Brown University

NSF Awards · FY 2024 · 2024-06

Both children and adults often display essentialist biases—assuming that groups, such as biological species, are uniform in their features—which can lead them to underestimate variability within-species and across generations. This project will examine learners’ understandings of biological variability, a key foundational concept in biology education, that is linked to understanding genetics and inheritance. The researchers will investigate the connection between children’s essentialist biases and their reasoning about the extent and dimensions of biological variability within species. The researchers will conduct a longitudinal study with four to twelve year old children and with adults to chart a clearer picture of how ideas about trait variability develop. This research will provide new insights into children’s categorization of species and into changes in children’s understanding of biological variability that occur with age and experience. This could ultimately allow educators to develop science education interventions targeted to individuals that are designed to increase students' understanding of this core biological concept and to allow understanding of biological variability and genetic inheritance to be evaluated more precisely. This project is supported by the ECR program which supports fundamental research that generates foundational knowledge that advances the research literatures in STEM learning and learning environments, broadening participation in STEM, and STEM workforce development. This proposal will investigate the development of learners' beliefs about biological variability in terms of phenotypic traits and their inheritance. Current methods in educational research for assessing students’ understanding of variability are typically cognitively demanding and time-consuming and have only been able to capture a coarse picture of children’s notions of biological variability. This proposal will introduce a cutting-edge method of mathematical modelling called Markov Chain Monte Carlo with People (MCMCp), an adaptive computer algorithm designed to assess and explore individuals' understanding of biological categories more accurately. MCMCp infers how representative or probable individual category members are in an individual’s category representation. It does this without having to specify all experimental stimuli a priori. Instead, the method explores children’s notions of representativeness adaptively– that is, it uses the learner’s previous responses in the task to inform which stimuli should be presented to the learner next. Using this approach will enable a more precise characterization of children’s and adults’ species concepts and the extent to which they accept variability in phenotypic expression within a species. The researchers will assess learner’s assumptions about within-species variability across a range of traits and organisms as well as their assumptions about genetic variability--variation between parents and offspring. They will also study non-animal categories (one natural kind, one artifact) to understand whether and how essentialist biases apply to non-biological kinds as well as biological kinds. This research will lay a foundation for designing effective, individualized early education curricula for central biological concepts. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2024-05

ABSTRACT Resident Memory CD8 T cells (TRM) in the female reproductive tract (FRT) have a proven protective role against viral infections. As such positioning of CD8 TRM of high quantity and quality that are durably maintained is a key goal to achieve protective antiviral immunity in the FRT. Detailed understanding of molecular cues that guide FRT TRM differentiation is essential to attain this objective. Cells in the local environment i.e., reproductive mucosa is thought to be a big source of signals that shape CD8 TRM differentiation. Rodent models have emerged as key to understanding these molecular signals and local interactions. However, the complex nature of the in vivo vaginal microenvironment along with technical issues associated with inefficient FRT TRM isolation process have limited execution of high throughput studies focused on identifying these cellular communications. We have established an in vitro three-dimensional vaginal epithelial organoid system (VEO) that accurately captures the features of in vivo multilayered stratified vaginal epithelium. By culturing these VEOs with CD8 T cells, we were able to induce CD8 TRM differentiation and the resulting TRM phenotypically and transcriptionally resembled antiviral TRM generated in mouse. We aim to leverage this VEO-CD8 coculture model to rapidly uncover fate-specifying regulators of FRT TRM and investigate fundamental interactions between the vaginal epithelium and CD8 T cells that govern TRM differentiation. In aim-1, we will execute a targeted RNAi screening approach to rapidly define transcription factors (TFs) that instruct TRM formation in the VEO system. We have previously found that the TF Runx3 supports TRM differentiation in diverse non-lymphoid tissues, and here, we will evaluate an unappreciated role for Runx3 in driving FRT TRM differentiation in vitro. Lastly, transcriptional profiling of VEO-induced TRM found an undescribed role for retinoic acid (RA) in promoting TRM formation in the vaginal epithelium. In aim-2, we will utilize the VEO-CD8 coculture system as well as in vivo infection models to test if CD8 T cell intrinsic or extrinsic RA signaling regulates TRM formation. The proposed study will establish a robust reductionist alternative to the in vivo mouse models currently in use and will provide novel mechanistic insights into epithelial-CD8 T cell interaction in the vaginal mucosa.

NSF Awards · FY 2024 · 2024-05

The tropical Pacific Ocean has a strong influence on global climate. This influence is evident during El Niño-Southern Oscillation (ENSO) events. Interannual ENSO variations in the tropical Pacific drive large shifts in global weather patterns, including regional rainfall extremes that can lead to floods, droughts, and wildfires. Decade-to-decade changes in the tropical Pacific also have large impacts on global climate, including the rate and pattern of global warming. Thus, to predict future changes in global climate and weather extremes we must know about the long-term state of the tropical Pacific and about changes in ENSO variability. However, the impacts of human activities since the start of the Industrial Revolution on conditions in the tropical Pacific are poorly known. This limits our ability to predict climate for the coming decades. Direct climate observations from the central equatorial Pacific are sparse prior to 1950, but this data gap can be filled by records of climate from geologic archives such as corals, tree rings, and ice cores. This project will use precisely dated coral records from the central equatorial Pacific to produce a record of ocean temperature since about 1800. This temperature record will be compared with climate model simulations to understand the observed trends and variability in ocean temperature, and their impact on climate. The project will support research by both graduate and undergraduate students. It will also develop outreach videos aimed at K-12 students and teachers. The project aims to generate up to 20 new precisely-dated records of monthly-resolved sea-surface temperature and hydrological variability in the central tropical Pacific during the period from 1800-1950CE using paired oxygen isotope and trace element measurements in modern and fossil corals from Kiritimati Island (2N, 157W). The proposed work builds on the success of recent "ensemble" approaches to coral-based climate reconstruction that allow for the development of high-fidelity, monthly-resolved records tropical Pacific climate with explicit quantification of uncertainties, grounded in calibration of modern corals against instrumental climate records over recent decades. Moreover, the application of paired coral d18O and Sr/Ca analyses allows for the separate identification of temperature and hydrological trends over the last centuries - filling critical data gaps and allowing for detailed data-model intercomparison with advanced ocean state reanalyses products. The proposed work includes the application of a wide variety of strategies to assess the robustness of the coral-based climate records, including detailed analysis of sample preservation, as geochemical alteration can introduce significant artifacts into coral-based climate reconstructions if it goes undetected. If successful, the proposed work would provide a blueprint for the extension of the short instrumental climate record throughout the Pacific Ocean, utilizing samples from extensive coral rubble fields that are present on many ocean islands. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2026 · 2024-05

