New York University School Of Medicine

NIH Research Projects · FY 2026 · 2024-11

Community violence exacts a devastating toll in the United States (US). A promising approach to reduce community violence focuses on investing in meeting the essential needs of communities that suffer from high levels of violence, such as housing, youth programming, and a well-maintained built environment. While these interventions have demonstrated success in reducing violence, they have been limited to particular neighborhoods or small geographic areas. Evaluations of investments to strengthen support services on a greater scale are limited by a lack of availability of robust data. To fill that gap, this project will use publicly available local budgets to build a detailed, longitudinal database of local funding expenditures for support services for the 50 most populous cities from 2010-2022 (Aim 1a). These include health, housing, education, financial support, the built environment (e.g., parks, green space), and community engagement (e.g., recreational activities and youth programming). The database will then be used to categorize cities into groups based on their trajectories in per-capita support service funding, and explore city-level predictors of these groups (Aim 1b). In Aim 2, the database will be used along with outcome and covariable data from the City Health Dashboard and various public sources to estimate the changes in homicides associated with increased levels of funding allocations for (1) housing, (2) family support, and (3) community engagement.. This research is urgently needed as evidence-based solutions are essential to reduce community violence. The research plan is complemented by an excellent interdisciplinary mentorship team and training plan to develop strong foundations in the theoretical understanding of community violence, practical knowledge of local budgetary processes, empirical knowledge of the effect of local funding expenditures on health outcomes, advanced causal inference methods for longitudinal studies, and communication skills for dissemination to various stakeholders. Building on the applicant’s background as a surgical trainee entering the field of trauma surgery, the combined research and training plan will prepare the applicant to successfully pursue a career augmenting clinical care of victims of violence with research to facilitate interventions that prevent interpersonal violence from occurring in the first place. It will also position him as a thought-leader and leader of empirical science on local funding as a factor that can impact health.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY/ABSTRACT Overdose (OD) and homelessness are two interlinked national crises in the United States (US). More than 1.25 million people experience homelessness each year, and drug OD is the leading cause of death among people experiencing homelessness (PEH). OD rates among PEH are 30–40 times higher than the general population. However, OD prevention interventions tailored for PEH remain underdeveloped, with limited evidence on effective strategies that reach this high-risk population. To fill this gap, this study will evaluate the implementation and impact of the New York City (NYC) Department of Homeless Services’ (DHS) Harm Reduction Strategic Plan (HRSP), a broad suite of shelter-based interventions tailored to PEH with the goal of reducing client OD risk. The HRSP—which combines universal harm reduction education provided to all clients at shelter entry (approximately 45,000 people annually) with an array of focused harm reduction and treatment services—is the first intervention of its kind implemented at scale in a large homeless services system in the US. We propose a rigorous, mixed-methods design that integrates epidemiological, data science, and qualitative methods to holistically evaluate the HRSP in collaboration with NYC DHS. Aim 1a is to estimate the impact of the HRSP shelter-based interventions on OD risk using epidemiological methods for impact evaluation applied to linked homeless services data, Medicaid claims data, and vital records. Aim 1b is to identify multidimensional subgroup heterogeneity (e.g., by race/ethnicity and other sociodemographic characteristics) in the impact of the HRSP interventions using a novel machine learning approach. Aim 2 is to identify optimal combinations of HRSP interventions to reduce OD risk using a two-stage machine learning strategy that will tease apart the impacts of simultaneously implemented HRSP component interventions. Aim 3 is to assess barriers and facilitators to implementation of the system-wide HRSP, and explore client and staff perspectives on substance use-related impacts using in-depth interviews and focus groups with DHS clients, staff, and key stakeholders. This innovative, community-partnered research is directly responsive to the CDC’s Overdose Prevention Research Priority of evaluating innovative OD prevention strategies tailored for populations facing a disproportionate burden of OD. This research is directly responsive to the current NOFO through its focus on a new and untested model of OD prevention delivered to a high-risk group in a community- based setting. In sum, we have a unique opportunity to rigorously evaluate the large-scale introduction of place-based OD prevention interventions tailored for PEH, a population that experiences a disproportionate burden of OD. The multidisciplinary investigator team will work with a Community Advisory Board to maximize the impact of the research, which has been designed to provide actionable evidence to inform local and national public health program and policy interventions.

NIH Research Projects · FY 2024 · 2024-09

Project Summary The objectives of this application are to characterize how age-related changes (1) in gene expression in niche cells and (2) in the niche microenvironment impact the process of spermatogenesis. It is known that decreased stem cell function with age is due at least in part to a decline in niche cell function and number. However, niche cell aging is poorly understood in most tissues. This proposal uses the adult Drosophila testis as a model for identifying age-related intrinsic and extrinsic processes in niche cell function. The work will capitalize upon the powerful genetics available in flies, as well as the ability to unequivocally identify all cells in the testis. The fly testis stem cell niche is formed by 12 quiescent niche cells (termed “hub” cells), which supports germline stem cells and somatic cyst stem cells (CySCs). The number of hub cells significantly declines during aging as they lose quiescence and transdifferentiate into fully-functional CySCs. The PI's published work shows that Activin signaling controls hub cell quiescence (and hence hub cell number) during aging. In young testes, Activin are inhibited by the secreted antagonist Follistatin (Fs). In older testes, there are more Activin mRNAs and less Fs mRNAs, leading to an increase in free local Activin proteins, which trigger the Activin receptor on hub cells. Autonomous Activin signaling causes hub cells to exit quiescence and transdifferentiate into new CySCs, resulting in the age-related decline of hub cells. These results support the model that age-related changes in Activin-responsive genes induce the cell cycle in aged hub cells. State-of-the-art transcriptomic techniques will be used in Aim 1 to identify genes differentially expressed in young and aged hub cells and genes whose expression is dependent on Activin signaling. Validated genes will be used to test the model that the differentially- upregulated genes causes hub cell proliferation, hub-to-CySC conversion, and, ultimately, hub cell loss. Other published work from the PI's lab shows an age-dependent change in the niche microenvironment: an extracellular matrix (ECM) surrounds the niche in aged but not young testes. When this ECM is inhibited, there is a significant increase in the number of hub cells in aged testes. These results support the model that the ECM in aged testes binds Activin, increasing the chance of Activin binding to its receptor. However, there are no reagents to monitor Activin or Fs proteins or pathway activity in vivo in flies. To overcome this barrier, new tools to monitor Activin components and signaling in flies will be developed in Aim 2. They will be used to test whether suppressing the ECM alters Activin and Fs distribution in aged testes and whether the ECM increases Activin near the surface of hub cells, resulting in more pathway activation in aged testes. The studies in this proposal will increase the knowledge base about how aging affects niche cell function and number in more complex systems and will foster new avenues of research into mechanisms and treatments for age-related male infertility.

