Brown University

NIH Research Projects · FY 2025 · 2021-06

Revised Abstract Section NIAAA identifies underage drinking as a public health issue with serious consequences. Lesbian, gay, and bisexual (LGB) youth who use alcohol have even worse consequences, such as increased risk of cancer, risky sexual behavior, and suicidal attempts. Hispanic LGB youth may be at even greater risk of developing alcohol use problems because of the additive status-based social stressors that may arise. Stress theories posit that youth who experience stressful events cope with psychological distress by using alcohol. To date, little is known about how Hispanic LGB youth respond to social stressors or how socio-cultural protective factors (i.e., coping strategies, social support) and negative and positive affect may mediate these stressors’ effects on Hispanic LGB youth’s use of alcohol. EMA is a unique method that can assess stress theories, psychological distress, and alcohol use in real-time, however it has not been used to assess this relationship with Hispanic LGB youth. The research aims of this Career Development Award (K08) are to: 1) Assess the acceptability and feasibility of social stressors, alcohol, and protective factor measures in ecological momentary assessment (EMA) between Hispanic and white LGB youth; 2) Examine the effects of social stress on LGB youth’s alcohol use and the mediating effects of affect; and 3) Examine the sociocultural risk and protective factors of alcohol use. This study will be conducted in 3 phases. In Phase 1, the measures will be developed using cognitive interviews with Hispanic and white LGB youth (N=20 or until saturation is reached). Phase 2 will consist of a pilot-EMA testing of the EMA with Hispanic and white LGB youth (N=20) over two-weeks and post- EMA cognitive interviews to assess the feasibility and acceptability of the EMA. In phase 3, the finalized EMA will be conducted over a 30-day period to assess social stressors, affect, and sociocultural protective factors of alcohol use among 50 Hispanic and 50 white LGB youth. This K08 proposed study and mentor plan will help the candidate develop expertise in 1) The development and progression of alcohol use in youth; 2) Risk and protective factors of alcohol use in LGB youth; 3) Ecological Momentary Assessment (EMA) methodologies; 4) Intensive longitudinal data analysis for analyzing EMA; and 5) cultural adaptation of measures and interventions for LGB youth. The training goals will build off the candidate’s prior training in 1) Positive youth development; 2) The effects of social stressors on substance use; 3) qualitative analysis, and 4) advanced statistical analysis.

NIH Research Projects · FY 2025 · 2021-04

Mitochondrial dysfunction is a common source of disease, affecting 1 in ~5000 individuals. The United Mitochondrial Disease Foundation states “every 30 minutes a child is born who will develop a mitochondrial disease by age 10” (www.umdf.org). The biology of mitochondria makes these problems tremendously complex. Mitochondrial function requires the coordinated expression of 37 genes encoded in mitochondrial DNA (mtDNA) inside mitochondria, and over 1000 nuclear-encoded genes whose products must be transported into mitochondria. The high mutation rate for mtDNA and the large target of nuclear genes for mutations ensures that every individual has a unique ‘mito-nuclear genotype’ that can alter fitness. Development in different environments can alter how different genotypes express adult traits. Thus, these sources of complexity are responsible for key gaps in our understanding of the genetic bases of mitochondrial disease, and more generally, the genetic variation for mitochondrial performance in natural populations. The Drosophila model we have developed provides a powerful genetic approach to dissect this complexity. We have introduced different mtDNAs into controlled nuclear genetic backgrounds and identified genetic interactions (‘mitonuclear epistases’) affecting fitness traits and gene expression. We have discovered that many of the genes with differential expression resulting from mitonuclear genetic interactions also show differential expression in response environmental perturbations. Our working hypothesis is that mitochondria integrate genetic pathways regulating changes in both the internal cellular, and external physical, environments. We will pursue three general questions. First, what signaling pathways underlie the shared gene expression responses to altered mitonuclear genotypes and altered physical environments? This will be addressed with gene expression and epigenetic experiments pairing mitonuclear genotypes and environmental stressors. Second, which nuclear genes regulate mtDNA effects on phenotypes? This will be addressed with genetic screens of the nuclear genome across a panel of variable mtDNAs. Third, do mtDNA mutations affect males more than females? The maternal inheritance of mtDNA allows direct selection in females but prevents selection in males. Male-specific deleterious mutations could accumulate in populations, a phenomenon known as Mother’s Curse. This will be addressed using sex-based phenotypic assays in a panel of mtDNA genotypes that span a range of genetic divergences. Each of these questions is relevant to current challenges in quantitative and medical genetics. The findings from this research could be informative regarding genetic questions in the identification of appropriate donors for mitochondrial replacement therapies.