Project Summary/Abstract Cardiorenal syndrome is an age-associated pathology where the dysfunction of the heart or kidney induces excess extracellular matrix in the other organ. We propose, and our data supports, that age-associated dysregulation between interorgan signaling promotes cardiorenal syndrome. Comorbidity, heterogeneity and gender differences may be better managed by understanding how age affects kidney-adrenal-heart communication and by what mechanisms these tissues induce fibrosis. This project will transplant adrenal and kidney tissue between young and aged mice to determine how altered interorgan communication drives aging- associated cardiac dysfunction. We will study the interaction of age-associated water-loss and interorgan communication to determine how this impacts cardiorenal aging. Because we find that mammalian renal steroid hormones can induce heart fibrosis in Drosophila by acting through a novel membrane receptor, we will determine how this receptor signals to induce fibrosis and identify the corresponding receptor in mammalian tissues. Overall, this proposal aims to understand how aging impacts interorgan communication to produce age- associated cardiorenal syndrome and fibrosis, using models of Drosophila and mice.

NIH Research Projects · FY 2026 · 2024-05

PROJECT SUMMARY Precise, coordinated regulation of gene expression is essential for the viability of all organisms and prevents the formation of many disease states. A critical challenge for the cell is to coordinate the regulation of thousands of genes that are distant from each other in the linear genome. Coordinate regulation of distant genes is key for diverse, essential biological processes from activation of the zygotic genome, to cellular differentiation, and dosage compensation. Our goal is to reveal how the correct genes are precisely coregulated spatially and temporally. Prior to the zygotic genome becoming activated, only a few key transcription factors (TFs), called pioneer TFs9, occupy their DNA targets. Pioneer TFs can bind closed chromatin, recruit chromatin remodelers, and target additional TFs and complexes to coregulate genes. We and others recently identified a new conserved mechanism by which GA-binding pioneer TFs coregulate genes through a new class of cis regulatory elements called tethering elements which mediate chromatin looping and are distinct from enhancers and promoters. However, it is critical to determine the mechanisms by which tethering elements function spatially and temporally to coregulate the correct targets. We leverage the conserved, dynamic process of male X- chromosome dosage compensation (DC) to define the mechanisms by which tethering elements co-regulate genes because hundreds of tethering elements co-upregulate thousands of non- contiguous active X-linked genes. Thus far, we have identified the following mechanisms that are necessary, but not sufficient to, drive the specificity of tethering elements during Drosophila DC, a powerful genetic and biochemical system: 1) long-range 3D chromatin loops mediated by a conserved pioneer TF that dimerizes and binds to clusters of GA-rich motifs; 2) competition between functionally similar GA-binding pioneer TFs; 3) pioneer TF interaction with long non- coding RNAs (lncRNAs). Based on these findings, we hypothesize that competition between similar GA-binding pioneer TFs that dimerize at clustered GA repeats and directly interact with lncRNAs drive the specific contacts that precisely co-regulate target genes spatially and temporally. We will answer the following key questions: Question #1: How does competition between pioneer TFs drive three-dimensional looping? Question #2: How does interaction between TFs and lncRNAs coregulate genes? Question #3: How is the spatial and temporal specificity of gene co-regulation determined? By defining how pioneer TFs and lncRNAs function together to accurately spatially and temporally coregulate distant genes, we will determine fundamental new mechanisms for gene regulation.

NIH Research Projects · FY 2026 · 2024-05

SUMMARY The ability to modify ongoing gait with precise, voluntary adjustments is what allows animals to navigate complex terrains and to execute skilled actions during ongoing pursuits. However, how the nervous system generates the signals to precisely control the lower limbs while simultaneously maintaining ongoing locomotion is still poorly understood. While there is some consensus in the role of spinal cord (SC) central pattern generators (CPGs) in the maintenance of locomotion, little is known about the role of primary motor cortex (M1), especially in the case of volitional adjustments to ongoing locomotion movements. Our own work suggests that M 1 plays at least a dual role in both the monitoring and the adjustment of the hindlimbs during locomotor adjustments, expressed in different subspaces (manifolds) of its neuronal spiking activity. We hypothesize that the emergence of these distinct neural subspaces plays a critical role in the dynamic sensorimotor cortical control of locomotion. Specifically, the emergence of distinct low-dimensional subspaces allows M1 to track sensed ongoing locomotion states, which are primarily driven by spinal-cord CPGs, and to generate occasional descending motor commands to drive volitional adjustments without destructive interference. Besides the basic neuroscience relevance, fully understanding the role of M1 in modulating locomotion is essential for the development of new mobility therapies, including brain-machine interfaces (BMls), for restoring walking and volitional leg control in people with paralysis. We have recently developed a new experimental paradigm to test these hypotheses in nonhuman primates. It enables wireless recordings from microelectrode arrays implanted in multiple sensorimotor cortical areas during natural locomotion and navigation around obstacles visually cued on a treadmill and other spaces. In addition to M 1, we plan to simultaneously record primary sensorimotor cortex (S1) and lower limb electromyography (EMG), while actively probing M1-S1-SC interactions via cortical and spinal electrical stimulation. There are 3 specific aims. AIM 1: To test the hypothesis that information streams necessary for the control of ongoing locomotion and volitional adjustments are coordinated in motor cortex activity via the emergence of distinct neural subspaces. AIM 2: To test the hypothesis that specific subspaces emerge to coordinate the bidirectional interactions between M 1 and S 1 during sensorimotor control of ongoing locomotion and volitional adjustments. Finally, we have previously shown that neural decoders trained on ongoing locomotion do not generalize to the decoding of volitional adjustments, thus motivating AIM 3: To develop adaptive BM I neural decoding approaches for locomotion under distinct regimes of sensorimotor cortical control. PUBLIC/HEALTH/RELEVANCE: This research's long-term goal is the restoration of movement in people with paralysis. The project will advance the understanding of sensorimotor control of locomotion and lead to better BM Is for restoring walking ability in humans with spinal cord injury due to partial damage of ascending and descending pathways.