NIH Research Projects · FY 2025 · 2024-09

ABSTRACT: The Managing Epilepsy Well (MEW) Network has developed several epilepsy self-management programs that have been shown to improve a range of health outcomes for people with epilepsy (PWE). Two of these programs are UPLIFT (Using Practice and Learning to Increase Favorable Thoughts), which focuses on depressive symptoms, and PACES (Program of Active Consumer Engagement in Self-Management in Epilepsy), which targets epilepsy self-management more broadly. In prior and current funding cycles, the NYU MEW Network Collaborating Center adapted UPLIFT for Hispanic PWE, evaluated the adapted program, and is currently conducting a replication trial in a diverse sample of PWE. UPLIFT and PACES are prime candidates for widespread dissemination given their efficacy, scalability, availability in English and Spanish, and implementation structure (e.g., national facilitator training and technical assistance programs). Implementation of UPLIFT and PACES in healthcare and community settings is ongoing but remains limited by the lack of discrete, sustainable funding models. To facilitate program adoption and maintenance, key questions related to costs and cost-effectiveness of the programs must be addressed. We propose to conduct economic evaluations of UPLIFT and PACES that will generate critical data to enhance adoption in clinical and community settings, and help identify strategies for reimbursement. We will analyze data from completed and ongoing RCTs testing these programs; collect surveys from the large national pool of trained UPLIFT and PACES implementers; and conduct prospective studies of UPLIFT and PACES in both healthcare and community-based settings in New York. PWE will be enrolled from epilepsy clinics at NYU Langone (Manhattan and Brooklyn) and from the Epilepsy Alliance of West Central New York. Guided by Gold et al.’s (2022) model of measuring cost data in implementation science, we will assess implementation, intervention, and downstream costs for the proposed economic evaluations. We will form an Advisory Board comprised of clinicians, administrators, community partners, implementation scientists, and program facilitators to ensure that all data needed to inform future decision making are collected. Our specific aims are to (1) Implement UPLIFT and PACES in healthcare and community-based settings; (2) Measure implementation, intervention and downstream costs of the two programs; (3) Conduct economic evaluations of UPLIFT and PACES; and (4) Continue and expand collaborations with other MEW Network centers. Our multi-pronged approach will allow us to evaluate the costs of implementing UPLIFT and PACES in both clinical and community settings, with diverse patients (including Spanish speakers), and with different facilitator types in order to better understand costs associated with these variations. By generating data on costs and cost-effectiveness of UPLIFT and PACES, we will provide critical evidence to inform strategies to enhance their adoption and sustainability, ultimately leading to improved health and quality of life among diverse PWE.

NIH Research Projects · FY 2025 · 2024-09

Visual impairment engenders mobility losses, debility, illness, and premature mortality. Visual impairment and related mobility losses correlate with high barrier volume in the healthcare domain, which can restrict equal access, widen gaps in health outcomes, severely compromising quality of life (QoL). In many cases, health and wellbeing are ‘attacked’ by vision loss in any form factor and psychosocial barriers such as anxiety and depression are compounding influences that increase as deficits scale. Imagine navigating a new hospital or clinic with little or no vision, using assistive technology that inconsistently operates or trying to read accessible content that is only employed in ‘some’ care areas. Navigating complex healthcare systems that require a client to ‘jump’ from island of accessibility to island of accessibility is not sustainable; the result is a tendency to directly avoid care centers, missing appointments or to create excuses to indirectly avoid this inaccessible quagmire. In fact, data suggests that patients with blindness and low vision (pBLV) are less likely to be screened for cancer and much more likely to be diagnosed with cancer later, on average, with larger tumor burden and higher stage, resulting in greater mortality rates. Our central hypothesis is that gaps in health outcomes stem, in large part, to inaccessible healthcare systems and require comprehensive frameworks that offer, maintain, and support reasonable accommodations. To better support pBLV and augment personal freedom and agency through the promotion of health and wellbeing, we seek to engage in a mixed-methods approach that leverages qualitative methods to systematically characterize the required support and accommodations and then quantitative methods to assess the performance of a new implementation framework with tailored performance metrics. Our Team is well-positioned to successfully execute all study goals, with unique leadership in accessibility and universal design, lived experience and care coordination/navigation, an evidence-based intervention to overcome factors impacting access to care. The proposal has three aims conducted across three phases, focused on characterization, creation and testing/validating this approach in an urban healthcare setting. First, we will identify factors that affect the accessibility of healthcare services for pBLV. We will then use intervention mapping to develop a patient navigation intervention to assist with the provision of reasonable accommodations for pBLV. Third, we will evaluate the navigation intervention to ensure the reasonable accommodations are both feasible and effective. Given this foundation and planned advances, we predict that this implementation framework will substantially mitigate barriers and associated adverse health outcomes, advancing equal access to high-quality care.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY Background: There is an urgent need for new medications for OUD that can improve treatment outcomes when used alone or in combination with existing treatments. Early stage trials of psilocybin for the treatment of substance use disorders have consistently shown robust effects on target drug use and underlying neuropsychopathology. Despite these promising findings, there are no published data on the clinical effects of psilocybin in OUD, either alone or in combination with empirically supported treatment. Objective: We propose to use the UG3/UH3 mechanism to jump-start research on psilocybin to treat OUD. The study will use an innovative “seamless” adaptive design and an equally innovative treatment model to test the efficacy of psilocybin in OUD patients who continue to use non-prescribed opioids despite adherence to methadone treatment. Method: We will recruit 240 participants (90 in the UG3 phase, 150 in the UH3 phase) from four opioid treatment programs (OTPs) serving predominantly minoritized and marginalized communities in New York and New Mexico. Psilocybin treatment—implemented as an adjunct to ongoing OTP treatment—will be provided by a clinician from an academic research center who has training in psychedelic treatment, working with an OTP staff member who has a clinical relationship with the patient. Participants will continue methadone treatment and will receive a single dose of investigational product (IP) during an all-day IP administration session. Weekly urine drug screens and continuous self-report of opioid and other drug use will be collected for 24 weeks after IP administration, along with measures probing OUD-related neuropsychopathology and functional outcomes. In the UG3 phase, participants will be randomly assigned to one of three groups: high dose psilocybin, medium dose psilocybin, and low-dose psilocybin control. In order for the study to continue to the UH3 phase, the UG3 phase must demonstrate successful completion operational milestones, and an interim analysis must demonstrate that pre-specified “Go” criteria for safety and efficacy have been met. Using a priori decision rules, the interim analysis will also determine which of the active treatment groups (high-dose, medium-dose, or both) will be retained of the UH3 phase of the trial. Significance: This rigorous, well-powered efficacy trial will rapidly and efficiently advance understanding of the potential value of psilocybin in the treatment of OUD. If the trial finds a robust efficacy signal, the data will provide strong evidence and a practical treatment model for a full-scale drug development program to achieve an FDA indication for psilocybin as a treatment for OUD.

