Brown University

NIH Research Projects · FY 2025 · 2022-08

PROJECT SUMMARY Epithelial ovarian cancer (EOC) is the most lethal gynecological cancer; frequently diagnosed after it has spread from the ovary to the omentum fat pad. A major challenge to understanding and targeting EOC is the heterogeneous nature of the disease, which makes it difficult to develop treatments that effectively target and destroy all cancer cells. This heterogeneity results in complicated molecular landscapes with subpopulations of highly invasive and chemoresistant tumor cells. It is critical to understand how this heterogeneity in cancer cells develops and contributes to EOC disease progression. Polyploidal giant cancer cells represent a small subpopulation of drug-resistant and dormant cancer cells that survive treatment and later awaken to form new tumor cells through amitotic budding. Single cell biophysical analysis of tumor organoid cultures will be used to determine how polyploidal giant cancer cells and other invasive cells contribute to EOC disease progression. In the EOC tumor microenvironment, cancer cells frequently encounter metabolic stress from nutrient deprivation, hypoxia, and toxic therapeutics, which can trigger metabolic reprogramming to promote cell survival. Cells can undergo a metabolic shift from glycolysis to oxidative phosphorylation to meet energy demands of survival and invasiveness; this shift in metabolism has been correlated with highly energetic mitochondria, lipid droplet disappearance (lipolysis), and autophagy. This is especially important in PGCCs, which have increased nutrient demands in part to their larger size and more invasive phenotype. Additionally, EOC metastases form from multicellular aggregates that are shed from the primary tumor into the adipocyte-rich abdominal cavity. Previous studies have demonstrated that peritoneal adipocytes can transfer free fatty acids to EOC cells to provide cellular energy for metastatic tumor growth. Fatty acids provide a rich energy source for ATP-dependent actin polymerization and actin-based protrusions are critical for cell migration and during metastasis. We hypothesize that invasive EOC cells store energy from exogenous lipid sources (including adipocytes and lipid-rich ascites fluid) in cytosolic lipid droplets, and under metabolic stress use these lipid droplets to generate mitochondrial ATP that is required for invasive cell migration through autophagy. To prove this hypothesis, we will use a novel 3D culture model and animal studies to track metabolic changes in individual chemoresistant EOC cells as well as study heterogeneity in lipid droplet metabolism. The proposed research will investigate the role of metabolic and treatment stress in activating lipid metabolism (Aim 1) and autophagy (Aim 2), and determine how metabolic alterations in subpopulations of highly invasive cells (including PGCCs) contribute to the development of aggressive tumors (Aim 3). The proposed studies will reveal novel mechanisms contributing to cellular heterogeneity and dysregulated metabolism, along with new therapeutic targets to investigate in EOC.

NIH Research Projects · FY 2025 · 2022-08

PROJECT SUMMARY This study will examine a new implementation strategy for the Youth Readiness Intervention (YRI), an evidence-based mental health intervention. The strategy will (a) leverage a delivery setting (schools) and workforce (teachers) used effectively in low- and middle- income countries; and (b) innovate with technology and mHealth tools to enhance mental health service delivery quality. The YRI will be implemented as an extracurricular resilience-building afterschool activity in Sierra Leone. Teachers will deliver the YRI and receive either mobile phone-supported supervision or standard in-person supervision. Mobile-based supervision will integrate WhatsApp, a free cross-platform messaging and voice service used widely throughout Africa, with a new mHealth app. The mHealth app was recently designed to support fidelity monitoring of Sierra Leonean lay workers delivering the evidence-based Family Strengthening Intervention (R21MH124071). The mHealth app will support supervision through key features, including voice activated content, fillable forms (i.e., YRI fidelity checklist), visual dashboards to monitor fidelity, and training videos to support school-based YRI delivery. The Exploration, Preparation, Implementation, Sustainment (EPIS) framework, a broad multilevel, context- sensitive implementation science model, will guide the study. A hybrid type 3 implementation-effectiveness design will allow for evaluation of both mobile phone-based supervision as a new implementation strategy, and clinical effectiveness of the YRI on youth mental and behavioral health as secondary outcomes. Aim 1 (Exploration and Preparation) will investigate barriers and facilitators to successful YRI implementation aided by mobile-based tools in Sierra Leone’s secondary schools. A mixed methods evaluation with teachers, principals, and government ministry officials will inform co-development of an implementation blueprint prior to YRI delivery. User-centered design methods will be used to adapt the mHealth supervision app and incorporate WhatsApp to create an integrated user model of mobile phone-based supervision. Aim 2 (Implementation) will examine the feasibility, acceptability, cost, and fidelity to the YRI delivered by teachers receiving mobile-based supervision compared with those receiving standard supervision via a mixed methods approach. Aim 3 (Impact of Delivery Approach on YRI Effectiveness) will compare the effectiveness of the YRI in improving mental health, emotion regulation and daily functioning in youth (aged 14-24) when delivered in school settings by teachers who receive either mobile-based supervision (N=480 youth) or those who receive standard supervision (N=480 youth). Aim 4 (Sustainment) will (a) investigate mechanisms of adoption and sustainment of the YRI delivered by teachers through a mixed methods evaluation with teachers, youth, and principals; and (b) conduct a cost-effectiveness and return on investment analysis to evaluate relative costs vs. benefits of the YRI from a broad societal perspective, including educational outcomes.

NIH Research Projects · FY 2024 · 2022-08

PROJECT SUMMARY Many young adults engage in heavy drinking and in turn experience negative consequences (e.g., severe injury, overdose). While personalized feedback interventions (PFIs) show promise among college students, non- college young adults are often excluded from research, effect sizes tend to be small to medium, gains are not usually maintained, and improvements in engagement and potential for reach are needed. Mobile technology can be harnessed to deliver intervention, but many mHealth platforms are not theoretically based or rigorously developed and tested. Preliminary work suggests that the morning after drinking may represent a “teachable moment” not yet exploited for harm reduction. We propose to examine mornings after drinking as an optimal time to provide repeated, personalized feedback with the goal of reducing hazardous drinking. Specifically, we will further develop and pilot test a novel theory-based PFI for heavy drinking young adults. Innovations include mobile delivery of feedback in multiple doses that occur close in time to drinking; choice of feedback; feedback informed by daily, mobile assessment of recent key drinking events; and use of personalized and dynamic goal setting to guide behavior change. In line with principles of the transtheoretical model (e.g., developing discrepancy), intervention strategies include personalized feedback (e.g., prior night blood alcohol concentration, consequences) contrasted with both drinking goals set at baseline and corrective normative feedback (e.g., how last night’s drinking compares to peers). We have promising preliminary data on this intervention; however, prior pilot participants included only college students. Further, they were paid for compliance with the daily surveys that informed their feedback, but engagement in the absence of monetary reward is essential to scalability. In the proposed study, we will incorporate end-user feedback on ways to increase engagement, and manipulate payment in order to determine engagement with a more scalable (i.e., unpaid) daily PFI. First, a refined version of our mobile daily PFI will be delivered in an open trial to 20 heavy drinking young adults (50% non-college). After four weeks of daily intervention, participants will return for individual interviews to inform further refinement of the intervention content. Finally, 132 participants (50% non-college) will be randomized to one of three groups: PFI with monetary incentives for daily surveys, PFI without monetary incentives, or survey assessment only. We will examine recruitment rates, retention rates, confirmation of intervention content delivery/intake, response rates to daily surveys, data quality, and ratings of intervention value. We will test whether these indicators of engagement differ between those who do and do not receive monetary incentives for daily surveys. Further, baseline, post-test, and 3-month follow-up assessments will allow us to estimate effect sizes for PFI vs control differences in drinks per week, frequency of heavy drinking, and negative consequences. The results of the proposed research will result in a novel and scalable intervention for alcohol misuse among young adults, with potential to have an important impact on the public health problem of high-risk drinking.

