to escape from neutralization by the decoy. The project will develop vectored immunoprophylaxis (VIP) in which high affinity ACE2 receptor decoys will be expressed by adeno-associated virus (AAV) and lentiviral viral vectors. These will be used to protect against and to treat SARS-CoV-2 infection. The decoys consist of the extracellular domain of ACE-2 fused to a truncated immunoglobulin heavy chain Fc region. The “microbody” neutralizes the virus by binding to the viral spike protein and will be active against all variants. Because the decoys are composed entirely of human-derived protein components, they will be well-tolerated by the human immune system. The decoys will be optimized to increase their affinity for the spike protein and will be produced with Fc regions that alter their tissue localization, half-life, antiviral activity and antibody effector functions. The decoys will be tested as recombinant protein for prophylactic and therapeutic efficacy in ACE2 transgenic mouse and hamster models against a panel of SARS-CoV-2 variants. Tissue localization and half-life of vector-expressed decoy proteins will be determined by live-imaging of decoy–luciferase fusions. Long-term protection against infection will be established with decoy-expressing AAV and lentiviral vectors in mice and hamsters by intranasal instillation and intramuscular injection. The animals will then be challenged with live virus up to a year post- administration. Serum and lung concentrations of the decoy will be measured and the host antibody response to the decoy protein will be tested. An optimized decoy will be designed based on the findings obtained with modified decoy proteins and its effectiveness will be studied in rhesus macaques, a model that closely resembles humans. The decoy approach will be valuable for rapidly establishing long-term protection, and will be of value to immunocompromised individuals for whom vaccination is less effective. The approach offers an off-the-shelf means with which to rapidly protect the population in the event of a novel zoonotic coronavirus pandemic. The lessons learned will be broadly applicable to other viruses for which a decoy receptor can be generated.

NIH Research Projects · FY 2026 · 2026-05

Project Abstract Understanding the evolution of regulatory DNA has been impeded both by the lack of functional genomics data available outside of a select group of organisms, as well as by the barriers to implementing genome engineering in diverse organisms for functional analysis. Given the low conservation of the genomic regulatory landscape, this presents a serious impediment to studying genome evolution and limits the value of a phylogenetic approach to understanding human genomic function. We recently developed the Big-IN genome engineering technology to rewrite large genomic loci in-place through delivery of DNA payloads upwards of 160 kb. Here we propose a new synthetic regulatory genomics approach for characterization of the regulatory function of genomic sequence across a phylogenetic tree. We will analyze the activity of a set of model loci in mouse embryonic stem cells by delivering orthologous sequences from 5 vertebrate species. We will employ two strategies to: (i) deliver larger regions (up to 160 kb) including the full gene replacing full orthologous mouse locus; and (ii) combinatorially assess pairs of shorter (~1 kb) candidate enhancer sequences. These data will open a novel approach to understanding genomic regulatory syntax through phylogenetic analysis, as well as a bridge to direct functional assessment of human disease-relevant loci.

NIH Research Projects · FY 2026 · 2026-05

Women who inject drugs (WWID) in the United States experience disproportionately high rates of HIV due to vulnerabilities related to drug use and sex. Despite the proven effectiveness of Pre-Exposure Prophylaxis (PrEP) in preventing HIV, its uptake among WWID remains critically low, in part due to mistrust and negative perceptions about the healthcare system among this population. This project introduces PrEP-RISE, a multi-level intervention designed to improve PrEP uptake and persistence among WWID by addressing hesitations about medication and negative attitudes toward this population. Building on our previous research and leveraging the participatory method of Photovoice (PV), the intervention integrates targeted PrEP education during PV sessions to empower WWID, build trust, and provide warm handoffs to same-day PrEP care at non-traditional healthcare settings. Negative perceptions about WWID will be addressed through PV exhibitions showcasing participants' experiences and suggestions for change, fostering dialogue and empathy among key stakeholders, such as healthcare providers and law enforcement. Guided by the Situated Information-Motivation-Behavioral Skills (slMB) model and intervention development frameworks (ORBIT, 6SQulD), this study will refine and evaluate PrEP-RISE through an exploratory randomized controlled trial involving 116 WWID and 100 community members. The study will assess feasibility, acceptability, and preliminary efficacy in increasing PrEP uptake and persistence among WWID and measure any change in attitudes about this population among community members. This R34 proposal aligns with NIDA priorities to reduce HIV rates and improve health outcomes for high-risk groups, while contributing to the evidence base for multi-level, participatory interventions in real-world settings.