NIH Research Projects · FY 2025 · 2024-09

Project Summary/Abstract The New York City (NYC) Cancer Prevention and Control Research Network Collaborating Center (CPCRN) builds on the multi-disciplinary expertise and community partner networks of the NYU-CUNY Prevention Research Center (PRC), including the City University of New York (CUNY) School of Public Health, the NYU Langone Health’s Department of Population Health, and NYU Langone Perlmutter Cancer Center, an NCI- designated Comprehensive Cancer Center. The goals of the NYC CPCRN are to employ social determinants of health (SDoH) strategies to reduce preventable cancers, increase early cancer screening and detection, and improve cancer equity among low-income, minoritized populations in urban areas. The technical assistance, training, and dissemination activities we offer are centered on participatory approaches, disaggregated data collection, cultural adaptation, and implementation of evidence-based cancer prevention and control strategies relevant to diverse, urban communities in place-based and clinical settings. For the five year period, we propose conducting two studies that will each leverage an established network of NYC community and clinical partners serving the Asian American, Black, Latine, and other understudied immigrant communities in order to reduce cancer disparities and improve cancer control. The first study is implementation evaluation to assess the factors that impact the reach, effectiveness, and adoption of clinical decision support and culturally and linguistically adapted materials to improve lung cancer screening rates among low-income, multi-ethnic communities in NYC. Using a participatory approach to engaging multiple stakeholders and diverse communities, we will apply RE- AIM and the Consolidated Framework for Implementation Research to evaluate, refine and optimize clinical- community strategies focused on improving lung cancer screening among Asian American, Black, Latine, and other understudied immigrant communities. We also propose a second formative research study, to inform a multi-level, healthcare provider intervention to improve human papilloma virus (HPV) vaccine rates among high- risk and understudied communities in NYC, specifically Arab- and Mexican American. The proposed NYC CPCRN application is aligned with Healthy People 2030 cancer-related objectives to increase the proportion of adults who receive screening for lung cancer and to improve HPV vaccination rates. Research will focus on strengthening community-clinical linkage models, employing CHW strategies for cancer patient navigation, and tackling SDoH to reduce cancer disparities and advance equity. The NYC CPCRN will also continue to actively engage and collaborate with partners across the network in joint work and interest group activities.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY Firearm violence is a persistent public health crisis that disproportionately affects young Black and Brown people. From 2019 to 2021, firearm homicide rates rose an alarming 46% among people aged 10–34 years, peaking at the highest levels seen in 20 years and exacerbating stark racial/ethnic inequities. Policies that address the conditions contributing to persistently high rates of firearm violence are needed. Two major categories of policies have a strong scientific premise but lack rigorous evaluations of their effectiveness in reducing firearm homicide and nonfatal firearm assault injuries (herein referred to as “firearm assault”). First, alcohol control policies (e.g., alcohol outlet density restrictions) are a well-established means of limiting alcohol availability thereby reducing alcohol-related harms. No studies have clearly established whether alcohol control policies prevent firearm assault. Second, economic support policies (e.g., income supplements) influence upstream causes of firearm assault including poverty and income inequality, but the impacts of these policies on racial/ethnic inequities in firearm assault are unknown. Local (city and county) policies, in particular, are likely to shape the environments in which firearm assault unfolds. Further, research assessing the synergy between these sets of policies is absent but essential to identify multifaceted solutions that maximize impact. This will be the first quasi-experimental study to test the impacts of a range of local alcohol control and economic support policies on overall rates and racial/ethnic inequities in firearm assault among young people. The study will leverage heterogenous policy changes introduced by county governments during the COVID-19 pandemic, which provide an unprecedented opportunity to rigorously assess impacts on firearm assault. The investigators will establish a cohort of ~90% of California residents ages 10-32 years, and construct a longitudinal hierarchical database by individually linking birth records, emergency department encounters, inpatient hospitalizations, and deaths, combined with comprehensive legal epidemiologic research on county policies from 1/1/2018 to 12/31/2022. The Specific Aims are to evaluate the impacts of county 1) alcohol control policies, 2) economic support policies, and 3) their interaction, on firearm assault, overall and by race/ethnicity among California young people. This study will provide critical evidence that local governments are urgently seeking on which policies they could enact or avoid to reduce firearm assault and promote health equity in communities. This project addresses Objectives 2 and 3 of RFA-CE-24-030 as it entails effectiveness research to evaluate alcohol control policies as place-based prevention approaches and economic support polices as structural approaches to reduce firearm assault. It also addresses NCIPC’s Cross Cutting Violence Prevention priority to “evaluate the effectiveness… of policies or community-level change strategies designed to enhance the economic and social environment to reduce multiple forms of violence throughout the lifespan.”

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY/ABSTRACT Racial and ethnic minoritized immigrant communities experience disproportionately higher rates of morbidity and mortality from type 2 diabetes (T2D), cardiovascular disease (CVD), and other chronic diseases than individuals born in the United States. Immigrant populations face significant challenges accessing healthcare and engaging in health-promoting behaviors due to barriers related to social determinants of health (SDOH). The NYU–CUNY Prevention Research Center (PRC) has developed effective approaches to improve access to care and reduce chronic disease disparities in partnership with immigrant and minoritized populations in urban settings. Since 2009, the PRC has played a leading role in generating, translating and adapting evidence-based interventions (EBIs), with a focus on effective models of community health worker (CHW) interventions. The PRC is an innovative and successful public–private partnership between a CEPH-accredited, minority-serving public school of public health (CUNY) and a leading academic medical school with a 15-year history of leadership in the national PRC Network (NYU). In the next cycle, the NYU–CUNY PRC Center will 1) expand and sustain its infrastructure and agenda to accelerate translation of chronic disease research evidence into policy and practice, 2) engage cross-sectoral partners to support translation of research findings into practice and widespread adoption of EBIs, 3) facilitate bi-directional training and technical assistance across partners and PRC networks to support translation of prevention research, and 4) disseminate research findings and translation products. For the PRC's core research project, we propose a type 2 hybrid implementation-effectiveness trial to test a multi- level implementation strategy that addresses key community-, clinic-, and patient-level barriers to uptake and adoption of diabetes self-management education and support (DSMES). We test: 1) a CHW-enabled community- clinic linkage (CCL) model across a network of federally qualified health centers and community-based organizations to improve clinical coordination and address social needs, followed by 2) a series of 24 culturally and linguistically tailored DSMES videos delivered by text message (mhealth) to improve knowledge, skills, and self-efficacy to manage T2D. We will test this multi-level strategy for DSMES uptake among low-income Hispanic and Asian immigrant adults with T2D. We will 1) identify facilitators/barriers to the implementation process and assess patient uptake of specific DSMES delivery strategies (primary implementation outcome); 2) examine the effectiveness of CHW-enabled CCL on reducing HbA1c at 6-months and the effectiveness of additional mhealth on sustaining glycemic control at 12-months (primary effectiveness outcome); and 3) assess and improve the sustainability and scalability of the package using participatory system dynamics modeling. Finally, the NYU- CUNY PRC will support the national PRC network to: 1) engage policymakers around SODH and health outcomes; and 2) adapt, implement, and translate EBIs. Our Center harnesses population health resources and prevention science expertise, and builds upon partnerships to reduce T2D and other chronic disease disparities.