NIH Research Projects · FY 2025 · 2021-03

Project Summary Nickel (Ni) is a major industrial metal and a common environmental contaminant that is firmly established as a human carcinogen. Inhalation of Ni compounds in occupationally exposed populations has been found to cause lung and nasal cancers. Tumorigenicity of different forms of Ni was linked to the intracellular presence of Ni(II) ions. Mechanisms of carcinogenic activity of Ni are poorly understood, as Ni compounds were weak or negative in the standard mutagenicity assays and Ni(II) ions do not react with DNA. Consequently, Ni is commonly described as a nongenotoxic carcinogen. However, Ni- treated cultured cells and lymphocytes from Ni-exposed workers have consistently shown the presence of chromosomal rearrangements that typically originate from DNA double-strand breaks (DSBs). Also contradicting its nongenotoxic description is the ability of Ni(II) to cause covalent DNA-protein crosslinks (DPCs) in experimental animals and in occupationally exposed individuals. The presence of chromosomal abnormalities and DPCs despite the apparent lack of mutagenicity and DNA reactivity suggests that Ni may engage some unusual genotoxicity mechanisms. Based on extensive preliminary results, this project is designed to investigate a novel hypothesis that Ni(II) causes DSBs, DPCs, and cell transformation by inducing genotoxic topoisomerase I-DNA products. The proposed studies will determine (1) mechanisms of Ni(II)-induced defects in homologous recombination repair of DSBs, (2) the importance of error-prone DSB repair in the production of oncogenic genetic changes by Ni(II), and (3) formation and pathophysiological significance of Ni-induced topoisomerase I-containing DPCs and DNA breaks. The completion of this work is expected to uncover molecular mechanisms of the formation of oncogenic genetic abnormalities by a nonmutagenic carcinogen Ni and identify novel biomarkers of DNA damage by this metal.

NIH Research Projects · FY 2025 · 2021-02

Project Summary Alcohol use and alcohol use disorders (AUD) in adolescents and young adults with autism spectrum disorders (ASD) have been considered rare by mental health professionals. This conclusion has primarily been based on clinical experience as the empirical literature on alcohol and other drug (AOD) use in the US is virtually nonexistent. Scandinavian health registry studies suggest AOD use is lower in the ASD population overall compared to the general public. Clinical studies also indicate lower rates of AOD in persons diagnosed with ASD compared to persons diagnosed with other psychiatric disorders. Nonetheless, rates of AOD use as high as 30% have been reported in the ASD population. In addition, there appear to be subgroups of persons with ASD, such as those with co-occurring Attention Deficit Hyperactivity Disorder (ADHD), with substantial rates of AOD use and AUDs that not only rival persons with other psychiatric disorders, but also indicate a need for proper identification and, when indicated, treatment. Importantly, prevalence estimates for ASD have increased in the past 10-20 years and a large proportion of that increase includes individuals with higher cognitive and language functioning. This subset of the ASD population is more likely to be included in and exposed to normative educational and social contexts, increasing risk for AOD use. The literature strongly supports the need for detailed and reliable information on the prevalence of AOD in a representative sample of adolescents and young adults with ASD in the US. In this application, we propose to assess a large, well-characterized, population-based ASD sample (Rhode Island Consortium for Autism Research and Treatment- RI-CART) that will enable us to provide, by far, the most in- depth characterization of AOD use and AUD prevalence in the ASD population in the US, as well as data regarding AOD onset and rate of progression to more severe use and AUDs. Equally important is the need to verify, or refute, risk and protective factors for AOD in this population. We will examine comorbid conditions, with specific focus on ADHD and anxiety disorders. We will also characterize the factors inducing risk of AOD use at critical junctions for adolescents and young adults with ASD, such as the transition to independent living, which is often associated with greater peer contact and less structure and social control. We propose to study a subsample of RI-CART participants (N=410) age 12-24 years, who either have an IQ ≥ 85 or an IQ ≥ 75 and are verbally fluent, in a 4-wave longitudinal, cohort-sequential study. We will examine AOD use in relation to age, as well as in relation to key developmental transitions (e.g., into and from high school, into supervised living or independent living/college).