NIH Research Projects · FY 2024 · 2022-08

PROJECT SUMMARY This study will examine a new implementation strategy for the Youth Readiness Intervention (YRI), an evidence-based mental health intervention. The strategy will (a) leverage a delivery setting (schools) and workforce (teachers) used effectively in low- and middle- income countries; and (b) innovate with technology and mHealth tools to enhance mental health service delivery quality. The YRI will be implemented as an extracurricular resilience-building afterschool activity in Sierra Leone. Teachers will deliver the YRI and receive either mobile phone-supported supervision or standard in-person supervision. Mobile-based supervision will integrate WhatsApp, a free cross-platform messaging and voice service used widely throughout Africa, with a new mHealth app. The mHealth app was recently designed to support fidelity monitoring of Sierra Leonean lay workers delivering the evidence-based Family Strengthening Intervention (R21MH124071). The mHealth app will support supervision through key features, including voice activated content, fillable forms (i.e., YRI fidelity checklist), visual dashboards to monitor fidelity, and training videos to support school-based YRI delivery. The Exploration, Preparation, Implementation, Sustainment (EPIS) framework, a broad multilevel, context- sensitive implementation science model, will guide the study. A hybrid type 3 implementation-effectiveness design will allow for evaluation of both mobile phone-based supervision as a new implementation strategy, and clinical effectiveness of the YRI on youth mental and behavioral health as secondary outcomes. Aim 1 (Exploration and Preparation) will investigate barriers and facilitators to successful YRI implementation aided by mobile-based tools in Sierra Leone’s secondary schools. A mixed methods evaluation with teachers, principals, and government ministry officials will inform co-development of an implementation blueprint prior to YRI delivery. User-centered design methods will be used to adapt the mHealth supervision app and incorporate WhatsApp to create an integrated user model of mobile phone-based supervision. Aim 2 (Implementation) will examine the feasibility, acceptability, cost, and fidelity to the YRI delivered by teachers receiving mobile-based supervision compared with those receiving standard supervision via a mixed methods approach. Aim 3 (Impact of Delivery Approach on YRI Effectiveness) will compare the effectiveness of the YRI in improving mental health, emotion regulation and daily functioning in youth (aged 14-24) when delivered in school settings by teachers who receive either mobile-based supervision (N=480 youth) or those who receive standard supervision (N=480 youth). Aim 4 (Sustainment) will (a) investigate mechanisms of adoption and sustainment of the YRI delivered by teachers through a mixed methods evaluation with teachers, youth, and principals; and (b) conduct a cost-effectiveness and return on investment analysis to evaluate relative costs vs. benefits of the YRI from a broad societal perspective, including educational outcomes.

NIH Research Projects · FY 2025 · 2022-08

Project Abstract Humans display tremendous flexibility in their everyday behavior, adjusting it rapidly when appropriate (i.e. adopting mask wearing after onset of Covid-19), but not when inappropriate (i.e. continuing to drive after involvement in an unavoidable car accident). Recent work has highlighted the role that transient fluctuations in arousal, thought to be mediated by activation of the locus coeruleus norepinephrine (LC/NE) system, play in behavioral adjustments. Increasing NE pharmacologically promotes behavioral updating in rodents and peripheral measures of arousal, such as pupil diameter and P300 orienting response, provide a window into the dynamics that underlie these behavioral adjustments in humans. A mechanistic understanding of these processes could provide a valuable therapeutic target for a wide range of psychiatric disorders in which behavioral flexibility is impaired. However, current theory falls short, in part because it fails to account for the contextual nature of arousal: that heightened arousal reflects more behavioral adjustment in some settings or individuals, but less in others. We believe that previous computational accounts of NE have likely failed to explain heterogenous effects on behavior because they have ignored the neural representations on which NE acts. Recent advances in computational neuroscience have highlighted the importance of neural representations for efficient learning in complex environments, and provided tools to measure them. Building on this work, we developed a computational model in which NE drives transitions in neural representation that lead to behavioral adjustment when new representations persist in time (ie. after Covid), but reduce behavioral adjustment when they do not (after a freak accident). We propose that representational dynamics evoked by NE are not random, but instead are governed by assumptions about environmental structure, which differ across settings and individuals, to produce heterogeneous effects of arousal on behavior. This idea could facilitate personalized predictions for how NE manipulations would alter behavior, potentially enabling better treatment of attention deficit and anxiety disorders. Achieving this goal would first require basic research experiments to better characterize how and why arousal differentially relates to behavior across task contexts, individuals, and learning. Here we conduct these basic research studies, first measuring arousal by proxy in adversarial task structures (i.e. post-covid versus post-accident) to dissect the computational mechanisms through which it modulates behavior. Next, we examine internal representations directly, using fMRI in a task with ambiguous structure, to understand whether and how inter-individual differences in representational structure give rise to inter-individual differences in behavior and its sensitivity to arousal. Finally, we extend our existing computational model such that it can learn structure through experience and make individualized predictions for behavior across a wide range of possible environments. We test these predictions, as well as their relevance to various mental health constructs, in a large-scale online validation study.

NIH Research Projects · FY 2024 · 2022-08

Repeated alcohol experiences can produce long-lasting memories for sensory cues associated with intoxication. These memories can problematically trigger relapse in individuals recovering from alcohol use disorder (AUD). The molecular mechanisms by which ethanol changes memories to become long-lasting and inflexible remain unclear. We recently demonstrated that formation of these memories results in expression of alternative transcript isoforms in memory-encoding neurons in Drosophila melanogaster. Drosophila rely on mushroom body (MB) neurons to make associative memories, including memories of ethanol-associated sensory cues. Decreasing expression of genes that play a role in splicing in adult MB neurons reduces formation of these memories, demonstrating the necessity of RNA processing in ethanol memory formation. Moreover, decreasing expression of genes that are alternatively spliced like the Dopamine-2-like Receptor (Dop2R) in adult MB neurons reduces ethanol memory formation. This suggests that the splicing changes in these genes has functional implications for future memory formation. The central hypothesis of this proposal is that the dynamic alternative splicing of Dop2R in response to alcohol exposure directs reward behavior by changing the activity of neural circuits. We generated mutant Drosophila that have forced expression of the naïve or trained Dop2R isoform, which allows us to interrogate how these splice variants affect neural dynamics and behavior at a highly mechanistic level. The applicant will reveal intracellular localization of DOP2R protein (Aim 1, how alternative splicing of Dop2R affects reward memory (Aim 2), and plasticity within memory circuits (Aim 3). By completing these aims, the applicant will gain scientific and technical expertise in cellular neurobiology and neurogenetics, behavioral assessment of Drosophila, super-resolution imaging, and 2-photon calcium imaging. Through a comprehensive training plan, this fellowship will facilitate the professional development of the applicant in robust experimental design and data analysis; written and oral scientific communication; and effective and inclusive mentoring. Successful completion of the project and training goals are fully supported by the interactive and supportive institutional environment of Brown University and in the Neuroscience Graduate Program, and will prepare the applicant for the next steps towards an independent scientific career.