NIH Research Projects · FY 2025 · 2024-09

Building on a robust, multi-sector partnership between the City University of New York (CUNY) School of Public Health, the NYU Grossman School of Medicine’s Department of Population Health, the proposed project aims to increase scholarly understanding of vaccine hesitancy and provide federally-qualified health centers with managerial and ethical guidance on how increase routine vaccine uptake among children 0-2yrs. Over the five year project period, NYUGSoM will lead on two research projects: one, a mixed-methods exploration of vaccine attitudes and beliefs among parents 0-2 years and a second, a managerial and ethical analysis of an evidence based practice for increasing pediatrics vaccination at a federally qualified health center. Throughout the project period, CUNY will lead activities to coordinate between the funded Collaborating sites and disseminate past and new findings through a robust partner network. The first piece of research gathers individual-level data about the roots of vaccine hesitancy and skepticism among parents of young children, and critically, how these attitudes have been overcome by individuals who subsequently vaccinated 0-2yr old children. We will design and field an online survey of parents of 0-2 years, recruiting participants via social media. The survey will be designed to assess the quality of parents’ relationship to health care providers and test the acceptability of various behavioral economics approaches to increasing vaccine uptake. The survey will also act as a recruitment device for follow-up interviews among select participants who report having once been vaccine hesitant or skeptical but now have children who are up to date on all vaccines. These interviews will generate data for analysis on how vaccine hesitancy and skepticism has been overcome. The second piece of research focuses on organizational-level efforts to increase vaccine uptake among 0-2 year olds, specifically in a federally qualified health center. Informed by behavioral economics and prior literature indicating effectiveness, a local FQHC adopted an “opt-out” approach to pediatric vaccination where parents are assumed to consent to vaccination unless they specifically object. Guided by implementation science frameworks, we will collect data on-site about how this “opt-out” approach is managed to create clear guidance for other FQHCs nationally that may want to adopt, or adapt a similar approach. Informed by staff perspectives as well as the previously mentioned parent survey, we will also generate a set of ethical considerations for using an “opt-out” approach to vaccination in an FQHC population which is often facing various sources of marginalization and disempowerment. The proposed project is closely aligned with at least four Healthy People 2020 Objectives: (1) to maintain the elimination of measles, rubella, congenital rubella syndrome and polio, (2) reduce proportion of children who get no recommended vaccinations by 2 yrs of age, (3) maintain the vaccination coverage level of 1 dose of the MMR vaccine in children by 2 years and (4) increase the coverage level of 4 doses of DTaP vaccine by 2 yrs of age.

NIH Research Projects · FY 2025 · 2024-09

Coronary heart disease (CHD) is the leading cause of mortality and disability worldwide, and accounts for 13% of global deaths and 370,000 deaths annually in the US. Accumulating evidence suggests exposure to inorganic arsenic (As) and other (often co-occurring) toxic metals may be an independent risk factor for CHD. Although most individuals are simultaneously exposed to different metals, most studies focused on the toxicity of individual metals. Combinations of exposures may have different, and possibly stronger, effects than each exposure separately. However, there were no large epidemiologic studies on either the effects of metal mixtures (specific combinations of metals) or metal–metal interactions on CHD risk. Moreover, the inadequacy of data on genetic susceptibility masks the effects of environmental exposures. Conversely, genetic studies often ignore that effects of genetic factors on CHD are modulated by varying levels of environmental factors. Data on gene–metal interactions can identify population subgroups with much higher disease risks. However, the few studies focused on gene–metal interactions in CHD had limited sample sizes (n = ~200), tested a single exposure only, considered only <200 genetic variants in <20 genes, and included homogenous study populations with a limited range of exposure to assess full dose–response relationship. Several genome-wide interaction studies (GWIS) on cardiovascular traits identified genetic markers not previously reported by genome-wide association studies. However, no GWIS has investigated gene–metal interactions in CHD. While studies on gene–metal interactions are critical to provide insights into disease biology, metabolomics—the systematic analysis of low molecular weight metabolites in response to external exposures—offers another approach to elucidate mechanisms by which metal mixtures may lead to CHD. However, no studies investigated the interplay of metal mixtures and metabolomics profiles in CHD risk. We propose to: 1) evaluate the roles of metals and metal mixtures in CHD risk; 2) assess genetic susceptibility to the effects of metals and metal mixtures on the risk of CHD; and 3) identify the potential urinary metabolites associated with both CHD risk and metals/metal mixtures. We will leverage data and samples from three prospective cohorts—the Health Effects of Arsenic Longitudinal Study (HEALS), the Strong Heart Family Study (SHFS), and the Multi-Ethnic Study of Atherosclerosis (MESA)—that include diverse adult populations. We anticipate our results will show that metal mixtures and genetic susceptibility both contribute to CHD risk . They may also increase knowledge of potential underlying mechanisms (altered urinary metabolites or genetic pathways) by which metals and metal mixtures promote CHD. Supporting studies of combined exposures or mixtures is one of the goals of the NIEHS Strategic Plan 2018–2023 to advance environmental health sciences. This project will address an important public health issue and clinical topic with the potential to provide evidence on the biological mechanism of metal mixture toxicity on CHD development and can improve clinical understanding for prevention and controlling exposures in the US and abroad.

NIH Research Projects · FY 2025 · 2024-09

Recent trends in admissions policies in higher education have the potential to alter the medical education learning environment. These changes affect not only undergraduate education but also extend to MD and MD-PhD programs. The full consequences of these policy shifts are currently unknown and present several important knowledge gaps that we seek to address in this study. Firstly, we will examine how trends in medical school applicants and matriculants have changed following the policy trends of the last 10 years. Second, we will describe how MD and MD-PhD programs are adapting applicant selection criteria in response. Third, we will characterize the application and matriculation experiences of MD and MD-PhD students under the revised admissions landscape. Our findings will be disseminated widely through peer-reviewed scientific publications, conference presentations, policy and advocacy reports, and podcasts to various stakeholders in education and health policy via partnerships with the Association of American Medical Colleges, the American Medical Association, and the National Academy of Medicine.

