New York University School Of Medicine

NIH Research Projects · FY 2026 · 2026-01

SUMMARY Nearly two-thirds of the 6.9 million Americans age 65 and older with Alzheimer’s disease (AD) are women. Women are more prone to AD than men due to hormonal, reproductive, lifestyle, and other biological factors, even when accounting for their longer life expectancy. Regardless of age, females tend to have more B cells and higher immunoglobulin levels than males, and to develop more intense antibody responses. However, it remains unclear how components of the immune system are related to the risk of AD in women. Autoantibodies (AAbs) are antibodies generated against an individual’s own components (self-antigens), in contrast to those induced by exogenous antigens. Certain AAbs (natural AAbs) mediate first-line defense against pathogens, clearance of apoptotic debris, and suppression of inflammatory responses, and some other AAbs play pathogenic roles in the central nervous system. Animal studies suggest that elevated levels of certain AAbs precede brain plaque and tangle development. Epidemiologic studies link both autoimmune disease-associated AAbs and AAbs unrelated to autoimmune conditions to cognitive impairment and AD. However, limitations of these epidemiological studies include that they: 1) assessed only a few candidate AAbs; 2) included a limited number of cases (n = 10–50); and/or 3) were retrospective studies that collected blood samples after the onset of AD, so levels of AAbs in cases could have been influenced by treatments or presence of disease. Given that the long preclinical phase of AD often starts at midlife, it is crucial to identify midlife AD biomarkers of susceptibility to address the critical need for early risk stratification and to better understand the etiology of AD. However, most blood-based markers are typically measured in late life. There were no prospective studies on AAbs and AD risk, and no study examined the associations of AAbs in midlife with late-onset (after the age of 65) AD. Recent characterizations of AAb profiles identified an abundance of circulating AAbs in apparently healthy individuals by using innovative technologies that allow reproducible omics-scale measurements using low-volume serum samples. We will conduct a prospective case-control study nested in the NYU Women’s Health Study (NYUWHS), a prospective cohort of 14,273 women who provided blood samples at enrollment in 1985–1991 (ages 35–65), with > 2,000 AD cases identified through linkage to the Centers for Medicare & Medicaid Services (CMS) during follow-up. Using the HuProt Human Proteome microarray, which is the most comprehensive array to date (> 21,000 probes), we aim to: 1) discover AAbs associated with AD risk in 300 matched case-control pairs; 2) validate the identified AAbs in an independent set of 600 case-control pairs; and 3) develop and validate a classification model that integrates midlife reproductive factors, lifestyle factors, chronic diseases, sex hormone levels, validated and/or top AAbs, and other AD biomarkers and assess its discriminatory performance. Our findings promise to discover novel blood biomarkers for AD, improve risk stratification in women, and eventually suggest novel therapies.

NIH Research Projects · FY 2026 · 2025-12

Project Summary/Abstract Postnatal development is a formative time for animals like humans and rodents that are born immature, dependent upon caretakers for survival and with brains that are still growing and changing. Many of these changes are subject to environmental influence, such that the characteristics of early-life surroundings can have potent and long-lasting effects on neural development. However, it has been challenging to study how the developing brain engages with its environment and changes with sensory experience. With newly developed methods for longitudinally tracking how neurons in the auditory cortex of young mice respond to sounds from the onset of hearing throughout development, this proposal seeks to overcome those challenges and gain novel insight into the postnatal plasticity of the auditory cortex. The long-term goal is to enhance our understanding of the neural and environmental factors that influence both healthy and disordered auditory system development. The K99 phase of this project will focus on how external auditory cues (Aim 1) and internal neuromodulators (acetylcholine, Aim 2) act upon excitatory and inhibitory neurons of the auditory cortex to shape their responses to sounds during a specific ‘critical period’ of postnatal auditory cortex development. Aim 1 will probe how distinct cell-types dynamically change their ‘tuning’ to different features of sounds over the course of the critical period. Aim 2 will utilize developmental imaging and additional training in in vitro electrophysiology and chemogenetics to reveal how cholinergic neuromodulation of cortical inhibitory circuitry changes during early development and affects critical period plasticity. Together, the K99 phase will test the overarching hypothesis that increased cholinergic neuromodulation of inhibition during development helps to dynamically change individual neurons’ sensory representations to reflect the sensory statistics of the early acoustic environment. The R00 will apply a similar combination of in vivo optical and in vitro electrophysiological approaches with functional manipulations to investigate the development of cholinergic (Aim 3) and oxytocin (Aim 4) neuromodulatory signaling in the developing auditory cortex and test if oxytocin plays a generalized or social-context-specific role in modulating critical period plasticity. Altogether these experiments will test the hypothesis that multiple neuromodulatory systems can regulate developmental plasticity by acting on developing inhibitory circuits, but that oxytocin neuromodulation particularly facilitates ‘social gating’ of experience-dependent plasticity. This project will involve advanced technical training (in in vivo optical methods, patch clamp electrophysiology, and computational approaches for analysis of large, multidimensional datasets) that can be optimally provided by the sponsor Dr. Robert Froemke’s laboratory and the host institution, the NYU School of Medicine, as well as an exceptional postdoc advisory committee that brings diverse expertise and experience. Finally, the sponsor and the broader institution have a proven track record in providing exemplary professional development training towards the candidate’s goal of obtaining a top faculty position and launching their own successful research program.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT Community violence (CV) is a pressing public health crisis in the United States (US), disproportionately affecting youth and young adults (YYA) ages 10-34. Racial and ethnic minority YYA experience a hugely disproportionate burden of CV, with non-Hispanic Black YYA nearly 10 times more likely to die from homicide compared to their non-Hispanic white peers. Despite recognition of violence as a public health issue, many jurisdictions rely on law enforcement to respond to crises and conflicts among individuals and between community members. Yet the use of law enforcement can escalate conflicts between community members (particularly between YYA) that could otherwise remain nonviolent, introduce risks of violence and arrest to YYA, and contribute to racial and ethnic disparities in enforcement. To prevent CV while mitigating these risks, some US cities have adopted non- enforcement community-centered safety models (CCSMs) to use community responders to de-escalate crises and conflicts before violence occurs and address underlying behavioral and social drivers of CV. CCSMs— including co-response models, which send trained community responders to calls for service alongside police; alternative response models, which send trained community responders to calls for service without police; and community violence interventions, though which trained community members proactively intervene in conflicts before escalation to violence—represent promising approaches to prevent CV among YYA. However, limited evidence exists on the effectiveness of CCSMs to prevent CV among YYA, the factors influencing the success or failure of CCSMs, and how CCSM modalities impact CV across diverse communities. This study will fill that gap. Aim 1 will use an implementation science approach to characterize CCSM operations in 15 US jurisdictions, documenting program characteristics, funding mechanisms, and scope to facilitate impact evaluation. Aim 2 will use an augmented synthetic control approach to estimate the overall and modality-specific impacts of CCSMs on a range of CV outcomes among YYA. Aim 3 will use feature importance analysis with Bayesian additive regression trees to explore which CCSM operational factors drive strong or weak estimates of CCSM effectiveness. This innovative research is directly responsive to the CDC’s Violence Prevention Research Priority to evaluate the effectiveness of community-level change strategies to reduce multiple forms of violence. This research is directly responsive to Research Objective 1 of the current NOFO through its focus on the evaluation of an innovative but understudied intervention to prevent CV with the potential for immediate benefit after implementation. In sum, by generating critical evidence about CCSMs, this project has the potential to reduce CV among YYA, inform policymakers as they design and deploy CCSMs in local jurisdictions, and promote health equity through innovative, evidence-based prevention strategies. The multidisciplinary investigator team will work with a Community Advisory Board to maximize the impact and reach of the research.