NIH Research Projects · FY 2026 · 2024-05

Project Summary Roughly 80% of persons living permanently in US nursing homes have a diagnosis of Alzheimer’s disease and related dementias (ADRD). They often experience avoidable hospitalizations, adverse process-of-care outcomes, and aggressive care of minimal benefit at end-of-life. Additionally, the Coronavirus disease 2019 (COVID-19) pandemic added an unprecedented challenge to providing long-term care. One of the most significant initiatives designed to improve nursing home long-term care quality has been the institutional special needs plan (I-SNP), a specialized Medicare Advantage plan for long-term care residents authorized under the 2003 Medicare Modernization Act. Not only does capitated payment to I-SNPs reduce incentives to hospitalize residents, but the plans are adopt care models designed to increase coordination between the plan and the nursing home to improve primary care. We estimate that both the number of I-SNP plans and enrollees have more than doubled since 2012, and that 7% of all long-term nursing home residents with ADRD were enrolled in an I-SNP as of 2018. The overall objectives of this study are to assess the impact of I-SNP enrollment on long-term care quality for nursing home residents with ADRD both during the pre- and post-pandemic periods, understand factors contributing to I-SNP enrollment and growth, and characterize how I-SNP care practices influence resident outcomes. Our central hypothesis is that I-SNP enrollees with ADRD experience fewer hospitalizations and better care quality than enrollees in traditional fee-for-service Medicare or other MA plans due to comprehensive care management. To test these hypotheses and accomplish our objectives, we propose a mixed-methods study. The quantitative component involves quasi-experimental econometric analyses on a retrospective cohort of long-stay nursing home residents with ADRD using Medicare claims, electronic health record, and other administrative data. The qualitative analysis will obtain key insights from nursing home leaders on I-SNP performance, facilitators, and barriers. This project will produce a comprehensive, nationally representative portrait of I-SNP effectiveness in serving persons with ADRD residing in U.S. nursing homes. Findings will allow residents, families, nursing homes and other providers to make informed decisions about I-SNP enrollment and participation.

NIH Research Projects · FY 2026 · 2024-04

PROJECT SUMMARY The female reproductive tract (FRT) mucosa is routinely invaded by pathogenic viruses. Resident memory CD8 T cells (TRM) have proven antiviral roles in this barrier tissue. Recent studies in mice and non-human primates have demonstrated that when present in sufficient numbers, TRM can mediate rapid antiviral protection. Responding CD8 TRM elicit immediate effector functions, recruit a network of antiviral immune cells and limit pathogen spread beyond the initial replication site. However, efforts to establish high density CD8 TRM that are durably maintained have yet to be realized. This is largely due to an incomplete understanding of the cellular and molecular signals that regulate CD8 TRM differentiation, enables their poised effector state and maintain them long term. Heterogeneity among TRM populations, which has recently become appreciated, further compounds this lack of understanding. This proposal seeks to understand the CD8 TRM diversity and define the processes that control CD8 TRM differentiation in the reproductive mucosa. Our phenotypic and single cell RNA sequencing studies have identified two major subsets of FRT TRM that are marked by mutually exclusive expression of CD103 and Ly6C. While both subsets were largely resident as determined by parabiosis, CD103+ cells resembled classical epithelial TRM cells but Ly6C+ cells displayed properties of circulating effector cells. Further exploration into their biogenesis showed that CD103+ cells were dependent on TGF-β signaling for their formation as well as maintenance. Interestingly, exposure to inflammation drove the formation of Ly6C+ TRM. We will utilize both in vivo infection models and a novel in vitro vaginal organoid system to understand the cellular and molecular drivers of these two distinct TRM subsets. We will pursue two aims. In aim-1, we will determine the role of type-1 interferon in promoting Ly6C+ TRM generation. We will also test if CD103+ and Ly6C+ subsets represent terminal TRM states or are capable of further differentiation. Importantly we will assess the relative protective roles of both TRM subsets against pathogen challenges. Finally, we will examine if vaginal microbial dysbiosis modulates the differentiation of each subset. In aim-2, we will investigate the cellular and molecular circuitry responsible for regulating TGF-β signaling in FRT TRM. Specifically, we will assess the timing and source of TGF-β signals necessary for establishing and maintaining FRT TRM. We will identify cells that support integrin-mediated activation of TGF-β in the FRT. These studies will be achieved by a combination of inducible genetic mouse models and antibody-based approaches. The overall purpose of this project is to understand the mechanisms driving the generation and maintenance of FRT TRM. The findings from this work will inform targeted therapies to improve TRM lodgment, functional tuning, and survival to achieve effective immune surveillance in the reproductive mucosa.

NIH Research Projects · FY 2025 · 2024-04

PROJECT SUMMARY/ABSTRACT Environmental contaminant exposure accounts for 20-30% of the known congenital heart disease and is a significant driver of adult heart disease. Likewise, exposure to environmental contamination also adversely affects ovarian health and is thought to be a significant factor in the global rise of infertility rates. Cardiac health is impacted by ovarian health and vice versa. While the heart supplies the ovary with necessary oxygen, the ovary produces estrogen, which is cardioprotective. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure is associated with both cardiac and ovarian dysfunction. However, the effects of TCDD exposure on organ health are often studied in isolation and, therefore, the interaction between the two systems is lost. This proposal investigates the central hypothesis that juvenile TCDD exposure affects female heart health by compromising ovarian function. There is a critical need to understand the mediators of TCDD toxicity in both the heart and ovary to provide effective treatment for heart disease and infertility. In Aim 1, I will determine the ovarian contribution to TCDD-induced cardiovascular toxicity. In Aim 2, I will use single-cell sequencing to identify unique and shared cellular and molecular targets of TCDD in the heart and ovary. In Aim 3, I will determine whether TCDD-induced infertility results from disrupted functioning of the blood-follicle barrier. My long-term goal is to become an independent investigator at an R1 institution studying reproductive toxicology. My lab will use zebrafish to model human reproductive development and exposure to environmental chemicals. I have designed a training plan that will expand my scientific skill set as well as guide my professional development. My mentor, Dr. Jessica Plavicki, and co-mentor, Dr. Jodi Flaws, will facilitate my growth and provide research and career support. I have assembled an advisory team that is made up of experts who will provide critical research and career guidance. By achieving the specific milestones outlined in my training plan and research strategy, I will develop a strong foundation for my future research program and academic career.