NIH Research Projects · FY 2025 · 2022-07

Women are disproportionately affected by Alzheimer’s disease and Alzheimer’s disease-related dementias (AD/ADRD) relative to men. Prior research focuses overwhelmingly on biological explanations for this disparity, but the consequences of social and behavioral factors may also be considerable. The proposed research will make progress towards understanding these consequences through two Aims. Both Aims leverage data from the Health and Retirement Study, a nationally representative panel survey of older U.S. adults that includes information on respondents’ cognitive state as well as demographic, social and economic, and health-related characteristics. Aim 1 is to characterize the contributions of education to trends in AD/ADRD for U.S. women and men. Analyses will first document women’s and men’s trends in AD/ADRD prevalence from 2000 to 2016. Variance decomposition will then be used to quantify how much of the observed changes in prevalence were due to changes in levels of education and to changes in effects of education on AD/ADRD. Aim 2 is to examine how education combines with work and occupation to produce patterns of AD/ADRD for U.S. women and men. First, patterns of workforce participation and occupational characteristics for women and men will be described by level of education. Path analysis will then be used to evaluate whether and how workforce participation and occupational characteristics mediate relationships between education and AD/ADRD for women and men. The proposed research builds on Dr. Zacher’s prior quantitative training and research on education and health. It will also require Dr. Zacher to build additional expertise in aging, AD/ADRD, and demographic methods. Towards this end, Dr. Zacher will undertake extensive training during the K01 award period with the guidance of an impressive mentoring team led by Dr. Susan Short, Professor of Sociology and Director of the Population Studies and Training Center at Brown University. Co-mentors include Drs. Eileen Crimmins, AARP Professor of Gerontology, USC Leonard Davis School of Gerontology; David Dosa, Associate Professor of Medicine and Health Services, Policy and Practice, Brown University; Richard Jones, Professor of Neurology and Psychiatry and Human Behavior, Warren Alpert Medical School, Brown University; and Vincent Mor, Florence Pirce Grant University Professor and Professor of Health Services, Policy and Practice, Brown University. Dr. Zacher’s training will support her short-term goal of completing the proposed K01 research successfully while also preparing her for her long-term career goal of becoming an independent investigator and expert on the demography of aging and AD/ADRD, with a special focus on patterns among women and men and by education.

NIH Research Projects · FY 2026 · 2022-07

With the majority of US states having adopted legislation to medically and/or recreationally legalize cannabis, public perception of the drug is now overwhelmingly favorable. Increased access and prevalence of use are accompanied by perceptions of low health risk and/or of therapeutic benefits associated with cannabis use. Aside from evidence for symptom relief in certain medical conditions, evidence regarding therapeutic effects of cannabis for many conditions remains elusive, leaving the decision regarding when and how to use cannabis to the user. Both therapeutic and recreational reasons (motives) for CU are largely shaped through exposure to messages about the effects of cannabis, yet little is known about the source of messaging, how it is transmitted to users, how it shapes their thinking, and ultimately its association with CU patterns. The proposed study will gather critical information about message sources, cannabis-promoting content, and risk warnings being disseminated to cannabis users as well as the messages being received, their effects on CU motives, and subsequent CU. The mixed-methods design will include two phases. Phase 1 involves semi-structured interviews conducted with 1) cannabis users, as well as with message sources, including 2) cannabis dispensary and retail outlet staff (budtenders), 3) growers, and 4) health care providers who discuss cannabis with patients. Additionally, extraction and coding of messaging content will be conducted across internet and social media messaging platforms. Observational coding of recreational/medical cannabis outlets will be conducted using validated surveillance tools. Together, these data permit characterization of cannabis messaging content across various types of sources and platforms (Aim 1) that will in turn inform Phase 2 methods. Phase 2 consists of a three-burst 4-week ecological momentary assessment (EMA) study with a sample (N=300) of weekly 18-74 year-old cannabis users. Participants will complete brief smartphone-based measures of exposure to messaging (source and content), cannabis motives, and use patterns in the natural environment. With these quantitative data, this will be the first study to examine prospective associations between a user’s exposure to cannabis messaging and motives and other cognitions (Aim 2). Further, we will test whether cannabis motives are a mechanism underlying the association between cannabis messaging and CU at both the between-person and within-person levels (Aim 3). Finally, we will explore user characteristics and message source characteristics as potential moderators of the effects of cannabis messaging and CU (Aim 4). This combination of complementary and highly rigorous data collection approaches will provide the most nuanced understanding of the messages being disseminated about the effects of cannabis to the cannabis user. Findings will arm policy makers and cannabis regulatory science with evidence-based information about the impact of cannabis messaging that can ultimately reduce potential harms from misuse.

NIH Research Projects · FY 2026 · 2022-07

PROJECT SUMMARY In low-resource settings, undernutrition and infections during the first 1000 days of life are prevalent, modifiable risk factors that may have lifelong effects on a child’s cognitive and psychological development. The rapidly developing fetal brain has increased nutritional and metabolic demands and is highly susceptible to the effects of inflammation. Protein, energy, and iron are key nutrients required for early brain development; yet, among women of reproductive age in Sub-Saharan Africa, 10% are underweight and 20% have iron deficiency anemia. Pregnancy infections are also common in Africa, where one in three women have a geo-helminthic infection, contributing to iron deficiency and inflammation. Hepcidin, a regulator of iron homeostasis, is stimulated by inflammation, yet there is limited research on hepcidin in pregnancy and how to optimize fetal iron bioavailability in the context of inflammation. Understanding the complex relationship between nutrition, inflammation, and neurodevelopment is a major research gap. The predominant approach to understanding mechanisms of prenatal brain development is derived predominantly from animal and observational studies. Here, we present an unprecedented opportunity to leverage an ongoing, independently funded randomized controlled trial (RCT) to examine casual relationships and rigorously investigate biological pathways by which prenatal nutrition and inflammation influence human fetal brain development in an undernourished and high- risk population in rural Ethiopia. In the parent trial, women in early pregnancy are randomized to receive: 1) standard prenatal care, 2) a package of strengthened nutritional support (iron-folate, iodized salt, fortified balanced energy protein (BEP) supplement), 3) a package of infection management (deworming, treatment of urinary tract infections), or 4) both packages. The proposed project will support advanced, multi-modal, infant neurodevelopmental assessments (EEG/VEP, cranial ultrasound, neurologic exam, elicited imitation tasks) at 6 and 24 months of age, and analysis of maternal and newborn cord blood for inflammation biomarkers (C- reactive protein, alpha-1 acid glycoprotein, Interleukin (IL)-6), neurotropic factors (IL-6 soluble receptor), iron stores (serum ferritin, soluble transferrin receptor, total body iron), and hepcidin. Our specific aims are to: (1) determine the effects of interventions on offspring neurodevelopment, (2) investigate the effects of interventions on maternal-newborn iron and inflammation biomarkers, and (3) examine the role of maternal- newborn iron status and inflammation on child neurodevelopment. Leveraging an ongoing RCT in Ethiopia, we will determine the effects of iron, BEP, and inflammation on advanced measures of childhood neurobehavior and function and will deepen the understanding of biological pathways and intervention targets. We will elucidate the complex dynamics of iron and inflammation in pregnancy and their effects on neural networks, brain structure, and behavior in childhood. Our work will help optimize prenatal intervention strategies to improve early human brain development in high disease burden and vulnerable populations globally.

