Brown University

NIH Research Projects · FY 2025 · 2018-08

Project Summary/Abstract It is currently feasible for small research groups to sequence individual genomes and for larger groups to sequence tens of thousands of individuals. Unfortunately, our ability to identify variants that impact phenotype has not kept pace with our sequencing capacity. This is particularly true of non-coding variants. This proposal presents a pilot screen of more than 32K variants from myCode and ClinVar that suggest 1-2% of exonic mutations affect splicing. The pilot study also revealed that splicing mutations are not uniformly distributed across disease genes or even within genes. This proposal will continue this effort on variants from UK biobank, AllofUs, ClinVar and GTEx that localize to actionable genes. Splicing mutations do not occur uniformly across exons. The proposal seeks to map susceptibility to splicing mutations and identify hotspot exons (exons unusually susceptible to splicing mutations) in the genome. In addition to identifying loss of splicing variants, the little studied problem of gain of splicing variants (i.e. single base mutations that can activate pseudoexons) will also be explored. Preliminary studies locate many intronic regions in pre-mRNA that contain all-but-one of the numerous cis-elements necessary for splicing. In addition to mapping susceptibility to splicing mutations, these efforts will contribute to the basic science of combinatorial signal recognition with a high-level approach that will define mechanisms of splice site selection. Finally, we present a principled method of restoring splicing to mutated exons using antisense oligonucleotides (ASO) that weaken flanking splice sites.

NIH Research Projects · FY 2025 · 2018-08

PROJECT SUMMARY/ABSTRACT This K24 midcareer research and mentoring program aims to provide the candidate with protected time from direct patient care to conduct patient-oriented research (POR) on adolescent alcohol misuse and to mentor early-career clinical investigators in translational research in addiction science. To meet the challenge of advancing treatment options for the millions of American youth who struggle to reduce their alcohol use, the field requires highly trained researchers who can integrate cutting-edge concepts and methods from a variety of areas. As our understanding of addiction has become more complex, so too has the training needs of early- career scientists. For more than two decades, the candidate has built a productive and continuously funded POR program that translates theory-driven hypotheses from preclinical and human laboratory research to real world applications. The proposed integrated plan will facilitate the candidate’s ability to mentor early-career clinical investigators in POR and augment his capabilities as an independent clinician scientist. The research plan, which focuses on improving treatment options for adolescent alcohol misuse through digital health, dovetails the mentoring goals by providing a vehicle for mentoring early career scientists in: i) mechanisms of alcohol use disorder pathogenesis and treatment effects, ii) clinical trial methods, iii) ecological momentary assessment approaches, and iv) training in the responsible conduct of research. The candidate’s goal is to further develop and refine an experimental therapeutics approach that yields high quality information to inform decisions about whether further development of novel treatments is warranted. This K24 will support the collection of pilot data for an integrative digital health platform based on gold standard psychosocial interventions for treating AUD among adolescents. Adolescence is a critical period for the pathogenesis of AUD. Alcohol use typically begins during adolescence and prevalence rates for AUD peak before age 21. Yet, despite clinical demand, AUD treatments for youth rely on psychosocial interventions that yield only modest benefits. One potential way to improve adolescent alcohol treatment is to augment the best available psychosocial interventions with innovative digital health solutions.

NIH Research Projects · FY 2025 · 2018-08

Abstract: The Emerging Infectious Disease and HIV Scholars Program (EIDS) program seeks to develop a physician-scientist workforce focused on clinical research to inform practical responses to HIV and associated infections over the next decades. The Alpert Medical School of Brown University has incorporated a Master of Science with specific coursework to provide an educational foundation for clinical research with a dedicated research block. The program offers financial support for pilot research projects and appropriate mentors will be assigned to guide scholars. Scholars in medical school will attend a relevant professional conference each year and program faculty and mentors will provide supplemental networking opportunities at these meetings. The program will work closely with the Rhode Island Department of Health to engage trainees in the investigation of ongoing epidemics in Rhode Island, such as HIV, COVID-19, monkey pox, hepatitis C, and escalating sexually transmitted infections including syphilis. In the first four years, we enrolled and supported 66 scholars who completed clinical research projects, resulting in 72 abstracts and 31 publications. This grant will continue to inspire, train, support, and retain a community of scholars to serve as “microbes hunters”. Specific Aim 1: Inspire future physician-scientists to rapidly address challenges of HIV associated infections and emerging epidemics. Specific Aim 2: Train future physician-scientists. Over the course of four years, medical students will complete coursework leading to a Master in Science degree. Specific Aim 3: Support future physician-scientists. All scholars will have access to resources to develop an independent research proposal. Support in clinical research tools, biostatistics, analysis, abstract development, and manuscript preparation will be provided through tailored coursework and program faculty, staff, and mentors, and funds will be available for scholars and program faculty and mentors to attend appropriate scientific conferences. Specific Aim 4: Retain the community of scholars throughout training. All aspects of the program will be evaluated on an ongoing basis in order to determine acceptability, relevance, and value of each component of the training program. Outcomes of interest include research project development and completion, abstract presentation and manuscript publication, and long-term engagement in clinical research related to emerging infectious disease.

NIH Research Projects · FY 2025 · 2018-06

PROJECT SUMMARY: In the context of the gut barrier, Vitamin A metabolite retinoic acid (RA) is central to immune homeostasis in the gut, coordinating both innate and adaptive immunity. Vitamin A directly regulates proliferation and differentiation in the intestinal epithelium, which is crucial for maintaining optimal gut barrier. Our work in the last funding cycle revealed that gut bacteria are crucial in regulating how dietary vitamin A is processed in the intestinal mucosa. Specifically, we showed for the first time that commensal bacteria suppress RA synthesis in the gut by modulating the intestinal epithelium’s vitamin A metabolic gene rdh7. Our findings delineated the previously unknown impact of commensal bacteria on the vitamin A homeostasis, thus opening up questions regarding the role of microbially regulated RA synthesis on mucosal immunity and epithelial regeneration. Using a mouse model that constitutively expresses rdh7 gene in IECs we now show that dysregulated epithelium intrinsic RA synthesis is detrimental to host and results in increased number of IFNγ producing T-cells and enhanced susceptibility to experimental colitis. We find that overexpressing Rdh7 gene in IECs results in decreased proliferation and repair upon damage compared to control mice. Additionally, our work establishes that commensal bacteria in the gut possess vitamin A metabolic activity and significantly increase RA concentration in the gut lumen. Precise role of bacteria derived RA on epithelial barrier and intestinal immune homeostasis remains to be discovered. We hypothesize that the host and bacteria collaborate to generate an RA gradient that supports optimal intestinal epithelium renewal and immune homeostasis. In this grant proposal we will:1) determine the mechanism by which IEC intrinsic RA regulates T-cell effector responses and whether impact of IEC intrinsic RA is restricted to T-cells residing in close proximity to IECs. Additionally, we will evaluate the role of IEC intrinsic rdh7 expression in regulating IFNγ dependent immunity against intestinal pathogens and infection burden (Aim1), 2) delineate the mechanism by which RA regulates stem cells and assess the role of rdh7 expression in remodeling stem cell niche during infection via interactions with underlying immune cells (Aim2), and 3) metabolic difference in ability of gut bacteria to produce RA from pro-form vs pre-form vitamin A to probe the exclusive role of gut-bacteria sourced RA on host physiology(Aim3). Our work will deliver an unprecedented and comprehensive understanding of the role of bacterially regulated vitamin A homeostasis in the host. Our Aims will generate new paradigms for investigating and understanding vitamin A-mediated ISC remodeling. Our work will provide microbial and dietary interventions that could be therapeutic for diseases with an underlying defect in ISC regeneration and mucosal immunity.

