George Washington University

NIH Research Projects · FY 2025 · 2022-09

PROJECT SUMMARY The goal of the Metabolic Dysregulation and Cancer Risk Consortium (MDCRC) is to identify tangible mechanistic/etiologic pathways that link obesity-related metabolic dysregulation with cancer risk to inform cancer prevention strategies. The Consortium proposes to accomplish this through developing common measures for obesity-related metabolic dysregulation for different cancer types, understanding how obesity- related metabolic dysregulation affects cancer initiation and development, characterizing signal cross-talk between key biologic processes that impact obesity-associated metabolic dysregulation and cancer risk, and determining the utility of emerging approaches for the discovery of novel obesity-associated metabolic targets in cancer risk and prevention. The Biostatistics Center (Center) in the Milken Institute School of Public Health (SPH) of the George Washington University (GW), the participating institution, proposes to serve as the MDCRC Coordinating Center (CC). The MDCRC CC will integrate this expertise and experience, drawing upon our successful history of coordinating center leadership in collaborative research consortia, capacity for innovation, and the extensive scientific expertise in obesity and cancer prevention, nutrition, exercise, metabolism, body composition, and bioinformatics/computational biology to form a CC that is rooted in scientific rigor and is flexible and responsive to the diverse challenges and scientific opportunities of the MDCRC. The specific aims of the MDCRC include to 1) provide scientific leadership and project management for collaborative cross-Consortium activities, including providing guidance on the selection of common measures and development of consistent protocols and manuals of operations, maintain private and public websites, establishing topical work groups, and spearhead outreach activities; 2) facilitate data harmonization, data sharing and results dissemination across the MDCRC sites and with NCI, including identification of opportunities for novel data collection to enrich the MDCRC data resources, developing a common data management platform, and training for site staff; and 3) establish a Self-Evaluation Core to promote timely self- evaluation, along with effective self-correcting actions, working with NCI and the Consortium investigators to establish criteria and outputs related to the “success” of individual investigators, study teams, and Consortium sites.

NIH Research Projects · FY 2024 · 2022-09

In Washington, D.C., violent crime has increased by 28% since 2021, and homicide rates rose 14% between 2020 and 2021, with the greatest effects in communities facing persistent social and economic challenges, and a particularly high impact on young males. To address this urgent public health issue, the Prevention and Community Health Department within the George Washington University Milken Institute School of Public Health (GWSPH), together with Mint, Inc., Don’t Shoot Guns, Shoot Cameras, DC Housing Authority/Highlands Addition Community Center, the DC Office of the Attorney General, and the DC Office on Gun Violence Prevention/Building Blocks, propose a collaborative effort to develop, implement and evaluate a community-level youth firearms prevention intervention in two phases – a developmental Phase One (UG3), and an implementation Phase Two (UH3). The proposed intervention, Changing the Narrative on Firearms Violence, will use a theory-driven approach to identify and implement positive, non-violent achievement pathways for youth with the support of a community collaborative structure, and to develop and disseminate media content that highlights the availability and benefits of these positive pathways. Specifically, the proposed project will: 1) Collaborate closely with the CLIF-VP cooperative agreement throughout all phases; 2) In Phase One (UG3), conduct formative research to refine intervention components, including the identification of non-violent youth pathways, intervention branding themes, and communication channels; establish a Community Steering Committee; and develop and pilot test data collection tools; 3) In Phase Two, implement the intervention, conduct data collection through baseline and two follow-up surveys with youth ages 12-16 and a parent/guardian, gather qualitative data to help assess impacts, monitor community violence data, analyze results, share findings through the CLIF-VP, and disseminate outcomes in partnership with community collaborators.

NIH Research Projects · FY 2026 · 2022-09

ABSTRACT Chikungunya virus (CHIKV) is an alphavirus spread by mosquitos that causes persistent arthritis in approximately 25% of people two years after initial infection. There is currently no standard evidence-based treatment for CHIKV chronic arthritis. The French guidelines suggest the use of methotrexate in the treatment of chronic CHIKV arthritis however there are no randomized placebo-controlled trials of methotrexate to support this recommendation. Our long-term goal is to guide the evidence-based treatment of CHIKV arthritis. The main goal of this proposal is to determine the efficacy and histopathologic effects of 6 months of methotrexate (n=100) versus placebo (n=50) on synovitis in chronic CHIKV arthritis in Colombia in a randomized controlled trial. Our central hypothesis is that methotrexate will significantly decrease chronic CHIKV arthritis disease severity compared to placebo and suppress leukocyte accumulation and inflammatory cytokine expression in synovial tissue. This hypothesis will be evaluated in 2 specific aims. In Aim 1, we will determine the efficacy of oral methotrexate treatment versus placebo for 6 months in chronic CHIKV arthritis. In Aim 2, we will determine the effect of methotrexate on synovial inflammation by obtaining synovial biopsy samples before and during treatment. Rationale: This work will define the role and mechanism of methotrexate in the treatment of chronic CHIKV arthritis with the goal of advancing the field towards an evidence-based standard treatment. The potential broader impact of this work is the potential identification of the pathologic mechanism of chronic viral arthritis and a possible therapeutic option.

NIH Research Projects · FY 2024 · 2022-09

PROJECT SUMMARY Attention is fundamental to parsing the dynamic, multisensory, and semantically rich environments we encounter in day-to-day life. The human sensory systems take in more information each moment than can be processed at once, so a subset must be prioritized for further processing through attentional mechanisms. Information about the same object or event can be initially processed by multiple sensory organs, so signals from different sensory systems must additionally be matched and integrated to create the perception of a coherent multisensory world. Disruptions to these attention and sensory integration mechanisms are thought to underlie the sensory processing issues commonly observed in neurodevelopment disorders (e.g., autism, ADHD). Patients either under-respond or over-respond to common sensory stimuli, causing distress and difficulty completing the tasks of daily life. The mechanisms underlying these sensory processing symptoms are ill defined because of critical gaps in our understanding of how attention operates in multisensory environments. Attention has largely been studied within each sensory system separately, thus many factors remain poorly understood in the audiovisual contexts that more closely resemble the environments we encounter in daily life. In the proposed research, I will investigate one of these factors, semantics, which is a critical guide of attention in vision but has only been studied narrowly in audiovisual contexts with stimuli that shared a source (e.g., a dog and its' bark). This narrow focus means the mechanism of audiovisual attention benefit remains unknown and could include any semantic relationship (a semantic-general mechanism) or be specific to the relationship of sharing a source (a source- specific mechanism). In Aim 1, I will characterize the degree to which semantic relatedness influences attentional prioritization, which will be measured both by visual search efficiency in study 1 and prioritization in early visual cortex at object locations in study 2. Attentional prioritization that scales with semantic relatedness would suggest a semantic-general mechanism. In Aim 2, I will identify the neural mechanism of the shared-source benefit in audiovisual search, specifically examining the time course to understand the relative contributions of attentional and semantic processing. Investigating these mechanisms will provide a more robust understanding of the role of semantics in guiding attention in real world environments, which are frequently both multisensory and semantically rich. Ultimately, understanding basic attentional principles will support future research into the sensory processing issues so common in neurodevelopment disease, including potential treatments that allow patients to better manage sensory under- and over-responsiveness.