NIH Research Projects · FY 2025 · 2025-09

Project Summary/ Abstract Disturbances in the curvature of the human cornea can lead to visual defects like myopia, hyperopia, astigmatism, or keratoconus. Therefore, understanding how such curved refractive surfaces develop is crucial for preventing or treating these disorders. In this research proposal, I plan to use the Drosophila corneal lens as a model for the human cornea. The fly is an attractive model organism due to its plethora of genetic tools and quick life cycle; and additionally, it about 70% of genes are conserved between humans and flies. The corneal lens is a biconvex ECM structure that focuses light onto the photoreceptor rhabdomeres. A major component of the corneal lens is the polysaccharide chitin, and my preliminary findings suggest that alterations in chitin levels affect corneal lens shape. To explore this idea further, I will use fly genetics, super-resolution and electron microscopy to study the detailed role of chitin in corneal lens morphogenesis (Aim 1; K99). The retina contains a fixed number of non-neuronal central cells which secrete the various corneal lens components and also provide support to the corneal lens. My preliminary data show that an excess of either central or lattice cells affects corneal lens morphology. I will first analyze how varying the numbers of central and lattice cells changes corneal lens architecture, and then using transcriptomics I will identify the genes expressed in these cells during the pupal stage (Aim 2; K99/R00). Central cells also secrete the pseudocone beneath the corneal lens, which is analogous to the mammalian aqueous or vitreous humor. Our previous work identified three proteins in the pseudocone that influence corneal lens shape. Additional pseudocone components will be identified using TurboID to find binding partners of one of these proteins. These as well as transporters and ion channels will be tested for corneal lens shape defects and glaucoma-like phenotypes in flies (Aim 3; R00). This work will provide mechanistic insights into corneal lens morphogenesis, which may be relevant to human corneal development and diseases. To accomplish the proposed research, I will combine my existing skills in developmental genetics, biochemistry and cell biology with new skills learned during my K99 training, including super-resolution microscopy and transcriptomics. During my transition into an independent position, I will solicit advice from my mentors Drs. Jessica Treisman, Gira Bhabha, Holger Knaut, Erika Bach and Hyung Don Ryoo. Their scientific advice on fly genetics, quantitative imaging and transcriptomics along with their experience of grantsmanship, mentoring, lab management, publishing and establishing fruitful collaborations will prove invaluable. My long- term career goal is to head a research laboratory that will investigate the genetic, biophysical, cellular, and molecular regulation of corneal lens shape determination. Although I have made significant progress toward this goal with research experience and publications, I firmly believe that the additional technical and career training proposed during the K99 mentored phase is necessary for my successful transition to independence.

NIH Research Projects · FY 2025 · 2025-09

Summary Neocortical layer 1 (L1), the outermost layer of the cortex and the “crowning mystery” of David Hubel, is a major target of cortico-cortical and thalamocortical projections that carry “top-down” information (behavioral saliency, expectations, predictions, and memories) to be integrated with the “bottom-up” sensory information received by pyramidal cells, the output neurons of the cortex, in order to produce percepts and context-dependent behavior. Understanding how top-down and bottom-up information streams are integrated is necessary to understand perception and behavior, and is of medical significance since disturbances in these processes are likely at the root of neurocognitive diseases such as autism and schizophrenia. L1 is unique among neocortical layers; it is the only layer that lacks excitatory neurons but instead contains the distal (tuft) dendrites of the pyramidal cells (PCs) located in L2-5. These apical dendrites receive the diverse long-range projections arriving in L1 and mediate the integration of these top-down inputs with the feedforward sensory input arriving at the basal dendrites of the PCs. L1 also contains a specialized population of GABAergic interneurons (INs) that sculpt how top-down information is delivered to the PC distal dendrites, but the mechanism by which these neurons regulate top-down processing is poorly understood. L1 INs are distinct from those in other layers that have been the subject of intense research in recent years. Our understanding of the cellular and circuit mechanisms of top- down signaling has lagged behind our knowledge of bottom-up sensory processing, largely due to the lack of molecular genetic tools that have helped elucidate IN and PC circuitry in other layers. We and others have recently discovered that both in mice and humans, the majority of L1 INs specifically express the marker neuron- derived neurotrophic factor (NDNF). Characterization of the properties of NDNF INs in the mouse revealed that there are two main subtypes: L1 neurogliaform cells (NGFCs) and an IN subtype that is unique to L1, the canopy cells. The evolutionary conservation of these two L1 NDNF IN subtypes has recently been confirmed in humans. The availability of genetic reagents to specifically label and manipulate these IN populations would provide unprecedented opportunities to advance our understanding of the circuit mechanisms of top-down processing. Thus, the goal of this exploratory R21 application is to develop and validate novel genetic approaches for the study of L1 NDNF INs. In Aim 1, we will utilize electrophysiology and neuronal reconstructions to assess the specificity and efficacy of a novel intersectional genetic targeting strategy (NDNF/Cxcl14) for the selective labeling and manipulation of canopy cells (Aim 1A). In Aim 1B, we will utilize our NDNF/Cxcl14 intersectional genetics to study the efferent connectivity of canopy cells using optogenetics. In Aim 2, we will leverage a recently developed intersectional inhibitory DREADD reporter mouse line with our intersectional NDNF/Cxcl14 genetic strategy to suppress the output of canopy cells. These experiments will allow us to generate hypotheses about the role of these neurons in regulating the integration of top-down information in the cerebral cortex.