NIH Research Projects · FY 2026 · 2026-05

Project Summary Ischemia with no obstructive coronary artery disease (INOCA) is a chronic disorder that is associated with angina, dyspnea, physical limitation, impaired quality of life, and elevated risk for cardiovascular morbidity. Coronary microvascular dysfunction (CMD) is a key mechanism of INOCA, but pathogenesis and factors associated with symptom severity are not well understood. Inflammation is prevalent in patients with CMD and may mediate vascular dysfunction and ischemia. However, it remains unknown whether inflammatory pathways are upregulated in coronary endothelium, to what extent endothelial abnormalities are systemic rather than localized to the coronary arteries, and whether endothelial dysfunction correlates with symptoms. Inflammation may be a driver of variability of symptoms in patients with CMD and could ultimately serve as a therapeutic target. We propose a complementary set of studies in 125 patients with INOCA who undergo invasive coronary function testing to: (1) directly harvest coronary artery endothelial cells and evaluate transcriptional profiles in individuals with and without CMD; (2) assess transcriptional profiles of brachial vein endothelial cells associated with CMD in INOCA; and (3) characterize relationships between endothelial transcriptional signatures and symptoms, quality of life, functional capacity, and physical activity at baseline and 1-year follow-up. We hypothesize that: (1) coronary endothelial cell transcriptional profiles from participants with CMD will demonstrate pro-inflammatory signatures, (2) transcriptional profiles of coronary artery and brachial vein endothelium are highly correlated in patients with INOCA and a score derived from differentially expressed brachial vein endothelial transcripts will identify individuals with INOCA due to CMD, and (3) coronary and brachial vein endothelial transcriptional profiles will identify participants with a high symptom burden and diminished functional capacity at baseline and 1-year follow-up. Transcriptional profiling is an unbiased approach that also permits us to explore pathways that are not related to inflammation in the endothelial cells of patients with and without CMD. The proposed study will be the first to collect human coronary endothelial cells and evaluate signatures of vascular inflammation in patients with INOCA with and without CMD, to correlate endothelial transcriptional signatures in coronary artery and peripheral veins in INOCA, and to evaluate correlations between endothelial transcriptional signatures and symptoms, physical activity, and functional capacity over time. Our results will provide critical insights into INOCA pathogenesis and identify patterns of endothelial transcription associated with symptomatic disease that may serve as the basis for novel diagnostics and precision medicine strategies for patients with INOCA. Ultimately this work may open new avenues of research into therapeutic targets for the treatment of CMD in INOCA.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY The prevalence of monoclonal gammopathy of undetermined significance (MGUS), a clinically asymptomatic bone marrow (BM) clonal plasma cell disorder, increases with age and is present in 5% of individuals over the age of 70 years. The risk of transformation to multiple myeloma (MM), a cancer requiring therapy due to clinical symptoms such as bone lesions, renal impairment, bone marrow suppression and frequent infections is approximately 1% per year. Currently no therapeutic intervention is offered to individuals with MGUS, instead they are monitored closely so that chemotherapy may be given swiftly if there is evidence of disease progression. Epidemiological and animal models link obesity with the development of MGUS and the transition from MGUS to MM. Clonal MGUS/MM cells are reliant on interactions with the BM microenvironment for cell growth and survival. Recent murine studies have shown that obesity and the resulting increase in BM adipocytes creates a permissive BM microenvironment enabling clonal MGUS/MM cells to survive and proliferate. The success of incretin mimetics in decreasing obesity rates and improving the prevalence of obesity-related diseases opens up the possibility that their use may be able to decrease the risk of MM progression, decrease the incidence of MGUS and the overall population burden of plasma cell dyscrasias. In order to investigate this, we will utilize two murine models of disease; one where MM does not develop in the normal fed state, but when animals are fed a high fat diet the BM becomes permissive and disease develops; the other where the BM is permissive and MM develops independent of diet/weight. We will determine whether weight loss alone, and/or treatment with incretin mimetics reduces the disease incidence and burden. In the same models we will determine the effects of weight loss and incretin mimetics therapy on the cellular composition of the BM microenvironment, including tumor cells, immune cells, adipose cells, and niche cells and determine how the permissive microenvironment is normalized following intervention. We will confirm findings and further define biological effects using a functional in-vitro model. Finally, we will determine if any differences are observed between the two main incretin mimetics classes, GLP-1 and dual GLP-1/ GIP-1 receptor agonists. The resulting data will provide supporting evidence for the development of clinical interception studies of incretin mimetics for individuals with MGUS with the aim of decreasing the amount of disease and the risk of transformation to MM.