NIH Research Projects · FY 2025 · 2024-09

After stroke, upper extremity (UE) motor impairment is especially disabling and has few effective therapies. Vagus nerve stimulation paired with rehabilitation training (paired VNS) has recently emerged as a promising therapeutic approach. Paired VNS delivers a burst of electrical stimulation to the cervical vagus nerve during a purposeful training movement. In rodent stroke models, paired VNS drives the release of pro-plasticity neurotransmitters that enhance cortical reorganization and boost motor gains. A recent Phase III clinical trial in chronic stroke patients also found that paired VNS improves UE motor impairment compared to rehabilitation without stimulation, but gains were generally modest and clinical benefit varied. It is likely that additional motor gains are possible if paired VNS therapy can be optimized. Understanding how paired VNS works in humans and in whom paired VNS works best will be a critical step in unlocking its clinical potential, allowing us to improve treatment regimens, individualize delivery, and select suitable therapeutic candidates. Preclinical and clinical evidence illuminates several candidate neural substrates for the actions of VNS, but these are yet untested in humans with stroke. Our central hypothesis is that VNS-induced changes in motor, cognitive, and affective systems underlie motor gains, and that sufficient neural integrity is required to achieve a clinically meaningful response. To test this hypothesis, we will study chronic stroke patients implanted with our next- generation VNS device. We will deliver blocks of active or sham VNS paired with UE rehabilitation in a randomized, blinded, crossover design. Before and after treatment blocks, we will characterize neural networks and their associated behaviors using transcranial magnetic stimulation, diffusion and functional MRI, and quantitative behavioral testing. In Aim 1, we will identify VNS-induced neural changes in motor, cognitive, and affective systems that mediate motor gains. In Aim 2, we will identify baseline structural, functional, and injury markers that predict clinical benefit from paired VNS. This project capitalizes on the combined strengths of its multi-PI leadership and investigative team, who bring complementary expertise in motor recovery mechanisms, VNS device development, clinical trial design and execution, and advanced neuroimaging and biostatistical analyses. At the completion of the study, we expect to have generated key mechanistic insights regarding paired VNS in human chronic stroke, providing a solid basis to optimize the efficacy of this therapy. More broadly, this study could reveal targetable pathways for other neuromodulation strategies and could launch new treatments for cognitive and mood disorders after stroke. The proposed research is thus an exciting next step in neurostimulation after stroke. These advances will enhance the clinical potential of paired VNS and will ultimately optimize neurorehabilitation for millions of patients with chronic stroke deficits.

NIH Research Projects · FY 2026 · 2024-09

PROJECT SUMMARY This Mentored Research Scientist Development (K01) Award will support my long-term goal of becoming an independent investigator who specializes in examining the techniques food companies use to market unhealthy products to Black communities, with a specific focus on advanced digital technologies, such as virtual reality (VR). Food marketing has been unequivocally linked to poor diet and risk of excessive weight gain in young people. Food companies disproportionately target Black consumers with more advertisements (“ads”) and the least healthy ads, contributing to nutritional disparities and nutrition-related diseases. To expand their reach, food companies have developed VR marketing experiences that are engaging, highly sophisticated, and may more powerfully elicit biological signals precipitating a motivation to consume foods. Although most food marketing studies focus on children and adolescents due to their inability to recognize persuasive intent, Black young adults may be especially at risk of the effects of food marketing exposure due to being highly targeted, shifts during this developmental period, and food/nutritional insecurity. No study has examined the effect of VR food marketing exposure on biological signal activation and purchase intention among Black young adults, or the interactions with food/nutritional insecurity. To address these gaps, I have developed the following specific aims/hypotheses. Aim 1 will be to determine the extent to which VR food marketing influences purchase intention and whether effects are more pronounced in Black young adults. I hypothesize that exposure to VR food marketing will influence purchase intention versus the VR non-food control, and Black (versus white young adults) exposed to VR food marketing will demonstrate higher purchase intention. Aim 2 will be to understand the influence of biological signal activation on the relationship between VR food marketing and purchase intention. I hypothesize that larger electrodermal amplitude and higher salivary reactivity will lead to stronger purchase intention in those randomized to VR food marketing versus the control and that the effects will be more pronounced among those with higher weight. Aim 3 will be to explore the interactions among race/ethnicity, food/nutritional insecurity, biological signal activation, and purchase intention among Black young adults exposed to VR food marketing. I hypothesize that those reporting low/ very low food security will demonstrate stronger electrodermal amplitude and higher salivary reactivity when exposed to the VR food marketing condition versus all others. I will develop a community-based young adult advisory board to assist with interpretation of the results. It will be necessary to obtain mentorship and training in VR, integrating biological measurements into an experimental paradigm, and applied statistical analyses for biological outcomes to complete this project and develop the critical research competencies to elucidate how advanced digital food marketing strategies influence nutritional disparities and nutrition-related disease risk among Black young adults. Findings can inform novel behavioral interventions and regulatory efforts, such as the Federal Trade Commission’s initiative to reduce stealth digital food marketing targeting certain groups.