NIH Research Projects · FY 2025 · 2024-04

PROJECT SUMMARY This collaborative project, Mindfulness and Integrative Health Data Network (MINDNET), responds to RFA-AT- 25-005 by creating a highly usable and accessible data repository of complementary and integrative health (CIH) interventions, producing high-quality reviews and methodology papers, and creating pilot awards and providing education, training, and communications to enhance impact. There has been exponential growth of clinical trials of CIH interventions and a strong need to stay abreast of new findings by efficiently synthesizing information across PICOs (Population, Intervention, Comparison, and Outcome), evaluating new models and formats of CIH programs (e.g., via mobile delivery), and fostering timely reviews and meta-analyses for key stakeholders including health insurers, policy makers, patients and providers. Greater support and resources are also needed for the scientific community to utilize CIH data with rigorous methodology, state of art practices, and to disseminate review findings for key stakeholders. The MINDNET project will build on our team’s expertise in systematic reviews and meta-analyses of mindfulness-based interventions (MBIs) and other CIH interventions, experience creating and maintaining a public repository for meta-analyses, and implementation science work with key stakeholders to identify the highest priority evidence needs and disseminating findings for evidence- informed policy and practice. Specifically, Aim 1 will involve creating a data repository of CIH interventions through systematic literature search and coding. Strategic planning meetings with advisory committee and NCCIH priority will inform the CIH intervention domains (e.g., mindfulness, yoga, tai chi, qigong, acupuncture, chiropractic) and outcome areas (e.g., pain, psychiatric symptoms). An open-access data repository will be produced as a result, with regular updates every 6 months. The platform will be built on prior success of Metapsy, a public data repository for reviews and meta-analyses of psychotherapy, and will incorporate advanced features for data interface. Aim 2 will capitalize on our team’s expertise to produce high-quality meta-analyses of MBIs, as well as methodology papers aiming to advance the science of CIH reviews and clinical trial methodology. Aim 3 will generate non-MBI focused pilot awards to produce systematic reviews and meta-analyses in key areas of CIH, with resources, coding support, and quality assurance provided by the core MINDNET team. Aim 3 will also include education and training via asynchronous and synchronous forms to foster rigorously conducted reviews, and communications to increase the impact of MINDNET and its research. The long-term vision of MINDNET is to (a) foster open science, transparency, and rigor in CIH reviews and clinical trials; (b) advance CIH science by providing clear synthesis of evidence, addressing key gaps in the current literature and identifying priorities for future research; and (c) foster collaboration and training of CIH scientists. In conclusion, this R24 grant application will provide a living, sophisticated, and advanced data repository of CIH interventions and foster efficient, high quality evidence syntheses used by key stakeholders for societal impact.

NIH Research Projects · FY 2025 · 2024-04

Perinatal brain injury resulting in intellectual impairment and cerebral palsy affects more than 10,000 infants each year in the United States (1 to 3 per 1000 births). There is no therapy other than supportive care to prevent brain damage in hypoxic-ischemic (HI) encephalopathy (HIE) in premature infants. Due to the complex nature of the pathophysiological events, single-mechanism drug interventions in clinical studies have failed, and there remains an unmet medical need for therapeutics that prevent secondary neuronal damage. Brain-derived neurotrophic factor (BDNF) through activation of its high affinity receptor, TrkB, is a key player in promoting learning, and therapeutic strategies to enhance BDNF signaling protect against HI- induced injury. Treatment with systemic BDNF is limited by its short plasma half-life and poor brain penetration. Our research has circumvented these limitations through the development of cyclized-peptides targeting PSD-95, a TrkB associated synaptic scaffolding protein required for BDNF-induced signaling. We developed a macrocyclic compound, Syn3, that specifically binds the PDZ3 domain of PSD-95. Syn3 increases the recruitment of PSD-95 to TrkB to augment prosurvival signaling. Attached to the macrocycle is a cell–penetrating C-R(7) moiety that further mediates neuroprotection by reducing mitochondrial membrane hyperpolarization and the generation of reactive oxygen species. In a series of preclinical studies in a HI rodent model we found that Syn3 rapidly penetrates the CNS to reduce the degree of injury. The overall goal is to investigate the efficacy of our newly defined neuroprotective and immunomodulatory peptidomimetic, Syn3, to attenuate HI-related brain damage in the neonate. We hypothesize that administration of the optimal dose of Syn3 during the therapeutic time window will reduce brain injury, decrease neuronal and glial cell death, decrease apoptosis, free radical exposure and improve short and long-term behavioral outcomes. In Aim 1 we will determine the optimal dose and therapeutic time window for neuroprotection with Syn3 after HI related brain injury in the neonate. Aim 2 will assess the short and long-term neuroprotective efficacy of Syn3 administration after HI related brain injury on molecular (Aim 2.1) and behavioral (Aim 2.2) outcomes.

NIH Research Projects · FY 2025 · 2024-04

PROJECT SUMMARY This project will extend methods for estimating daily temperature, humidity, and fine particulate matter air pollution at high resolution across large regions by utilizing NASA and new USGS satellite measurements to generate estimated exposures at the neighborhood level across the Northeast US. This detailed exposure record can be used in health studies to further consider extreme weather and air pollutant as a health risk. These new daily models will be developed for 2007-2023 at a <1 km resolution and thus include billions of point-day temperature, humidity, and particulate matter estimates. While it is well established that particulate matter increases the risk of preterm birth, less is known about how extreme weather events (including temperature and humidity) and air pollution contribute to the onset of spontaneous preterm birth. Pathophysiology builds throughout a lifetime & during pregnancy, yet the onset of preterm labor and/or rupture of membranes is acute. In this way, we investigate potential environmental triggers to ask, “Why today?”. The epidemiologic application of these novel exposure models will be demonstrated by testing the association of temperature, humidity, and particulate matter with a dataset of spontaneous preterm births and residential addresses from a comprehensive New York statewide administrative database. We will use address-level exposures in the 7 days prior to a spontaneous preterm delivery with matched days in the same fixed two- week period as a comparison (time stratified case-crossover design) for 17 years of spontaneous preterm births statewide – making this among the largest environmental epidemiology studies of spontaneous preterm birth with more than 170,000 cases. Given the large number of cases and the variation in population characteristics across New York State, the association between extreme weather, air pollution patterns and spontaneous preterm birth will be further tested for effect modification by sex, race, gestational age, urban/rural, and neighborhood deprivation. A follow-up analysis will use carefully phenotyped spontaneous preterm cases from large hospital systems in Philadelphia. Our epidemiologic models will improve on prior work on the acute impacts of extreme temperature and air pollution on preterm birth that have relied on coarse exposure assignments via ecological time series models, inappropriately long time strata for case-crossover comparison, or overly broad outcome definitions that included medically-indicated preterm births. Given the global coverage of satellite remote sensing, our approach – which can generate daily exposure estimates that are highly spatially resolved (<1 km) to capture ambient exposure at the home address – is broadly applicable to better understand the role of extreme weather and air pollution as a stressor in both chronic and acute health outcomes using big data registries.