NIH Research Projects · FY 2026 · 2026-05

Summary: Neuroimaging and histopathology represent two cornerstone methodologies in the study of age-related cognitive impairment and dementia, each offering unique and complementary insights into underlying disease mechanisms and therapeutic strategies. With the advancement of noninvasive imaging techniques aimed at probing the causal pathways and enabling robust early diagnosis of Alzheimer’s disease (AD) and AD–related dementias (ADRD), there is a growing need for postmortem validation studies to confirm the pathological underpinnings of early imaging biomarkers – particularly those related to vascular contributions to cognitive impairment and dementia (VCID). Although postmortem MRI has emerged as a valuable bridge between imaging and pathology, significant technical and methodological challenges persist. This workshop aims to foster the advancement and sharing of cutting-edge technologies, methodologies, and biomedical materials that bridge human neuropathology with neuroimaging research. By capitalizing on rare post-mortem data, the event seeks to deepen our understanding of the pathophysiological processes underlying imaging markers of AD/ADRD. We are requesting funds to support the “Tools and Resources to Understand Pathophysiology with Post-mortem Studies of in vivo Neuroimaging Findings in AD and ADRD” workshop which will take place on August 13-14, 2026, in New York University (NYU) Grossman School of Medicine, New York. The workshop has three specific aims. Aim 1: Bring together thought leaders and experts in the area of post-mortem AD research to advance the field and accelerate the pace of discovery; Aim 2: Foster career development in the field of neuroimaging and neuropathology of age-related dementias, supporting recruitment of new ideas and innovations in this uniquely growing research discipline; and Aim 3: Raise public awareness of and communicate the value of new tools, resources, and biomaterials of neuroimaging and neuropathology research in AD and ADRD to a broader audience. To achieve these aims, the program includes: (i) optimized protocols for postmortem imaging and histopathology; (ii) multidisciplinary topics—including forensic medicine—addressing postmortem interval (PMI) and fixation effects; (iii) daily presentations by Early Career Investigators and trainees selected from abstracts; (iv) new ideas and emerging leaders in VCID research from both in vivo and pathology perspectives at four dedicated panel discussions; (v) hands-on training and demonstrations of advanced tools developed across collaborative sites, including hemisphere imaging, multi- contrast/multi-scale registration, and proteomics; and (vi) shared access to pre- and postmortem MRI data and digital biomaterials for the research community. This unique workshop will serve as a vital forum for idea exchange, fostering new collaborations, and cultivating the next generation of postmortem researchers. Additionally, it aims to advance the translation of ex vivo findings into clinical diagnostics and therapeutic strategies that contribute to the prevention and treatment of Alzheimer’s disease.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY This project aims to uncover the circuit and computational mechanisms that support olfactory perception. Odors evoke spatially distributed patterns of activity across olfactory bulb (OB) glomeruli, which in turn drive temporally structured responses in mitral and tufted cells (MTCs), the OB’s output neurons. These responses are shaped by local inhibitory circuits before reaching higher-order regions such as the piriform cortex (PCx). However, how spatiotemporal OB activity is organized, transformed by local interactions, and decoded by the PCx remains unclear. I will combine two-photon calcium imaging with fast GCaMP8 indicators, patterned optogenetics, and large-scale silicon probe recordings to study these dynamics in awake mice. Aim 1 (K99 phase) will determine how glomerular input and MTC output sequences are structured during odor responses. I will test whether the temporal order of glomerular activation predicts MTC excitability, shaped by lateral inhibition. I will map functional glomerulus to MTC connectivity and relate temporal features to odor tuning. Aim 2 (K99) will probe how recurrent MTC interactions shape odor representations. Using a novel all- optical method combining 2P stimulation and imaging, I will characterize how MTCs influence each other based on tuning similarity. I hypothesize that recurrent motifs enhance similarity among similarly tuned MTCs and decorrelate dissimilar ones. In Aim 3 (R00) I will extend this survey to the cortex and determine how OB output is integrated by PCx and modulated by experience. I hypothesize that MTCs with similar odor tuning and timing preferentially converge onto shared PCx targets, and that this convergence is shaped by Hebbian-like learning. I will test this with two-photon imaging of glomerular odor tuning, optogenetic stimulation of targeted glomeruli and large-scale PCx recordings and examine how repeated odor experience modifies the structure of OB to PCx functional connectivity. This work will define how spatiotemporal odor codes are transformed from OB to PCx and how experience refines this transformation. The K99 phase will develop circuit mapping and all-optical methods (Aims 1–2); the R00 phase will expand my focus to PCx decoding and plasticity (Aim 3). These studies will provide fundamental mechanistic insight into sensory computation and provide me training in advanced techniques for recording and manipulating neural activity, as well as computational expertise. These research goals will be achieved by direct guidance from my mentors, Dr. Dmitry Rinberg and Dr. Gyorgy Buzsaki, my postdoctoral committee, as well as the collaborative environment at NYU. My training plan provides a detailed strategy to acquire technical, computational, and conceptual skills that are crucial for these proposed experiments. Importantly, these skills will also serve as the foundation of my independent laboratory, focusing on the transformation from sensory processing to behavior.