NIH Research Projects · FY 2024 · 2024-09

ABSTRACT RASopathies encompass a spectrum of genetic disorders caused by germline gain-of-function variants in genes encoding critical components of the RAS/MAPK pathway, leading to dysregulation and hyperactivation of the pathway in cells. The RASopathies, including Noonan, Cardio-facio-cutaneous, and Costello syndrome, are characterized by overlapping clinical features, such as delayed growth, cardiovascular abnormalities, developmental challenges, tumor predisposition and many others. Although individually rare, when combined, RASopathies represent one of the most common congenital disorder. Despite their high prevalence and pathway identification, therapeutic options remain limited, and novel treatment strategies are urgently needed. Emerging preclinical and clinical evidence suggest that RASopathies often lead to metabolic and bioenergetic abnormalities. In addition, our preliminary research supports the critical role of mitochondrial disfunction and metabolite alteration in the pathophysiology of a RASopathy preclinical model. Therefore, this project aims to elucidate the role of mitochondrial function in RASopathies. Specifically, in Aim1 we will analyze mitochondrial morphology and function, including enzymatic activities and oxygen consumption, in tissues from a RASopathy mouse model that highly recapitulates the clinical features of these syndromes. In Aim 2 we will focus on identifying the signaling pathways and/or metabolites that contribute to mitochondrial dysfunction in the RASopathies. By leveraging advanced techniques and models, our research aims to gain further insights into the understanding of RASopathy pathogenesis. Ultimately, findings from this study hold promise for informing the development of targeted therapies to address the metabolic phenotype associated with RASopathies, thus improving outcomes for affected individuals.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY Eccrine sweat glands are the most abundant glands in human skin and are essential for thermoregulation and water balance. Patients with severe burn injuries and congenital sweat gland deficiencies cannot properly maintain body temperature, which can lead to heat stroke and organ failure. The recent identification of multipotent stem cells in sweat glands presents great potential to help these people to thermoregulate efficiently by opening the way for de novo sweat gland regeneration. Nonetheless, regeneration of fully functional sweat glands will require better understanding of the endogenous signals that normally regulate differentiation of sweat gland stem cells. Precise innervation and neuronal control are indispensable for sweat glad function since neuronal signals elicit sweating, and further, as we previously discovered in our lab, these signals are critical for sweat gland maturation. Sweat glands and neurons rely on each other for precise co-development. However, very little is known about how neuronal inputs influence sweat gland development, especially sweat gland stem cells. We hypothesize that neuronal signals are critical for the specification of sweat gland stem cells during development. Using mouse sweat glands as a model, we will investigate the molecular changes in sweat gland stem cells during development when lacking innervation, and further identify the downstream pathway within sweat gland stem cells that mediate the effect of neurotransmitters upon stem cell maintenance. Through combined use of mouse genetics, immunofluorescent confocal and light sheet imaging, single-cell RNA sequencing, fluorescence-activated cell sorting, and tissue explant and cell culture systems, we plan to: 1) investigate the effect of denervation during sweat gland development and homeostasis; 2) dissect the roles of specific neurotransmitters in sweat ducts and sweat gland development; and 3) understand the mechanism(s) by which calcium mediates neuronal control of sweat gland stem cell fate. Completion of our proposed studies will provide novel insights into molecular mechanisms by which nervous system influence sweat gland morphogenesis and cell fate determination at each developmental stage, as well as better understanding on how sweat glands and nerves co-develop into a functional unit. Ultimately, our proposed work will contribute to regenerative therapies for patients suffering from sweating deficiency.

NIH Research Projects · FY 2024 · 2024-09

Living donor kidney transplantation is the best treatment for selected patients with end-stage kidney disease (ESKD). However, living kidney donation is not without medical consequences and risks. As in the general population, long-term health risks in donors vary by race, sex, and age. Post-donation sequelae have been primarily studied in national registry data linked to mortality and ESKD data, with comparison groups of “healthy non-donor controls” contrived from unrelated cohort studies. One notable risk to donors is developing ESKD, the very condition their donation sought to fix.   Our team has been working for more than a decade to understand risk factors for kidney living donors. Several environmental, lifestyle, and genetic risk factors have been demonstrated among the general population, and the fact that biological relationship to the recipient is a risk factor for ESKD in donors suggests a possible gene-mediated risk in living donors. LKDs, however, are biologically distinct from the general population and donor risk factors for ESKD might or might not align with those in the general population. On the one hand, loss of one kidney and hyperfiltration of the existing kidney may increase the impact of genetic or other risk factors; on the other hand, that donors are healthy at the time of donation may mean that some risk factors have decreased or no impact. Unfortunately, the impact of many genetic, clinical, social, and lifestyle risk factors that may confer added risk of ESKD in kidney donors is unknown, forcing donors to make a life-altering decision with inadequate information. We aim to improve the counseling and selection of living donors by developing tools for tailored risk prediction according to donor characteristics. However, this cannot be done prospectively because it takes so long for living donors to develop ESKD. This work will prepare us to use an innovative case-cohort study design to address this gap. We propose to use qualitative research to inform recruitment strategies and messaging to maximize recruitment of black donors. We will conduct semi structured interviews with 30 living kidney donors to understand willingness to participate in a case cohort study and undergo genetic testing and counseling for research purposes. We will also gather their perspectives to inform our recruitment strategy. We will also conduct community engagement activities via a community advisory board (Living Kidney Donor Research Advisory Council) to build trust and inform future research approaches. In this process, we will also obtain feedback and recommendations for how to best produce videos to be used for recruitment purposes.

NIH Research Projects · FY 2025 · 2024-09

Project Summary Aging has a pronounced effect on the human brain, yet differences between individuals can be substantial, and are likely influenced by genetic, environmental lifestyle factors, including several modifiable risk factors that may impact brain aging and play a role in the onset of Alzheimer’s disease (AD) and AD related dementias (ADRD). However, timely recognition and understanding of accelerated brain aging and the onset of neurodegeneration underlying AD is needed in order to identify individuals at risk and take preventive measures. So far, most brain-age research uses structural neuroimaging to index brain volume, which sensitivity is inherently limited to the millimeter resolution of MRI. Instead, we will use advanced, yet clinically feasible diffusion MRI, which provides a unique window to the mesoscopic scale, intermediate between molecular and voxel dimensions, where aging and distinct pathological processes happen. We hypothesize high sensitivity of dMRI to determine brain-age and deterioration due to AD/ADRD. In addition, the role of white matter in aging and AD/ADRD is still unclear, and particularly the exact contribution of both neuro-inflammatory processes (gliosis, astrocytosis, macrophage infiltration) and neurodegenerative processes (demyelination, axonal degeneration and loss). The desired specificity is attainable using our mesoMRI modeling approach. In response of RFA-AG-24-018, we propose to develop a biologically relevant multi-scale model of brain aging using our in vivo mesoMRI approach, which holds enormous untapped potential to bridge the meso-macro gap and disentangle the extent of neuro-inflammation and neurodegeneration. We will leverage the unique presence at NYU Langone Healthy (NYULH) of a large series of mesoMRI scans of control, patient and subjects of the well-characterized cohort of the Alzheimer’s Disease Research Center (ADRC) along with a large collection of brain specimen of both controls and various dementia diagnosis. We propose in the R21-phase to create a large advanced, multi-shell dMRI dataset, unifying several large- scale dMRI datasets along with our local NYULH cohort extracted from routine clinical MRI datasets and electronic health record data. We will generate brain charts of quantitative dMRI and mesoMRI markers across the life-span, to then create a brain microstructure age framework. In the R33-phase, we evaluate the effect of race/ethnicity, sex and life style factors on aging and evaluate the sensitivity of brain microstructure to increased aging, neuro-inflammation and neuro-degeneration along the continuum of AD/ADRD, in addition to validation in postmortem human brain using histopathology and proteomics, and evaluation of longitudinal changes. Impact: Achieve a brain-age framework based on clinically feasible dMRI scans with robust sensitivity that provides meaningful insight into the microstructural processes underlying brain aging and AD/ADRD and will enable quantitative assessment of treatment response to future symptomatic and disease-modifying therapies.