NIH Research Projects · FY 2026 · 2024-03

Project Summary/Abstract Biomaterials enable the local, controlled delivery of therapeutics like proteins and cells to target tissues damaged by injury or disease. Customization of these biomaterial-therapeutics systems is essential to overcome challenges of specific microenvironments and achieve functional regeneration. The heart after myocardial infarction (MI) is one such injury bed that necessitates localized treatments for re-establishing microvessels and delivering new cardiomyocytes (CMs). The permanent decline in heart function in patients post-MI is due to CM death and compromised perfusion, leading to the onset of heart failure in over 3 million Americans. Persistent ischemia in the myocardium after acute MI limits the recovery and contractility of the surviving heart muscle, and treatments have yet to replace the lost CMs. Attempts to deliver (a) angiogenic growth factors to regenerate the vasculature and (b) new CMs derived from human induced pluripotent stem cells (hiPSCs) to the post-MI heart have suffered from multiple challenges due to a lack of optimized delivery systems. This project addresses this gap by advancing biomaterial systems for heart regeneration post-MI by integrating a revascularization strategy for repair and a remuscularization strategy for regeneration. Our long- term goal is to re-engineer contractility in the heart with a holistic approach to restore myocardium through the vasculature and replenish CMs using engineered human myocardium (EHM). The overall objective of this proposal is to demonstrate efficacy of customized biomaterials using an optimized angiogenic protein cocktail and EHM to alleviate arrhythmia risk and improve contractility. These studies aim to understand how repair and regeneration ensue by using longitudinal imaging to reveal dynamics of perfusion and contractility as well as integrated 3D analyses of structure, perfusion, excitation, and contractility. Our central hypothesis is that increasing perfused microvessel density in the infarct and EHM implant using local delivery of biomaterials for microvascular regeneration and EHM for remuscularization will promote tissue preservation and maturation of hiPSC-CMs to reduce arrhythmias and enhance contractility. We will rigorously test this hypothesis in two aims with implantation of an angiogenic biomaterial film alone or with EHM in a rat model of ischemia/reperfusion MI. Aim 1 is to evaluate how local controlled release of an angiogenic factor cocktail alters post-MI ventricular remodeling, perfusion, arrhythmia risk, and contractility. Aim 2 is to elucidate how angiogenic co-therapy modulates cellular remuscularization with EHM for post-MI regeneration of perfusion, excitation, and contraction. The parallel aims develop our understanding of how biomaterials and tissue engineering advance revascularization and remuscularization as effective angiogenic, anti-arrhythmic, and contractile therapies for the heart. This project uses innovative technologies and analyses to accelerate novel treatments to the clinic by revealing mechanistic insights into revascularization and remuscularization for heart repair and regeneration.

NIH Research Projects · FY 2026 · 2024-03

Project Summary/Abstract Sensing viral infections in epithelial cells plays a crucial role in the frontline defense against enteric viral infections. The RIG-I like receptors (RLRs) act as critical sensors for RNA viral infections by inducing interferon signaling. While there has been extensive research on the cell intrinsic regulation of the RLR sensing pathway and viral evasion, the role of neighboring bystander cells in robust interferon (IFN) responses from the RLR sensing pathway remains understudied. This research proposal aims to utilize a murine norovirus (MNoV) infection model in mice to demonstrate a key immune evasion strategy for the global suppression of the RLR sensing pathway. Preliminary results from this study propose a novel concept of intestinal epithelial sensing of viral infection and evasion of viral RNA sensing, highlighting the importance of non-tuft bystander enterocytes for IFN-λ responses as well as the viral counteraction through the utilization of a cellular receptor for the secreted viral protein NS1 to suppress the RIG- I/MDA5 pathway. We identified Syndecan-4 as a putative cellular receptor for the virokine NS1. The central hypothesis of this research proposal is that the secreted virokine NS1 achieves tissue-wide suppression of the antiviral RIG- I/MDA5 sensing pathway through direct binding to the cellular receptor SDC4 on the epithelial cell surface. The proposal aims to explore how NS1 mediates the suppression of RIG-I/MDA5-IFN-λ immunity and the physiological relevance of this host-virus interaction.

NIH Research Projects · FY 2026 · 2024-02

ABSTRACT Neuroscience is one of the fastest growing areas of biomedical research, with many unanswered questions about the basic mechanisms of brain function and how dysfunction at the genetic, cellular, and systemic levels leads to neurological diseases and disorders. All of these areas of research are increasingly incorporating cutting-edge computational research techniques, thus competitive neuroscience research training programs must teach these skills for a successful research career. Our goal is to provide world-class hands-on training in computational brain science and career building skills to undergraduate students. We aim to increase the readiness and competitiveness of trainees as they prepare for careers in the biomedical research workforce. We designed a nine-week summer training program to enhance the research career trajectories of undergraduates through a coordinated set of elements focused on neuroscience research, building computational fluency, and professional skills development. We will recruit participants through The Leadership Alliance (TLA), an organization devoted to developing students into outstanding leaders and role models. Through TLA’s Summer Research Program, undergraduates gain research experience and mentoring in the principles underlying the conduct of research to prepare them to pursue competitive applications to PhD or MD-PhD programs. The Aims of our program are: 1) Engagement in individualized research projects in an interdisciplinary research environment; 2) Enhancement of coding and computational research skills; 3) Exposure to a breadth of neuroscience methods and research; and 4) Skills development to prepare for careers in the biomedical sciences. To accomplish these goals, each participant will join a lab where they will work closely with the faculty trainer and a near-peer mentor to conduct a research project. We will enhance students' computational fluency through a short course to establish fundamentals of adopting and using programming languages and interfaces. To learn about the broad range of neuroscience topics, participants will participate in weekly neuroscience research techniques series with faculty trainers. They will build professional development skills through workshops with a graduate student mentor. The summer will culminate in the presentation of a poster featuring their research project at The Leadership Alliance National Symposium. Overall, this R25 program merges individual lab experience in computational neuroscience with structured research skill building and professional development programming. Participants will build computational research skills that will serve them well in their future research endeavors.