NIH Research Projects · FY 2026 · 2026-05

Summary The goal of this grant is to understand the regulation of SHH-driven hair follicle neogenesis (HFN) in adult wounds. While much research focuses on wound healing, scarring, particularly from burns, trauma, and surgeries, remains largely overlooked. Scarring affects over 50% of the U.S. population, with 50 to 80 million new scars formed annually, resulting in significant cosmetic, psychological, and social burdens. Yet, no effective anti-scarring therapy currently exists. We previously developed a model in which large wounds in mice can lead to efficient hair follicle regeneration, opening the door to understanding the molecular mechanisms of HFN. Our lab has identified Sonic Hedgehog (SHH) as a critical factor in determining whether wounds heal with hair follicle regeneration or fibrosis and how SHH interacts with WNT and BMP signaling pathways for successful HFN. These findings raise new possibilities about the roles of SHH in the unresolved issue of wound scar remodeling: Can SHH remodel existing scars? If so, how long after wounding is it effective? And can this approach be applied to human scars? Furthermore, a longstanding question is how a developmental signal like SHH can be induced after wounding and what prerequisites are necessary for this signal to occur. This project aims to investigate the effect of SHH on old scars long after healing (Aim1), explore one of the upstream mechanisms we’ve identified as essential for SHH induction in large wounds (e.g., angiogenesis) (Aim 2), and examine how SHH signaling can similarly induce HFN using human fibroblasts (Aim 3).