NIH Research Projects · FY 2025 · 2022-08

PROJECT DESCRIPTION US-German Research Proposal for Collaboration in Computational Neuroscience: Efficient representations of social knowledge structures for learning from a computational, neural and psychiatric perspective (RepSocKnow) US-side PI: Prof. Gabriela Rosenblau, Ph.D., Assistant Professor, Department of Psychology, The George Washington University, 2115 G Street NW, Washington, DC 20052 German-side PI: Prof. Christoph W. Korn, Ph.D., Assistant Professor & PI Emmy-Noether Group, Section Social Neuroscience, Department of General Psychiatry, University of Heidelberg, Vossstraße 4, 69115 Heidelberg, Germany Consultant 1: Prof. Daniela Schiller, Ph.D., Associate Professor, Department of Psychiatry, Department of Neuroscience, and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, 1470 Madison Ave, New York 10029, NY Consultant 2: Jan Gläscher, Ph.D., PI Bernstein Research Group, Institute for Systems Neuroscience, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany 1. Aims and hypotheses This is a resubmission of our last year's CRCNS proposal, which received good and very good scores from reviewers. Reviewers were excited about the general neuro-computational approach that builds on the complementary skills of the PIs. In this revision, we address the reviewers' requests for clearer descriptions of the planed experiments and analyses. Importantly, our new proposal has direct relevance for clinical practice. By leveraging ideas from computational psychiatry [1–4] and from the Research Domain Criteria (RDoC; e.g., [5, 6]), we aim to apply our neuro-computational approach to improve the understanding of core social deficits shared by many pervasive neuro-psychiatric disorders. The general goal of this proposal is to establish comprehensive—and clinically relevant—neuro-computational models of aberrant learning in social contexts via behavioral and functional magnetic resonance imaging (fMRI) experiments. Learning about others is crucial for successful social interactions [7]. Social interactions strongly predict wellbeing [8]. Different types of impairments in social functioning accompany a variety of clinical conditions and constitute core symptoms of Autism Spectrum Disorders (ASD) [9–11] and Personality Disorders with a Borderline pattern qualifier (BPD) [12–16]. We harness our neuro-computational approach to investigate how social knowledge structures shape—and in turn are shaped by—learning about others. The mechanisms underlying knowledge representations and learning that we propose in our computational modeling approach are not “social” per se and we deem it a strength that they can be applied to learning across various (non-)social domains. Here, we focus on social learning to specify commonalities and differences between healthy individuals and individuals with marked social deficits associated with ASD or BPD. While these two clinical groups probably both employ overly rigid social knowledge structures, they exhibit different types of malfunctioning: ASD are characterized by under-mentalizing, i.e., insufficient inferences about mental states of others—possibly due to poor or unspecific social knowledge[17–19]. In contrast, BPD show over- mentalizing and overly negative interpretations of others' personality or intentions[12, 13]. Our novel neuro-computational framework can improve the understanding social malfunctioning along dimensional and categorical psychiatric criteria of ASD and BPD. We aim to test and refine computational models that formalize adequate strategies for acquiring and employing social knowledge structures during learning. Our models offer normative perspectives on social learning by specifying how ideal agents could learn in our controlled but ecologically valid tasks. Thereby, we can quantify how much humans—particularly clinical populations characterized by pervasive social deficits—deviate from computationally specified “optimal” benchmark strategies. In conjunction, this project aims to reveal the neural computations underlying the representation of social knowledge structures and their flexible deployment during learning. The project addresses three specific aims:

NIH Research Projects · FY 2025 · 2022-08

Nearly 6 million Americans ≥65 years suffer from Alzheimer’s disease (AD) or AD-related dementias (ADRD). AD/ADRD poses significant emotional, physical, and financial burdens on patients, families, and societies. There is no cure for AD/ADRD, and apart from the June 2021 controversial “accelerated approval” of aducanumab, no new symptom-modifying drug has been approved since 2003, highlighting the need for AD/ADRD prevention. Currently, no drug is available to delay the onset of AD/ADRD. The prohibitive cost of developing new drugs or repositioning partially developed drugs for AD/ADRD treatment would be even more prohibitive for AD/ADRD prevention as the latter would require larger sample size and longer follow-up. An alternative cost-effective and efficient approach is to repurpose from >20,000 FDA-approved drugs for AD/ADRD prevention. However, repurposing of drugs is often accidental. A timely and purposeful discovery of new clinical benefits of old drugs requires a systematic examination of large comprehensive clinical databases with longitudinal records and long follow-up, using innovative, sophisticated mixed machine learning and statistical tools. This application has been prepared in response to the NIA PAR-20-156 entitled “Translational Bioinformatics Approaches to Advance Drug Repositioning and Combination Therapy Development for Alzheimer’s Disease”. We propose a 3-Step Medication-Wide Association Study Plus (MWAS+) approach. Our MWAS+ will employ innovative explainable deep (machine) learning, a powerful artificial intelligence tool for noisy, nonlinear data. We will use Veterans Affairs (VA) electronic health record (EHR) data of >3 million Veterans ≥65 years (54,411 women; 202,000 African American), ~600 prescription drugs (each used by ≥10,000 Veterans), ≥10 years of history and ~200,000 AD/ADRD cases. In Step 1 (Aim 1), we will conduct a hypothesis-free exploratory case-control MWAS (akin to GWAS) to identify drugs associated with AD/ADRD in the VA EHR data. Drugs identified in Aim 1 will be reviewed by a panel of experts for plausible mechanistic pathways and 10 drugs will be recommended for hypothesis testing in Step 2 using VA EHR data (Aim 2) and external validation in Step 3 using Medicare data (Aim 3). In Aims 2 and 3, we will conduct outcome-blinded cohort studies using new user design. Marginal structural models and other causal inference methods, including doubly-robust inference procedures, will be used to estimate time- fixed (“intent-to-treat”) and time-varying (“as-treated”) effects of those drugs on incident AD/ADRD. The proposed project is highly significant because it will rigorously accelerate the identification of already approved drugs that have a high potential to be repurposed to delay and prevent AD/ADRD, a rapidly growing public health crisis. The project is innovative as it combines state-of-the-art deep learning and statistical methods to conduct an MWAS+ study that has never been used before for AD/ADRD prevention. In addition, the VA EHR contains high quality clinical data including pharmacy fill records and rich phenotypic information including fitness and frailty. Findings from this project will inform future clinical trials to repurpose approved drugs for AD/ADRD prevention.