NIH Research Projects · FY 2025 · 2018-06

Summary This is a resubmission of the competitive renewal of the ongoing R01 grant. Visual perceptual learning (VPL) is an important tool that can be used to better understand visual plasticity. The long-term goal is to comprehensively understand the mechanisms of VPL and their underlying plasticity, which may provide important information for the development of training and rehabilitation tools and programs for improving and restoring damaged, declining or degraded vision. This proposal aims to examine the roles of global processing, such as reward and arousal, in the specificity of VPL, which is one of the most important characteristics of VPL. VPL is generally characterized as specific to the trained feature and the retinal location in which the feature is presented, minimally transferring to other features or locations. The specificity of VPL may impose serious restrictions on the use of VPL in clinical applications that require generalized effects in everyday life. Early studies suggested that the specificity of VPL comes from properties of neurons in early visual areas. However, later studies indicate that the specificity is greatly influenced by global processing that does not originate in early visual areas. The current proposal aims to examine the roles of global processing such as reward and arousal in the generalizability and specificity of VPL. No research has ever been conducted to test whether and how reward and arousal each influence the generalizability/specificity of VPL. There are two types of VPL. Task-irrelevant VPL (TIVPL) refers to the learning resulting from passive exposure to a task-irrelevant feature or object, whereas task-relevant VPL (TRVPL) refers to the learning of a task-relevant feature or object through a given task. Significantly different mechanisms may underlie these two types of VPL. Thus, the abovementioned questions will be addressed for TIVPL and TRVPL in Specific Aims 1 and 2, respectively. Our preliminary results consistently suggest the following aspects: (1) Arousal plays a role in generalizing the trained feature or object to untrained features or untrained objects within the same category of the trained object, whereas reward is not involved in the generalization of VPL and rather plays a role in inducing the specificity of VPL. (2) Generalization due to arousal is not involved in reinforcement processing, which may play an important role in the specificity of VPL due to reward. The information that will be obtained from the research results is expected to be important for the development of a clinical training method, for which the generalization of VPL is crucial. We will test the following hypotheses by psychophysics. Hypothesis (H)1: Reward plays a role in increasing the specificity of TIVPL and TRVPL. H2: Arousal plays a role in increasing the generalizability of TIVPL and TRVPL. H3: H1 and H2 are valid for both VPL of a primitive feature and VPL of an object. H4: Reinforcement processing is involved in the role that reward plays in the specificity of TIVPL and TRVPL, whereas it is not involved in the role of arousal in the generalizability of TIVPL and TRVPL.

NIH Research Projects · FY 2026 · 2018-01

This proposal seeks continued support for the Postbaccalaureate program at Brown University (renamed ‘PREP@Brown) to advance our work in developing a highly-talented pool of knowledgeable and well-trained individuals who go on to pursue Ph.D. degree training and careers in the biomedical sciences. This work responds to the need to expand the U.S. STEM workforce. Informed by best practices and lessons learned from our ongoing work, we describe an innovative program characterized by a comprehensive and customizable set of interventions to support and advance students' academic and career development and success.   Each year, our program will recruit and support six research-oriented baccalaureate graduates (The Scholars) and provide them with interdisciplinary research experiences, individualized academic planning, professional development, and skill-building activities to increase their competitiveness and readiness for high-caliber doctoral programs. Participating departments for Brown’s PREP@Brown program are those in the Life and Medical Sciences Division and include biology, neuroscience, molecular microbiology and immunology, pathobiology, public health, and cognitive, linguistic, and psychological sciences. In addition to intensive interdisciplinary research experiences and knowledge development, multiple mentorship and community-building opportunities permeate the activities of PREP@Brown. This will create a community of scholars that will help participants successfully navigate training needed for readiness for graduate studies. The use of Individual Development Plans (IDP) will ensure that PREP@Brown research, educational and professional development activities are tailored to address each Scholar’s academic and career goals. The PREP@Brown Program will also create opportunities for faculty to engage in conversations about the importance of developing a talented workforce in the biomedical and behavioral sciences. We have developed a comprehensive evaluation plan to assess outcomes and progress toward meeting the overall goal and aims of this project and monitor quality assurance across the proposed interventions.   As designed, PREP@Brown has begun to, and will continue to increase the production of highly-qualified students who obtain a doctoral degree in the biomedical sciences and institutionalize best practices on training and mentoring – practices that can be shared among the Brown community and beyond.

NIH Research Projects · FY 2026 · 2017-04

Project Summary Heart failure currently drives a significant proportion of health and economic burden in the United States. Although steps have been made in developing effective treatments, the incidence, morbidity, and mortality of heart failure continues to rise. Thus, it is important to seek out new, more effective therapeutics through the study of molecular mechanisms responsible for cardiac dysfunction. Maladaptive cardiac remodeling is driven by changes in gene expression and protein synthesis in cardiomyocytes. How post-transcriptional modifications control the outcome of gene expression to regulate the synthesis of specific proteins in the heart is unclear. We found that METTL3, the methylase responsible for m6A formation on mRNAs, is a critical regulator of cardiac hypertrophy and is essential for the maintenance of cardiac homeostasis. However, the mechanisms through which METTL3 impacts remodeling has yet to be fully understood. In this proposal we examine the role of METTL3-dependent methylation in regulating mRNA translation for maintenance of heart function at baseline and in adaptation to stress. Utilizing METTL3 gain- and loss-of-function mouse models, we aim to uncover the mechanisms through which METTL3 regulates hypertrophic heart remodeling. Considering the critical importance of this enzyme in the heart we will also address the mechanisms regulating its function and specificity. These findings will further our understanding on how post-transcriptional modifications control cardiac gene expression, while also uncovering new targetable pathways for therapeutic development.