NIH Research Projects · FY 2025 · 2024-09

Modified Abstract: In collaboration with the Shelby County Health Department, which has jurisdiction over Memphis as well as rural northwest Mississippi and Arkansas, we propose to inform policy decisions towards improving HIV outcomes for population-level and subgroup-specific HIV goals in three different settings that together typify high incidence locations in the U.S. HIV epidemic (New York City, Memphis, and northwest Mississippi). We will use mathematical modeling to simulate alternative ways to distribute resources across interventions, settings, and target populations to reduce HIV incidence and improve overall health. Our analyses will be distinguished by incorporating screening and responding to CASM conditions (Conditions of Alcohol, Substance and Mood), measures of dispersion-aversion (i.e., willingness to trade-off some aggregate benefit in order to distribute it more evenly) towards vulnerable subgroups, and the promising new modalities of long-acting-injectable PrEP and ART. Our partners at the Shelby County Health Department and their larger group of stakeholders will provide context on local HIV infection patterns and feasibility and acceptability constraints to inform modeling analyses. Modified Narrative: In collaboration with the Shelby County Health Department and other health jurisdictions, we will simulate alternative policies to maximally reduce HIV incidence and improve overall health in three settings (New York City, Memphis, and northwest Mississippi). We will place special emphasis on the role of alcohol, substance and mood disorders on HIV transmission and progression. We will also incorporate measures to address uneven health burden in vulnerable subgroups.

NIH Research Projects · FY 2025 · 2024-09

Abstract: Neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) have different underlying pathophysiological substrates. It follows, then, that these disorders may affect the visual system in different ways. Structural and functional changes in the visual system are critical to understanding and treating symptoms and impairments that impact quality of life. Structure, as revealed by imaging of the retina, an outgrowth of the brain that is amenable to direct visualization, can provide potential biomarkers to aid in the monitoring of disease progression. Advances in in vivo optical coherence tomography (OCT) imaging over the past few decades have shown that eyes of patients with AD and PD have generalized thinning of inner retinal layers associated with the ganglion cells, and microvascular changes. However, such changes likely do not directly reflect the primary pathology across the spectrum of neurodegenerative diseases. Deciphering different manifestations of the ocular component to neurodegenerative disease requires a clear step forward in the level of detail provided by approaches to image the retina. To achieve this, we propose to develop and optimize the next generation of visible light optical coherence tomography (OCT), with 1 micrometer depth resolution, and associated machine learning tools, for imaging and quantifying ocular neurodegeneration. Our visible light OCT instrument achieves 3-5x better resolution than commercial near-infrared OCT systems. The improved resolution provides a uniquely stratified view of cellular architecture in the inner nuclear layer (INL) and of synapses in the inner plexiform layer (IPL), potentially providing in vivo insights into circuit- or cell-specific retinal changes that have been reported in both AD and PD. Performing OCT in the visible light range is also significant because macular pigments, which are associated with cognition, are detectable and quantifiable through novel approaches. In addition, hyperspectral information in the visible light range purportedly detects protein deposits in the retina. In fact, our preliminary results suggest the ability to both localize hyper-reflective features in an amyloid AD mouse model and to decipher their hyperspectral signatures. Guided by basic studies in mice that verify the relationship of imaging features to disease pathophysiology, we will investigate the potential for visible light OCT measures and markers to distinguish eyes of persons with MCI (AD) and PD, both between disorders and with comparison to cognitively and neurologically normal controls of similar age. Based on the premise that oculomics is enhanced by placing the eye in the context of the entire visual pathway, our research plan, supported by our team’s expertise, will integrate advanced imaging with visual function testing and quality of life measures.

NIH Research Projects · FY 2024 · 2024-09

Drug use among older adults has increased sharply over the past decade. The combination of the aging and increasing use of psychoactive drugs, including misuse of prescription psychotropic medications, creates a growing public health problem with rising numbers of older adults at risk for experiencing harm from drug use. This problem is exacerbated by the fact that older adults are more susceptible to the harms of drug use due to age-associated physiological changes, social factors such as increased isolation, increases in comorbidity, and use of medications that may interact with other drugs. There is a lack of reliable estimates of drug use among older adults that may contribute to the perception that they do not engage in use, making them less likely to be screened for use. As such, we believe the prevalence of drug use among older adults is underestimated. More focused surveys assessing drug use aimed at older adults are needed. Additionally, intentional and unintentional underreporting of drug use remains common across populations. Combining surveys with biological testing could detect underreporting and unintentional exposure to drugs, and this combination can also be used to adjust estimates of use. Thus, assessing drug use through surveys plus biological testing will provide important information that informs how both researchers and clinicians screen and address drug use in this population. Our multidisciplinary team has extensive expertise in drug use epidemiology among older adults, survey design, population sampling, and advanced toxicology testing. We will administer a rapid drug survey to query use of ~100 illegal drugs and a variety of prescription psychoactive drugs in 300 adults aged ≥65 in New York City. We will calculate the prevalence of use of a wide variety of drugs and assess the value of adding saliva testing and hair testing to the survey. We will apply a targeted street intercept sampling approach to reach diverse older populations often overlooked by national surveys, including people experiencing homelessness. We can test exposure to >1,000 drugs including over 100 fentanyl analogs. The aims of this project are to: 1) determine if and to what extent saliva and hair testing add to the prevalence of self-reported drug use, 2) delineate risk factors for testing positive for exposure after not reporting use (discordant report) and deduce the extent to which discordant report is from unknown adulterant exposure vs. misreporting, and 3) characterize use of cannabis and other illegal drugs in terms of reasons for use, route(s) of administration, and whether adverse effects (including substance use disorder) have resulted from use. This interdisciplinary research spanning aging research and drug use epidemiology will inform public health responses and improve age-friendly health systems to address the increase in psychoactive drug use and its adverse health effects among older adults. This study will not only inform how researchers and clinicians screen and address psychoactive drug use, but these methods will inform more largescale epidemiology studies estimating drug use and associated effects in this population overlooked in drug use epidemiology.