NIH Research Projects · FY 2026 · 2021-01

PROJECT SUMMARY. The PI’s research program in human population genetics focuses on the coalescent-based inference of popula- tion histories from whole genomes, and identifying the genetic basis of adaptation and disease at multiple bio- logical scales—from mutations to genes to gene subnetworks. Global investments made in biobanks sampling millions of people around the world are revealing new challenges for human genetics. Biobanks demonstrate how ubiquitous genetic admixture—gene flow between previously isolated populations resulting in a population that is descended from multiple sources—has been throughout human history, yet methods for detecting genetic targets of natural selection are not calibrated for admixture. Relatives are increasingly sampled in biobanks, but are routinely discarded in population-genetic analyses, thereby limiting understanding of both recent population histories and complex trait architecture. Biobank participants are affected by heterogeneous environmental ex- posures, which confound our understanding of genetic influences on complex traits. Addressing these challenges requires new methods in human population genetics, the study of the evolutionary forces that produce and main- tain human genetic variation. This renewal application describes a series of projects motivated by three open questions in human population genetics: : (1) How do we infer the detailed histories and selection pressures that shape admixed populations? (2) How can we gain new insights into recent histories and complex traits from relatives’ genomes? (3) How can biobanks help us understand the role of environments in shaping human com- plex traits? The future research plans draw on the PI’s expertise in coalescent theory, Bayesian inference, pop- ulation genetics, and statistical genetics combined with scalable, efficient algorithms for analyzing biobank da- tasets such as the UK Biobank and All of Us Research Program. The proposed research in this MIRA renewal application will have wide-ranging impact, from characterizing how natural selection interacts with population histories to shape human genetic variation, to gaining new insights into complex traits and histories through the genomes of relatives, to countering the misuse of genetics research.

NIH Research Projects · FY 2025 · 2021-01

PROJECT SUMMARY/ABSTRACT Head and Neck Squamous Cell Carcinomas (HNSCCs) are devastating upper airway tumors that are associated with an immunosuppressive network impacting the tumor microenvironment, bone marrow and the peripheral blood compartments. The development of novel biomarkers of cancer immunity have not kept pace with breakthroughs in our understanding of cancer-associated inflammation and its relationship with abnormal hematopoiesis and the production of immunosuppressive leukocyte populations. Nor have biomarkers kept pace with clinical indications for use of immunomodulatory therapies. Here, we address the gap in clinically applicable immune biomarkers by first developing unique immuno-methylomic tools to identify aberrant peripheral immune cell populations, followed by the application of such tools for studying HNSCC survivorship. The FDA recently approved pembrolizumab with or without chemotherapy as a first-line treatment for metastatic, or unresectable recurrent disease, which is poised to dramatically increase the number of patients receiving immunotherapy for HNSCC, further underscoring the critical need to identify biomarkers of response to treatment, even before de facto issues of drug cost. Further, recent successful trials of immunomodulatory agents treating late stage HNSCC reveal that there is a crucial role for the immune system in disease survival and prognosis. To understand and quantify immune status, we propose to apply novel DNA methylation-based immune phenotyping biomarkers that will define the immune suppressive state and allow us to intensively study its relationship to immunotherapy treatment response in HNSCC. The proposed study will draw from two independent, comparable, prospectively collected patient cohorts at NCI-designated Comprehensive Cancer Centers. Results from single cell tracing approaches to follow clones of cells in-vivo in cancer patients showed dramatic evidence that the intrinsic ability to attract new immune cells to the tumor results in improved checkpoint blockade activity. This finding strongly supports our approach to identifying biomarkers of checkpoint blockade response through measures in the peripheral blood. As new immunotherapies are developed for HNSCC, it is crucial to mediate the effects of the host’s compromised immune system. The new generation of epigenetic techniques for immune profiling will provide biomarkers that are useful both in assessing immune status and in addressing mechanisms of immune modifiers.