NIH Research Projects · FY 2026 · 2017-02

This is the 1st renewal of the Brown Respiratory Research Training Program (BRRTP). The overall goal of the program is to provide predoctoral candidates and postdoctoral fellows training in the pathobiology and/or outcomes, prevention, and epidemiology as it relates to pulmonary/ critical care/ sleep disorders. This unique program at Brown University fosters close interactions and collaborations between trainees and faculty from multiple disciplines and training backgrounds in both the medical school and across all the teaching hospitals in the Brown University system. We propose to continue to train 4 predoctoral and 4 postdoctoral trainees per year. The predoctoral trainees will be enrolled in PhD programs, while the postdoctoral trainees will have completed their PhD, MD, or MD/PhD degrees. Individuals completing this program will be well positioned to contribute to understanding of lung diseases, to develop independent research careers, to translate advances in basic, clinical, and health services research to clinical applications and teaching, and to address health issues critical to society. The predoctoral training program continues to focus on the pathobiology of respiratory diseases and to capitalize on strengths in the areas of infection and immunity. In this renewal, we have added pulmonary vascular biology to the pathobiology focus, enhancing faculty and trainee participation and enlarging the range of research interests. The postdoctoral training program consists of two inter-related tracks —pathobiology of respiratory diseases plus health services/ outcomes and epidemiology of respiratory diseases.

NIH Research Projects · FY 2025 · 2016-09

Metals are essential for human health yet potentially toxic in excess. Our understanding of metal homeostasis stems prominently from studies of inherited diseases of metal deficiency and excess. The molecular basis of manganese (Mn) homeostasis is poorly understood relative to other metals, given that inherited Mn-related diseases were only recently identified. In 2012, mutations in a metal export protein SLC30A10 were reported in patients with Mn excess, liver and neurologic disease, increased red blood cell counts, and erythropoietin excess. Mn excess was attributed to impaired biliary Mn excretion, while liver, neurologic, and hematologic defects were ascribed to Mn toxicity. Employing our expertise in mammalian metal homeostasis, we recently demonstrated that murine Slc30a10 is not only essential for systemic and biliary Mn excretion but also for Mn export by the small intestine into the lumen of the gastrointestinal tract (Mercadante et al., J Clin Invest., 2019). This indicates that the role of SLC30A10 in Mn homeostasis is more complicated than anticipated and that extrahepatic organs contribute to Mn excretion. In exploring the mechanistic basis of Mn excess in SLC30A10 deficiency, we also observed that Slc30a10-deficient mice develop paradoxically increased Mn absorption despite severe Mn excess. Our preliminary data suggest a multi-step model underlying this surprising observation. First, excess Mn aberrantly stimulates the liver to express the hormone erythropoietin. Second, erythropoietin excess indirectly suppresses expression of the hormone hepcidin, an inhibitor of dietary iron absorption. Third, hepcidin deficiency leads to increased Mn absorption. As a role for hepcidin in Mn homeostasis is not well-established, this last novel step in our model is based upon our observation that pharmacologic stimulation of hepcidin expression decreases Mn levels in Slc30a10-deficient mice . We propose that SLC30A10 deficiency is a unique pathophysiological context in which hepcidin plays an unexpected but pivotal role in development of Mn excess. The goal of this proposal is to establish the mechanistic link between hepcidin and Mn absorption in SLC30A10 deficiency and to explore pharmacologic stimulation of hepcidin expression as a treatment for Mn excess in SLC30A10 deficiency and other conditions. This will be accomplished using genetic, metabolic, pharmacologic, radioisotopic, dietary, and microscopic techniques. The proposed studies will enable us to not only further establish the molecular basis of mammalian Mn homeostasis but also to design therapeutic strategies for Mn-related diseases based upon our understanding of underlying mechanisms of Mn homeostasis.

NIH Research Projects · FY 2026 · 2016-09

PROJECT SUMMARY (OVERALL) Retrotransposable elements (RTEs) comprise ~45% of the human genome. Known as ‘mobile DNA’ they can insert into new genomic locations using a 'copy and paste' mechanism. This process, retrotransposition, can be deleterious at multiple levels, and has largely been viewed as molecular parasitism. Not surprisingly, host organ- isms have evolved multiple silencing mechanisms to protect their genomes. This competitive and adversarial relationship between RTEs and their hosts is evident in the evolutionary record of genome sequences. This record is silent on the activity of RTEs in somatic tissues, since this information is not passed from one generation to another, and RTEs were thought to be largely silent in somatic cells. However, in the past 10-15 years evi- dence started emerging that somatic RTE activity is more frequent than anticipated, with members of this PPG contributing important early evidence. Five years ago, this debate culminated in the submission of this PPG, founded on the hypothesis that the somatic activation of RTEs represents a novel and hitherto unappreciated molecular aging process. Our research program was designed to test this hypothesis and elucidate the underly- ing mechanisms. The next five years saw a validation of this hypothesis, not just by our team, but also many other groups. It is now apparent that with aging, multiple host defense mechanisms become compromised, and repetitive sequences in general, not just active RTEs, increase their expression. As to the underlying mecha- nisms by which this somatic onslaught 'can hurt us' we were in for a surprise: we discovered that RTEs dere- pressed during aging, in particular LINE-1 (L1) elements, can generate cytoplasmically localized cDNA reverse transcripts. These cDNAs are potent activators of a Type-I Interferon (IFN-I) response, which in turn stimulates the innate immune system. We believe this leads to a phenomenon known as 'sterile inflammation' or 'inflam- maging', a known hallmark of aging that has been implicated in a variety of age-related diseases. In a nutshell, the host organism perceives RTE activation as an invading virus and mounts an appropriate anti-viral response – unfortunately, given that the invader is embedded in our genomes, this response is futile and ultimately coun- terproductive. Interestingly, the central nervous system (CNS) appears to be a 'privileged site' for RTE activity, with relatively high levels of expression and ease of further upregulation. Multiple lines of evidence indicate that RTE activation is associated with pathology, and in particular neuroinflammation. Neurodegenerative diseases, and in particular dementias such as Alzheimer's Disease (AD), are among the most devastating and feared diseases of aging. The goal of this PPG will be to explore in detail the newly discovered somatic L1 lifecycles in neuronal and non-neuronal cells of the CNS, the L1 surveillance mechanisms in the CNS, how they fail, the consequences of that failure, and ultimately, how we can fix this. We will use human induced pluripotent stem cell (iPSC) models as well as directly reprogrammed neurons, Drosophila and mouse models of AD, and human postmortem tissue. F.H. Gage, a widely-known AD pioneer, joins the original PPG team on this quest.

NIH Research Projects · FY 2025 · 2016-08

PROJECT SUMMARY: Alcohol is the widely abused drug in the world, yet our understanding of the molecular mechanisms by which it regulates brain function and behavior is rudimentary. Many of the molecules implicated in alcohol-induced behaviors have broad roles in regulating diverse processes such as cell signaling, transcription, and neuronal plasticity. The complexity of these processes has led to confusion about alcohol’s molecular underpinnings, which has been further compounded by lack of the ability to manipulate gene expression with precise temporal and spatial control within a well-defined neural circuit. The temporal and spatial specificity for manipulating gene expression afforded in the fruit fly, Drosophila melanogaster, provides the ability to define where and when and where alcohol is acting in the brain to influence both naive and learned behavior. Our unbiased forward genetics approach in Drosophila has revealed the importance of the Notch signaling pathway in regulating formation of memories of a sensory cue associated with the intoxicating properties of alcohol. Notch is a highly conserved cell-signaling mechanism that involves cell-to-cell contact and initiates a transcriptional cascade important for determining cell fate and function. Notch signaling also plays a key role in multiple forms of cancer and immune disorders, as well as cardiovascular, kidney, liver, respiratory and neurodegenerative disease. We recently demonstrated that rewarding doses of alcohol activate Notch signaling in memory-encoding neurons, and this affects expression of novel Notch transcriptional targets such as dopamine receptors. What remains to be understood are the mechanisms through which alcohol activates Notch, and how this ultimately affects dynamics of memory circuits, both acutely and with chronic alcohol use. We hypothesize that Notch plays an important role in activity-dependent transcription required for memory formation and thus ultimately shapes future reward seeking. The goal of the proposed work is to use a genes-to-circuits-to-behavior approach to provide a causal Notch-dependent mechanism through which alcohol-induced cellular activity can guide a transcriptional cascade that influences future alcohol seeking. This increased molecular understanding of the lasting sensory memories for intoxication will ultimately inform more effective targets for pharmacological treatment of alcohol use disorder.