NIH Research Projects · FY 2026 · 2022-08

Summary Extravasation of inflammatory monocytes across the blood-brain barrier (BBB) in response to human immunodeficiency virus type-1 (HIV) is a critical event that leads to chronic neuroinflammation, neurologic injury, and subsequent loss of cognitive abilities in a significantly large number of infected individuals. However, given the heterogeneity of monocytes that exists in HIV-infected individuals receiving anti-retroviral therapy (ART), it remains unknown as to whether the neuro-modulatory actions of monocytes are limited to select subset of monocytes. Directly relevant to the goals of RFA-21-250, our supporting data reveals that the ART-treated HIV- infected individuals harbor higher numbers of inflammatory monocytes (CD14lowCD16hi) in their circulation. These cells also exhibit characteristic features of clonal hematopoiesis (CH), such as loss of DNA methyltransferase 3A (DNMT3A) and Tet methylcytosine dioxygenase 2 (TET2) with concurrent increase in the expression of janus kinase-2 (Jak2 ; these three gene products, and few others, are often termed as CH drivers). Interestingly, subsequent experiments in various models suggested that this monocyte subset (1) translocate to the central nervous system (CNS) in response to ART, in platelet-dependent manner, (2) is neuro-modulatory in action, and (3) can be expanded following exposure of monocytes to activated platelets and ART. Based on these findings, we posit that the priming of monocytes by activated platelets potentiates ART-mediated clonal hematopoiesis in monocytes, leading to HIV-associated neurologic injury. In this model, we propose that the composite effect of activated platelets and ART results into clonal expansion of inflammatory (CD14lowCD16hi) monocyte subset with CH, and subsequent demethylation/induction of PSGL-1 gene in them. Functionally, these events facilitate the transmigration of such monocytes into the perivascular spaces within the CNS, where these cells differentiate into macrophage phenotype, while retaining CH profile, and contribute to the neuronal dysfunction. This model then, in full accordance with the available literature, accounts for how neurologic manifestations are initiated and maintained due to immune-CNS interaction in ART-treated HIV- infected individuals.

NIH Research Projects · FY 2025 · 2022-08

PROJECT SUMMARY ABSTRACT The goal of the Exercise and Nutrition Interventions to Improve Cancer Treatment-related Outcomes (ENICTO) Consortium is to support and enhance exercise and/or medical nutrition intervention research designed to evaluate interventions that may improve cancer treatment-related outcomes among patients being treated with curative of life-extending intent. The aims of the ENICTO Coordinating Center are to facilitate the work of the ENICTO consortium by: 1) supporting the scientific goals of the ENICTO consortium through collection, harmonization and analysis of common data across Consortium sites, 2) facilitating communication within the Consortium and between the Consortium with external audiences, and 3) coordinating administrative functions of the ENICTO consortium. Under the direction of the ENICTO Steering Committee, the ENICTO Coordinating Center will work with Consortium investigators to identify common data elements and procedures across Consortium sites, harmonize cohort variables, and identify opportunities for novel data collection to enrich the ENICTO data resources. The Coordinating Center will organize training sessions for Consortium site staff to ensure the quality, consistency, and completeness of the data across sites, develop and implement a data management platform for data collection and reporting from the Consortium sites, and train and support Consortium sites on platform use. The Coordinating Center will lead analyses for cross-consortium pilot projects examining common research questions, and make the harmonized ENICTO data available to qualified researchers based on Consortium policies and data sharing agreements. The Coordinating Center will plan and coordinate the ENICTO Consortium Annual Meeting and meetings of the Steering Committee, establish email listservs, develop and maintain a website for the ENICTO Consortium, plan and facilitate communication among the scientific working groups, support the distribution of research materials such as study protocols and education materials, and disseminate research findings to the scientific and cancer communities. Administrative functions of the Coordinating Center will include development and implementation of ENICTO operating policies and procedures pertaining to data sharing, publications and presentation, external collaborations and ancillary studies under the guidance of the ENICTO Steering Committee, and an evaluation system to track U01 site performance and project progress. The Coordinating Center will prepare meeting agendas, compile meeting materials, record meeting minutes and action items, and provide general administrative support and oversight.

NIH Research Projects · FY 2024 · 2022-08

Project Summary This project's goal is to develop an assessment that captures the process of shared decision-making (SDM) for persons who cannot advocate for themselves because they lack the cognitive capacity to decide for themselves and the ability to communicate their wishes. Current SDM assessments are not designed for these individuals and generally focus on encounter outcomes rather than the process by which SDM unfolds. To address this knowledge gap, a team of multi-disciplinary researchers, healthcare stakeholders, and care partners will collaborate to design and test the observer-rated Standardized Process Assessment of Relationship-Centered Shared Decision-Making (SPARCSdm), informed by our relationship-centered SDM process model. In Aim 1, we will observe, interview and analyze patient- practitioner-care partner triad encounters where decisions are made. These observations will be used to define modifiable collaboration and information exchange skills, identify items and rating scales for the SPARCSdm, and design a prototype assessment including administration procedures. In Aim 2, assessors will be trained using an online, competency-based training developed specifically for this project; once trained, they will observe videotaped SDM encounters and separately score care partners and practitioner on the SPARCSdm. These data, analyzed using the many facets Rasch model (MFRM) to adjust for assessor severity/leniency and encounter complexity, will provide preliminary evidence of SPARCSdm psychometrics, facilitate appraisal of the assessment's conceptual and structural validity, and inform refinements of the online training. In Aim 3, we will apply the Knowledge to Action implementation science strategy to scale up the prototype for future testing by identifying supports and barriers, usability, and acceptability. This project advances care for persons with chronic disabilities and their care partners by developing a process assessment that is relationship-centric, inclusive of multiple perspectives, and user-friendly. As such, it is highly responsive to AHRQ's request for projects that develop an SDM process assessment, informed by a conceptual model, to capture multiple perspectives for priority populations such as persons with disabilities who need chronic care. This assessment is needed because clinical supervisors and medical educators currently struggle to identify when SDM has taken place and which practitioners and care partners need support with SDM skills. Attention to usability and integration of supports and barriers to implementation throughout the design process ensures this project will effectively set the stage for larger scale testing of the SPARCSdm, and longer-term, for measuring the effectiveness of intervention programs aimed at improving SDM.

NIH Research Projects · FY 2025 · 2022-08

Project Summary/Abstract Over 70% of breast cancer are ERα+ and endocrine therapy is the standard treatment for these patients. Unfortunately, resistance to endocrine therapy develops over time and remains a major problem. The cause for resistance is not fully understood, but aberrant ERα activation is an underlying factor. Therefore, identifying new component of the ERα signaling and understanding its role in breast cancer holds a great promise for treatment of ERα+ cancer and will particularly benefit patients with advanced and metastatic tumors that are refractory to current endocrine therapies. Our preliminary results showed that chromatin remodeling protein AT-rich interaction domain 4B (ARID4B) is an essential transcription co-activator (not a co-repressor) for ERα and mammary gland-specific ablation of Arid4b inhibits tumorigenesis. Analyses of large-scale genomic datasets (TCGA and other breast cancer cohorts), genome-wide transcriptome, and IHC analyses showed that ARID4B is amplified and its expression elevated in ERα+ breast cancer. Interestingly, high ARID4B expression in ERα+ (but not ERα-) breast cancers is associated with increased risk of cancer recurrence and decreased survival, suggesting that ARID4B is involved in the cancer development and progression to therapy resistance. To gain mechanistic insight into its function, preliminary results revealed that ARID4B is recruited to the promoters of ERα target genes that are far away from the identified ERα-bound enhancers. In addition, DHX9 was identified as a novel ARID4B-interacting protein and is involved in ERα activation. DHX9 is an NTP-dependent helicase capable of resolving transcription-coupled ‘R-loops’ that is inhibitory to productive transcription. Based on these findings, our central hypothesis is that ARID4B activates ERα signaling to promote tumorigenesis and endocrine therapy resistance by: (1) mediating promoter-enhancer looping via interaction with ERα and (2) by recruiting DHX9 to resolve the transcription-coupled R-loops on promoters and enhancers to promote productive transcription. In Aim 1, the in vivo function of ARID4B in tumor initiation, cancer growth, and endocrine therapy resistance will be investigated using several breast cancer cells in tumor xenograft models, patient-derived resistant tumors in PDX, and a newly generated ARID4B knock-in mouse model. In Aim 2, we will investigate how ARID4B-mediated enhancer-promoter looping regulates ERα activation and identify the important functional domain(s) on ARID4B to provide in-depth understanding of ARID4B-ERα and ARID4B-DHX9 interactions. Furthermore, we will investigate whether resolution of “R-loops” on the promoter and enhancer by DHX9 is required for the activation of ERα. Finally, we will demonstrate that targeting the ARID4B-DHX9 axis by suppressing DHX9 expression or activity inhibits tumorigenesis and resistance to antiestrogens. Our study will fill the crucial gap in understanding the function and mechanism underlying the emerging oncogenic activity of ARID4B and establish ARID4B-DHX9 axis as a therapeutic target for breast cancer.