NIH Research Projects · FY 2026 · 2026-05

Acute kidney injury (AKI) is associated with worse morbidity and mortality in pediatric intensive care unit (PICU) patients. No effective interventions exist to prevent or treat AKI, and known risk factors for its development are non-modifiable. The identification of targetable, modifiable risk factors is necessary to improve AKI outcomes, and nutritional status may be such a factor. People with AKI experience metabolic reprogramming that leads to energy deficits, and children who lack nutritional reserves are at high risk of these energy supply demand mismatches. In preliminary metabolomic studies, alterations of certain amino acids and essential nutrients contributed to AKI development in mice and humans, and supplementation of said nutrients prevented AKI in mice. However, few studies in PICU patients comprehensively evaluate nutritional risk. The objective of the Surveillance of Nutritional risk for Acute kidney injury in Critically ill Kids (SNACK) study is to evaluate whether poor baseline nutritional status is a modifiable AKI risk factor. We will do this by rigorously characterizing nutritional status beyond anthropometrics with specific and objective nutritional assessments, identifying novel blood-based nutritional risk biomarkers, and evaluating the association between these nutritional factors with AKI development and progression. In Aim 1, we will characterize baseline nutritional status in the SNACK cohort and evaluate its association with AKI development or progression by enrolling 200 PICU patients at high AKI risk, collecting basic anthropometrics, and performing detailed dietary questionnaires, malnutrition screening tools, mid upper arm circumference, skin fold thickness, hand grip strength, and muscle ultrasound measurements to subphenotype nutritional risk. We will evaluate whether these nutritional risk subphenotypes associate with AKI by serum creatinine and UOP criteria. In Aim 2, we will identify metabolomic signatures of nutritional risk in SNACK by sending blood for metabolomic profiling and comparing metabolomes of patients with vs without nutritional risk. In Aim 3, we will assess the association of metabolomic markers of nutritional risk with AKI development or progression by comparing metabolites associated with nutritional risk between patients who develop AKI vs those who do not. The primary objective of this application is to support Dr. Hasson’s goal of becoming an independent investigator dedicated to the translational study of AKI in critically ill children. Her aims of improving identification of children at greatest nutritional risk and understanding how nutritional and metabolomic alterations are associated with AKI is in line with the NIDDK’s mission to improve the lives of patients with nutritional and kidney disease. She will gain skills in 1) advanced statistical methods, 2) advanced nutritional practices, 3) biomedical informatics, and 4) the integration of metabolomic analysis and clinical nutrition. Successful completion of this project will lead to an R01 application that will utilize these nutritional assessments to prognostically enrich a randomized clinical trial to investigate a targeted nutritional supplementation intervention for prevention of new or worsening AKI.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY Paralysis due to spinal cord injury, stroke, or amyotrophic lateral sclerosis (ALS) can lead to debilitating communication deficits. Implanted brain-computer interfaces (BCIs) are a promising approach to treat these patients. BCIs leverage neural activity to create a desired computer output, such as text. To characterize the relationship between the neural data and the computer output, a decoder is trained on data from many repeated trials. Unfortunately, this training trial burden limits the practical utility of communication BCIs in many patients. There are several contributing factors to this training burden. First, there is an incomplete understanding of the neural codes which underlie complex, skilled behaviors in humans such as handwriting or speech. Second, standard decoders rely on neural network architectures which are extremely flexible but require a substantial amount of training data to achieve acceptable predictive accuracy. Communication BCIs are often based solely on intentions of motion, which creates an additional technical challenge. Due to unobservable variability in the timing of patients’ intentions from trial-to-trial, data-driven methods for aligning neural activity across trials can substantially aid in the analysis of these datasets. I have developed Bayesian time warping for this purpose, a neural activity alignment approach which learns a probability distribution over possible alignments for each trial and response profiles for each neuron based on the observed data. In this project, I propose that the uncertainty estimates generated by this method will provide insights into approaches that can improve the data-efficiency of communication BCIs. To determine if these insights can be generalized across distinct BCI strategies, I will analyze data from two different communication BCI approaches: one which decodes characters from attempted handwriting, and another which decodes phonemes from attempted speech. In Aim 1, I will use probabilistic clustering methods on the model outputs to determine if there are subpopulations of electrodes aligned to distinct features of communication, such as attempted movement onset versus character/phoneme-specific movements, and test if subpopulation-informed BCI decoders require less training data to achieve acceptable performance. In Aim 2, I will use the model outputs to inform the creation of synthetic training datasets of varying size with varying degrees of outlier corruption and systematically characterize the robustness and data-efficiency of decoding architectures ranging in complexity. This project will discover avenues to substantially ease the training trial burden, and therefore, advance the practicality of BCI usage for a larger number of paralyzed patients.