NIH Research Projects · FY 2025 · 2016-07

ABSTRACT – OVERALL The universities, hospitals, government agencies and community organizations in Rhode Island are well positioned to bridge the gaps between the worlds of clinical and basic science. Rhode Island’s small size, population demographics, and organizational structure are assets and present opportunities to implement and test transformative clinical and translational research. The health care delivery environment within the state is highly conducive to clinical research due to the relatively limited number of health care systems. Further contributing to Rhode Island’s translational research infrastructure are a number of well-organized Institutional Developmental Award (IDeA) Programs, each with core facility, faculty development and collaborative research resources. But despite Rhode Island’s impressive educational institutions, streamlined clinical environment, and successful IDeA sponsored research and mentoring programs, the majority of these resources have not been coordinately focused towards developing a multi-institutional, clinical and translational research infrastructure that would serve to improve the effectiveness of clinical practice and health care policy in Rhode Island. The objective of the Advance Clinical and Translation Research Award (Advance-CTR) is to bridge these infrastructure gaps by creating an overarching, multidisciplinary, central organization to better coordinate and leverage existing resources for program management and thereby provide the infrastructure necessary to address current and future health concerns in Rhode Island. The goals of the Advance-CTR are to: 1. Educate, mentor and encourage young investigators in clinical research professional development. 2. Eliminate the obstacles that may prevent researchers from pursuing clinical research initiatives that can lead to funded research programs. 3. Bring together clinical research resources to provide a virtual home that facilitates new collaborations and enhanced efficiencies. 4. Facilitate research to gather preliminary data necessary for developing competitive research proposals. 5. Provide contemporary infrastructure for clinical and translational research including research planning and implementation, advanced biostatistics and epidemiology support and biomedical informatics. 6. Foster coordination between translational researchers at our participating entities so as to create new productive collaborations with translational outcomes. 7. Sustain a clinical translational research environment by providing the necessary management and coordination of resources. 8. Create an innovative Tracking and Evaluation program that will combine support requests with use and cost data and apply lessons learned in the CTSA program to the CTR environment. SPECIFIC AIMS - OVERALL There is a tremendous opportunity for clinical and translational research discovery in Rhode Island. Although RI is the smallest state by land area, the population of over one million is larger than six other states and among the residents, 70 percent never leave the state. This translates not only into vibrant, tight-knit communities, but into a population that serves as an excellent testbed for longitudinal, community-engaged clinical and translational research. When Advance-CTR was funded in 2016 by an IDeA-CTR award from NIGMS, we entered a research partnership with established norms and protocols for conducting research within institutions, but not necessarily between institutions. With major healthcare systems and academic research institutions only a few miles apart, we had the unique opportunity to unify and synergize cross-institutional collaborations in ways that are less feasible in larger states. This has been a central goal in the first four years of our funding, an area where we have made tremendous progress, and an area where we continue to see opportunities. The infrastructure we have established has facilitated the transformation of clinical and translational research across our partner institutions which includes two academic partners, Brown University and the University of Rhode Island (URI), and three academic health systems, Lifespan, Care New England, and the VA Providence Healthcare System. These partners contribute expertise in biological, clinical, public health, pharmacy, nursing, epidemiological, health services, mental health, and community-engaged research. Combined, our partner healthcare systems provide care to more than 75% of the Rhode Island population. Other key collaborators include the Rhode Island Quality Institute (RIQI), home of the state’s only designated health information exchange CurrentCareTm, Rhode Island’s single Department of Health (RIDOH), and the Rhode Island Public Health Institute (RIPHI). Advance-CTR uses its resources to initiate programs not previously available: pilot grants for clinical research, career development support, and biostatistical and biomedical informatics services. In less than five years, we have established Advance-CTR as a research hub and training umbrella for the RI investigator community. We created a statewide research mentoring program to enhance the ability of established investigators to foster early career investigators’ success at all five partner institutions. We have fueled cross-institutional collaborations by awarding pilot projects, mentored research awards, big data awards and grant resubmission awards to 84 investigators. We have met a critical need by providing investigators at all career levels with research design and support services that have resulted in extramural awards, publications, and ongoing, cross-institutional collaborations. In so doing, we have enhanced patient-centered research and accelerated discoveries and health innovations to the benefit of our communities and in service to our state. Nonetheless, challenges remain which we will address with new cores (Community Engagement and Outreach), new training models (Advance-R) and important community needs (COVID supplements). Advance-CTR and the Universities, hospitals, and community organizations in Rhode Island are well positioned to address these important opportunities in clinical and translational research. Whether it is through efforts to bring new discoveries from the “bench-to-bedside,” to effectively test new clinical applications, or to address health priorities among vulnerable populations, our clinical and translational research enterprise seeks to address Rhode Island’s most pressing health concerns and to improve health across the translational research continuum. In this application, the words “transformation,” and “evolution” will appear frequently. We have identified these as our “watch words” because they best embody what we have accomplished in the last four years and where we are headed. The Specific Aims of our IDeA-CTR program, drawn from the Funding Opportunity Announcement, are: Specific Aim 1: To support the enhancement of infrastructure and human resources required to address clinical and translational research needs in Rhode Island. Specific Aim 2: To strengthen clinical and translational research that addresses the broad spectrum of health challenges faced by populations in Rhode Island. Specific Aim 3: To foster and coordinate collaboration in clinical and translational research across our partner institutions in Rhode Island and with other institutions in the IDeA-CTR network. Throughout this proposal we describe our efforts and the future directions for Advance-CTR. We outline in detail the approach and metrics we will use to demonstrate our ability to continue to meet the objectives of the IDeA-CTR Program.