NIH Research Projects · FY 2025 · 2022-08

PROJECT SUMMARY Primary metabolic pathways in cancer are useful targets for therapeutic intervention. However, intratumoral heterogeneity in cancer metabolism is a major challenge for anti-cancer therapy. Reducing metabolic variance by reprogramming cancer metabolism is essential to enhance efficacy of inhibitors targeting metabolism. Our long-term goal is to overcome metabolic heterogeneity through reprogramming metabolic networks to increase the number of cancer cells vulnerable to metabolic inhibitors. To reach this goal, our novel strategy is to reduce metabolic variance among cancer cells by targeting BACH1, a master regulator of metabolism-related transcription in triple negative breast cancer (TNBC), to obtain maximal response of drugs targeting metabolic pathways. Our previous molecular and metabolomic profiling of breast tumors revealed that BACH1 suppresses mitochondrial metabolism. Thus, BACH1 depletion made TNBC cells more sensitive to mitochondrial inhibitors. These findings led to the novel concept that BACH1 depletion increases the proportion of cancer cells with higher dependency on mitochondrial respiration and restricted tumor metabolic plasticity. Our preliminary studies indicate that BACH1 also suppresses lactate catabolism, which is a primary pathway for lactate oxidation in mitochondria of cancer cells. In support of this finding, recent clinical studies showed that lactate catabolism depends on lactate transporter (MCT1). In TNBC cells, BACH1 represses transcription of genes that encode enzymes involved in lactate catabolism, including lactate transporter (MCT1), lactate dehydrogenase B (LDHB), and mitochondrial pyruvate carriers. Specifically, BACH1 depletion sensitized cancer cells to blockade of MCT1 or LDHB. Based on our preliminary data, we hypothesize that BACH1 is the key determinant of whether cancer cells produce lactate or consume lactate. The primary objective of this proposed study is to link BACH1 contribution to lactate catabolic variance, and to better understand regulation of lactate oxidation in TNBC. Using multiple innovative approaches, including in vitro and in vivo breast tumor models and a combination of transcriptomics and metabolomics, we will interrogate BACH1 regulation of lactate catabolism and define the underlying molecular regulatory mechanism in breast cancer cells. Furthermore, using patient-derived xenograft and syngeneic mouse models, we will investigate whether BACH1 inhibition (through the repurposed non-toxic FDA-approved drug, panhematin) increases breast tumor vulnerability to drugs targeting the lactate transporter MCT1. By combining cell biology and in vivo assays, this study will provide comprehensive insights into how cancer cells use lactate as a substrate, whether metabolic variances are reduced by targeting BACH1, and how to achieve better therapeutic strategies using lactate catabolism inhibitors.

NIH Research Projects · FY 2023 · 2022-07

ABSTRACT The advent of effective combination antiretroviral therapies (cART) has increased the life expectancy for HIV-1 patients, however, these patients are still prone to comorbidities, such as HIV-associatiated neurocognitive disorders (HAND), which affect up to 50% of HIV-infected individuals. Persistent inflammation due to the overactivation of the innate immune system is one of the main underlying causes of HAND. Nucleotide binding domain, leucine rich repeat pyrin domain containing protein-3 (NLRP3) inflammasome has emerged as a druggable target for the management of HIV-1-associated neuropathologies. The NLRP3 inflammasome is shown to be activated in response to a wide array of pathogen- and danger-associated molecular patterns (PAMPs and DAMPs, respectively). A key step in the activation process is a homotypic interaction between the pyrin domains in NLRP3 and an adapter protein, apoptosis-associated speck-like protein containing a CARD (ASC). NLRP3 activation leads to the release of pro-inflammatory cytokines, such as, interleukin-1 (IL-1) and IL-18, causing neuronal pyroptosis and death. Disruption of NLRP3 signaling via small molecules, such as MCC950, is reported to display beneficial effects in the transgenic mouse models. Our recent studies identified a small molecule, AMS-17, that thwarted the NLRP3 activation in N9 microglia both in vitro and in vivo. Subsequent mechanistic analysis revealed that the NLRP3 inhibitory activity of AMS-17 is attributed to its ability to bind to NLRP3 pyrin domain, thus preventing the interaction between NLRP3 and ASC. This proposal is focused on developing AMS-17 analogues with improved biological activity, low toxicity, and high drug-likeness. Aim 1 described in this proposal is focused on the computer-assisted design, synthesis and chemical characterization of AMS-17 analogues. Aim 2 will involve testing of the lead candidates in the humanized mouse model of HAND. The proposed studies are highly significant since they will provide new therapeutic options to minimize HIV-associated neurocognitive dysfunction. The proposal incorporates expertise in the area of synthetic medicinal chemistry (Dr. Kulkarni), biological screening (Dr. Bukrinsky), and computer-assisted drug design (Dr. Adzhubei). It is fully consistent with the goals of this RFA and is expected to define NLRP3 inhibitory compounds working through a novel mechanism different from that of any other currently used drug.