NIH Research Projects · FY 2025 · 2022-07

Project Summary The long-term objective of the proposed K08 Mentored Clinical Scientist Research Career Development Award is to support the applicant in building an independent program of research. The applicant is dedicated to a career as a clinical scientist with a research focus on the examination of risk and protective factors for alcohol- related sexual violence and bystander behavior. Ultimately, she aims to conduct research that will inform violence prevention efforts to reduce the occurrence of alcohol-related sexual assault and its associated public health burden. Her career development plan has been tailored to expand upon her interests and training to date and launch her career as one of the few experts in the growing research area of bystander alcohol intoxication. Through the unique training experiences made possible by this award, she will develop expertise in qualitative methods and analysis, intensive longitudinal data collection, and advanced statistical analysis for multilevel data. These skills will be solidified over the course of a 5-year training plan, which involves mentored training experiences (including guided readings, manuscript development, grant writing, meetings) and independent training activities (including coursework, seminars, workshops, and presentations). Members of the mentorship team are experts in their respective fields and their complementary expertise will address distinct training needs of the applicant. Brown University’s Center for Alcohol and Addiction Studies in the School of Public Health provides an exceptional training environment with an extraordinary record of research and an impressive history of successfully mentoring early investigators through the transition to independence. The primary objective of the proposed research project is to answer key questions about bystanders in drinking contexts. Bystander-focused sexual violence prevention has proliferated in the last decade, though a consideration of the importance of bystander alcohol use has emerged much more recently. Alcohol use—one of the most robust predictors of sexual assault—is commonly present when bystanders have an opportunity to combat sexual assault risk. The proposed project will use weekend morning reports about the prior evening to elucidate the event-level effects of bystander alcohol intoxication and related contextual predictors on bystander outcomes. Focus groups will be used following completion of the weekend morning reports to deepen understanding of the quantitative results and inform bystander-focused sexual violence prevention. The proposed award is consistent with training and research priorities of NIAAA’s strategic plan, including cultivating a talented and diverse research workforce to advance the frontiers of scientific knowledge and continuing to support research with implications for alcohol-related violence prevention.

NIH Research Projects · FY 2026 · 2022-07

The effects of cannabinoids are diverse and dose dependent. For instance, low doses produce anxiolysis whereas high doses induce anxiety; similar effects have been seen on memory and cognition. However, the reasons for this are not clear. At the synapse level, the cannabinoid receptor 1 (CB1R) is known to impact transmitter release through inhibition of presynaptic calcium channels, including the N-type (CaV2.2) channels that are paramount in coupling neuronal activity to transmitter release in the hippocampus (HPC). This brain area is important for emotional processing and learning, and CaV2.2 channels are essential in one of the best-studied circuits in the brain. Our long-term goal is to decipher the regulation and function of CaV2.2 channels at specific HPC synapses to inform basic mechanisms of HPC activity, and enable novel therapies based on CB1R signaling. Alternative splicing is a cell-specific mechanism that impacts the function and regulation of CaV2.2 channels. Splicing of exon 18a generates the +18a-CaV2.2 and D18a-CaV2.2 splice variants. Neurotransmission in synapses that express +18a-CaV2.2 variants exhibit enhanced probability of transmitter release, and reduced modulation by CB1R agonists compared to those that express the +18a-CaV2.2 variants, but the underlying mechanisms are unknown. +18-CaV2.2 splice variants contain a 21 aminoacid insertion in the region that interacts with the release machinery. Our central hypothesis is +18a-CaV2.2 splice variants enhance transmitter release and prevent CB1R inhibition of neurotransmission via differential interaction with SNARE proteins. To test this, we will use validated mouse models with restricted splice choice (+18a-only or 18a-only) and recombinase-based labeling of specific neurons in HPC for electrophysiology in acute slices, and biochemical assays to evaluate protein interaction. The specific aims of the project are: 1) To determine the functional impact of +18a-CaV2.2 and D18a-CaV2.2 splice variants on transmitter release in HPC, and 2) To determine the role of +18a-CaV2.2 and D18a-CaV2.2 splice variants on CB1R modulation of transmitter release in HPC. The results of this project are expected to provide insights into the basic mechanisms underlying hippocampal function, as well for the contradictory effects of cannabinoids. Novel cell-specific effectors of CB1R signaling could positively impact development of cannabinoid-based therapeutics

NIH Research Projects · FY 2026 · 2022-07

PROJECT ABSTRACT Synthetic opioids including fentanyl and its analogs have flooded the unregulated drug market in the United States and are responsible for nearly three quarters of the nation’s fatal drug overdoses. Concurrently increased challenges of buprenorphine initiation and maintenance treatment in patients with fentanyl use including risk of precipitated withdrawal and inadequate control of withdrawal and cravings at standard doses are being reported. Buprenorphine research and clinical protocols were based on heroin using populations. There are no updated standardized buprenorphine maintenance dosing protocols for patients using fentanyl. Data from our own clinical practice and other buprenorphine maintenance providers suggests higher daily doses of buprenorphine (24 mg) are well-tolerated, safe, and better control cravings in populations with a history of fentanyl use, yet this strategy has neither been tested prospectively or retrospectively in a randomized controlled trial (RCT) nor compared to standard dosing to assess treatment outcomes in populations using fentanyl. Treating opioid use disorder (OUD) with buprenorphine decreases mortality by 50% and confers other personal health and social benefits. Return to use rates for patients on buprenorphine treatment are high; a recent study reported rates greater than 50 % within 3 months of treatment initiation. Additionally, It has been estimated that 40% of patients on medications for opioid use (MOUD) continue non-prescribed opioid use during treatment, yet we lack understanding of how or why ongoing fentanyl use occurs during buprenorphine therapy, the effects of treatment outcomes, and the impact of buprenorphine dose on fentanyl use practices. For this reason, we will first conduct a quantitative and qualitative mixed method study (UG3) to evaluate if there is an association between daily dose of prescribed buprenorphine and occurrence of non-fatal and fatal overdose and determine the optimal high buprenorphine maintenance treatment dose to use in the subsequent RTC. After successful completion of the UG3, we will conduct a RCT (UH3) in 250 patients with a history of non-prescribed fentanyl use to compare efficacy of standard vs. high dose maintenance buprenorphine protocols. Participants will be actively followed via surveys and UDS assessments at clinic appointments for 1, 3 and 6 months. Passive surveillance will continue throughout the study period to evaluate treatment retention on buprenorphine, non-fatal and fatal overdose at 1 month, 6 months, and 12 month intervals using administrative database linking of state-wide PDMP, ME, EMS, and ED datasets. This study will provide novel data on optimal buprenorphine dosing efficacy in patients with fentanyl use to inform best practices for clinical treatment of OUD.

NIH Research Projects · FY 2026 · 2022-06

PROJECT SUMMARY Transgender and gender diverse (TGD) people in the United States (US) experience significant health disparities throughout the life course relative to cisgender people. While extensive community-based research drawn from convenience samples and a burgeoning body of research using population-level data has assessed the healthcare utilization of TGD individuals, much of this research has focused on younger TGD people. Little national data exist on the health of older TGD people (i.e., 55 and older). Older adults, regardless of gender identity, are at increased risk of developing comorbidities that burden the healthcare system. TGD older adults are expected to be at even higher risk of developing multiple, concurrent health problems than cisgender people due to the stigma-related stress they experience throughout their lives. Further, like all people, TGD people require routine care and, often acute and post-acute care as they age; however, TGD individuals also have unique medical gender affirmation needs (e.g., hormones or surgery) and a dearth of research has explored the ways in which the use of these services shape older TGD people's use of other routine and acute care. The long-term goal of this research agenda is to improve healthcare quality and ultimately the health of older TGD people. The overall objective of this study is to create a comprehensive understanding of the comorbidities and healthcare use of older TGD adults. Consistent with NOT-MD-19-001: “Research on the Health of Sexual and Gender Minority (SGM) Population,” we propose to do use novel algorithms to identify a sample of 30,000+ older TGD people in Medicare data and follow their outcomes across 10 years of outpatient, acute- and post-acute claims and assessment data. We will also link Medicare data to state-level data and use qualitative methods to understand the multilevel factors that shape health outcomes for older TGD adults. To achieve these goals, we propose the following Aims: 1) To describe the prevalence and incidence of single and comorbid chronic conditions among TGD Medicare beneficiaries and to compare the healthcare utilization of TGD and cisgender beneficiaries; 2) To understand how individual, healthcare system, and community factors influence health and healthcare use of older TGD adults relative to older cisgender adults; and 3) To contextualize the quantitative findings by qualitatively assessing (via patient and provider interviews) the individual, healthcare system, and community-level barriers and facilitators to optimal health and healthcare utilization for older TGD adults that can be addressed in future multilevel interventions. This project is innovative because we will use datasets, methods, and outcomes that have not been previously applied to understanding the health of the older adult TGD population. This work will have a significant impact as it will yield novel, clinically-important, and policy-relevant evidence about how older TGD adults are cared for as they become more significantly ill. Finally, completion of this study will lay the groundwork for future multilevel interventions to improve the care of and health of the older TGD population in the US.