NIH Research Projects · FY 2025 · 2025-09

Project Summary For the more than 140,000 people waiting for a kidney transplant (KT), there is a profound loss of function due to aging, numerous comorbid conditions, and dialysis. Five years after addition to the KT waitlist, only 56% of candidates receive a KT and 15% die waiting. Given the adverse physiologic changes associated with dialysis, the long wait times for KT, and high waitlist mortality, interventions to enhance KT candidates' physiologic reserve are desperately needed. Prehabilitation refers to a myriad set of interventions seeking to enhance functional capacity to tolerate upcoming surgery's physiologic stresses. Prehabilitation's rationale—especially in KT candidates—is sound. In a single-arm pilot study of 24 patients, our group previously demonstrated a 64% increase in physical activity over 8 weeks with no adverse events; however, prehabilitation studies are plagued by significant heterogeneity, low enrollment, and poor adherence. Our pilot study was no exception. Major barriers to broad implementation are that these heterogeneous programs are often developed with a conjectural approach—based on individual investigators' conception of what such a program should be, rather than an empiric approach that incorporates key stakeholder input. Indeed, there is no consensus definition as to what defines “prehabilitation” or what components are needed. With potential for faster recovery, shorter length of stay, fewer readmissions, and earlier return to functionality, there may be a strong case for prehabilitation; however, a robust, empiric-based prehabilitation program must be developed before it can become a routine clinical practice. We first aim to elicit expert opinion to identify KT-specific prehabilitation constituent components and strategies to enhance enrollment and adherence through the conduct of 2 scoping reviews and a Delphi study of experts in nephrology, transplantation, renal nutrition, gerontology, and physical medicine and rehabilitation. Next, using novel applications of marketing research methodology, as well as in-depth patient interviews, we will identify KT candidates' preferred component combination(s) to design an empirically designed, maximally implementable, KT-specific prehabilitation intervention that incorporates the aspects valued by experts and patients alike and is most likely to be embraced by patients. Finally, we will perform a randomized controlled pilot trial of this KT-specific intervention. Prehabilitation has the potential to improve outcomes for the 42,000 people in the US added to the KT waitlist each year. We will perform the foundational work necessary to define the “optimal,” maximally implementable, KT-specific prehabilitation program. If successful, the knowledge gained will provide compelling data that will inform the need for a multicenter clinical trial to test prehabilitation in KT candidates. This proposal will provide novel data essential to design and plan that trial.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Deep brain stimulation (DBS) has been a cornerstone in treating neurological disorders, utilizing electrical impulses to target deep brain structures. While effective, DBS is limited by its invasive nature and inability to selectively target specific cell types. Optogenetics offers unparalleled cellular precision but is constrained by the penetration depth of visible light in biological tissue. To address these challenges, we propose a novel approach using nanomaterial-mediated photon conversion to create a fully noninvasive, cell specific technological platform for modulating various structures in the nervous system. This approach centers on molecularly engineered, intravenously delivered nanocrystals capable of converting tissue-penetrating stimuli into visible light, thereby enabling precise optogenetic control over targeted cells. While our prior efforts employed upconversion nanoparticles (UCNPs) for near-infrared (NIR)-to visible light conversion, their low upconversion efficiency and invasive delivery significantly hindered the application. To overcome these limitations, we will adopt a multifaceted strategy. By molecularly tailoring ultra-bright UCNPs, we will push transcranial NIR upconversion optogenetics to unprecedented depth in the deep brain. By employing focused ultrasound-assisted blood-brain barrier (BBB) opening, we will intravenously deliver the nanocrystals to target tissues, achieving full noninvasiveness. By leveraging nanoscintillators that can convert X-ray to visible light, we will develop X-ray scintillation optogenetics that can offer unparalleled stimulation depth. We will also showcase how our new technology may go beyond brain neurons and modulate diverse structures in the nervous system that are conventionally hard to reach. Overall, our nanomaterial-based platform offers novel approaches to remotely modulate various neural components across species with unprecedented depth and precision, holding the potential for developing next- generation noninvasive neurological treatments.

NIH Research Projects · FY 2025 · 2025-09

Cr(VI) compounds are carcinogenic to humans. The underlying mechanism remains unknown. Neural Precursor Cell Expressed Developmentally Down-regulated Protein 9 (NEDD9), a multi-domain scaffolding protein, is crucial for tumorigenesis. High expression of NEDD9 is correlated with advanced clinical stage of non-small cell lung carcinomas (NSCLC). Autophagy is a key regulator that maintains p62 at desired levels. Upregulation of p62 is associated with various carcinogenic processes. Our preliminary studies show that in Cr(VI)-transformed cells, NEDD9 is upregulated, and autophagy is impaired, resulting in the upregulation of p62, Nrf2, and Bcl-2. Knockdown of NEDD9 decreases p62 and Nrf2 expression and reduces the malignancy of Cr(VI)-transformed cells. Knockdown of p62 or Nrf2 suppresses tumorigenicity of Cr(VI)-transformed cells. Overexpression of p62 in BEAS-2B cells causes malignant cell transformation and tumor growth. Among the six main domains/regions of p62, the TNF receptor-associated factor 6 (TRAF6)-binding domain (TB) binds to and phosphorylates TRAF6, leading to NF-κB activation, and the Keap-interacting region (KIR) binds to Keap1, causing constitutive Nrf2 activation. HIF-1α, a key regulator of angiogenesis, is upregulated in Cr(VI)- transformed cells and knockdown of NEDD9 reduces its expression. The central hypothesis is that in normal cells ROS generated by Cr(VI) overwhelms the protection of autophagy, causing NEDD9 upregulation, eventually malignant cell transformation, that in Cr(VI)-transformed cells NEDD9 upregulation impairs autophagy, causing upregulation of p62, which then activates NF-κB and Nrf2, and subsequently upregulation of its downstream anti-inflammatory and anti-apoptotic proteins, and that NEDD9 positively regulates HIF-1α, resulting in tumorigenesis of Cr(VI)-transformed cells. Aim 1 will test the hypothesis that chronic exposure of cells to Cr(VI) generates ROS and induces autophagy, that autophagy protects against Cr(VI)-induced malignant transformation by decreasing ROS level through facilitating mitochondrial turnover, and that ROS generated by Cr(VI) overwhelms the protection of autophagy, resulting in NEDD9 upregulation and eventually malignant cell transformation. We will investigate the protective role of autophagy against Cr(VI)-induced cell transformation via the decrease of ROS through facilitated mitochondrial turnover and the role of NEDD9 upregulation by Cr(VI)-induced ROS in malignant cell transformation. Aim 2 will test the hypothesis that in Cr(VI)-transformed cells upregulation of NEDD9 impairs autophagy, causing accumulation of p62, subsequently activation of NF-κB and Nrf2, and that NEDD9 upregulates HIF-1α, leading to increased cell survival, angiogenesis, and tumorigenesis. We will investigate that NEDD9 upregulates p62, then NF-κB activation and constitutive Nrf2 activation, and its downstream inflammatory and anti-apoptotic proteins, as well as HIF-1α in tumorigenesis of Cr(VI)-transformed cells. Aim 3 will investigate the role of NEDD9 in the mechanism of Cr(VI) carcinogenesis using NEDD9 wild-type and knockout animals exposed to Cr(VI).

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Over 250,000 kidney transplant (KT) recipients depend on lifelong immunosuppressive therapy to prevent rejection and graft failure. However, immunosuppression increases the risk of complications such as infections, cancer, and cardiovascular disease (CVD), which together account for >70% of deaths in KT patients. To optimize transplant outcomes while minimizing immunosuppression-associated adverse drug events (ADEs), clinicians aim to choose the most appropriate immunosuppression regimen for the individual recipient's risk profile. Nonetheless, this practice is often empirical and rudimentary because little clinical evidence guides it. Our previous study found substantial disagreements between transplant centers' protocols, suggesting that over- or under-immunosuppression could be prevalent. Efforts to develop such evidence have been hampered by the limited granularity of current KT data. Existing large-scale datasets primarily focus on transplant-specific outcomes like graft failure and death but fail to capture broader clinical data, such as infections or blood glucose levels, which are essential for understanding immunosuppression-associated ADEs. To address this gap, we plan to use Epic Cosmos, a nationwide electronic health record database that launched in 2019 and now covers over 274 million individuals. Our preliminary dataset includes 69,418 KT recipients (39% of the total) between 2014-2022, encompassing detailed longitudinal data such as lab values, diagnoses, procedures, and prescriptions. Additionally, traditional regression-based analyses are ill-equipped for evaluating individual treatment effects (ITE) because they focus on average treatment effects, neglecting individual differences. To overcome this, we propose using meta-learners, a class of machine learning algorithms designed to model ITE based on individual characteristics. These algorithms can also identify the clinical factors that make specific treatments more suitable for the individual recipient. Leveraging the newly introduced database and the cutting-edge inferential method, we propose to create a quantitative framework for immunosuppression individualization with the following aims: 1) to quantify the individualized treatment effects of immunosuppression regimens on immunosuppression-related side effects, 2) to leverage the granular data from Cosmos to improve our proof-of-concept (PoC) meta-learners on transplant outcomes, and 3) to develop a clinical decision support tool for immunosuppression tailoring. This project will create the first framework to address the long-standing challenge of evidence-based immunosuppression tailoring. This framework will be implemented to an open-access web application for clinicals, potentially improving the survival and well-being of over 250,000 KT recipients. Our experience of using meta-learners on large real-world datasets can potentially be leveraged to transform clinical decision- making in diverse medical specialties.