NIH Research Projects · FY 2025 · 2016-06

PROJECT SUMMARY We propose to strengthen and extend the research capacity of the COBRE Center for the Computational Biology of Human Disease (CBHD) at Brown University and affiliated hospitals. High throughput data from multiple ‘omics-level’ technologies are fundamental factors in the identification and treatment of human disease. The acquisition of these data is now straightforward, but the efficient and creative interpretation of these data remain a serious impediment to progress for junior faculty in both the basic and translational aspects of biomedical science. The underlying principle of this Center is that close collaboration between laboratory scientists working with model systems and data scientists working with computational and bioinformatics tools can accelerate the implementation of human disease research. In Phase 1, we established the CBHD COBRE around a Computational Biology Core (CBC) and support for junior faculty Project Leaders (9) and Pilots Project leaders (8). These Project Leaders have been awarded six NIH R01s, an R35 MIRA, an NIH T32 Training Grant, an NIH R21, a USDA grant, a Sloan Award, and a Searle Award, totaling ~$17.9M. In Phase 2 we will strengthen this research environment with support for four new Project Leaders and a plan for growth and sustainability of the CBC that serves as the analysis and training hub of this COBRE. Our innovative joint mentoring strategy where each Project Leader is advised by both computational and biological or clinical senior faculty members has proven successful, and this will be extended. Moreover, we will build sustainable support for the CBC through expanded collaboration with COBRE graduates and other faculty on external grant support plus internally funded staff data scientists. The long-term goal of the Center is to grow a nexus of computational biology infrastructure for the greater Brown and hospital environments that will benefit all of Rhode Island. The objective of this proposal is to strengthen the infrastructure of the CBHD COBRE to ensure the transition of junior faculty Project Leaders to R01-funded scientists, and raise the computational proficiency and diversity of the broader biomedical research community. The three Aims are: Aim 1. Support the research of junior faculty Project Leaders pursuing biological and computational approaches to human disease. Aim 2. Broaden the CBHD research environment through enhanced Pilot and Mentoring programs that increase faculty recruitment and promote funding independence for Project Leaders. Aim 3. Strengthen the Computational Biology Core through enhanced staffing and broader access across the Brown biomedical community to build sustainability. The four new Research Projects are: 1. Local Regulation of T-cell Differentiation and Function in the Reproductive Mucosa; 2: Profiling Gene Expression and Mechanophenotype in Circulating Tumor Cells Ex Vivo; 3: Mapping Long-range Allosteric Pathways in CRISPR-Cas9; 4: Modeling Long-range Regulatory Interactions to Predict Gene Expression Using Graph Convolutional Networks.

NIH Research Projects · FY 2025 · 2015-09

PROJECT SUMMARY Coronary artery disease causes over 360,000 annual deaths, primarily among older adults, and over $100 billion in medical expenditures. Despite improvements in outcomes, treatment remains beset by unwarranted variation in care coupled with underuse of high-value care. To address these problems, CMS has introduced several bundled payment reforms focused on cardiac procedures, including PCI and CABG. The most recent program – Bundled Payment for Care Improvement Advanced (BPCI-A) – is a voluntary program that creates incentives for hospitals to improve patient outcomes and reduce spending across a 90-day post-discharge episode. Despite the promise of bundled payment, its effects on outcomes for common cardiac procedures are not well understood. Incentives to improve care coordination and quality may encourage hospitals to reduce periprocedural complications and tightly manage post-acute care referrals. At the same time, incentives to reduce spending may encourage hospitals to avoid higher severity patients. In this context, we propose the following aims: Aim 1. Evaluate the role of hospital and patient selection related to PCI and CABG episodes in BPCI-A. We will link hospital participation in BPCI-A with Medicare data and data from the CathPCI and Society of Thoracic Surgeons Adult Cardiac Surgery registries. We will compare hospital and patient severity profiles with claims alone (the status quo in BPCI-A) and claims supplemented with registry data (the gold standard). We will then test whether hospitals with 1) lower claims-based severity compared to registry-based severity were less likely to participate in BPCI-A; and 2) patients with lower claims-based severity became less likely to be treated at participating hospitals after BPCI-A. Aim 2. Evaluate the effects of BPCI-A on periprocedural and post-discharge outcomes. Using Medicare claims and linked data from thousands of hospitals participating in the registries, we will estimate econometric models to test whether BPCI-A was associated with improvements in periprocedural complications and post-discharge outcomes. Aim 3. Evaluate how changes in BPCI-A and delivery system disruptions from COVID-19 inform the future design of bundled payment. We will exploit a change in the design of BPCI-A to examine whether including spending associated with cardiac rehabilitation in the episode led to lower cardiac rehabilitation. We will also compare hospital quality performance using claims-based and registry-based measures and test for shifts in patient severity profiles for patients receiving inpatient and outpatient PCI. Finally, we will examine the accuracy of target prices before and after COVID-19. This proposal is significant because it will be the first to understand the effects of BPCI-A on selection and outcomes for cardiac procedures using high quality registry data. The proposal is innovative in its use of novel data linkages and statistical methods to understand the impact of this critical policy question affecting millions of older adults with coronary artery disease.

NIH Research Projects · FY 2024 · 2013-09

Abstract This is a competitive continuation application of our Brown University R25 program “Promoting Research Training During Psychiatry Residency.” Exciting advances in basic and clinical psychiatry/neuroscience and genomics hold the promise of revealing the causes and potential new treatments for mental illnesses. However, a critical shortage of physician-scientists poses a threat to our ability to advance and translate discoveries from basic science into effective prevention and treatment approaches. The overarching goal of our Research Training Program (RTP) is to train the next generation of psychiatry residents to design and conduct rigorous, innovative and impactful research and develop successful careers as independently funded research-oriented physician-scientists in psychiatry/neuroscience. In the first five years of this program we have achieved our recruitment and training goals, and our residents have been remarkably successful with their research and early career development. Conducting innovative and rigorous research, our RTP residents have presented and published their findings widely and in top-tier journals. RTP residents have successfully competed for travel and poster awards, and their research projects have been funded by numerous national and local research funding awards. Our program combines an intensive longitudinal mentored research experience with an individualized research didactic curriculum and career development activities in a rich, multidisciplinary environment at Brown University. The cohesive program leadership team and Advisory Committee balance research and clinical training, monitor research and career development progress, and solicit feedback for program improvement. This application seeks to carry out the following aims: 1) Continue to recruit and train highly-qualified psychiatry residents to develop independent research careers, and 2) Build upon our existing successful program to further support resident research and career development with new and innovative components. Continuation of funding for this program would enable us to train 10 research- focused residents (two per year) over the next 5 years, thereby expanding the number of highly trained physician scientists in research domains central to the NIMH mission. The outstanding research training environment in psychiatry and brain science at Brown, characterized by internationally recognized, externally funded, innovative research programs and investigators, cross-disciplinary collaborations, and exceptionally well-qualified and dedicated mentors, makes our psychiatry residency an ideal environment in which to train the next generation of physician-scientists in psychiatry and neuroscience.