NIH Research Projects · FY 2025 · 2024-01

ABSTRACT: OVERALL Rehabilitation and long-term services and supports (LTSS) are high-value, effective interventions for improving the lives of persons with disability and chronic conditions. As with most health care, inequities in access to and quality of rehabilitation and LTSS exist. Efforts to address these inequities have never been more important, given that chronic conditions affect more than half of U.S. adults, with 27% having multiple chronic conditions (MCC), and one in four US adults living with a disability. MCCs are associated with preventable and high healthcare costs, hospitalizations, emergency department utilization, and disability. Chronic conditions are costly, accounting for 75% of US healthcare dollars. Furthermore, the proportion of persons living with MCC and/or disability is steadily increasing, disproportionately affecting persons 65 years and older, those living in poverty, and those from some racial or ethnic minority groups. A learning health systems (LHS) approach offers potential solutions to minimizing disparities in rehabilitation and LTSS, by embedding knowledge and best practices into care delivery, thereby supporting improvement, innovation, and equity. This application seeks to create the Learning Health systems training to improve Disability and chronic condition care (LeaHD) center which will build upon an established, NIH-funded P2C resource center, the Learning Health Systems Rehabilitation Research network (LeaRRn). LeaHD’s long term goal is to improve the health-related quality of life of persons with disability and chronic conditions by improving access to and quality of rehabilitation and LTSS. Our overarching objective is to train embedded scientists to conduct PCOR/CER and dissemination and implementation (D&I) research that will inform improvements in health system operations, quality of care, and, thus, health outcomes for persons with disability and chronic conditions. LeaHD will build upon a well- established infrastructure and collaborative relationships at Brown University, University of Pittsburgh, and Boston University, faculty expertise and nine health system partners. Our specific aims are to: 1) establish meaningful and inclusive health system partnerships to identify and develop important questions focused on rehabilitation and LTSS for persons with disability and chronic conditions; 2) recruit and develop a diverse cadre of highly-skilled scientists poised to conduct embedded research; 3) leverage existing resources to provide mentored training for embedded scientists through core LHS research training, individualized training plans, and experiential learning; 4) facilitate embedded PCOR, CER, and D&I research through mentorship and methodological and operational expertise and support; and 5) utilize a comprehensive evaluation framework to assess LeaHD’s impact on embedded scientist professional development, health systems operations, and individual, family, and community-level outcomes.

NIH Research Projects · FY 2024 · 2023-09

Project Summary/Abstract Heavy drinking is common among young adult men who have sex with men (MSM), which increases likelihood of engaging in sexual behaviors with risk for HIV. Text messaging - a ubiquitous technology- is starting to be used to address alcohol/HIV risk, but more theory-based work is needed to rigorously develop and test the content of text messages to optimize behavior change. Thus, in this MOSAIC K99/R00, the applicant will, in the K99 phase, develop and refine, and then, in the R00 phase, test the efficacy of an interactive text messaging program to reduce heavy drinking and HIV risk utilizing construal level theory (CL T) to define intervention targets. Both prior evidence and theory inform this proposal. Specifically, CL T suggests that individuals can think about a behavior or behavior change (e.g., drinking less) abstractly (e.g., why the person wants to drink less) or concretely (e.g., how the person will limit their drinking). Interventions and experimental manipulations based on CL T use the why/how paradigm to ask participants a series of why/how questions intended to induce abstract or concrete thinking, respectively. Evidence suggests that abstract thinking may enhance motivation to change whereas concrete thinking may facilitate effective implementation of behavior change; however, CL T has largely been applied to facilitate weight loss and reduced smoking. Despite its applicability and potential, CL T has yet to be applied to alcohol and HIV research. In this proposal, the applicant seeks to develop and test CL T-based why/how text messages to induce abstract/concrete thinking, respectively, about alcohol and HIV risk and in turn reduce alcohol use, risky sexual behaviors, and negative consequences of drinking, at the day-level. During the K99 phase, the applicant, working with an advisory panel of young adult heavy drinking MSM, will develop and refine the text messaging protocol (Aim 1; months 1-9). We will then conduct a series of pilot tests and exit interviews (2 rounds of n=12 participants) to iteratively assess and improve feasibility and acceptability of the intervention (Aim 2; months 10-24). During the R00 phase, participants (N=240) will first complete baseline assessment and GamePlan - an existing brief alcohol/HIV intervention to enhance motivation to change with demonstrated promise. Participants will then be micro-randomized at the day-level (i.e., randomized every day) for 8 weeks to receive (1) CLT-concrete messages; (2) CLT-abstract messages; (3) control messages; or (4) no messages. Participants will complete assessments daily and at the end of the intervention. These aims are in line with the applicant's goals to acquire training in (1) developing and testing behavioral interventions (Dr. Christopher Kahler); (2) conducting micro-randomized trials (Dr. Stephanie Goldstein), and (3) analyzing intensive longitudinal data (Dr. Jennifer Merrill}, and to facilitate a successful transition to independence. This project will enable the applicant to work with a highly skilled, experienced team, and provide data for a future R01 to test the effectiveness of the intervention on a larger scale, as well as provide critical theoretical information regarding potentially novel mechanisms of behavior change in alcohol/HIV research.

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY This proposal requests funding for the Mesoamerican Migration Project to gather and disseminate high quality data on authorized and unauthorized migration to the U.S. from Mexico, El Salvador, Guatemala and Honduras. The first two decades of the twenty-first century mark a new period in Mexico-U.S. migration. From 2007 to 2016, the estimated number of unauthorized Mexicans in the U.S. declined from 6.95 to 5.45 million. Mexico-U.S. migration has also changed from a largely circular flow of unauthorized men to a settled population of families and increasingly authorized migrants. As unauthorized migration from Mexico has declined, migration from El Salvador, Guatemala and Honduras has steadily increased. From 1990 to 2015, the number of persons from these three countries resident in the U.S. grew from 975,000 to 3.0 million. The majority of this migration, like the earlier stages of Mexican migration, is unauthorized. Also similar to the case of Mexican migration, what started largely as male-led migration has increasingly involved women and children. The prospect for continued migration from Mexico and Central America remains high. The Mesoamerican Migration Project will fill an important void in the data available for studying these new migration flows. The public use data provided by this study can be used to describe, monitor and analyze current developments and long-term trends in migration, as well as inform new theory with respect to the migration of children, women and families, and the impact of adverse climatic events, crime and violence. The proposed Mesoamerican Migration Project builds on many of the core study design features of the NICHD-funded Mexican Migration Project which conducted household surveys in 174 Mexican communities from 1987 to 2019. It will provide migration data that is comparable across the four countries and backwardly comparable with four decades of survey data collected in Mexico by the Mexican Migration Project (MMP) and in Central America by the Latin American Migration Project (LAMP). Innovative features of the Mesoamerican Migration Project include: a stratified sampling plan that leverages municipal variation in levels of violence and drought; the use of referral sampling, social media, and telephone interviewing for U.S immigrant samples; parallel questionnaire content for household heads and spouses; questions on family migration and the migration of children; questions on multiple border crossings, transit through Mexico, and experiences of abuse; questions on violence and gang intimidation, crop and livestock loss, and food insecurity; compilation of weather, climate and homicide data at the municipal level; compilation of Twitter tweets on violence, weather, climatic events and migrant caravans.