NIH Research Projects · FY 2026 · 2025-09

Methadone is a highly effective treatment for opioid use disorder and is increasingly needed to prevent overdose in the era of fentanyl. However, access to methadone in the U.S. is very limited as historically it could only be dispensed through opioid treatment programs (OTPs) operating in fixed-site locations. Most U.S. counties do not have an OTP, and federal and state regulations make it difficult to open new OTPs. As a result, most patients - and particularly those who are unhoused, institutionalized, or live in rural areas - struggle to access OTPs, exacerbating treatment and overdose in these communities. In 2021 the U.S. Drug Enforcement Administration issued a new rule allowing existing OTPs to establish mobile methadone units (MMUs). MMUs have the potential to transform methadone access by delivering methadone to areas that otherwise do not have access (e.g., rural areas), to patients who cannot travel to OTPs (e.g., incarcerated), and to other groups (e.g., unhoused) who may benefit from a low-threshold treatment environment. As a result of this rule, the New York State (NYS) Office of Addiction Services and Supports recently launched a program to support the creation of 10 MMUs across rural and urban areas of NYS by early 2025. This represents the first statewide effort to scale up MMU delivery and can provide critical lessons on the value of this intervention. However, robust evaluations of the real-world impact of MMUs are needed. The current proposal applies a mixed-methods and quasi-experimental design to conduct a comprehensive evaluation of the impact of the NYS MMU program on health outcomes, patient and provider experiences, and cost considerations that would inform sustainability long-term. Following the RE-AIM (Reach, Effectiveness, Adoption, Implementation & Maintenance) framework, we propose to (1) Assess the reach of MMUs in the first year of the program and their impact on methadone treatment initiation and retention; (2) Examine the effectiveness of MMUs in reducing overdose and acute healthcare utilization, and how this varies across patient subgroups and rural/urban areas; (3) Examine MMU adoption considerations among OTPs and ongoing implementation challenges and successes from the perspective of patients, providers, administrators, and government officials; and 4) inform maintenance considerations related to costs of operating these programs for providers and policy makers considering expanding MMUs across multiple states. This study involves a unique multi-PI partnership between academic researchers and NYS government officials that allows for unique access to administrative datasets. Additionally, a national stakeholder engagement plan will draw direct input from individuals with living experience on methadone, and widely disseminate findings to addiction providers, policy makers, and drug user groups. As such, this work responds to NIDA’s NOSI for health services and economic research to maximize availability and delivery of efficient and effective drug treatment programs, while ensuring research translation to inform real-world practices to reduce overdose.

NIH Research Projects · FY 2025 · 2025-09

Abstract Selectively targeting IgG recycling at the maternal-fetal interface to reduce pathogenic IgG by inhibition of the fetal neonatal Fc gamma receptor (FcRn) and acceleration of IgG destruction, carries the potential to eradicate autoantibody mediated diseases affirming the prediction “no antibody, no disease.” The nearly invariant finding of high titer autoantibodies reactive with SSA/Ro52kD and 60kD ribonucleoproteins in pregnancies complicated by cardiac neonatal lupus (cardiac-NL), strongly implicates these autoantibodies as required for the development of disease. Maternal IgG accessibility to the fetal circulation is mediated by binding to syncytiotrophoblast expressed FcRn. Importantly, we recently demonstrated anti-SSA/Ro52kD and 60kD in cord blood and serosal cavities from 3 midtrimester fetuses dying with cardiac-NL, proving very early transplacental passage. The signature cardiac disease, detected in the midtrimester, is irreversible 3° atrioventricular block with extensive endocardial fibroelastosis, valvular dysfunction, and cardiomyopathy in some cases. Cardiac-NL is fatal in nearly 20%, requires life-long pacing in survivors, and can result in cardiac dysfunction by early adulthood in 30%. The risk in fetuses exposed to high titer anti-SSA/Ro autoantibodies with no prior affected siblings approaches 4% as supported by the ongoing Surveillance and Treatment tO Prevent AV Block Likely to Occur Quickly (STOP BLOQ) trial. Our group has shown that hydroxychloroquine (HCQ) reduces cardiac-NL recurrence from an historic benchmark of 18% to 8%. Accordingly, the development of monoclonal antibodies that block FcRn, recently shown safe and effective in fetal hemolytic disease, presents an unprecedented preventative strategy. Driven by the rationale that cardiac-NL will be thwarted by a dual mechanism of action, lowering maternal anti- SSA/Ro autoantibodies and blocking placental transport, we propose AVERT (Atrioventricular block Elimination by Rozanolixizumab Treatment) led by STOP BLOQ mPIs, Jill Buyon (rheumatologist, immunologist) and Bettina Cuneo (fetal cardiologist) complemented by Justin Brandt (maternal fetal medicine). Rozanolixizumab (roza) is an FcRn blocker FDA approved for myasthenia gravis. In Aim 1, an open label prospective single arm study of pregnant subjects with high titer anti-SSA/Ro and a previous cardiac-NL offspring will address whether roza 10mg/kg weekly from 14-25 weeks plus HCQ will significantly reduce the recurrence rate. Limiting study drug to before and during the vulnerable period for cardiac-NL should decrease the need for maternal or neonatal IVIG rescue. A very low recurrence rate of 2% is expected and will be compared to 8% (HCQ alone) with 80% power, Type I error rate of 5%. The first stage of this Simon’s 2 stage design will enroll 35 patients with termination due to inefficacy if ≥ 2 cardiac-NL occur out of 35. Stage 2 will recruit 54 additional patients; the drug will be considered efficacious if < 4/89 develop cardiac-NL. In Aim 2, timing and durability of anti-SSA/Ro52kD and 60kD will be evaluated following treatment with roza. Aim 3 will determine fetal, neonatal and maternal safety of roza. Positive results may set precedent for universal anti-SSA/Ro testing in pregnancy.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY / ABSTRACT The demand for heart transplant (HT) in the United States (US) far exceeds the number of HTs performed, resulting in dire consequences for candidates on the HT waitlist. The applicant’s recent European Heart Journal publication refutes the long-held assumption that US HT volume is limited by a shortage of donors. It showed that the US utilizes only 44% of potential donors for HT and that adopting the more liberal donor acceptance practices of the Eurotransplant (ET) consortium would lead to hundreds more US HTs annually. The barriers to doing so include 1) lack of evidence on which donor risk factors impact HT outcomes and 2) difficulty synthesizing a wide array of clinical datapoints during donor selection. The applicant’s proposed research aims will address both barriers, with the goal of increasing heart donor utilization in the US. The first aim is to investigate the impact of donor risk factors on HT outcomes, focusing on coronary artery disease (CAD), left ventricular dysfunction and hypertrophy (LVH), and older age. Each is a common reason for donor heart non-acceptance. ET registry data will be used to test the hypothesis that mild CAD and LV dysfunction, in the absence of other risk factors, do not confer increased risk. Data from a novel US-wide cohort will be used to test the hypotheses that donor LVH is often transient or spurious and does not impact post-HT outcomes. Finally, the impact of a large HT center's strategy to utilize older donors will be evaluated. The second aim is to develop prediction models to rationalize donor heart assessment and selection. Having already produced an online tool to predict donor acceptance for HT, the applicant will employ machine learning algorithms to develop three additional decision-support tools to inform donor assessment. The first prediction tool will predict the likelihood of donor CAD and thereby inform selection of which donors need screening coronary angiography (which is highly time- and resource- intensive). The other prediction tools will quantify 1) the impact of a donor’s risk factors on predicted post-HT mortality and 2) how long a HT candidate will expect to wait before receiving a better donor offer. The expected impact of this research is to enable a more data-driven and systematic approach to heart donor selection, leading to discard of fewer viable donor hearts and thus more lives saved through HT. The K08 training plan will enable the applicant’s growth as an independent clinician-investigator in the field of HT policy and outcomes research, via expert mentorship and skill development in 1) machine learning and decision analytic modeling; 2) clinical informatics and observational research; 3) leadership and organization; and 4) oral and written communication. This skillset and the above research output will enable the applicant to lead prospective studies under a subsequent R01 grant to demonstrate the impact of increased donor utilization.