NIH Research Projects · FY 2025 · 2022-07

As terminologies change and are used over time by different entities, there can develop changes and divergence in what the use of a single code or a set of codes represent. These can range from adding a new, more special meaning, to a code set (e.g., adding another possibility to codes whose meaning was first listed as a NEC (not elsewhere classified) code, to a major version change (as in the transition from ICD-9CM to ICD-10CM), and to local adaption (e.g. using a more general code to indicate a more specific condition by an institution.) Such altering of the semantics of codes presents a challenge that can be termed representational semantic integrity (RS integrity). If multiple codes or multiple combinations of codes can represent the same phenotype, cohort identification or cohort variable assignment based on the codes becomes problematic. As numerous research projects utilize large electronic health record (EHR) datasets containing standardized terminology codes, violations of RS integrity would be expected to propagate errors in subsequent analyses and findings. The proposed project seeks to address the question: How to assess and improve RS integrity in longitudinal and heterogenous EHR data using automated methods? We propose to develop novel data driven methods to analyze the temporal pattern and the context of EHR variables. Using ICD-9CM, ICD-10CM, CPT and SNOMED codes as our use cases, this study will leverage very large, longitudinal, heterogenous datasets: the Clinical Data Warehouse of the Veteran Administration (VA)’s national EHR system, the Cerner Real World Data (RWD) and the EHR data repository from a large medical center at University of Alabama at Birmingham (UAB). Our aims are: 1) Develop data-driven approaches to assess RS integrity in longitudinal EHR data. We will develop statistical and deep learning models to perform multivariate time-series analysis for the purpose of detecting aberrant signals in codes in EHR records; 2) Develop data-driven approaches to improve RS integrity in longitudinal EHR data. We will analyze the contexts of codes over time and across data sources using embedding techniques and develop a semantic matching tool that generates semantic equivalent clusters for data from different time periods and facilities; and 3) Validate the assessment and improvement approaches on different coding sets and data sources. We will also assess the impact on predicative modeling.

NIH Research Projects · FY 2025 · 2022-07

The Scholars in HIV/AIDS Research Education (SHARE) Program at The George Washington University, grounded in Social Cognitive Career Theory and Intersectionality Framework, seeks to enhance, in both number and quality, the HIV-research pipeline and workforce. This objective will be achieved by the following aims: Aim 1. Develop a competency-based approach to mentoring with a triad of integrated mentors (i.e., career, science, and peer) in HIV and Substance Use Disorders (SUD), and assess cognitive-related mediators (i.e., self-efficacy and science identity) of mentoring effectiveness and career success. Aim 2. Implement activities for 30 participants (six undergraduate or recent graduate participants per year over five-year project period) for mentored hands- on research experience (prospective research study or secondary data analysis) on a high-priority focused HIV/SUD research topic (e.g., HIV prevention and care continuum; comorbidities). Aim 3. Implement activities for educational and professional-career enrichment experiences through didactics and professional-career enrichment seminars. For these program aims, we will evaluate the impact and effectiveness of SHARE Program on outcomes achieved and career trajectories of the participants and disseminate program success. Expected short term outcomes will include promoting development of a cadre of undergraduate students committed to pursuing behavioral, social and health science research careers in HIV/SUD. The long-term outcome and impact of the program aligns with the priority of the National Institute of Drug Abuse (NIDA)--to increase the number and quality of well-trained researchers in the behavioral and social sciences of HIV and SUD, to reduce their societal consequences and improve individual and public health.

NIH Research Projects · FY 2026 · 2022-05

Four decades into the global HIV pandemic, HIV/AIDS remains a pressing public health challenge contributing to almost 1 million deaths per year. Highly efficacious biomedical interventions have emerged, including multiple modalities of long-acting anti-retroviral-based treatment and prevention. However, not all people have equal access to these lifesaving technologies. Many of the same multi-level factors (e.g. individual: awareness of prevention options, relational: provider communication, environmental: clinic access) that have historically constrained HIV protective behaviors, limit the potential for people and communities to benefit from the real-world impact of these new technologies. Although there is increasing attention in the field to the role of multi-level factors on prevention and treatment, substantial gaps exist about how best to conceptualize, research, and develop effective interventions to address the influence of these factors on HIV prevention, treatment and care outcomes. The proposed predoctoral Training Program in Approaches to Address Multi-Level Factors Related to HIV will prepare the next generation of community-engaged researchers to rigorously study and strategically intervene on these factors to end the HIV epidemic. The program will leverage the multi-faceted strengths of the Departments of Prevention and Community Health and Psychological and Brain Sciences at the George Washington University Milken Institute School of Public Health and the College of Arts and Sciences, respectively, the School of Public Health’s Department of Epidemiology, and the George Washington School of Medicine’s Department of Psychiatry and Behavioral Sciences. Pre-doctoral trainees will undertake a rigorous program of coursework including a solid foundation in multi-level theory, multiple research methodologies, and multi-level intervention development and evaluation. Trainees will participate in cross-cutting and integrative activities including a monthly seminar series, mentored research projects, and community and stakeholder engagement rounds. Trainees will be supported by a group of 18 program faculty members with expertise in addressing HIV and related health outcomes. Proposed Co-Program Directors, Dr. Lisa Bowleg and Dr. Deanna Kerrigan, are recognized leaders in the United States and global HIV response and are executive committee members of the District of Columbia Center for AIDS Research, which serves as a foundational platform for the program.

NIH Research Projects · FY 2026 · 2022-04

The Global Burden of Disease (GBD) study estimated that over 42 million people died globally from non- communicable diseases (NCDs) in 2019 and they are also of one the leading causes of disability. Africa has one of the highest burdens of NCDs and related disabilities and Zambia has one of the highest NCD burdens where it contributes to one in five premature deaths and up to 32% of all deaths annually. We propose a training program to develop Zambia’s capacity to recognize, measure, and to respond to the chronic health and economic consequences of major risk factors for NCDs. This program will be based on close collaboration between two institutions – the George Washington University Milken Institute School of Public Health (GWSPH), USA and University of Zambia School of Public Health (UNZA-SPH), Zambia to respond to two critical gaps – lack of trained human resources and lack of data. The overall goal of the United States-Zambia Addressing Risk Factors for Non-Communicable Diseases in Zambia (US-Zambia Risk-NCD) program is to strengthen research capacity on the long-term health and economic consequences of major risk factors for NCDs across the lifespan in Zambia through an innovative model of sustainable capacity development. Our model will use US expertise to strengthen a Zambian institution, promote a sustainable research enterprise focused on major risk factors for NCDs and enable dissemination of research to influence policy in Zambia through the following specific aims. Specific Aim 1: To develop a core group of researchers focused on major risk factors for NCDs at UNZA. We will offer (1) a long-term training program for trainees from UNZA within the Master of Public Health (MPH) and Master of Medicine (MMed) degrees at UNZA; (2) short-term training workshops at UNZA- SPH including both basic and advanced components each year; and (3) online courses and webinars from GWSPH on key priority topics in measuring the long-term health and economic consequences of risk factors on NCDs. Specific Aim 2: To promote research around key national priorities for NCDs and risk factors in Zambia. We will work with trainees to conduct research around three domains: (1) development and use of national databases relevant to the use, consumption and impact of major NCD risk factors; (2) evaluation of impact of sex on NCDs in Zambia to understand how risk factors for NCDs differ between and among different sexes; and (3) advance implementation research to support identification of locally relevant, effective policies and interventions for NCDs and their risk factors. Specific Aim 3: To develop NCD risk factor “Research to Policy (RTP Forum” in Zambia. We will co-host an RTP Symposium in collaboration with the Zambian Ministry of Health for an annual research-to-policy dialogue on risk factors and NCDs. Specific Aim 4: To create a formal research unit on NCDs and risk factors in Zambia. We will work on complementing individual training by working with UNZA to establish a dedicated research unit that provides a home for faculty across UNZA and enhances sustainability of our efforts.