NIH Research Projects · FY 2025 · 2024-09

Project Summary/Abstract The axial neuromuscular system plays a critical role in many essential motor behaviors in mammals, including breathing, postural stability, and integration of movement by the trunk and limbs. While the mechanisms that allow for molecular and functional diversification of limb innervating motor neurons (MN) have been relatively well characterized, less is understood about how axial motor circuits are specified during development. Further, it is not well understood whether axial MNs exist in discrete pools that innervate distinct muscle populations to achieve motor activities through activation of specific muscles. It is also not known whether the molecular identities of axial motor neurons are related to a set of functional properties in tetrapods, nor if these molecular identities dictate the connectivity patterns of spinal premotor interneurons that modulate activity of downstream muscle targets. The proposed work in this study seeks to elucidate the fate determinants that govern organization of molecularly distinct populations of motor neurons within the medial motor column (MMC). In Aim1, I will characterize the molecular subtypes and anatomical organization of MMC neurons. I will use single nuclear (sn) RNA-seq to define the molecular diversity of MMC MNs in mouse embryos. I will then use immunohistochemistry (IHC) and hybridization chain reaction RNA-FISH (HCR) to further characterize the anatomical organization of molecularly defined MNs. I will also use retrograde tracing in embryos and early postnatal mice to determine whether molecularly unique populations of MMC neurons correspond to motor pools. Aim 2 explores the role of fate determinants in axial MN diversity and muscle target specificity. I will use snRNA-seq, IHC and HCR to map the molecular diversity and organization of MMC MNs in mice with mutations in three classes of fate determinants, Mecom/Prdm16, Satb2, and Lhx3/4. Further, I will use mice that co-express the Hb9-GFP reporter to assess the pattern of axial muscle innervation. Finally, to define the epistatic relationships between these transcription factors in the MMC gene network, I will use chick neural tube electroporation to misexpress Mecom, Satb2 or Lhx3 in all MNs and examine the impact on axial MN specification. Aim 3 seeks to elucidate the role of MMC molecular identity in axial circuit assembly and function. I will use monosynaptic rabies tracing to define the distribution of spinal premotor inputs targeting MMC in control and mutant mouse models. I will also perform motorized treadmill assays while recording muscle activity from epaxial muscle, in addition to capturing gait and posture during locomotion. This work will provide an understanding of how axial motor systems are developed, their functions, the molecular identity of unique axial motor pools, and the role of fate determinants in specifying circuits that dictate the function of axial muscle. Understanding this is essential to our understanding of the function of axial MNs and their larger role in spinal cord injury and disease. Further, this project could serve as a model for childhood developmental disorders such as scoliosis.

NIH Research Projects · FY 2024 · 2024-09

Hirschsprung disease (HSCR), or congenital intestinal aganglionosis, is a male-biased, rare developmental defect with multifactorial inheritance, high heritability, syndromic associations, and genetic heterogeneity. More than 24 genes and 9 loci underlie HSCR pathogenesis and explain 62% of its population attributable risk (PAR). Molecular diversity is extensive in HSCR with coding and regulatory, rare and common, single nucleotide, insertion/deletion and copy number variants, from segregating pathogenic alleles or de novo mutations (DNMs). Despite this heterogeneity 53% of HSCR variants disrupt signaling of two key proteins, RET and/or EDNRB, which along with 11 genes comprising a gene regulatory network controlling RET and EDNRB gene expression in the developing enteric nervous system. We have just completed whole genome sequencing of 766 unrelated HSCR cases, their 99 affected and 1,293 unaffected first-degree relatives. Here we propose state-of-the-art data analyses to enable a near complete genetic characterization of HSCR by improved detection of all variant types in coding and cis regulatory elements (CREs). In addition, using other available genetic data, we test whether HSCR genes contribute to the risk of associated neurocristopathies, to explain the wide spectrum of HSCR phenotypes.

NIH Research Projects · FY 2025 · 2024-09

Over 90% of Asian American (AsA) adults are either first-generation (foreign-born) or second-generation immigrants, experiencing a substantial environmental and sociocultural transition in this country. Yet, most environmental epidemiology cohorts have rarely included sufficient numbers of AsA. The FAMiLI (Food and Microbiome Longitudinal Investigation), is the only large environmental epidemiology cohort, incorporating a broad spectrum of AsA. We uniquely capture environmental, diet acculturation, and sociocultural factors—pre and post-immigration at baseline, and with repeated assessments during follow-up. A biobank, including buccal and stool samples, will greatly advance biological discoveries in the oral and gut microbiomes, metabolomics, human genomics, and other omics markers. The overarching rationale for FAMiLi is to examine environmental, sociocultural, diet, and biological factors that influence health outcomes (cancer and cardiometabolic diseases) in AsA and other populations. Initiated in 2018, we completed an initial recruitment and biospecimen collection of 13,000 study participants (aged 35–75 years), including 6,000 AsA. Through this U24, we propose to maintain FAMiLI data and biospecimens and enrich the cohort through additional recruitment, data collection, biorepository, and data management collaboration. The FAMiLI is a unique nationwide resource with extensive data and biospecimen collection to answer important scientific questions advancing environmental health science relevant to NIEHS strategic plan, including the microbiome, the exposome, individual superstability, and data science/big data. The cohort is particularly well suited to investigate critical windows of environmental changes and the factors underlying increased disease risk, and trends in health outcomes.

NIH Research Projects · FY 2024 · 2024-09

Project Summary Numerous observations both in humans and in experimental animals support the notion that acetylcholine (ACh) is important for learning and memory. However, the cellular and circuit mechanisms through which ACh’s biochemical control over the excitability of cortical cells reorganizes cortical dynamics and mediate learning and learning related plasticity, or other cognitive functions, remain poorly understood. This application takes advantage of technological advances in the last decade that facilitate exploring how cortical neurons are modulated under physiological circumstances of ACh release, as well as determine the contribution of these modulations to the physiology of cortical neurons and networks during behavior. We have implemented a simple associative learning task that has been shown to depend on changes in cortical circuitry in the whisker representation area of the primary somatosensory cortex (wS1) and is well suited to investigating the cellular and circuit mechanisms by which ACh promotes associative learning. We have obtained preliminary evidence that acquisition of the association of the conditioned stimulus and a reward requires ACh release in wS1. The goal of this exploratory R21 grant is to demonstrate feasibility of several experimental strategies to study the cellular and circuit mechanisms by which ACh promotes learning in the task we have implemented and to begin testing hypotheses about cholinergic mechanisms responsible for the behavior. For these goals, we propose two Aims. In Aim 1, we investigate the requirement of ACh during different phases of the associative learning task. In Aim 1A, we use 2-photon microscopy with a genetically-encoded fluorescent ACh sensor to investigate the magnitude and time course of ACh release in wS1 during the acquisition and consolidation of the associative learning and during performance of the task after the association has been learned. In Aim 1B we develop a chemogenetics strategy for the transient suppression of cholinergic activity in wS1 during specific phases of the associative learning. In Aim 2 we begin to develop a pharmaco-genetic strategy using cell-specific genetic ablation of specific cholinergic receptors in different types of excitatory neurons and inhibitory interneurons to begin to discover cholinergic actions that are important for associative learning in our task. These experiments will help develop a framework for understanding how dysfunction in ACh signaling results in neurocognitive disorders associated with the cholinergic system, and provide insights into potential cell-type specific interventions.