NIH Research Projects · FY 2026 · 2022-06

PROJECT SUMMARY/ABSTRACT Connectivity between neurons as part of neural networks governs information flow through the nervous system and therefore shapes behavioral output. Guidance of axon to their correct targets is a key step in neural circuit assembly during embryonic development, and understanding this process is critical, as neuronal miswiring can cause circuit dysfunction and disease. We report identification of a novel axon guidance cue, WFIKKN2, as a ligand for several DCC family receptors and propose to investigate the biochemical nature of these signaling complexes and their functions in neuronal wiring. DCC is a receptor for the attractive axon guidance cue Netrin- 1, and this ligand-receptor pair shapes neuronal connectivity in organisms as diverse as nematodes and humans. In vertebrates, the DCC family comprises five members, and Netrins can bind two of these – DCC and Neogenin. Three additional family members – Punc, Nope, and Protogenin – have diverged considerable over the course of evolution, do not bind Netrins, and their functions in axon guidance have remained elusive. We found that the secreted multi-domain protein WFIKKN2 binds Punc, Nope, and Protogenin, but not DCC and Neogenin. We provide evidence that developing sensory and motor neurons express these newly identified receptors for WFIKKN2, while WFIKKN2 is expressed in multiple tissues in the body periphery. Additional preliminary results show that WFIKKN2 acts as an attractant for motor axons and a repellant for sensory axons, and phenotype analysis of WFIKKN2 knockout mice strongly supports the idea that WFIKKN2-mediated repulsion helps sensory axons navigate to their peripheral targets. We propose a multidisciplinary approach to study WFIKKN2 and its receptors further and test hypotheses about their functions in neural circuit formation. We will use protein interaction assays to map the domains mediating ligand-receptor interactions and determine how ligand binding specificity arises within the DCC family. We will also combine axon guidance assays using cultured neurons with functional manipulations to dissect the contributions of Punc, Nope, and Protogenin to WFIKKN2-dependent axon attraction and repulsion, and we will use biochemical approaches to identify downstream mediators of WFIKKN2 signaling. To elucidate the axon guidance functions of WFIKKN2 and its receptors in vivo, we will employ mouse genetics and state-of-the-art neuroanatomical methods. Our work will uncover mechanisms of motor and sensory axon guidance, and it expands the known molecular toolkit for neuronal wiring by discovering a novel, bifunctional axon guidance cue and its receptors. Our studies further have the potential to identify new intracellular mediators of guidance cue signaling. In the long term, our work can help elucidate how the evolutionary diversification of axon guidance receptor gene families may allow the wiring of more complex nervous systems. Overall, by providing important insights into mechanisms of neuronal wiring, this research will contribute to our understanding of neurodevelopmental disease etiology, and it can aid in the development of novel therapeutic approaches for neural circuit repair and nerve regeneration in various disease states.

NIH Research Projects · FY 2026 · 2022-06

Project Summary: Alzheimer's disease (AD) and Related Disorders (ADRD), including frontotemporal dementia (FTD), Parkinson's disease (PD), dementia with Lewy bodies (DLB), and amyotrophic lateral sclerosis (ALS), cause significant morbidity and mortality in aging populations. Despite decades of research, there are still no effective treatments to prevent or delay progression of these illnesses. Currently, there are tests available to identify individuals at risk of developing AD, but these tests require either a cerebral spinal fluid assay or positron emission tomography (PET) to measure amyloid levels, which are invasive or cost prohibitive, respectively, limiting their usefulness. While blood based diagnostic tests using amyloid and tau biomarkers are being developed to diagnose AD pathology in symptomatic individuals, their predictive value for preclinical disease is still unknown. Furthermore, there are currently no blood-based tests available for ADRDs. Since AD and ADRD develop over a prolonged period that can span decades, there is a need to identify individuals during this preclinical period when potential interventions may be more effective. To address our inability to diagnose at- risk individuals, we have put together a multidisciplinary team of investigators at Brown University and Rhode Island Hospital with the long-term goal to discover easily accessible biomarkers that can be used in a clinical setting to identify individuals at increased risk of developing AD or ADRD dementias prior to the onset of proteinopathies. Our group recently published that AD-related mRNA transcripts can be detected in extracellular vesicles (EVs) isolated from saliva in patients with traumatic brain injury. Our preliminary data show that patients with mild cognitive impairment (MCI) and mild AD have 43 mRNA transcripts and 5 miRNAs that show altered representation in salivary EVs. In addition, cognitively normal individuals with a PET scan that is positive for amyloid β42 have mRNA and miRNA profiles that are similar to the MCI and mild AD patients. Based on this data we hypothesize that the mRNA, miRNA, and protein composition of salivary EVs will provide valid biomarkers for early diagnosis and following disease progression in patients with AD and related neurodegenerative disorders. To test this hypothesis, we will use transcriptomic and proteomic approaches to define a set of RNA and protein biomarkers present in salivary EVs that predict an individual's risk of developing AD in Specific Aim 1. Specific Aim 2 will extend these investigations to identify RNA and protein biomarkers in salivary EVs isolated from individuals with FTD, PD, DLB, and ALS. In Specific Aim 3 we will determine the dynamics of changes in salivary EV composition during preclinical-to-AD clinical progression by following a cohort of cognitively normal individuals with positive amyloid β42 blood test over a period of 3-5 years. The data obtained in this project will allow us to identify biomarkers present in salivary EVs that can be used as a simple, noninvasive screening mechanism to detect patients at risk of developing AD during the preclinical phase when treatments may be more effective.