NIH Research Projects · FY 2024 · 2023-09

Project Summary Coronavirus Disease 2019 (COVID-19) continues to cause significant morbidity and mortality across the world. Characterized by crowded detention facilities and limited medical safety resources, US criminal legal settings (CLS) have experienced some of the largest COVID-19 outbreaks. Persons involved with CLS (PCLS) additionally experience significant barriers to health care upon release, and often return to environments impacted by syndemic factors rooted in structural racism: lower vaccine access, fewer testing facilities, medical mistrust, and higher COVID-19 prevalence. A complex interplay between individual and social network-level factors may be driving the adverse COVID-19 outcomes among PCLS. But, despite their importance, social network influences – and the effect of their interaction with individual ands structural factors on COVID-19 testing, vaccination and broader health behaviors – are not routinely examined. To systematically address this gap, we will leverage two existing RADx-UP studies across eight US states. The “Community Network Driven COVID-19 Testing Among Most Vulnerable Populations in the Central United States” (C3) study is unique in that it has collected longitudinal social network data on testing, vaccination and health behaviors among PCLS in five US states. Additionally, the “COVID-19 Testing and Prevention in Correctional Settings” (CTC) study has assessed COVID-19 testing, vaccination, and mitigation strategies for PCLS in three US states. We will integrate the common data elements collected through the CTC project with the network determinants estimated from the C3 data to develop an agent-based network model (ABNM) – a dynamic systems modeling technique that provides the ability to simulate emergent interaction between individual behaviors, social structures, policy implementation, and downstream assessment of population outcomes. The proposed modeling study will: (1) use machine learning to quantify the impact of network-level influences on COVID-19 testing, vaccination, and health behaviors within PCLS communities; (2) build an agent-based network modeling (ABNM) platform that integrates the individual common data elements (CDEs) of testing and vaccination collected from the CTC study and network determinants from the C3 study; (3) simulate the effects of interventions on COVID-19 vaccination, testing and broader health behaviors in PCLS and their communities. This approach will provide insight on the potential impacts of network-informed interventions using RADx-UP data, social network analysis, machine learning, and agent-based modeling to identify interventions to reduce COVID-19 morbidity and mortality among PCLS and their communities.

NIH Research Projects · FY 2026 · 2023-09

Summary (NIH) Age-dependent changes in Drosophila represent the key Hallmarks of Aging. While the progression of these Hallmarks is delayed by intervention within the nutrient sensing axis, there is no consensus for how nutrient sensing mechanistically coordinates Hallmarks or how retarded Hallmarks coordinate to regulate lifespan. We will address this issue with new genotypes of the Drosophila insulin/IGF receptor (dInr) that differentially affect nutrient sensing where each extends lifespan. Canonical long-lived dInr mutants are insulin-resistant. Remarkably, a new dInr mutation within the kinase insert domain (KID) strongly increases lifespan but retains insulin sensitivity. We conducted RNA, metabolomic and methionine-isotope labeling analyses to gain insight on how nutrient sensing regulates aging hallmarks. We found insulin-resistant dInr increases cellular methionine cycle flux, whereas insulin-sensitive dInr decreases this flux. Notably, the methionine cycle is a control hub for epigenetics, proteostasis, stress resistance, and stem cell regulation – underlying processes of aging hallmarks. We therefore hypothesize the methionine cycle provides a central mechanism to control multiple Hallmarks of Aging in response to nutrient sensing. This proposal will establish how nutrient regulation of the methionine cycle integrates Hallmarks of Aging.

NIH Research Projects · FY 2024 · 2023-09

Project Summary Major hallmarks of aging and neurodegeneration include cognitive decline, altered body composition, dysregulation of circadian rhythms, and changes in neuroendocrine systems. The hypothalamus is the brain region that harbors a diversity of neuronal subtypes that coordinate these important functions. Yet, the extent to which changes in the hypothalamus underlie functional decline in normal aging and neurodegeneration is not well understood. Intriguingly, interventions targeting the hypothalamus can significantly extend lifespan in mice, with a discrepancy in females versus males. Moreover, alterations in sleep and body weight can occur prior to the onset of neurodegeneration, for example in Alzheimer’s Disease (AD). One challenge in understanding the aging process is that it is highly heterogeneous, meaning that different cell-types age differently. For example, in brain aging, within individuals, the immune cells (microglia) age very differently from neurons. Moreover, across individuals, women are more susceptible to age-associated neurodegenerative diseases such as Alzheimer’s disease (AD) than men. However, the selective vulnerability of different cell-types in the brain in aging and AD, and the cell-type specific mechanism underlying female bias in brain aging are largely unknown. For the F99 phase of this proposal, in Dr. Webb’s laboratory at Brown University, I will build on my foundational work in which I defined the cell-type transcriptional changes that occur in the aging female mouse hypothalamus. I will perform machine learning analysis to identify signatures of cell vulnerability and resilience with age and extend this work to a model of neurodegeneration (AD mouse models and human post-mortem tissue). Understanding the selective vulnerability in aging and AD can help develop precise interventions to specifically target the vulnerable neurons to slow down brain aging and promote health span. For the K00 phase of this proposal, I will seek to understand the epigenetic mechanisms regulating sex-differences in brain aging. My previous analysis found increased expression of Xist, the master regulator for silencing one of the two chrX in females in eutherian mammals, in aging and AD brain. Given that chrX is enriched for neural and immune genes and the known loss of heterochromatin in aging, I hypothesize that Xist is required for maintaining chrX silencing to protect neurons in brain aging. I will test this hypothesis by epigenetically activating or silencing Xist in induced neurons derived from aged fibroblasts to determine the impact on neuronal aging, and in vivo to reveal the cell-type specific response to the chrX-specific perturbation. This work will contribute to the understanding of the heterogeneity, especially cell-type specific and sex-specific vulnerability, in normal brain aging and AD. Further, it will lead to the discovery of novel biomarkers to assess age and AD status at single cell resolution, which will contribute to the development of cell-type specific interventions. To successfully complete these goals, I will gain extensive training from a team of experts in computational biology, biology of aging, neurodegeneration, and neuroscience.