NIH Research Projects · FY 2026 · 2022-04

Project Summary Observers of children or young animals will notice how much learning about the world depends on being able to move within it. Indeed, studies in humans and other primates have shown that the motor cortex (M1) is involved in working memory, empathy, and language. Could motor dysfunction contribute to the various cognitive and affective deficits that occur in neurodevelopmental disorders (NDD)? Conversely, could improving motor function improve other aspects of NDD phenotypes? Recent work from my lab provides evidence that this may be the case. We have been studying Rett Syndrome (RTT), which is caused by loss-of-function mutations in the X- linked gene methyl CpG-binding protein 2 (MECP2) and is a leading monogenetic cause of NDD, affecting 1 in 10,000 live female births. The phenotype is striking for its postnatal onset: affected girls appear to develop normally and reach the appropriate milestones for the first year or two of life before they regress, losing most acquired skills and developing motor, cognitive, and social abnormalities. Both male and female Mecp2- deficient mice replicate this natural history, and the delayed onset strongly suggests that although MeCP2 is expressed from early development, it has additional, as-yet unclear functions in maintaining mature neurons and synaptic connections. We therefore set out to ask two questions: 1) how does MeCP2 deficiency affect the process of learning at the motor circuit level, and 2) would motor learning exert beneficial effects beyond the particular skill learned? We used calcium two-photon imaging to simultaneously record excitatory activity in layers 2/3 and 5a while 8-week old wild type and null male mice learned to adapt to changing speeds on a computerized running wheel over two weeks of training. We found that a subgroup of M1 neurons in layers 2/3 and 5a strengthen their functional connectivity while the rest of the population decreases functional connectivity, likely to maintain flexibility for learning new skills. Loss of MeCP2 attenuates but does not abolish this reorganization: although cross-layer connectivity was much lower in the null mice, and the functional connections between neuronal pairs in the null M1 circuit last half as long as those in WT, the null M1 circuit retains enough plasticity to support motor skill learning. Moreover, trained null mice showed less anxiety-like behavior and lived ~20% longer than untrained mice (manuscript under re-review). This is all the more remarkable given that the entire brain is disrupted by loss of MeCP2. This work laid the foundation for the current proposal, which seeks to understand the contributions of cortical inputs and inhibitory neurons to L2/3 plasticity during learning, determine the effects of motor learning on M1 in female Mecp2 heterozygous mice, and shed light on how 'normal' the M1 circuit actually is in presymptomatic RTT mice.

NIH Research Projects · FY 2026 · 2022-04

The past decade in the US marked pivotal changes in the policy and retail environments regarding marijuana (MJ), the most commonly used federally illicit drug, particularly prevalent in young adults and certain high-risk subpopulations. Despite controversy regarding recreational MJ, further legalization is likely, and states will continue to navigate its implementation. Thus, states with legalized recreational MJ provide an opportunity and a need to monitor recreational MJ retail and impact on various subgroups, as MJ regulatory frameworks are in their infancy and require advancements given the nuances of MJ retail (e.g., specialty stores, uniquely diverse products, progressive promotional strategies). The overall goal of this research is to inform regulatory efforts to minimize MJ use in vulnerable populations, in states with legalized recreational MJ and those that subsequently legalize it. The immediate objective of this proposal is to examine the recreational MJ market, MJ use, and related perceptions in consumer segments of disproportionately-impacted groups, particularly diverse young adults. Our scientific premise builds on literature indicating that licit drug retail marketing – both brick-and-mortar and online – target certain high-risk populations and the consequences of such marketing on substance use in these groups. The MJ retail has largely lacked standardized industry marketing surveillance tools, which have been critical in establishing the impact of tobacco and alcohol retail marketing and informing regulation. This proposal leverages our team’s prior work; we developed surveillance tools to characterize point-of-sale practices (e.g., age verification), product availability, promotional strategies, and product pricing at brick- and-mortar shops and online – now used broadly in research and practice. Findings indicated several issues with policy compliance (e.g., age verification), promotional strategies appealing to young people and high-risk populations, various health claims, and minimal health warnings. Our team has also shown the utility of identifying young adults at high-risk for substance use and likely marketing exposure by using industry market segmentation based on psychographics (e.g., values, attitudes, lifestyle); the extent to which psychographics vs. sociodemographics inform industry marketing strategies, particularly among targeted populations, is not well known. Using a Socioecologic Framework and Diffusion of Innovations, we aim to: 1) determine whether neighborhood demography is associated with marketing and POS practices among recreational MJ retailers over time, accounting for policy context; and 2) compare young adult market segments defined by sociodemographic characteristics vs. psychographic characteristics in relation to MJ use, perceptions, access, and advertising exposure in states with differing MJ policy contexts (recreational, medicinal, no legalized MJ policy) over time. Led by a by uniquely-poised research team, this proposal is: a) responsive to NOT-DA-19-065 (public health research on cannabis); b) based on a strong scientific premise and rationale; c) highly integrative across aims/data sources; and d) based on rigorous methods integrating innovative applications. We include a robust dissemination plan involving representatives from state/local agencies overseeing MJ retail implementation to speed research translation to practice.

NIH Research Projects · FY 2026 · 2022-03

Project Summary Adolescent men who have sex with men (AMSM) accounted for 79% of new HIV infections among youth ages 13-19 in the United States (US) in 2018. Less than a quarter of AMSM have ever taken an HIV test. Despite these stark disparities in HIV incidence and testing, interventions to reduce sexual risk and increase HIV testing among AMSM remain extremely limited. Notably, the very few intervention approaches that are currently being explored for AMSM exclude parents. The omission of parent-focused approaches represents a glaring gap in national efforts to end the HIV epidemic given parents’ well-documented ability to shape adolescent sexual health, including for AMSM. Consistent with NIH priorities (PA-20-144) the goal of the proposed research is to test the efficacy of a parent-focused intervention designed to reduce HIV risk and increase HIV testing among AMSM. Parents and Adolescents Talking about Healthy Sexuality (PATHS) is an online intervention we created for parents of AMSM that works to increase parent communication about sexuality and HIV, as well as other parent behaviors supportive of sexual risk reduction. Our NIH-funded pilot RCT with a national sample of 61 racially/ethnically diverse parent-AMSM dyads revealed that PATHS increased both parent and child reports of multiple parent behaviors supportive of sexual health. Building on the promising effects PATHS had on parent behaviors, the goal of the proposed study is to test whether PATHS improves sexual health outcomes in AMSM ages 14-19. We will conduct an RCT of PATHS with 350 parent-AMSM dyads recruited online (50% racial/ethnic minority). Parents will be randomized to receive either PATHS or an active control, and then assessed every 3 months over a 1-year period. Primary outcomes will be evaluated at 6 months post-intervention, and then the control arm will crossover and receive PATHS, and dyads will be followed for another 6 months. This allows us to further test the effects of PATHS in the control arm while simultaneously modeling the longer 9- and 12-month effects in the original intervention arm. The primary (P) specific aims are to: (P1) Test the efficacy of PATHS in improving the degree to which AMSM are prepared for intercourse (operationalized as: having access to condoms, demonstrating accurate condom skills, expressing intentions to use condoms, receiving HIV testing, understanding what PrEP is, and expressing positive attitudes toward PrEP); and (P2) Test the efficacy of PATHS in reducing condomless anal/vaginal intercourse. Secondary (S) aims are to: (S1) Examine the degree to which intervention effects observed in P1 and P2 persist to 1-year post intervention; and (S2) Examine how parent behaviors mediate effects of PATHS on AMSM outcomes. If proven efficacious, PATHS will be among the first interventions demonstrated to reduce sexual risks and increase HIV testing for AMSM – the population of youth at highest risk for HIV infection in the US. Moreover, as other adolescent-focused interventions emerge, PATHS’ unique focus on parents will offer a complementary, additional means for reaching AMSM who are not touched by other intervention options.