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY/ABSTRACT Pagni aspires to become a leader in clinical neuroscience and identify circuit- and network-level properties underlying the efficacy of psychedelic therapies in alcohol use disorder (AUD). His long-term goal is to direct a clinical and basic science laboratory dedicated to understanding the brain basis of integrative health practices through the use of state-of-the-art multimodal imaging and computational methods. To develop this future research program, Dr. Pagni requires additional training in randomized clinical trials and advanced neural imaging and computational techniques. His basic science training provides a strong foundation in the neurobiology of addiction and depression. He has also acquired clinical experience in adults with autism ranging from neuropsychological assessments to classic functional MRI analyses. Dr. Pagni’s career development plan expands on this skillset with professional and training activities in dynamic functional connectivity analysis (dFC, for network-level temporal variability), effective functional connectivity (for circuit-level causal inferences), and machine learning techniques (ML, for brain-behavior relationships). NYU Grossman School of Medicine affords an optimal professional training environment through the clinical expertise of Drs. Bogenschutz and Ross, paired with the neural imaging expertise of Drs. Goldstein and Chen. Through this protected time, Dr. Pagni will be well prepared to direct a research program focused on the therapeutic neural mechanisms of psilocybin-assisted therapy (PAT) in AUD. Research Project: A Phase II clinical trial led by his mentor examining PAT for the treatment of AUD demonstrated rapid, robust, and enduring efficacy, including significant reductions in percent heavy drinking days and improvements in mood at an 8-month follow-up. Despite the promising clinical data for improvements in mood and drinking outcomes in AUD, the neurobiological mechanisms supporting clinical efficacy have yet to be characterized. Dr. Pagni’s central hypothesis is that PAT exerts therapeutic effects by modulating both transdiagnostic (depression & anxiety) and addiction-specific brain circuits. Specifically, he hypothesizes that PAT will increase variability in network connectivity during self-referential processing (nonspecific, transdiagnostic) and increase top-down executive control during alcohol cue-reactivity (AUD specific). The goal of this K99-R00 Award is to apply advanced neural imaging methodology to a large clinical trial dataset (N = 120) and directly test this hypothesis in three specific aims. Aim 1 (K99 phase) will use static fMRI functional connectivity to characterize psilocybin-induced changes in network-level connectivity in the default mode, salience, and executive control networks. Aim 2 (K99-R00 phase) will leverage dynamic fMRI measures to characterize PAT-induced changes in time-varying connectivity patterns (via dFC) and the causal architecture (via EC) of self-reflection and alcohol cue-reactivity neurocircuitry. Aim 3 (R00) will use machine learning regression techniques to identify mechanisms underlying depression, anxiety, and AUD symptom change. This project is stepping-stone to launch Dr. Pagni’s career developing targeted PAT treatments in AUD.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY Tumor draining LNs (tdLN), are harbingers of aggressive disease, where the presence of metastases signals risk for recurrence and poor survival in melanoma patients. The tdLN basin, however, is also antigen-rich and may promote immune reinvigoration on immunotherapy. Indeed, recent neoadjuvant trials demonstrate increased efficacy when immune checkpoint blockade (ICB) is delivered prior to surgical resection, which may depend in part on the tdLN basin. Given that large-scale clinical trials failed to demonstrate the benefit of prophylactic, complete LN dissection in high-risk, LN-positive melanoma patients, there is an opportunity to consider the therapeutic potential of tdLNs as key hubs for continued tumor immune surveillance. Future progress, however, depends upon a mechanistic understanding for how anti-tumor immune surveillance in tdLNs is maintained and the impact of standard of care clinical therapy. Recent studies, both preclinical and clinical, have identified a subset of stem-like memory (TSL) cells CD8+ T cells that are produced as a function of suboptimal antigen presentation and are enriched in tdLNs. These TSL are reinvigorated upon ICB and required for response to therapy. Despite the fact that TSL are required for response to immunotherapy in mice and associated with outcome in patients, however, we lack an understanding for what might determine their differential abundance or functionality in situ. The underlying hypothesis of the proposed work is that maintaining TSL in the draining lymphatic basin will support systemic immune surveillance in patients. We therefore leverage our deep expertise in the lymphatic system, paired with new tools to track and perturb specialized T cell populations in the context of melanoma to generate mechanistic insights that can guide future strategies for clinical management of the lymphatic basin in the context of neoadjuvant therapy. We propose that understanding the mechanisms that maintain LN TSL will lead to new strategies to boost systemic immune surveillance. Successful completion of this work will aim to 1) map the differentiation trajectory of egressing CD8+ T cells as they seed draining LNs; 2) determine the dependence of TSL on lymphatic transport; and 3) define the TSL niche in mouse and human. We expect that the basic immunological insights generated here can be used to guide the application of neoadjuvant therapy in melanoma and other solid tumors. Further, this work will nominate new candidate targets or therapeutic schedules to improve local tumor control and protect against tumor recurrence and distant metastasis.