NIH Research Projects · FY 2025 · 2025-09

SUMMARY Annually, over 800,000 individuals provide unpaid support to patients with end-stage kidney disease (ESKD), such as care coordination, activities of daily living, nursing tasks, and emotional support. Much like caregivers of patients with other life-limiting illnesses, ESKD caregivers experience psychological distress and adverse health outcomes, including cardiovascular disease and poor self-rated health. This is problematic, because lack of adequate caregiver support is associated with poor patient outcomes. One of the largest inflection points for both patients and their caregivers along the treatment continuum for ESKD is listing for kidney transplantation. However, this process is fraught with uncertainty, ranging from timing of organ offers to post- transplant risk of infection and graft failure. To our knowledge, no interventions exist to address the needs of caregivers facing kidney transplantation. To address this gap, my interdisciplinary mentoring team and I have developed an intervention called Project ANCHOR (Addressing the Needs of Caregivers to Help Optimize Resilience), based conceptually on the Windle and Bennett framework for resilience in the context of caregiving and on prior evidence-based interventions. Project ANCHOR employs a telehealth coaching approach to provide supportive care to family caregivers of patients awaiting kidney transplantation, consisting of six weekly sessions and monthly follow-up led by a trained lay coach. Content includes management of kidney disease, skills for coping with stress, ensuring effective social support, improving self-care, and planning for the future. The overall goal of this exploratory sequential mixed methods research study is to conduct a formative intervention adaptation and a small-scale pilot randomized controlled trial of a supportive care intervention for family caregivers of patients listed for transplantation. We will assemble an advisory group of patients, caregivers, transplant providers, and lay navigators to elicit feedback on the design, implementation, and results of Project ANCHOR using focus groups and qualitative formative evaluation interviews. The newly tailored intervention will then be tested for feasibility, acceptability, and potential efficacy in a small scale RCT vs. standard-of-care for 60 caregivers, allowing us to 1) to assess instruments and observed differences between the intervention and standard-of-care group; 2) to collect pilot data to evaluate the RCT design to prepare for a larger intervention study in the future, and 3) to identify strategies to recruit and retain participants. Results from this study will allow us to provide tailored support to family caregivers of patients awaiting transplantation and reduce caregiver burden, improve post-transplant outcomes by providing tools and resources to mitigate caregiver burden, and improve informed consent for caregivers considering living donation.

NIH Research Projects · FY 2026 · 2025-09

Abstract The underlying biological causes of Alzheimer’s disease (AD) and AD-related dementias (AD/ADRD) remain unclear. Although a vascular component in AD has been discussed since the 1960s, its importance has increased with advancements in biomarkers and imaging techniques, and the current interest in disease heterogeneity. A significant limitation in defining the vascular component of AD is the frequent coexistence of cerebrovascular disease. Recent studies indicate that vascular dysfunction and neuroinflammation may synergistically contribute to AD progression, yet the precise mechanisms remain unclear. Our preliminary data indicate that circulating markers of vascular and immune dysfunction, such as platelet aggregation and neutrophil levels, are associated with dementia risk and increased AD biomarkers in cognitively unimpaired people and in people with high risk of cardiovascular disease events. To further understand this relationship, multidisciplinary studies integrating biofluid data with advanced imaging techniques are needed. This proposal will examine the association between markers of vascular and immune dysfunction (platelet, neutrophil activity, and proteomic data) with MRI measures of cerebrovascular burden in two cohorts: the Framingham Heart Study, and the ARISE-DP cohort, which includes a diverse population with a high prevalence of cardiovascular risk factors (Aim 1); Study the relationship between these markers and PET measures of amyloid and tau pathology, exploring potential interactions between cerebrovascular burden and amyloid positivity (Aim 2); and to determine whether baseline vascular and inflammatory markers associate with cognitive decline and AD biomarker progression (p-tau181 and 217). By integrating biofluid biomarkers with imaging data, this study aims to identify novel biological mediators and therapeutic targets in AD/ADRD, ultimately increasing our understanding of how vascular and immune dysfunction contribute to disease progression

NIH Research Projects · FY 2025 · 2025-09

The 2014 new US Kidney Allocation System heavily prioritized sensitized kidney transplant candidates to provide them with more access to transplantation. However, disparities persist as high-sensitized patients (measured by CPRA level), particularly those with blood type B and O, continue to be underserved. Moreover, about 25% of kidneys recovered for transplant were not utilized in 2023. We propose to evaluate the new kidney allocation policy that extends the eligible candidate pool by allowing ABO-compatible kidney transplants, expanding predominantly ABO-Identical current US kidney allocation. The ABO-compatible kidney allocation can save recovered kidneys at risk of nonuse from waste by serving them to kidney transplant candidates in the greatest need. The policymakers were reluctant to introduce ABO-Compatible, fearing that the problem of lower transplant rates for some blood types would worsen. We propose a novel ABO-adjusted CPRA metric that can prioritize the most disadvantaged candidates to offer them kidneys first. We propose these aims: (I) Estimate the impact: we will use simulated allocation models to evaluate the impact of ABO-Compatible kidney continuous allocation policy, predicting impacts on nonuse rate, and on transplant rates stratified by candidate sex, ethnicity, blood type, and CPRA after a policy change. (II) Identify beneficiaries: we will build models to identify kidneys at high risk of nonuse and candidates requiring increased access or priority that are likely to accept these kidneys. The goal is to build the models and identify the donor and candidate populations who would benefit most from ABO-compatible kidney allocation. (III) Develop optimal ABO-compatible Policy: we will use simulation optimization algorithms to inform the design of an ABO-compatible kidney continuous allocation policy that minimizes organ nonuse and maximizes access. We will estimate the tradeoffs between maximizing transplant rates stratified by sex/ethnicity /blood type/CPRA and increasing the nonuse rate to navigate future allocation policy changes. The introduction of an ABO-adjusted CPRA metric is also proposed to better identify those with the greatest need for a transplant, potentially increasing transplants for highly sensitized candidates. This project aims to directly address the White House Executive Order on Advancing American Kidney Health, by removing overly restrictive policies and providing more opportunities for transplant to highly sensitized candidates of any blood group.