NIH Research Projects · FY 2026 · 2022-05

PROJECT SUMMARY A decline in neuronal function occurs with age and is the hallmark of neurodegenerative diseases (NDs). Neurodegenerative diseases (NDs), characterized by the functional loss of discrete neuronal populations due to complex sources of cellular dysfunction, reduce the quality and duration of life for millions of individuals. Once considered two quite different NDs: frontotemporal dementia (FTD), affecting neurons of the frontal and temporal lobes, and amyotrophic lateral sclerosis (ALS), typified by death of upper and/or lower motor neurons, are now known to share a genetic basis, with clinical and pathological overlap. One of the most efficient and effective means for elucidating the molecular mechanisms underlying complex cellular processes, like ALS/FTD, is by the identification of genetic modifiers that restore function. We have identified genetic variants that alleviate a loss of motor function and neurodegeneration associated with different models of ALS/FTD. The modifying genes act in carbohydrate metabolism and nucleotide biosynthesis, with the gene encoding Transketolase (Tkt), a central enzyme in the pentose phosphate pathways (PPP), playing a critical role in regulating flux through glycolysis, nucleotide biosynthesis, and oxidative PPP, to meet the cell’s energy demands and counteract oxidative stress. These metabolic pathways are highly conserved across evolution, so the powerful genetics of Drosophila will enable the elucidation of the genetic interactions that regulate these metabolic pathways. Our research program aims to elucidate the mechanistic basis of tkt-meditated suppression of neurodegeneration. Our experimental design makes use of two newly generated patient allele CRISPR-Cas9 knock-in models in the endogenous Drosophila dSod1 locus, and the controlled expression of GGGGCC (G4C2)- repeats whose expansion in the human C9orf72 gene is the most common cause of familial ALS. Since biological systems respond to perturbations by modulating system homeostasis, the complex genetic basis of ALS/FTD will likely not be obtained by studying a single genetic mutation related to the disease. Therefore, we will study multiple models of ALS/FTD and combine an unbiased approach of functional assessments of genetic perturbations, with specific molecular readouts such as, redox state, autophagy, as well as comparative metabolite profiling, transcriptomics, and chromatin state to obtain a global, biomarker readout of disease versus suppressed state. This comprehensive understanding of the molecular landscape will identify the changes that correlate with restoration of neuronal function and motor activity in ALS/FTD. The resulting data will accelerate progress towards a translational goal by highlighting targets where therapeutics could intervene to restore, or even prevent, the loss of neuronal function responsible for the devastating motor and cognitive decline associated with ALS/FTD.

NIH Research Projects · FY 2026 · 2022-05

PROJECT SUMMARY/ABSTRACT Mindfulness-Based Stress Reduction (MBSR) is a promising approach to treat major health problems, such as depression, anxiety, and chronic pain. The last extensive MBSR systematic review was for trials (k=101 studies; N= 8,135 participants) available through 2015. It showed a moderate evidence level using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system, with a call for more and higher quality randomized controlled trials. This literature has expanded with hundreds of clinical trials. It is past time to conduct a systematic review and meta-analysis to determine how strong the evidence is. This will inform whether and how MBSR should be included in health insurance coverage to reduce the global burden of disease and to aid development of better MBSR-related treatments. To do so, scientists recommend integrated knowledge translation (iKT), where researchers and knowledge users co-create knowledge. Although iKT has been used in systematic reviews, it has not been used in a mindfulness systematic review. Primary aims are: 1. Perform stakeholder evaluations to identify: (a) Key questions they have to make decisions about if, how, and when MBSR should be covered by health insurance; (b) what is the highest priority evidence they need on MBSR’s effectiveness and cost-effectiveness; (c) barriers that are important to understand and resolve in order for MBSR to be covered by health insurance. 2. Through a systematic review and meta-analysis, determine the impacts of MBSR on key health-related outcomes informed by the iKT strategy in Aim 1b, such as: (a) anxiety, (b) depression, (c) stress, (d) physical functioning, (e) quality of life, (f) pain with related opioid use, and (g) cost effectiveness. 3. Evaluate whether meta-analytic effects differ based on implementation-related factors informed by stakeholders, such as length adherence (e.g., session length), program fidelity (e.g., teacher training, home practice), delivery modality (in-person vs. online), setting and population (e.g., clinical vs. non-clinical), and effect sustainability (e.g., whether benefits last ≥1 year). Aim 1 methods include stakeholder meetings to conduct formative evaluations involving qualitative interviews and a modified Delphi approach. Methods for Aims 2 and 3 will be state-of-the-science systematic evidence syntheses. These will utilize all major databases to identify MBSR trials that address the primary health outcomes; examine the robustness of evidence across both randomized controlled trials and uncontrolled trials (facilitated by a comprehensive behavior change technique taxonomy to characterize active content); and analyze effect sizes following the best standards. Throughout the review process, we will engage stakeholders, guided by the SPIRIT (Supporting Policy In health with Research: an Intervention Trial) Action Framework. Overall, these evidence syntheses will provide evidence that may transform not only the science of MBSR and related treatments but also increase health insurance coverage and access for millions of people

NIH Research Projects · FY 2026 · 2022-05

PROJECT SUMMARY/ ABSTRACT Many specifics of the pathological process of Alzheimer’s disease (AD) remain unknown, such as the precise, functional relationship between tau accumulation and cognitive decline as a function of age, as well as other biomarkers that may modify these relationships. Conventional statistical approaches cannot easily answer questions about the relationship between tau and cognition, due to their dynamic relationship, unknown time lags, and complex measurement error structures. Mathematical modeling techniques—commonly used in infectious disease epidemiology and computational biology—are specialized for the study of complex relationships between biological variables, while incorporating prior knowledge about the relevant physiologic system. The proposed project leverages my quantitative expertise from dissertation research on infectious disease, using data from across the age span of AD onset to elucidate the relationship between tau-PET measures and cognition. As more tau-targeting drugs move through the pipeline, it is important to determine the optimal timing and duration of treatment for trial design and for post-approval clinical guidelines. The ideal timing for tau-targeting therapies may depend on factors such as age, amyloid, or vascular burden. Existing and emerging blood- based biomarkers may offer important information about how tau spreads in the brain and the timing of subsequent atrophy and cognitive decline longitudinally. A growing number of studies now perform tau-PET, and including repeated neuroimaging, making it possible for an improved understanding of the dynamics of tau and cognition in relation to other biomarkers. We propose a biologically motivated, mathematical modeling approach to understand how neuroimaging and other biomarkers can be used to better understand Alzheimer’s disease biology. We plan to fit mechanistic models to data from three cohorts across the age span of AD diagnosis: Alzheimer’s Disease Neuroimaging Initiative (ADNI), Longitudinal Early-onset Alzheimer's Disease Study (LEADS), and The 90+ Study. The long- term objective of this research is to improve our understanding of the age-specific pathophysiology of AD, determining the precise relationship between tau and cognition, with the ultimate goal of guiding therapeutic development and trials for AD treatment. The proposed training activities include hands-on research experience, as well as didactics, advanced coursework, and directed readings and mentorship with the primary mentor Professor M. Maria Glymour and co-mentor Professor Gil Rabinovici, MD. Scientific advisors Professors María Corrada (MPI: The 90+ Study; University of California, Irvine), clinical neuropsychologist and Professor Adam Staffaroni, and Professor Roy Anderson (Imperial College London) will also contribute their expertise.

NIH Research Projects · FY 2026 · 2022-04

Project Summary/Abstract Glioblastoma (GBM) is an incurable brain tumor for which improved therapies are badly needed. There are roughly 10,000 cases diagnosed in the US each year, and median survival is ~14 months. Evidence has been accumulating over recent years linking cytomegalovirus (CMV) to GBM and other cancers. However, the role of CMV in GBM remains poorly defined. CMV is a prevalent virus in humans, where it resides lifelong in a latent state but can be reactivated under certain conditions. Several clinical trials targeting CMV using diverse approaches including immunotherapies and the anti-viral drug CMV have shown very promising responses in GBM patients, but the underlying mechanisms are not clear. To improve our understanding of this area we have developed an immunocompetent murine model of intracranial GBM grown in the context of a systemic latent CMV infection. This consistently leads to significantly shortened survival compared with mock infected controls in multiple distinct murine GBM models. These effects can be reversed by treatment with anti-viral drugs. Our new preliminary human data shows reduced progression free survival in CMV seropositive humans and similarities in patterns of differentially expressed genes supporting the relevance of the mouse model. Our model features increased blood vessel formation, with accumulation of perivascular pericytes, increased CD8+ T cell infiltrates and resistance to chemotherapy. We discovered that platelet-derived growth factor-δ (PDGFD) is upregulated by CMV infection of tumor cells, and that CRISPR-mediated knockdown of PDGFD prevents pericyte recruitment and severely impairs tumor growth. Therefore in Specific Aim 1 we will further investigate PDGFD as a potential GBM therapeutic target. Also, we have preliminary data with a replication- defective viral mutant suggesting that CMV replication is critical to this phenotype, and we will use this mutant to explore the mechanisms by which CMV enhances tumor progression. We also have shown that the tumor microenvironment is significantly impacted by CMV, therefore in Specific Aim 2 we will examine the therapeutic implications of CMV on tumor/immune interactions, and the importance of viral replication in these effects. In Specific Aim 3 we will use our model to investigate the interactions of CMV with standard of care chemoradiation, in terms of viral reactivation and sensitization to therapies by anti-viral drugs. Results from the proposed experiments will bring us to a deeper understanding of the impact that CMV has on GBM progression, providing badly needed targets and rational therapeutic combinations for future clinical trials in this devastating disease.