NIH Research Projects · FY 2026 · 2022-02

Project Summary Nucleotide excision repair (NER) is the major pathway to remove bulky DNA lesions induced by UV irradiation, environmental mutagens, and chemotherapeutic agents. Deficiency of genes involved in NER has been linked to Xeroderma Pigmentosum (XP) and skin cancer. There are two mechanisms to detect DNA damage by NER, one is global genome NER(GG-NER) and another is transcription-coupled NER(TC-NER). GG-NER occurs anywhere in the genome, whereas TC-NER is responsible for the accelerated repair of lesions in the transcribed strand of active genes. The both pathways are divided into early and late steps. The early step is the sequential actions, in which XP proteins recognize, unwind, and incise the DNA lesion. The latter step is identical in both mechanisms and is characterized by gap-filling repair synthesis, in which DNA replication proteins fill in the ~30 nucleotide gap, followed by ligation. Compared to the well-characterized early step, the molecular mechanism regulating the activation of gap-filling DNA synthesis at late step remains largely unknown. Even less is known about the physiological impact of such a regulatory pathway. And-1 is an acidic nucleoplasmic DNA-binding protein and its yeast ortholog, Ctf4, was originally identified as a critical gene for chromosome stability. Interestingly, yeast cells with depletion of Ctf4 gene are hypersensitive to UV lights, suggesting a role of And-1 in UV-induced DNA damage response. However, how And-1 regulates NER remains largely unknown. In this study, we now have extensive preliminary data demonstrating that And-1 is critical for NER by regulating gap-filling DNA synthesis. Our hypothesis is that And-1 regulates DNA polymerase activity at UV-lesion sites to activate gap-filling DNA synthesis at the late stage of NER. To test this hypothesis, we plan to pursue three specific aims. Aim 1: Determine the mechanism by which And-1 regulates DNA polymerase activity in NER. Aim 2: Determine the unique mechanism by which And-1 is recruited to UV-lesion sites. Aim 3: Determine the role of And-1 in NER and skin tumorigenesis using And-1 deficient mouse models. The completion of proposed studies will not only advance the field by uncovering a novel And-1-mediated pathway to regulate NER, but also provide us with the in vivo evidence to elucidate a novel role of And-1 in NER and skin tumor.

NIH Research Projects · FY 2026 · 2021-12

Abstract The susceptibility to Multiple Sclerosis (MS) is believed to be due in part to neuroinflammation and disease burden linked to neurodegeneration. It is well established that females have a more robust immune response than males however, neurodegeneration and disease progression are more sever in males. Thus, in the context of MS, this raises an intriguing question. Do females, by virtue of having a more robust inflammatory responses, have endogenous protection/repair mechanisms to protect the central nervous system (CNS) from inflammation induced pathology, that males do not have or that are not as effective in males? This proposal is based upon extensive preliminary and published data demonstrating that tmTNF/TNFR2 signaling in females, but not males, significantly improves motor function and reduces neuropathology in EAE by activating endogenous repair programs in neurons and oligodendrocytes. Based upon these and other results, our first experimental goal is to interrogate sex differences in tmTNF/TNFR2 induced improvements in motor function and neuropathology. Further, we have very novel pharmacological and genetic data that ligation of TNFR2 on both neurons and oligodendrocytes induce regenerative responses, through IRE1-dependent mechanisms. Based upon these and additional data our second experimental goal is to investigate the intersection between TNFR2/IRE1 signaling and to determine if the therapeutic effects of TNFR2 activation are dependent upon IRE1 activation. These goals will be tested in the following aims: Specific Aim 1: Investigate the sex-specific effects of tmTNF/TNFR2 signaling in the improvement of motor function and neuropathology. A) We will investigate the role of sex hormones in tmTNF/TNFR2 signaling in the improvement of motor function and neuropathology in male and female mice. B) We will investigate the role of sex chromosomes in tmTNF/TNFR2 signaling in the improvement of motor function and neuropathology in male and female mice. Specific Aim 2: Investigate TNFR2 induced endogenous repair mechanisms in male and female mice. A) We will interrogate TNFR2 induced endogenous repair mechanisms oligodendrocytes and determine if they are required for motor recovery in females. B) We will interrogate TNFR2 induced endogenous repair mechanisms neurons and determine if they are required for motor recovery in females, in vivo and in vitro.

NIH Research Projects · FY 2026 · 2021-12

PROJECT SUMMARY Recently, several genital anaerobic bacteria that are not classically associated with sexually transmitted infections (non-STI) were linked to increased heterosexual transmission of HIV, likely by inducing immune responses that enhances HIV target cell activation and recruitment to the genital mucosa. This project seeks to close critical knowledge gaps regarding acquisition and persistent carriage of this new HIV risk factor. Our long-term goals are to elucidate the determinants of genital microbiome composition and the biological mechanisms that link genital bacteria to host susceptibility to HIV, and to leverage this knowledge to develop innovative solutions to prevent HIV. The objective is to understand the heterosexual transmission dynamics of genital bacteria associated with HIV risk and to determine the abiotic and biotic factors that impact acquisition and persistence of these genital bacteria in men. Our central hypothesis is that perturbations affect penile microbiome composition—including acquisition, loss, or persistence of genital bacteria associated with HIV risk—predictably based a set of abiotic and biotic factors. The rationale for this project is that, by understanding the abiotic and biotic factors that determine acquisition, loss, or persistence of specific genital bacteria, we will be able to identify and develop new strategies to prevent or reduce colonization. Aim 1. Elucidate the sexual transmission of genital bacteria and the determinants of the penile microbiome after sex. We will test this by: (i) Characterize the genital bacteria strains present in adolescent boys before and after sexual debut (n = 200) and (ii) Determine the effect of pre-coital host (penile) and partner (vaginal) genital pH, oxygenation, moisture, metabolites, anti-bacteria IgA, and microbiome on the acquisition or persistence (1, 8, and 72 hour post-sex) of genital bacteria in the host (n = 106 couples). Aim 2. Elucidate the determinants of the penile microbiome after antimicrobial treatment. We will test this by comparing pre- and post- treatment (Day 3, 8, and 28) penile microbiomes in 1 control arm and 4 treatment arms, including 3 topical treatments: (i) 2% clindamycin, (ii) 1% H2O2, (iii) 0.75% metronidazole, and (iv) oral tinidazole. Aim 3. Validate the impact of abiotic and biotic factors on the penile microbiome response to perturbation using an in vitro model. We will achieve this aim by adding: (i) donor vaginal microbiome and (ii) topical antimicrobials to penile microbiome in organotypic foreskin model to assess the effect of abiotic factors and bacterial strains on microbiome outcome. The proposed research is innovative, in our opinion, because it represents a departure from the status quo by elucidating transmissible dysbiosis, and doing so with absolute abundance metrics, innovative study designs, and a novel co-culture model. The proposed research is significant because it is expected to reveal how sex and antimicrobials impact penile microbiome and what drives outcome.