NIH Research Projects · FY 2025 · 2025-09

ABSTRACT The utilization and subsequent disposal of plastics and plastic based products continues to rise exponentially. Current pervasiveness of micro- and nanoplastic particles (MNPs) in the environment results in significant exposure to human populations via inhalation and ingestion. MNP contaminants have been discovered in the air we breathe, the food we eat, and in 81% of tap water samples tested around the globe. Samples taken from human subjects, including our preliminary data, identify MNP deposition in tissues (e.g., lung, heart, blood, thrombi, and placenta) and excreta (e.g., semen, breast milk, bronchoalveolar lavage fluid, and feces). These findings indicate that not only are humans exposed to MNP, but these pervasive part icles bypass protective anatomical barriers, accumulating within systemic tissues. Animal models reproduce these findings in a laboratory environment, resulting in MNP accumulation in systemic tissues and associations with pathologic changes. MNPs have also been identified in the placenta and fetal organs of rodent models after pulmonary or gastric exposure. Our preliminary data suggest maternal transfer of MNP to the offspring, with MNP deposition remaining in offspring tissues for at least 2 weeks after birth, 16 days after the last maternal exposure. Despite the extent of world-wide MNP exposure, the quantified concentration of MNP within systemic tissues is unknown. Analyses have been conducted using microscopic fixed tissue analyses or chemical extraction- based techniques. Unfortunately, these methodologies cannot currently be adequately compared. Currently, there is no “gold standard” methodology that meets all requirements for identifying MNPs in biological tissues. Furthermore, the role of sex, age, and ethnicity in the accumulation of MNPs in human tissues has not yet been explored. This project will investigate inter-tissue MNP accumulation in rodent models of MNP exposure via intratracheal installation or gavage, using overlapping state-of-the-art detection methodologies to quantify and confirm MNP deposition. We will then compare these concentrations to those obtained from human autopsy samples. Innovative statistical methods for integrating calibration samples with results from different analytical methods will be employed to correct for measure errors. These translational studies will provide further rationale to relate human and laboratory MNP translocation and deposition studies. To fully assess MNP toxicities, we must first understand the measured mass deposition based on known exposure doses. Successful completion of these studies will provide the foundational physiological doses to advise fut ure in vitro and ex vivo MNP toxicological studies.

NIH Research Projects · FY 2025 · 2025-09

PROJECT ABSTRACT This proposal is a large hybrid type 1 implementation effectiveness randomized controlled trial evaluating the comparative effectiveness of long-acting injectable buprenorphine (XRB) versus sublingual buprenorphine (SLB) among incarcerated adult volunteers with opioid use disorder (OUD) who are preparing for release. Both treatments are FDA-approved for OUD, and XRB offers the potential to improve adherence and reduce barriers to consistent medication use in correctional and community settings. The study will address the urgent need for high-quality data comparing these two buprenorphine formulations in corrections-to-community transitions, where individuals face heightened risks for overdose and poor treatment engagement. Participants will be recruited from three diverse Department of Corrections sites: Yale/Connecticut DOC, Dartmouth/New Hampshire DOC, and Friends Research Institute/Delaware DOC. The study team, which includes experienced PIs and academic partners, has long-standing collaborations with these sites, established protocols for XRB and SLB administration in correctional settings, and strong linkage systems to community care. A total of 300 adult participants with moderate-to-severe OUD will be randomized 1:1 to XRB or SLB prior to release, with the primary outcome being retention on buprenorphine at 12 weeks post-release. Secondary outcomes will include substance use measures, overdose events, qualitative feedback from participants, implementation feasibility, and cost analyses. This open-label, hybrid type 1 implementation-effectiveness trial leverages an innovative design to evaluate not only the clinical effectiveness of these medications but also the feasibility and relative costs of their implementation in correctional settings. As the first large multi-site trial of XRB versus SLB in this population, the study addresses key public health priorities and aligns with the NIH HEAL initiative’s goals to reduce opioid overdose deaths and improve treatment engagement during the critical post-release period. Findings from this study have the potential to inform best practices and expand the accessibility of medication for opioid use disorder (MOUD) in underserved carceral populations.

NIH Research Projects · FY 2025 · 2025-09

Children with poor sleep health are at increased risk for mental health problems, substance use, underachievement and cardiometabolic disease. There are well-documented disparities in sleep health across the lifespan with observable differences in childhood. Social factors operating at the neighborhood level are increasingly recognized as critical factors to understanding and preventing a range of health disparities with their roots in childhood. Conceptual frameworks point to multiple facets of the neighborhood context (physical and social) that may influence sleep health in children; however, there is limited work examining factors at the neighborhood level and children’s sleep health in children of color living in urban neighborhoods. Such information is essential for advancing population-level approaches to promote sleep health in an important health disparity population. The goal of this study is to advance understanding of the role of neighborhood factors on sleep health disparities among first and second graders. This study merges an innovative and comprehensive publicly available data set on neighborhood factors with an investigator non publicly available longitudinal data set on nearly 600 children (primarily Black) in NYC. The publicly available data set is the Child Opportunity Index 3.0 (COI 3.0), a comprehensive database of the quality of neighborhood resources and conditions that matter for children’s healthy development. The investigator longitudinal dataset comes from a completed follow-up study of mental health and educational outcomes from a school-based, family centered preventive intervention implemented during Pre-K. The dataset includes parent-reported measures of multiple dimensions of child sleep health and a novel teacher-reported measure of child daytime sleepiness. The proposed study applies two approaches to consider a broad range of neighborhood factors as predictors of multiple dimensions of sleep health. The long-term goal is to translate study findings to: 1) optimize existing child and family-level sleep preventive interventions by considering neighborhood context and 2) develop structural interventions for sleep health promotion among children and families of color. Aim 1 examines individual neighborhood physical and social environment characteristics and their relative importance in predicting multiple dimensions of sleep health. Aim 2 creates typologies of neighborhoods across physical and social environment characteristics for all NYC neighborhoods and explores how neighborhood typology predicts sleep health. This project will advance understanding of the influence of neighborhood factors on sleep health disparities among a large sample of children of color (primarily Black) living in urban areas. Results will inform optimization of existing, and development of new, sleep health preventive interventions to promote population health in children of color living in urban neighborhoods.