NIH Research Projects · FY 2025 · 2012-05

Aging is a fundamental biological process and age-related diseases are the leading causes of death in modern societies. The Brown University Training Program in the Molecular Biology of Aging (MBoA) aims to train a next generation of scientists to attack the immensely challenging yet important task of understanding and successfully managing human aging. In its first 9 years the MBoA had 4 predoctoral slots per year and has operated under the auspices of two existing and well-established graduate programs, the Molecular Biology, Cell Biology and Biochemistry Graduate Program (MCBGP), and the Pathobiology Graduate Program (PBGP). The MBoA has generated much interest and has attracted very talented students. Nineteen trainees have tracked through the MBoA since 2012 with only one attrition (5%). Eight students have graduated with an average of 4 papers each, and all remain engaged in research or science-related careers. The MBoA has grown from 13 faculty trainers in 2012, drawn from 6 departments, to 19 current trainers in 8 departments. This escalating interest in the biology of aging is fueled by an increasing realization that many degenerative disorders are profoundly influenced by basic aging processes, and conversely, that many core molecular mechanisms, such as regulation of chromatin, influence aging. Our understanding of aging has reached a watershed in the past 10-15 years that was enabled by the increasing use of invertebrate model organisms; Brown has a strong base of investigators applying these systems to study a wide-ranging array of biological questions. Brown has increased its presence in neuroscience with the 2018 naming of the Carney Institute in Brain Science, generating new hires and heightened interest in aging biology among its faculty. Building on this momentum we propose to increase the number of MBoA trainers to 26 and affiliate the MBoA with 3 additional graduate programs (in neuroscience, molecular pharmacology, and biomedical engineering). We request the continuation of our 4 predoctoral slots and the addition of 2 postdoctoral slots. The MBoA has supported its predoctoral trainees for a period of 2 years, typically in years 2-3, which we propose to continue. We propose to support postdoctoral trainees for 2 years during early stages of their careers (NIH levels 0-3). The MBoA is part of the new Brown Center on the Biology of Aging (founded 2018) which supports a broad array of programming, including a seminar series, local workshops, retreats, a graduate course on aging and an annual symposium, providing many learning, mentoring and networking opportunities for our trainees. The MBoA is fully engaged in initiatives across the University to provide a training environment in which trainees will successfully gain didactive, conceptual, technical and professional skills that will allow them to conduct creative and rigorous research. The goal of the MBoA is to provide strong academic, experimental and career mentoring in the current landscape of molecular aging research, and thus equip our trainees with the skills and qualifications to compete and succeed in the US biomedical workforce.

NIH Research Projects · FY 2024 · 2010-09

: Alcohol misuse impacts the depth and breadth of the HIV epidemic through multiple pathways—increasing sexual risk behaviors, reducing adherence to antiretroviral therapy, and increasing the risk for HIV-associated comorbidities and mortality. To reduce the incidence of HIV, approaches must be developed that concurrently address alcohol misuse in the context of HIV testing and behavioral and biomedical prevention approaches. Likewise, to increase rates of HIV viral suppression and reduce HIV-related comorbidities, alcohol misuse must be addressed effectively in diverse populations across a spectrum of HIV care settings. The Brown University Alcohol Research Center on HIV (ARCH) has been supporting collaborative research to develop scalable alcohol-HIV interventions, including video counseling, telehealth, and web-enabled applications, that can be delivered broadly and efficiently using centralized personnel and technological resources. This application to renew the Brown ARCH is organized around the central theme that in order to achieve population impact, interventions addressing alcohol misuse in HIV prevention and care need to be evaluated with an emphasis on real-world effectiveness, scalability, and sustainability, according to the principles of implementation science. Specifically, we propose three projects that leverage our unique strengths in (a) training professionals in alcohol misuse interventions, (b) utilizing video counseling and telehealth as scalable means of reaching populations and providing continuing care, and (c) utilizing behavioral intervention technologies to provide alcohol interventions and ongoing support for change. Research Component 1 (MPI: Wray and Monti) extends our work on the role of alcohol use in HIV transmission among men who have sex with men (MSM) by testing the effectiveness of a web-based intervention that addresses both alcohol use and sex risk in MSM completing HIV self-testing. Research Component 2 (PI: Kahler) extends our work on behavioral telehealth interventions to reduce alcohol misuse in HIV-infected MSM by testing our previously developed video counseling and text messaging interventions in a diverse sample of patients in HIV care at four large, urban federally-qualified health centers. Research Components 1 and 2 share a Hybrid Type 1 effectiveness-implementation trial design, providing data on real-world effectiveness while gathering data related to implementation to inform future studies. Together, these projects—supported by an Administrative Core, Research Methods Core, and Program Advisory Committee and complemented by an outstanding training program in alcohol-HIV research with robust pilot funding opportunities—will make a substantial impact in translating basic and applied knowledge on alcohol and HIV into scalable approaches to reducing the negative impact of alcohol misuse on HIV prevention and care.

NIH Research Projects · FY 2024 · 2010-09

Project Summary The ribosome is the macromolecular machine, conserved throughout evolution, that is responsible for the synthesis of proteins and is therefore a fundamental component of gene expression. Because of its central role in biochemistry, the ribosome has become the target of more than half of all antibiotics, and the evolution of antibiotic resistance due to mutations in the ribosome has become a major threat to human health. Understanding the molecular basis of antibiotic resistance therefore has significant implications for the fight against the threat of resistance. In deciphering the mechanism of antibiotic resistance, fundamental insights into the mechanism of ribosome function can also be acquired, leading to possible novel antimicrobial agents through rational drug design. Through an ongoing collaborative effort, this proposal capitalizes on the ability of the PIs to combine genetics and structural biology to address fundamental questions of ribosome structure and function and provide a framework for future development of novel antimicrobial agents. The Aims of this proposal are: (1) Dissect 30S subunit conformational dynamics during tRNA movement through the ribosome; (2) Define the role of two intersubunit bridges in 30S-50S rotation during translocation; (3) Determine the structural basis for signaling pathways through the ribosome. Achieving these aims will involve exploiting the expertise of the three PIs to generate and characterize functionally impactful mutants and determine their structures by X-ray crystallography or cryo-electron microscopy. The strengths of our proposal include: (1) extensive expertise in the experimental methods to be applied; (2) a long track record of effective collaboration between the PIs; (3) an extensive publication track record in the field of ribosome structure and function; (4) a large volume of preliminary data and ongoing studies, including multiple studies nearing completion. Accomplishing these goals will significantly advance the field by answering long-standing questions about antibiotic resistance mechanisms, while simultaneously expanding our understanding of the basic underlying mechanism of the ribosome.