NIH Research Projects · FY 2026 · 2021-09

Abstract Serious stress-related public health concerns exist for today’s Latin American-origin youth. Chronic and/or severe exposure to adversity can elevate stress processes in the family (e.g., increased maternal depression) and manifest through youth’s behavioral health (e.g., unhealthy diet), and biology (e.g., flatter diurnal slopes of daily cortisol output). These stress processes can increase mental health and chronic disease risks and limit social mobility for Latino/a youth making the consequential transition to adulthood. We propose major expansions to Caminos, an NICHD-funded study collecting 8 time points of data at 6-month lags (2018-2021) for a diverse sample of 547 Latin American-origin adolescents (88% U.S. born) and mothers (80% foreign born) in suburban Atlanta, GA. The proposed study will add five time points of annual data, extending current measures into the transition to adulthood and assessing hair and salivary cortisol indicating chronic and acute stress, waist circumference, and survey reports of chronic disease risk and social mobility. The 13 time points of data (2018 to 2026) will trace the onset of behaviors from as early as age 11 and occurring during a time of important societal changes. We will use state-of-the-art methods to multiply impute intentionally and unintentionally missing data for a cohort of mother-child dyads with high retention in the ongoing study. Guided by family stress models and contextual-developmental theory, cross-lagged path models and latent growth mixture models will test the hypothesis that family, biological, and behavioral health stress processes mediate associations between adversities (e.g., low interpersonal support) and youth’s mental health risks (internalizing and externalizing symptoms, substance use), chronic disease risks (e.g., asthma, diabetes), and social mobility (e.g., educational attainment). Using tests of moderated mediation, we will identify community-, family-, and individual-level protective factors that mitigate impacts of stress on youth outcomes. Sex as a biological variable will be examined as a key modifier. Unique from other national and cohort studies, the proposed research will identify how accumulated adversities shape Latin American-origin youth’s health outcomes and social mobility over time. In addition, the proposed study is uniquely situated to assess factors within and outside of the residential neighborhood, namely, within mothers’ daily activity spaces. Elevating study impacts, findings will inform preventive interventions and programs that can improve health for youth as they prepare for adulthood.

NIH Research Projects · FY 2024 · 2021-09

Abstract The proposed diversity supplement extends the parent grant's research on magnesium (Mg) supplementation in patients with diabetes mellitus (DM) and heart failure (HF), examining its differential impact across diverse racial, ethnic, and gender groups. This research addresses the knowledge gap surrounding the safety and efficacy of dietary supplements, particularly in the absence of FDA approval and comprehensive post-marketing surveillance. Preliminary data from the parent grant's pilot study suggest that Mg supplementation may reduce HF risk in patients with DM and enhance outcomes in those with HF. Given the substantial impact of HF and DM on millions of Americans, further investigation is essential. The diversity supplement comprises three specific aims to investigate Mg supplementation's role in diverse subpopulations. Aim 1 focuses on patients with DM from the parent grant, investigating whether oral Mg supplementation is associated with reduced incident HF risk, varying by race, sex, and ethnicity, with sub-hypotheses examining differences among African-American, Hispanic, and male Veterans. Aim 2 concentrates on patients with incident HF, exploring the relationship between oral Mg supplementation and the risk of death and hospitalization among HF patients, considering diverse populations. Aim 3 seeks to understand provider and patient perspectives on self-reported consumption of over-the-counter Mg supplementation in the context of HF prevention and management. Aims 1 and 2 will be achieved by interrogating the Veterans Affairs (VA) national EHR data that includes over 2 million Veterans with DM and 1 million with HF with ~20 years of longitudinal data on Mg supplements, serum Mg, and outcomes. As for Aim 3, in identifying and recruiting participants for the provider group, we will employ a strategic snowball sampling approach, guided by local champions. This method will facilitate the formation of two distinct focus groups: one comprising patients and the other consisting of physicians. The findings generated by this proposed supplement will offer valuable insights into the disparities in HF incidence and outcomes among different demographic groups, particularly those defined by race, ethnicity, and gender, while shedding light on the potential influence of mg supplementation in mitigating these disparities. This research addresses a critical gap in cardiovascular literature and has the potential to inform targeted interventions for at-risk populations and promote health equity in the context of HF.

NIH Research Projects · FY 2025 · 2021-09

Project Summary/Abstract This program is a response to the growing burden of trauma and injuries (inclusive of intentional and unintentional trauma and injuries; henceforth ‘T&I’), the acute and chronic consequences of T&Is and their risk factors (alcohol, speed, urbanization) and their social and economic consequences which are all neglected public health issues in Zambia. Two critical gaps in addressing T&Is in Zambia are a lack of trained human resources and limited data on health, social and economic impacts. The overall goal of the United States- Zambia Trauma and Injury Research Training Program (US-Zambia TIRP) is to strengthen research capacity on the health, social and economic impact of trauma and injuries across the lifespan in Zambia through an innovative model of sustainable capacity development. Our approach will be based on close collaboration between two institutions–the George Washington University Milken Institute School of Public Health (GWSPH), USA and University of Zambia School of Public Health (UNZA-SPH), Zambia – each with a great commitment to understanding the impact of T&Is, experience and expertise in research, and a history of collaborative work. The specific aims of US-Zambia TIRP are: aim 1: to develop a core group of researchers focused on T&Is in Zambia. This aim will allow for the development of research expertise focused on the health, social and economic impact of T&Is at key institutions in Zambia. Aim 2: To promote research around key national priorities for T&Is in Zambia. We will enhance the production of relevant research on T&Is in Zambia around three domains: (a) documentation and measurement of risk factors (e.g. alcohol, speeding, emergencies); (b) the evaluation of interventions that will address major trauma and mass casualties (e.g. humanitarian emergencies, natural disasters); and (c) exploration of the social and functional impact of T&Is across the lifespan. Aim 3: To develop a T&I “Research to Policy (RTP) Forum” in Zambia. Under this aim, we will use the experience of our institutional collaborations and the national standing of UNZA-SPH to promote the utilization of research evidence on the impact of T&Is on communities to influence appropriate policy in Zambia. We will co-host an RTP symposium in collaboration with the Zambian Ministry of Health for an annual dialogue on T&Is; this platform will involve the focal point for T&Is in the Ministry of Health, Government of Zambia, while UNZA will be the secretariat. Aim 4: To create a formal ‘Center for T&I research’ in Zambia. We will complement individual training by working with UNZA to establish a center for research that provides a home for faculty across Zambia and enhances sustainability of our efforts. This program will be housed within the UNZA but will serve the country and will work to support research and training on T&Is. In summary, we are proposing an innovative US-Zambia TIRP that transforms the T&I research landscape in an increasingly research-intensive country in sub-Saharan Africa. We will implement a capacity development model for Zambia by Zambians with technical assistance from the US to address a major gap in the health research enterprise.