NIH Research Projects · FY 2025 · 2025-09

Project Summary Metabolic-associated steatotic liver disease (MASLD), previously referred to as nonalcoholic fatty liver disease (NAFLD), affects approximately 25% of the global population. It is the most common cause of chronic liver disease (CLD) and is the leading cause of liver-related morbidity and mortality. MASLD encompasses a spectrum of liver diseases, ranging from simple steatosis to metabolic-associated steatohepatitis (MASH) – formerly known as nonalcoholic steatohepatitis (NASH). The main characteristic of MASH involves hepatic inflammation and chronic cellular injury, which can further lead to liver fibrosis and cirrhosis. In March 2024, the FDA approved Rezdiffra (resmetirom, Madrigal Pharmaceuticals) as the first medication for treating adult patients with MASH who have moderate to advanced liver fibrosis. Despite its potential, recent clinical findings suggest that ~50% of the patients do not respond well to this treatment. Liver biopsy is the current gold standard for assessing MASH and was used to assess treatment response in the clinical trial that led to the FDA approval of Rezdiffra. However, liver biopsy poses significant challenges that limit its routine use in clinical settings for monitoring treatment response. As a result, novel non-invasive markers that can simultaneously assess liver fat, inflammation, and fibrosis – the three pivotal aspects of liver pathology in MASH – are highly desirable. MRI is a promising modality to meet this need, providing different imaging markers for CLD, including proton density fat fraction (PDFF), T2*/R2*, and MR elastography (MRE)-derived stiffness for quantifying liver fat, iron, and fibrosis, respectively. However, none of these markers adequately captures lobular inflammation in the liver, a crucial pathological hallmark of MASH. T1 relaxation time is an MRI parameter that could potentially serve as a useful marker for inflammation and fibrosis in the liver. However, standard T1 mapping methods typically measure composite (fat/water/iron-mixed) T1 of the liver. This can result in substantial bias due to the increased fat and iron content in fatty livers. Therefore, accurate T1 mapping of the liver needs to include appropriate compensation for the influence of both fat and iron. Thanks to the initial support from the NIH (R21EB032917, PI: Feng), our team has developed a new MRI technique called MP-Dixon-GRASP (Magnetization-Prepared Golden-angle RAdial Sparse Parallel Dixon-MRI), which enables rapid 3D quantification of PDFF, R2*, and iron-corrected water-only T1 (referred to as c-water T1) in the liver during free breathing. The broad objective of this application is to continue the development, optimization, and validation of MP-Dixon-GRASP as a rapid and robust multiparametric MRI technique for the evaluation of MASH. Our Central Hypothesis is that c-water T1 can be an effective marker for chronic liver inflammation, and its combination with MRE-stiffness can provide complementary information to facilitate the non-invasive monitoring of treatment responses in patients undergoing therapy with Rezdiffra, thereby improving the management of this patient cohort.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT Persons with blindness or low vision (PBLV) lead more sedentary lifestyles, with reduced mobility, lower physical activity, and an increase in associated non-communicable diseases. PBLV often fear travel/journeys, given frequent dependence on others and the looming threat of getting lost or stranded. PBLV also face substantial increases in mechanical trips, falls, and fractures. These barriers lower their health outcomes, some of which could be mediated by physical exercise. Despite an intensive evidence base supporting physical activity to promote health, there is a large practice gap for PBLV in almost every country, including urban/city centers, such as NYC. Digital technologies can close this access and implementation gap by providing wayfinding and scene understanding support to guide safe exercise within public parks in a manner that does not require additional physical infrastructure (e.g., signs, beacons). In this proposal, we will implement our wearable and smartphone application, VIS4ION-FiT (Visually Impaired Smart Service System for Spatial Intelligence and Onboard Navigation for ¬Fitness) and evaluate effectiveness to improve physical activity in PBLV. VIS4ION-FiT is a customizable personal mobility solution that uses artificial intelligence (AI) to process camera/sensor data, both locally on the system, and remotely on servers, to provide safe guiding instructions delivered as speech, audio alerts, and tactile feedback. Our central hypothesis is that PBLV who use VIS4ION-FiT will increase their ‘moderate-equivalent’ minutes of physical activity per week and therefore improve personal health metrics (blood pressure, resting heart rate, weight). The proposal has three aims to validate this approach. First, we will interview 10 PBLV to identify key access barriers to physical activity. Then, we will update our AI-based navigation technology with GPS to create a more robust and precise hybrid solution for wayfinding. We will map walking routes and places of interest in large public parks (e.g., Central Park in NYC). User testing (25 sighted, 25 PBLV) will include the evaluation of our navigation and scene understanding assistance. Second, we will conduct a randomized controlled crossover trial with 40 PBLV using VIS4ION-FiT for 6 months over a 12-month period, providing everyone with park access for exercise. We will measure physical activity metrics, adherence, and health-related changes across the 12-month period. Our primary outcome is moderate-equivalent minutes of physical activity per week, with daily steps, blood pressure, resting heart rate, and weight, as secondary outcomes. Users will also provide feedback on VIS4ION-FiT’s acceptability, appropriateness, and feasibility. Third, we will perform a process evaluation of our implementation strategy using the RE-AIM framework, gathering data on how the intervention facilitated physical activity and health. Collective results will guide future directions to enhance physical activity for PBLV in urban/city areas across the US.

NIH Research Projects · FY 2025 · 2025-09

Cardiovascular disease (CVD) is the leading cause of death among Asian American, Native Hawaiian, and Pacific Islander (AsA-NHPI) adults, with rates varying across subgroups. However, the distribution of CVD risk factors in AsA-NHPI populations and how these factors influence CVD remain poorly characterized. Research addressing these gaps is needed to better understand CVD in AsA-NHPI populations. This study aims to investigate the relationship between the gut microbiome and coronary artery calcium (CAC)—a validated measure of current coronary atherosclerosis and a predictor of future cardiovascular events—beyond traditional risk factors. While animal models suggest a causal link between gut microbiota and atherosclerosis, human data, particularly in early subclinical stages, remain limited. No studies have examined this relationship in AsA-NHPI populations. Our preliminary data indicate that AsA-NHPI have distinct gut microbiome profiles, differing from White, Black, and Hispanic populations but also shaped by contextual factors. Additionally, our preliminary data indicate that some of these microbial species are associated with early atherosclerosis. Taken together, investigating the microbiome’s impact on cardiovascular health is crucial for guiding personalized, microbiome-informed prevention strategies. This study is the first to integrate bacterial, fungal, and viral microbiomes with CAC imaging, positioning it to transform both mechanistic understanding and prevention of CVD in AsA-NHPI populations. This study will leverage the NIH-funded MOSAAIC cohort of over 10,000 AsA-NHPI participants across five field centers, with baseline exams, questionnaires, biospecimens, and annual follow-ups. This R01 will generate critical data on CAC in 4,000 AsA-NHPI adults aged 40 and older. We propose two aims: (1) Characterize the current coronary atherosclerosis burden in AsA-NHPI adults, and (2) Investigate the relationship between gut microbiota and coronary atherosclerosis. Characterizing coronary atherosclerosis through CAC in AsA-NHPI populations will provide essential data to guide prevention strategies and improve cardiovascular health. Identifying gut microbiota associated with coronary atherosclerosis will enable early identification of high-risk individuals, laying the foundation for personalized prevention and targeted therapies.