NIH Research Projects · FY 2025 · 2010-08

Project Summary Candida albicans is a frequent commensal of the human microbiota and an important opportunistic pathogen. This fungus is chameleon-like in its ability to grow in alternative cellular states and different morphological forms, and this plasticity is critical for infection of diverse niches in the body. Here, we examine the transcriptional regulation of cell fate decisions that drive key developmental programs in C. albicans including filamentation, biofilm formation, and phenotypic switching. Each of these programs contributes to the ability of this fungus to colonize and/or cause disease in the mammalian host. Previous studies have identified multiple transcription factors (TFs) that regulate these developmental programs and showed that they act together in highly coordinated networks to drive gene expression. However, a major knowledge gap exists as to how cell fate-defining TFs act together in a coordinated manner rather than as individual entities. To address this gap, we highlight preliminary data revealing that network TFs can undergo liquid-liquid phase separation (LLPS) and demonstrate that this process enables the formation of complexes containing multiple network TFs. We further show that phase separation is driven by prion-like domains (PrLDs) present in each TF and, critically, that targeted mutation of these domains can abolish both LLPS and TF function. To build on these exciting observations, experiments outlined in Aim 1 will determine how the composition of PrLDs promotes LLPS and the formation of multifactorial complexes in vitro and in cells. We also address how changes in LLPS relate to the function of C. albicans TFs within key networks, including those controlling phenotypic switching and biofilm formation. In Aim 2, we will identify additional regulators of C. albicans cell fate using an overexpression library covering all TFs in the C. albicans genome. Preliminary data indicates that multiple novel regulators can be uncovered by this approach, and newly identified TFs will be integrated into existing transcriptional networks using a variety of approaches including the use of complex haploinsufficiency (CHI) analysis. In Aim 3, we examine how phase separation of C. albicans TFs impacts their function during commensalism and pathogenesis by testing mutant TFs in murine models of infection. These experiments will be facilitated by a barcode sequencing (barcode-SEQ) approach in which multiple strains can be evaluated in parallel for their competitive fitness. Together, these studies will lead to new insights into the fundamental mechanisms by which transcription factors regulate cell fate decisions in C. albicans, with an emphasis on how LLPS enables the formation of functional, multifactorial TF complexes. We will also identify novel TFs in these networks and test these TFs for their role in infectivity. Given the central role of TFs in regulating C. albicans cell fate, these studies will identify new targets for therapeutic intervention against this important human pathobiont.

NIH Research Projects · FY 2026 · 2009-08

This is the 4th renewal application of Warren Alpert Medical School Basic Translational Research (BTR) summer program with an overall goal of providing medical students with the opportunity to have a mentored research experience under the guidance of Brown University faculty who are the principal investigators for research programs focused on the molecular basis and pathology of cardiovascular, pulmonary, and blood diseases and/or disease outcomes and prevention. In this revised renewal application, we propose to train 12 medical students from the Warren Alpert Medical School and engage them in a 9-week summer research experience that includes a collaborative, multidisciplinary, mentored research project, didactic training, and career development activities to enhance their understanding, to provide them with hands-on experience by exposing them to the critical role played by physician-scientists in translational research, and to inspire these students to embark on this career path of exploration and discovery. The NIH has consistently made translational and ‘bench-to-bedside’ research a priority for physician-, nurse-, dentist-, and veterinary-scientists. However, the increase in NIH support of biomedical basic research has not necessarily correlated with expansion in the discovery of efficacious therapies or diagnostics to battle human diseases. In fact, there continues to be decreases in the number of physicians who pursue research careers, as well as a lack of varied scientific and training backgrounds in those who pursue research careers. In addition, developing knowledge base and research skill competencies for clinically trained physicians is time-consuming and often occurs outside of medical school didactics with few clinicians affiliated with basic science departments. During the clinical years, medical students tend to work with clinical educators, since physician scientists are often not on clinical service, thus, exposure to and mentorship from this cohort of research-based educators is lacking. The BTR program is designed to promote the development of future physician scientists by partnering medical students with successful and active mentors engaged in cutting edge research and exposing these students to the excitement of biomedical research discoveries related to cardiovascular, pulmonary and blood health and diseases during their didactic years. By engaging medical students early in their training, we hope to stimulate a lifelong drive of scientific inquiry and a successful research career

NIH Research Projects · FY 2026 · 2009-04

Summary The long-term goal of the proposed project is to elucidate the underlying mechanisms of visual perceptual learning (VPL) for artificial and natural stimuli, which will be instrumental in developing rehabilitation programs aimed at enhancing damaged or deteriorating vision. The specificity of VPL to the feature and location of the trained visual stimulus is a fundamental characteristic of VPL. To investigate the specificity, one effective way is to use an artificial stimulus such as a Gabor patch as the trained stimulus, as it has been widely used to investigate basic visual processing. Simultaneously, to create an impactful rehabilitation program, the resulting improvements must be generalized to untrained features and locations in visual stimuli encountered in everyday life, including natural scenes (NS). However, it remains uncertain whether the same mechanisms underlie the generalization and specificity in VPL for artificial and NS stimuli. In Specific Aim (SA) 1, we aim to examine basic mechanism of the specificity using a Gabor patch. According to a prevailing theory, early visual processing (e.g., 0 to 150ms after the stimulus onset) primarily involves input-level feedforward signals. In contrast, late processing (e.g.,150-300ms after the stimulus onset) involves recurrent processing. To better understand the mechanism of the specificity of VPL it is crucial to clarify whether early or late processing is involved. Additionally, it remains unclear whether the specificity of VPL involves excitation on the trained feature and location or inhibition on untrained features and locations. Therefore, we will test Hypothesis 1 (H1): Late processing (H1- a) or early processing (H1-b) plays a role in the specificity of VPL, and H2: Excitatory signals (H2-a) or inhibitory signals (H2-b) are involved in inducing the specificity of VPL. We will employ two methods. The backward masking (BM) is used to disrupts and reveal roles of late processing. In preliminary results, BM applied to the trained orientation eliminated the orientation specificity in VPL, supporting H1-a. A Rhythmic Synchronization Orientation Decoding Change (RSDC) method is a novel method that examines at which band(s) of rhythmic synchronization from EEG the decoding performances of trained and untrained features and locations change after VPL training. Preliminary results suggest that trained orientation signals are enhanced at both trained and untrained locations during early processing, while those at untrained locations are inhibited during late processing, leading to the location specificity. In SA2, we will examine the specificity and generalizability of VPL for NS. Our first step is to test H3: VPL for the dominant orientation in NS is specific (H3-a) or generalized (H3- b) to other orientations. Preliminary results support H3-b. If true, we will further investigate the aspects in NS that induce the generalization of VPL. Preliminary result suggests that higher-order statistics, involving correlations between different orientation and spatial frequency channels derived from NS, play a role in the generalization of VPL for NS. We further aim to test H1 and H2 for NS images, using both the BM and RSDC methods.