NIH Research Projects · FY 2026 · 2026-04

Project Summary New York City (NYC) is the first jurisdiction in the United States (US) to implement a cordon-based congestion charge, with the goals of alleviating traffic and increasing revenue to improve NYC’s transit system. The objective of this proposal to use a quasi-experimental approach to evaluate the health impacts of the NYC congestion pricing policy. Early predictions using simulation models suggest that the NYC congestion pricing policy will improve air quality in the congestion zone and surrounding areas because of a reduction in traffic- related air pollutant emissions due to lower vehicle-miles travelled and time spent idling in traffic. Our overall hypothesis is that a policy that influences traffic and reduces emissions can improve air quality and health outcomes related to air pollution. However, traffic diversions into communities outside of the congestion zone might translate in differential impacts of the policy on communities in the region in short-term. The premise underlying this proposal is provided by studies that show: 1) road traffic influences health through emitted air pollutants and the effect is present at levels below current standards, 2) cordon-based policies can reduce emission and improve air quality, and 3) differential impacts of cordon-based policies in subgroup residents of affected areas is largely unknown. Specific Aims are: 1) Identify the impact of congestion pricing policy on rates of asthma acute care events and cardiovascular events, by comparing trends in the congestion zone 7 years before and 1, 2, and 3 years after policy enactment with comparison areas; 2) Create a time-series model of air quality using local monitor data in NYC 7 years before and 1-3 years after policy enactment and compare trends in and outside the congestion zone; and 3) Evaluate the air quality and health impact of the policy on “spillover” communities outside of the congestion zone, stratifying by whether or not they are projected to experience increased or decreased traffic with policy implementation. We will leverage multiple sources of health data, i.e., Medicaid claims data from residents in the US Northeast and all-payer claims from residents of New York State. The project will also incorporate spatially refined measures of air pollution measures from the NYC Community Air Survey. Innovations include the use of a natural experiment design with synthetic control matching and the integration of data from a unique air monitoring system in NYC with high spatial resolution. This study will be the first to examine differential impacts on health in communities that might experience more congestion due to traffic conversion in the short-term. Results from this study will provide an evidence base for other urban areas considering the adoption of cordon-based road pricing policies.