NIH Research Projects · FY 2025 · 2025-09

The Housing Choice Voucher (HCV) program is the largest rental assistance initiative in the U.S., providing support to 5 million people annually. These vouchers help families rent homes in the private market, with recipients paying 30% of their income toward rent. As housing costs have risen, vouchers remain essential in alleviating rent burdens. However, despite the program’s importance, research on its causal impacts on health is limited. Conversely, little is known about the reciprocal relationship—how recipients’ health status might affect their success in using HCVs. This is a critical gap considering that just over half of recipients successfully use their voucher. To fill these gaps, we propose a study leveraging the New York City Housing Authority (NYCHA) HCV waitlist. In June 2024, NYCHA randomly selected 200,000 applicant households to be placed on its waitlist, in random order, to receive HCVs over the next several years. This randomized waitlist design offers a rare opportunity to study the causal impact of HCVs on a range of housing and health outcomes. Our study will employ both quantitative and qualitative methods to evaluate how baseline health status shapes voucher use and how voucher receipt affects health (primary) and housing outcomes. We will also explore how HCV use affects health through mediation analyses and qualitative interviews. Aims 1 and 2 use NYCHA HCV waitlist data (including HCV recipients and non-recipients) linked with statewide Medicaid data and other housing-related datasets. Aim 1 will examine the impact of baseline health status on voucher lease-up or success rates. Aim 2 will exploit the randomized waitlist design to estimate the impact of HCVs on housing and health outcomes, both overall and for policy-relevant subgroups. Aim 2a will examine housing outcomes including housing stability and quality. Aim 2b will examine health outcomes including health care utilization (emergency department visits, hospitalizations, outpatient primary and specialty care) and pharmacy claims data across a range of physical and mental health conditions. Mediation analyses will explore how specific housing factors contribute to health outcomes. Aim 3 will assess barriers and facilitators to successful HCV use and explore pathways between HCVs and health using in-depth qualitative interviews with voucher recipients. The proposed study, submitted in response to RFA-NR-25-001, will be carried out by a multidisciplinary investigator team that brings deep expertise from both the health and housing sectors. The investigators will work closely with a Study Advisory Board—including robust plans for meaningfully including and amplifying the voices of people with experience of housing insecurity—to maximize the impact of the research. This unique research will provide actionable evidence for health and housing practitioners in NYC and nationally to help them tailor, implement, and scale interventions to boost HCV success rates and maximize the impact of the voucher program and other housing interventions.

NIH Research Projects · FY 2025 · 2025-09

This proposal will continue to test the hypothesis that host-derived aldehydes are a critical component of host immunity against Mycobacterium tuberculosis. In the past funding period, we used bacterial and mouse genetics, biochemistry, immunology and cell biology experiments to test this hypothesis. We have identified bacterial mutants that are more sensitive than parental strains to various aldehydes. We have shown that these mutants are attenuated in mice with defects in aldehyde detoxification, showing that host-derived aldehydes can contribute to bacterial control. We continue to characterize the bacterial and host pathways. We are now working with TB Alliance to test frontline TB drugs on mice defective for aldehyde detoxification to determine if repurposing an FDA-approved drug that inhibits ALDH2 could improve TB treatment.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT This collaborative proposal aims to identify novel molecular targets and mechanisms of treatment responses in AUD based on the evolving knowledge of a novel mitochondrial mechanism of epigenetic regulation and therapeutic target for AUD. Our cumulative findings and work from others showed: 1) Administration of LAC, a pivotal mitochondrial metabolite synthesized by the mitochondrial enzyme CrAT, ameliorates executive function, which is affected in AUD, and leads to the activation of specific HATs with the corresponding up-regulation of key genes (BDNF, mGlu2) in the hippocampus and ventral striatum, which are substrates implicated in AUD. 2) LAC also protects against AUD-related oxidative stress and neuroinflammation.3)In AUD patients, LAC reduces heavy drinking days and ameliorates cognitive function.Yet, the targets and mechanisms by which LAC-related mitochondrial metabolism contributes to the epigenetic regulation of treatment responses in AUD are unknown. Based on these compelling preclinical and clinical findings, we set out to test the central hypothesis that, by facilitating LAC-related activity of HATs, expression of CrAT in neuronal exosomes contribute to GEXR response in AUD. We have exciting preliminary data: i)Lowest CrAT expression in these specific exosomes, worst cognitive dysfunction;ii)Potential role of mitochondrial metabolism in HAT activity; iii)Specific baseline traits, including cognitive impulsivity, predict GEXR response; iv)Potential role of this novel signaling pathway in GEXR response. Aims:1)Determine the role of baseline and longitudinal changes in central mitochondrial metabolism of LAC for treatment response; 2) Determine the role of central mitochondrial metabolism of LAC in the epigenetic regulation of gene expression for treatment responses in AUD; we will further map topographical and cellular specificity of changes. In addition to the primary features of this mitochondrial signaling, we will assess a broader set of related mitochondrial, epigenetic and transcriptomic markers focusing on oxidative stress, glutamate, neurotrophic and inflammatory pathways in neuronal exosomes isolated from plasma of AUD subjects from the NIAAA-sponsored randomized controlled trial of Gabapentin enacarbil extended-release (GEXR, N=338). Utilizing mixed effect models, machine learning and clustering algorithms, we will model the separate and combined features of the primary and related pathways in predicting changes in heavy drinking days unadjusted for likelihood of responding to GEXR (primary analysis) and separately in causal inference models of likely responders. This study will also determine the relationship between central and peripheral molecular pathways of interest (peripheral RNAseq, samples and clinical characteristics are already available in our newest NIAAA-funded R01, PI Marmar), and how these pathways are modified by specific known AUD comorbidities. This contribution is significant as it will advance understanding of mechanisms and targets of AUD treatment and identify critical sex differences. Mechanistic insights into central and peripheral markers of GEXR response is impactful as they will aid to develop new treatment models targeted at endogenously adjusting mitochondrial metabolism to function within the epigenetic milieu for personalized AUD treatment. This proposal is also innovative as we use innovative approaches that we are using in other NIH-funded studies to link in vivo molecular targets and pathways to treatment responses over-time. We have a published track record in this area.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Pregnancy represents a developmental window of profound change across virtually every tissue in the maternal body. While central roles for the uterus and mammary gland in this process are well established, we lack fundamental knowledge about the cellular changes that occur at other sites and how they affect short- and long-term maternal health. In this work, we will investigate tissue remodeling in the small intestine; an organ that must increase its nutrient uptake massively to absorb an estimated excess of 50,000 kcal throughout human pregnancy and 500 kcal per day during lactation. While gross anatomical changes of the intestine during pregnancy have been documented for decades, and reduced intestinal motility is one of the most common pregnancy symptoms, the cellular, molecular, and tissue-level mechanisms that remodel the intestine at this stage are not understood. The goal of this project is to identify unique aspects of the pregnant body that stimulate stem cells and drive intestinal remodeling to support maternal physiology. Cardiovascular disease, diabetes, and other metabolic disorders are among the leading causes of maternal morbidity and mortality during and in the year after pregnancy. We will use pregnancy as a model to study fundamental principles of tissue regeneration, while providing urgently needed insights into the poorly understood biology that underlies rising incidences of these pregnancy-associated diseases. The New Innovator Award would allow me to apply my expertise in epithelial tissue regeneration and nutrient metabolism to establish an urgently needed baseline of mechanistic understanding of the programs that remodel maternal digestive organs during pregnancy.