NIH Research Projects · FY 2026 · 2022-04

PROJECT SUMMARY/ABSTRACT Cannabis is the most common psychoactive drug co-used with alcohol among individuals with alcohol use disorder (AUD). The current proposal advances our team’s research on the impact of cannabis use (CU) and cannabis-alcohol co-use on alcohol-related outcomes. Findings from clinical studies indicate that CU is strongly linked with alcohol use, although evidence regarding whether cannabis reduces or increases drinking is mixed. Our research has demonstrated that Δ-9-tetrahydrocannabinol (THC) acutely reduces relative alcohol value and consumption in heavy cannabis and alcohol co-users under controlled laboratory conditions. Evidence from animal models on cannabidiol (CBD) suggests CBD may also reduce alcohol craving and consumption. An important gap in current clinical research is lack of human laboratory studies that examine alcohol consumption in relation to cannabis varying in cannabinoid composition (THC and CBD). Moreover, aside from data on pharmacodynamic interactions between cannabis and alcohol, no human laboratory studies have examined the combined effects of alcohol and cannabis (i.e., marijuana; simultaneous use-SAM) on alcohol consumption. Finally, no previous study has evaluated the impact of cannabis on alcohol use within the same individual under both controlled laboratory conditions and in the natural environment. This project will provide the most comprehensive tests of the impact of cannabis on alcohol outcomes using a multi-method design: (1) controlled laboratory administration of THC versus CBD smoked alone versus simultaneously with alcohol and (2) ecological momentary assessment (EMA) of event-level contextual factors that can help elucidate the associations between CU and alcohol-related outcomes in daily life contexts. The laboratory phase will employ a 3 (within-subjects cannabinoid dose: 12% THC/<1% CBD, 12% CBD/<1%THC, placebo) X 2 (between-subjects: cannabis + an alcohol-priming dose versus cannabis + alcohol placebo) mixed factorial design to examine these effects on subsequent drinking in 200 nontreatment-seeking heavy episodic alcohol drinkers who use cannabis weekly (Aim 1). Data from this laboratory phase will be integrated with smartphone- based data on CU patterns (amount, THC/CBD ratio, potency, mode), context (location, social), alcohol craving, consumption, and consequences collected from the same individuals over a 4-week EMA period. Integration of laboratory and EMA data enables examining the unique influences of laboratory-based cannabis state-dependent alcohol response variables and field-based CU and contextual factors on alcohol craving, consumption, and consequences (Aim 2). Cannabis (medical and recreational) and SAM motives and AUD severity will be explored as potential moderators of the associations between CU and alcohol behaviors in the natural environment (Aim 3). This research is well-aligned with the objectives of the Collaborative Research on Addiction at NIH and has important implications for cannabis regulatory science and AUD treatment by addressing the relative impact of specific cannabinoids as well as contextual risk in cannabis-alcohol co-use.

NIH Research Projects · FY 2025 · 2022-04

From 2020 to 2023, infectious disease and related health conditions have devastated nursing home residents in the US, nearly half of whom are diagnosed with Alzheimer's and other related dementias (ADRD). To limit resident exposure to infection and expand safe access to desperately-needed care from physicians and advanced practice providers, Medicare dropped previously tight restrictions and temporarily allowed SNFs to broadly use telemedicine to obtain care for residents. Dropping these restrictions helped facilitate a rapid adoption of telemedicine in SNFs, from <1% of SNFs billing for any telemedicine services in Oct-Dec 2019 to 55% in Apr- May 2020. Telemedicine has long been regarded as a promising, but underused, delivery innovation for SNFs addressing two major gaps in care. First, SNF clinicians are not always onsite, so medical issues that present during off-hours are often addressed by transferring patients, often unnecessarily, to the emergency department. Second, due to both financial and logistic reasons it is very difficult for SNF residents to obtain specialty care, including specialties critical those with ADRD like neurology or psychiatry. A limited literature suggests that telemedicine can bridge both of these care gaps, but more rigorous evidence is needed. In 2021, understanding the adoption and clinical impact of SNF telemedicine for the vulnerable population of older adults with ADRD has new urgency. We propose to use Medicare claims, the Minimum Data Set and a national survey on SNF telemedicine implementation to answer the following specific aims: 1) Evaluate the patient-level association of SNF adoption of telemedicine in 2020 with health care use and clinical outcomes for SNF residents with and without ADRD. 2) Use group-based trajectory models to characterize 2020-2021 SNF-level patterns of telemedicine use (e.g., sustaining vs. de-adopting) and SNF characteristics associated with different trajectories. 3) Survey a national sample of SNFs, stratified by their trajectories measured in Aim 2, to assess facility leadership perceptions of telemedicine use and telemedicine implementation strategies. Understanding how SNFs have used telemedicine and its association with clinical outcomes is essential to inform how Medicare and state Medicaid programs should regulate and promote telemedicine use in SNFs. Our findings will also help guide clinicians who care for SNF residents with ADRD on the clinical impact associated with telemedicine use and how it is being used nationally.

NIH Research Projects · FY 2026 · 2022-03

Time spent in a postdoctoral research position is a critical stage in the biomedical career path to becoming an independent researcher. However, in recent years, fewer U.S. Ph.D. graduates in the life sciences are pursuing postdocs than ever before. Even if trainees pursue postdoctoral training, many leave academia despite traditionally “successful” track records. The root causes that lead to the attrition of talented individuals from research careers are many and they accumulate over the course of each individual's career. Actions can be taken to mitigate the attrition. We will leverage Brown’s commitment to the success of all our talented trainees and the commitment of our faculty, from across brain and quantitative sciences, to enhance the pool of highly qualified neuroscientists contributing to neuroscience research. We propose new programming focused on three key areas: 1) structured mentorship, 2) professional and quantitative skills development, and 3) supported research experiences. This plan aims to: cultivate a cohort of highly competitive and successful postdoctoral trainees who excel in neuroscience research and who successfully transition to the next career phase (Aim 1); create a dynamic program that responds to training and mentoring needs of our participants, that continually incorporates best practices from across the U.S., and that disseminates the results and know-how beyond Brown (Aim 2); contribute to a culture at Brown and beyond that strives for high quality research and free enquiry in all aspects of scientific training and mentorship, and access to opportunities (Aim 3). A system of multi-level input from participants, mentors, internal and external advisors include regular assessment and feedback that inform ongoing program improvements. A comprehensive dissemination plan will ensure broad impact and contribute to fundamental cultural change, at Brown University and beyond, that prioritizes high-quality research and knowledge of cutting edge technologies in all aspects of scientific training. By building mentoring, research, and training, participating faculty and mentoring teams will support the continued growth of the postdoctoral trainees. These actions will develop cohorts of talented neuroscientists who will progress in research careers to advance discoveries, technology development, and innovations that contribute to diagnoses, treatments and cures for diseases and disorders of the brain and nervous system.