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY/ABSTRACT Among those with AUD, cannabis is the most commonly used psychoactive substance. Although initial evidence suggests an overall detrimental impact of cannabis use (CU) on longitudinal AUD treatment outcomes, there is significant divergence about how CU impacts alcohol consumption and craving. Competing theories about the association between CU and alcohol focus on whether CU acts as a substitute (i.e., replacing the effects of alcohol, resulting in decreased craving, use, and harms) or complement (i.e., enhancing the effects of alcohol, resulting in increased craving, use, and harms). Preliminary work in non- treatment engaged samples suggests important mechanisms (e.g., craving) and moderators (e.g., frequency of CU, history of simultaneous use, trait impulsivity) may elucidate these competing theories. An important gap in the literature is in the examination of prospective and momentary effects of naturalistic CU on alcohol craving and consumption among individuals in alcohol treatment. The proposed study aims to address this gap using an intensive longitudinal design to comprehensively examine within- and between-person patterns of CU on alcohol outcomes over the critical first year after treatment initiation. Key outcomes among those early in treatment are alcohol craving and risky alcohol consumption patterns (rate of consumption and volume consumed). Use of alcohol biosensors allow for the objective measurement of these alcohol consumption patterns as they naturally occur. The proposed project will be the most comprehensive examination to date of the impact of CU on alcohol treatment outcomes and the first to examine these associations in the natural environment using the BACtrack Skyn to passively mesure transdermal alcohol concentration (TAC). Alcohol craving will be measured as an important outcome of CU in the moment, as well as a mechanism by which CU leads to alcohol consumption. A longitudinal ecological momentary assessment (EMA) burst design (four 10- day bursts at baseline, 1, 2, and 3 months) will be used to isolate the momentary impact of CU on alcohol craving and consumption (measured via TAC) in a stratified sample of recent cannabis users. Following this EMA phase, participants will engage in 6, 9, and 12 month follow-ups to fully capture CU and alcohol patterns/AUD remission over the first year after treatment initiation. This research will directly inform: a) clinical decision-making about the risks of CU during alcohol treatment, b) future intervention development for AUD, and c) policy in the wake of expanding cannabis legalization; and is well-aligned with the objectives of the Collaborative Research on Addiction at NIH.

NIH Research Projects · FY 2025 · 2023-09

Project Summary Adolescent suicide rates have increased over the past two decades, with the recent COVID-19 exacerbating pre-pandemic risk factors including increases in online social messaging. We propose that online social messaging for adolescents serves as a “social zeitgeber” (an environmental “time giver” that synchronizes diurnal rhythm) and that late night online social messaging contributes to delays in sleep onset. Over time, delays in sleep onset in combination with inability to phase shift the wake time for adolescents, contributes to impairments in cognitive and emotional capacity for managing daily stress, resulting in overall vulnerability throughout the day as well as a shift of vulnerability to the evenings when research has shown increases in adolescent suicidal thoughts and behaviors. The present research longitudinal research will examine these processes in the real world using a combination of (1) text extraction of online social messaging during the intensive sampling period, (2) ecological momentary assessment (EMA), and (3) wearable technology in combination with predictive algorithms. Findings will inform interventions that can range from ecological momentary interventions to adaptations to interventions such as Interpersonal and Social Rhythm Therapy.

NIH Research Projects · FY 2024 · 2023-09

Project Summary Adolescent suicide rates have increased over the past two decades, with the recent COVID-19 exacerbating pre-pandemic risk factors including increases in online social messaging. We propose that online social messaging for adolescents serves as a “social zeitgeber” (an environmental “time giver” that synchronizes diurnal rhythm) and that late night online social messaging contributes to delays in sleep onset. Over time, delays in sleep onset in combination with inability to phase shift the wake time for adolescents, contributes to impairments in cognitive and emotional capacity for managing daily stress, resulting in overall vulnerability throughout the day as well as a shift of vulnerability to the evenings when research has shown increases in adolescent suicidal thoughts and behaviors. The present research longitudinal research will examine these processes in the real world using a combination of (1) text extraction of online social messaging during the intensive sampling period, (2) ecological momentary assessment (EMA), and (3) wearable technology in combination with predictive algorithms. Findings will inform interventions that can range from ecological momentary interventions to adaptations to interventions such as Interpersonal and Social Rhythm Therapy.

NIH Research Projects · FY 2025 · 2023-09

: Hispanic Americans with various identities have been identified as under-resourced communities that may be at increased risk for binge drinking behavior and alcohol-related problems. These issues have been linked to various social stressors and may be mitigated through accessing resilience and various sources of strengths. There is one promising intervention, CAMI that has shown efficacy in decreasing alcohol misuse within Hispanic Americans. Specifically, CAMI is a tailored intervention for Hispanic Americans individuals that targets stress related to adapting to a new host culture and has shown strong promise in its reduction of alcohol misuse. However, CAMI only address singular forms of social stressors and does not account for various sources of support, strengths, and resilience. Therefore, CAMI will be adapted using an evidenced based, theory driven model of adaptation of behavioral therapies to address various forms of social stressors that Hispanic Americans encounter, in efforts to decrease high rates of alcohol misuse. The new intervention will be delivered via telehealth, it will be available in English and in Spanish, with traditional motivational interviewing used as the controlled condition. The study will be conducted in New England (NE) and in the Southwest (SW) to account for geographical differences among Hispanic Americans. The study will be conducted in three phases: in-depth qualitative interviews with Hispanic Americans (n=20) and clinic stakeholders from NE and the SW (n=10; aim 1) to capture strengths and social stressors and links to alcohol misuse and receive feedback on the adaptation of the manual; the second phase will be open series where it will focus on examining feasibility and acceptability of the novel intervention and it will be tested with 16 Hispanic Americans (n= 8 from NE; n= 8 from SW) and feedback will be incorporated into the treatment protocol (aim 2); the third phase will be a pilot randomized controlled trial (RCT) with 60 Hispanic Americans with 30 participants from NE and 30 participants from the SW (15 receiving the new intervention and 15 receiving MI from each region; aim 3). The goals of the current study are consistent with NIAAA’s identified special populations and strategic plan. The current K23 will facilitate the applicant’s development of expertise in randomized-controlled trials, addiction science, and community-engaged research.