NIH Research Projects · FY 2026 · 2008-08

Project Summary All movements involve dynamic interactions between passive elastic structures and muscle contractile elements, but our understanding of the consequences of this interaction for both normal and pathological muscle function is limited. Our long-term goal is to define the mechanical influence of elastic elements on muscle force production and gait. This project aims to understand how the mechanical interaction between internal muscle elastic elements, fluid pressure, and contractile elements define muscle force, speed and power output. Previous work shows that this interaction is highly three-dimensional and significantly influences muscle performance. A dominant paradigm of muscle force production as a one-dimensional process determined primarily by contractile element properties has limited our understanding. The project aims to use a combination of modeling and experiment to test novel hypotheses about how multi-scale, three- dimensional interactions influence muscle mechanical output. A combination of direct measurement of contractile behavior of muscles in different animal systems and physical models is used to test mechanistic hypotheses about how structures at multiple scales interact to influence mechanical output. The specific aims of the project are: 1) to test the hypothesis that fluid forces contribute to muscle force output, 2) to determine whether stiffened connective tissue in older muscle reduces force and work output, 3) to test the hypothesis that muscle fluid volume influences passive muscle stiffness, and 4) to test the hypothesis that dynamic changes in muscle architecture provide a mechanism for intramuscular elastic energy storage and recovery. In most cases the mechanistic link between structural pathologies in muscle and functional deficits is poorly developed. We will test novel hypothesized mechanisms for how changes in extracellular matrix and muscle fluid content can alter muscle mechanical output with the aim of determining structure-function relationships that may underpin functional deficits in a range of conditions, including dystrophies, cerebral palsy, aging, and secondary to stroke and spinal cord injury. These models will inform the design of rehabilitative strategies and interventions to improve muscle-tendon function. An improved understanding of how muscle elastic elements influence the mechanical behavior of healthy muscle-tendon units may also aid in the design of prosthetic devices.

NIH Research Projects · FY 2025 · 2008-07

SUMMARY This is a competitive renewal application for the Brown University Community and Clinical Research Training Program, currently funded through NIMH R25MH083620. Our goal is to train the next generation of researchers to end the HIV epidemic and to conduct research related to reducing racial disparities in HIV outcomes in the Southern United States. This renewal application is led by Dr. Amy Nunn and Dr. Leandro Mena, who have worked collaboratively on these topics for over a decade in Mississippi and beyond. This program was initially funded in 2008 and exceeded its key objectives during the last 11 years; we trained 40 investigators during the last funding cycle. During the last five years, our fellows attributed 492 peer reviewed articles and 53 successfully funded grants to this training program. This renewal application continues our focus on racial disparities and community engaged scholarship, with greater emphasis on ending the epidemic in the South and in jurisdictions most heavily impacted by the HIV epidemic. This initiative and the mentoring curriculum will align with the US Plan to End the HIV Epidemic (EtHE). The program will prioritize training investigators from communities historically underrepresented in the sciences, with emphasis on training investigators from or conducting practice-oriented research in geographic hotspots of HIV infection, with a focus on the South. This structured mentoring program will focus on community-engaged scholarship, geographically circumscribed interventions, reducing racial disparities in HIV infection, partnering with health departments, and delivering proven HIV prevention and care interventions through novel means in the rural South. The program has the following specific aims: Specific Aim 1: To train the next generation of researchers in the communities most heavily impacted by the epidemic in HIV/AIDS research to develop, implement, and evaluate interventions to reduce racial disparities in HIV prevention and care, including HIV screening, PrEP, and HIV treatment. This training includes formal coursework, quarterly mentoring workshops, one-on-one mentoring, epidemiological design, and clinical service delivery experiences in real-world clinical and community settings. Specific Aim 2: To train investigators from communities enumerated in the EtHE plan, particularly African Americans and Hispanic/Latinos in the South. These investigators will lead scientific investigation addressing social, structural and behavioral drivers of the epidemic; lead clinical, epidemiological and implementation research to mitigate HIV/AIDS disparities; and develop, implement, and evaluate culturally appropriate and geographically circumscribed interventions focused on the South.

NIH Research Projects · FY 2025 · 2007-09

The complex health care needs, poorer outcomes, high spending, and sociodemographic composition of the population living with Alzheimer’s Disease and Related Dementias (ADRD) pose serious challenges to families, providers, and health systems. Although the population living with ADRD is expected to triple by 2050, many recent policy changes aim to maximize the value of care for the “average” patient, without specific consideration of their consequences for high-cost, high- need populations, such as those with ADRD. The P01 project will undertake four synergistic projects testing the effect of recent national policies and payment changes on persons with ADRD in different states of disease progression, in different care settings, and exposed to different policies. Project 1 seeks to determine the effects of Medicare Advantage (MA) contract terminations on outcomes for enrollees with ADRD. Project 2 examines the impact of a federal policy to suspend Medicaid redeterminations on health outcomes for people with ADRD. Project 3 evaluates the impact of the MA Hospice Carve-In policy on end-of-life care for persons with ADRD. Finally, Project 4 evaluates the impact of a home health payment change on access and outcomes of patients with ADRD. Each project aims to understand differential effects of financing and payment policies among persons with ADRD by race, ethnicity and socioeconomic status and/or focus the analysis on patients with low income or other key sociodemographic characteristics. All projects rely upon the Primary Data Collection and Partner Engagement Core (Core B) and the Data Management and Methods Core (Core C). Core B uses qualitative methods to gather perspectives from healthcare providers, payers, care partners, and persons living with ADRD themselves. This will generate critical information about how organizations interact to enact policies and implement practices that affect healthcare choice, access, use, and outcomes for persons with ADRD. Core C will make important contributions on three key challenges related to health policy research in ADRD: (1) accurately identifying the presence of dementia among enrollees in MA plans, (2) developing novel approaches for causal inference study designs following disruptions to the healthcare system or economy, and (3) integrating data across multiple payers, and institutional and community-based care. Our robust dissemination plan includes updating and maintaining http://www.ltcfocus.org, a web-site designed for federal and state policy makers and news media with health and aging interests; and working with our Strategic Partner Engagement Panels and National Advisory Committee to maximize the impact and relevance of our findings. Our project will provide timely, novel and rigorous evidence about the impact of recent payment and financing policy changes for persons living with ADRD and inform policies that improve care and health outcomes for this important population.

NIH Research Projects · FY 2024 · 2007-06

Project Summary The goal of this short-term research training program is to utilize research training opportunities in the areas of cardiovascular, pulmonary, hematologic, and sleep disorders to increase the readiness and competitiveness of students traditionally underrepresented in these areas as they train for and enter careers in the biomedical research workforce. The limited pool of qualified UR groups applying to graduate programs points to a clear need for focused mentorship and training for students from UR groups as they prepare for graduate training. To address this need, Brown University requests a competitive renewal of NIH NHLBI funding for the Short-Term Training Program to Increase Diversity in Health-Related Research to permit 17 UR undergraduate students per year to participate in an intensive 9-week summer research training experience with exposure to multidisciplinary research directly related to cardiovascular, pulmonary, hematologic, and sleep disorders. This will be achieved by creating immersive learning environments inside and outside the lab. Selected students are paired with faculty sponsors for training in the lab and interact with peer and faculty mentors in other academic settings. The specific aims of this program are: a) Enhance the scientific education and research skills of its participants; b) Instill self-affirming practices in participants of this program who, in turn, will model this success to their peers; c) Initiate the process by which participants become life-long learners by helping them to develop the skills and habits of scientists and scholars; d) New Initiative: Foster a continuity of mentorship and training to support the progression of underrepresented students along PhD and MD-PhD training pathways and into the biomedical workforce; e) New Initiative: Expose underrepresented students to research and role models to increase their competitiveness for PhD or MD-PhD training programs. This project builds on our previous successes and fortifies efforts to increase the ranks of underrepresented scholars in doctoral programs and the scientific workforce.