NIH Research Projects · FY 2026 · 2022-02

Kidney failure is a life-threatening condition that disproportionately impacts Black, Hispanic, Native American and low-income populations. Approximately 88% of patients with kidney failure initiate hemodialysis treatment, where in-center care typically requires thrice-weekly treatments and a permanent bloodstream catheter that predisposes patients to infectious and vascular complications. Alternatives to in-center hemodialysis include kidney transplantation, which is associated with lower mortality and improved quality of life, and home dialysis, which is associated with lower costs and can offer greater flexibility and independence. But these treatments are substantially underused, and substantial and persistent racial disparities have been documented in receipt of home dialysis and in all steps leading to transplantation. In January 2021, the Centers for Medicare and Medicaid Services (CMS) initiated the End-stage Renal Disease Treatment Choices (ETC) Model. This mandatory model – the first of its kind – randomly assigned dialysis facilities and managing clinicians in 30% of the US to receive financial incentives to increase rates of home dialysis and kidney transplantation. Although observational studies suggest that payment incentives may increase home dialysis, causal evidence is lacking, and no evidence exists on the impact of payment reforms on disparities in kidney failure treatments. More broadly, CMS and other payers have advanced value-based payment policies to improve quality of care, but evaluations of these strategies have been hampered by the absence of appropriate control groups, often due to uniform policy implementation across the U.S. Further, value-based payments may inadvertently lead to increasing disparities in access to care if safety-net providers have fewer resources to respond to performance incentives, or if performance measures fail to account for patients’ social risk. This proposal will test the hypothesis that although the ETC Model will increase home dialysis and referral/evaluation for transplantation, it will also widen disparities in these outcomes because facilities that disproportionately serve low-income patients will make lower performance gains and will be more likely to receive financial penalties. Our specific aims are: 1. Examine the impact of the ETC Model on the use of home dialysis and racial/ethnic and socioeconomic disparities in home dialysis, 2. Identify the effects of the ETC Model on disparities in access to kidney transplantation and 3. Examine consequences of the ETC Model for dialysis facilities according to their patients’ social risk. The proposal is innovative, as we leverage an unprecedented randomized payment reform to estimate causal effects of financial incentives on disparities for a high-cost, high-need population. We will derive neighborhood socioeconomic characteristics by geocoding patient addresses and maximize the comprehensiveness of our evaluation by including patients who lack traditional Medicare coverage. Thus, this work will provide rigorous, causal evidence about the impact on health disparities for one of the largest randomized tests of payment reform ever conducted in the U.S.

NIH Research Projects · FY 2025 · 2022-01

PROJECT SUMMARY Children of low-income families face myriad social risks that interfere with healthy development, behavior, and academic achievement. Mothers of these children experience a high rate of depression, itself associated with lasting effects on children. In 2009, the National Academy of Medicine published a landmark report, Depression in Parents, Parenting, and Children, in which it called for community-based interventions to prevent parental depression and to help engage depressed parents in treatment. Consistent with this report, our research group has conducted a series of NIH-funded studies aimed at alleviating symptoms among mothers at risk for depression in Head Start – a federally funded preschool program that provides services for ~1 million low-income US families. In the present project, we aim to improve outcomes for Head Start children by deploying a stepped-care intervention, in which mothers with low level depressive symptoms are offered a prevention program based on the Problem Solving Education model, and mothers with greater symptoms are offered Engagement Sessions to link them with formal mental health services. Both components of the model have strong randomized trial evidence; but they have yet to be synthesized and tested within a coordinated intervention, applicable to a broad population base. Harnessing a research network of Head Start centers in Massachusetts, we propose an efficacy trial (n=388) of this stepped-care model. Our primary aim is to determine the model’s efficacy in decreasing the rate at which Head Start mothers experience depressive symptom episodes; mothers’ likelihood of engaging with mental health services when referred; parental functioning; and child absenteeism from Head Start. Our second aim is to determine mechanisms of action by which improved maternal wellbeing promotes child resiliency. To do this, we will assess mothers’ perceptions of stress, family conflict, and mother-child interaction patterns; and we will assess child outcomes in the affective, interpersonal and cognitive domains. Finally, to prepare for a subsequent effectiveness trial, we will conduct a single arm pilot study among 20 additional mothers to assess the feasibility of incorporating intervention delivery into usual Head Start workflow. Our proposal represents a high-priority research area for NICHD because it addresses social and environmental factors that impact children’s adaptive behaviors and school readiness. Our study plan enhances the rigor of prior research because it tests the efficacy of a comprehensive depression management model, and because our design allows us to study both maternal and child outcomes – and the mechanisms that link them – among a true community-based sample. Our ultimate goal is to reduce mental health disparities for low-income mothers and to improve outcomes for them and their children.

NIH Research Projects · FY 2026 · 2021-12

PROJECT SUMMARY We have recently identified a novel human neurogenetic disorder caused by loss-of-function mutations in the mitochondrial enzyme glutamate pyruvate transaminase 2 (GPT2). Genetic metabolic diseases, such as GPT2 disease, offer a powerful lens to investigate mechanisms of metabolism in human brain. Also, metabolic diseases may be amenable to treatments via dietary restrictions or supplements. GPT2 disease involves postnatal undergrowth of brain and progressive spastic paraplegia. Based on our extensive preliminary data, we have established potential treatment strategies for GPT2 disease. To guide these interventions in children, we propose to complete needed pre-clinical studies. GPT2 localizes to mitochondria and is upregulated during postnatal brain development. GPT2 catalyzes the reversible addition of an amino group from glutamate to pyruvate, yielding alanine and a-ketoglutarate, a metabolite in the tricarboxylic acid (TCA) cycle. Our preliminary data provide support for disease mechanisms, wherein GPT2 plays a critical role in neuronal growth by regulating neuronal alanine synthesis and anaplerosis. Anaplerosis (filling-up) is the metabolic process whereby TCA cycle intermediates are replenished. Anaplerosis is important during high biosynthetic demand, when TCA cycle intermediates are consumed for synthesis of macromolecules for cell growth, a process known as cataplerosis. Therefore, the central objective of this R01 application is to define the role of GPT2-mediated mechanisms in neuronal development and health, and to study the efficacy of mechanism- based treatments. Aim 1 is focused on in vivo studies of Gpt2-mediated growth of motor neurons. Our Gpt2- null mouse recapitulates key aspects of disease, such as hindlimb motor abnormalities, akin to spastic paraplegia seen in patients. In Aim1 and in Aim 2, we are developing mechanism-based rescue strategies to treat motor defects in vivo through metabolite supplementation in the diets of Gpt2-null animals. Aim 3 will define GPT2-mediated metabolic mechanisms governing neuronal growth and treatments in vitro. These studies are in both primary mouse neurons, as well as in human neurons (from stem cells) in order to translate advances back to the human context. We have a strong and multidisciplinary team permitting a powerful integrated translational approach, bridging patient-oriented studies to experimental models. In summary, research in this proposal will have a sustained impact on both fundamental neuroscience and treatment development. We will evaluate therapeutic strategies that could be rapidly implemented in patients with GPT2 disease, which currently has no known treatment. This progress would pave the way for early intervention, and potentially, prevention of neurologic damage in patients with GPT2 disease. Finally, these studies have broad significance, as we will define basic metabolic mechanisms required for growth and health of long-projecting neurons, including long-projecting motor neurons that are vulnerable in a variety of neurological diseases.