NIH Research Projects · FY 2026 · 2026-04

Project Abstract/Summary Candidate: I am a joint postdoctoral scholar in the laboratories of Drs. Morgan Huse (Memorial Sloan Kettering Cancer Center), Jason Cyster (UCSF/HHMI), and Orion Weiner (UCSF). My previous PhD research provided extensive training in infectious diseases, humanized mice and other types of advanced infection mouse models, chemistry, and computational biology. This background will be helpful as I investigate how myeloid cells control plasma membrane homeostasis and how plasma membrane abundance functions as an integrator to discriminate between the cellular programs of migration, phagocytosis, and NETosis. While the proposed research is rooted in my current postdoctoral work, it moves far beyond this foundation to better understand the molecular logic used by innate immune cells to choose between different cellular programs and how this relates to infection, autoimmunity, and neurological disease. Research: Neutrophils act as the first responders to viral, bacterial, or fungal infections and are important sentries of the innate immune system. Neutrophils must make complex decisions about when to migrate and when to stop and engage in antimicrobial effector response like phagocytosis and NETosis. How neutrophils assimilate information from their environment to decide between these different functional programs is not well understood. Recently, I discovered that two G-protein subunits (Gα12 and Gβ4) regulate neutrophil phagocytosis, migration, and NETosis by modulating plasma membrane homeostasis. My proposed studies will determine how plasma membrane composition and abundance control neutrophil and more generally professional phagocyte decision-making, both in the context of well-controlled in vitro assays and in animal models of infection and disease. My specific aims are to: 1) investigate the upstream and downstream effectors of Gα12 and Gβ4 in plasma membrane homeostatic regulation, 2) determine how plasma membrane abundance controls functional decision making by utilizing novel in vitro cell culture systems and a suite of in vivo mouse models I have created, and 3) determine how loss of Gβ4 and mis-regulation of plasma membrane abundance lead to aberrant phagocytosis of the myelin sheath on neurons in the context of Charcot Marie Tooth Disease, which is the most prevalent demyelination neuropathy of the peripheral nervous system. The fundamental principles elucidated from my studies could impact the development of novel immune based therapies to treat infections, cancers, autoimmune disorders, and neurological demyelination disorders. Environment: I am currently part of a unique environment where I interact daily with colleagues from the microbiology, immunology and cellular biophysics departments at both MSKCC and UCSF. These affiliations have provided a rich set of collaborative, technical, and scientific resources, and I hope to create a similar niche in my own independent lab and department/institute.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY/ABSTRACT We led the landmark trials in kidney (U01AI134591; NEJM 2024) and liver (U01AI138897) to establish the safety and efficacy of HOPE transplants, resulting in the 2024 HHS decision to expand HIV D+/R+ kidney and liver transplantation beyond research protocols to clinical practice. Yet the HOPE Act promise of heart transplants remains unrealized. People with HIV have twice the risk of clinical heart failure as the general population (6.5% prevalence), and HIV-associated cardiomyopathy is a major long-term complication of HIV infection. Transplanting hearts from donors with HIV (HIV D+) could lead to substantial public health benefit by decreasing the organ shortage, wait times, and waitlist mortality for people with and without HIV on the heart waitlist. Heart transplantation from donors without HIV to recipients with HIV (HIV D-/R+) confers a substantial survival advantage (77% vs 33% at 5 years), with post-transplant survival comparable to recipients without HIV. We performed the world’s first HIV D+/R+ heart transplants, and our 6 recipients are alive with follow-up as long as 3 years. In the proposed multicenter trial, we will evaluate the safety and efficacy of HIV D+/R+ heart transplantation. Furthermore, we will conduct important mechanistic studies to characterize dysregulated adaptive immune responses common to HIV and transplantation, linking them with allograft inflammation/fibrosis and clinical endpoints in the trial. Participants with HIV will be offered HIV D+ and HIV D- (including false positive) hearts as they become available in a quasi-random process mimicking a randomized trial. We will compare outcomes in 40 HIV D+/R+ and 40 HIV D-/R+ heart transplant recipients, enrolled over 5 years at 25 transplant centers. We aim: (1) to compare heart transplant outcomes (rejection, graft failure, and mortality) between HIV D+/R+ and HIV D-/R+, (2) to investigate whether dysregulated adaptive immune responses are associated with increased progression of inflammation and rejection after transplantation, in HIV D+/R+ recipients versus HIV D-/R+ recipients, and (3) to investigate whether HIV D+/R+, versus HIV D-/R+ recipients, demonstrate more intragraft inflammation and fibrosis, particularly whether inflammation and subclinical fibrosis in HIV D+ donor hearts is associated with clinical endpoints of the trial, and whether rejection in HIV D+/R+ has a distinct phenotype from rejection in HIV D-/R+. The proposed trial will determine whether the use of hearts from HIV D+ donors is safe and effective. If HIV D+/R+ transplantation can be implemented, the additional donors will help save the lives of both patients with and without HIV. The mechanistic studies have been designed to complement clinical endpoints, ensuring the knowledge gained will be novel and informative regardless of outcomes.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY – OVERALL Xenotransplantation has the potential to provide nearly unlimited organs for transplantation. Extension of xenograft survival in nonhuman primates (NHP) and xenotransplants to living and brain-dead humans have advanced the field toward clinical trials. Four gaps in knowledge remain to be filled before any human clinical trials of xenotransplantation can begin. We must first define the: 1) optimal immunosuppression regimen, 2) optimal genetics of the source animal, 3) humoral and cellular response to xenografts in humans, and 4) ability of the pig kidney to appropriately regulate human physiology. Only pig-to-human xenotransplants can provide this information. At NYU Langone, we developed an innovative decedent model to study the results of xenografts transplanted to humans and gain experience in the clinical management of xenograft recipients. We have now performed five decedent xenotransplants and monitored them up to 61 days after the transplant. Our preliminary data show that decedents have normal immune responses to xenografts, and that we can diagnose and treat antibody-mediated rejection of Gal-knockout thymokidneys. We now propose to perform 20 thymokidney xenotransplants and monitor the clinical, immunological, and physiological results in the decedents for up to 60 days, studying the human adaptive immune response to xenografts for the first time. Our program’s overarching hypothesis is that the decedent model will reveal critical information on the immune response to xenografts and the physiologic function of pig kidneys in recipient humans. Our program consists of four projects: Project 1 will study the effect of different immunosuppression regimens and different genetic modifications to the pigs on xenograft function and survival; Project 2 will use an innovative multi-omic approach to profile the human immune response to xenografts and assess physiologic changes in the decedent; Project 3 will examine the donor-specific T-cell response to xenografts (effector and regulatory T cells) and study the role of follicular T cells on potentiating the humoral immune response; and Project 4 will study the physiologic function of the pig kidney in the human milieu and in the context of possible immunologic injury. Findings in each project will inform, extend or complement studies pursued by other projects. The projects will be supported by a Molecular Science Core that will standardize and support multi-omic data collection and analysis. We also have an Administrative Core providing budgetary, logistical, and scientific oversight and statistical guidance. Collectively, these projects will provide a new level of understanding of the management of xenograft recipients and the human immune response to xenografts. Upon successful completion of the proposed research, we expect to be able to appropriately define the donor pig and treatment approach for the first clinical trials of kidney xenotransplantation, with the long-term goal of developing xenotransplantation into a standard clinical treatment option for organ failure.