NIH Research Projects · FY 2024 · 2020-09

SUMMARY Alzheimer’s disease (AD), a progressive neurodegenerative disorder affecting millions of people worldwide, is currently incurable. As the population ages, AD and related dementia are becoming the biggest epidemic in medical history: the number of people aged 65 and older with AD is projected to increase between two- and three-fold by 2050. As shown by imaging and biomarker studies, age is a major risk factor for developing dementia, and the pathophysiological processes of AD begin more than a decade before the diagnosis of dementia. However, AD is a heterogeneous and multifactorial disease; thus, it is challenging to fully understand how the multiple etiologies and age-related prodromal processes contribute to its pathophysiology. Among other factors, deficits in cerebral microvascular structures and functions may play a key role in the onset and development of AD. Despite its importance for early diagnosis and as a therapeutic target, it is still unclear whether they are a causal factor for AD pathogenesis or an early consequence of multifactorial conditions that lead to AD at a later stage. Especially, two critical knowledge gaps exist: (1) Temporal relationships between vascular and other key factors during the onset and development of AD are not clear; (2) Little has been studied about how individual defects in various microvascular structural and functional properties distinctly correlate with and/or contribute to neuronal degeneration. Here, we will develop, optimize, and integrate experimental and computational technologies for the lifespan tracking and analysis of progressive microvascular alterations in AD versus normal aging in model mice. First, we will optimize our optical coherence tomography imaging and 3D image processing techniques to track the time-course of 32 vascular and non-vascular measures longitudinally over the mouse’s lifespan, including microvascular structure, microcirculation, functional reactivity, Aβ plaque accumulation, neuronal loss, and cognitive decline (Aim 1). These unprecedentedly comprehensive temporal dynamics data and advanced statistical/correlation analyses will enable us to determine whether the microvascular deficits precede neuronal loss or Aβ accumulation, and how those alterations are correlated, directly addressing the first knowledge gap. In Aim 2, we will improve our computational model of microvascular flow and functional hyperemia, and then combine the model with the experimental data of Aim 1 to investigate complicated cause- effect relationships. Our computational model will enable us to essentially “turn on” and “turn off” each microvascular deficit (e.g., thinner vessels, tortuous capillaries, hypoperfusion, capillary stalling) and test its effect on oxygen delivery to neurons, which is difficult and sometimes impossible to achieve experimentally. This combined approach will provide a powerful and unique strategy for testing the role of vascular deficits in neuronal degeneration, directly addressing the second knowledge gap, and informing future research for diagnosis and therapeutic target development.

NIH Research Projects · FY 2024 · 2020-09

PROJECT SUMMARY Concurrent with a dramatic rise in social media use, youth in the United States are reporting high rates of peer victimization and mental distress. Treatment-modifiable elements of the relationship between online social messaging, mental distress, and peer victimization are unclear. This lack of clarity is partly because prior work relies primarily on “snapshots” of these social connections, in which youth self-report on their social media use and related experiences at a single point in time. More intensive sampling and real-time characterization of adolescents’ social worlds is needed to develop better interventions and guidance for clinicians, youth, and parents. This work is particularly urgent among youth with high rates of online and in-person victimization. We have previously recruited and retained high-risk samples of youth from the emergency department (ED), who report high cross-sectional and longitudinal rates of peer victimization, mental distress, and social media use, for both intervention and cohort studies. This research project, developed in response to PA 19-373, proposes an innovative combination of methods from our prior work. We will enroll 240 adolescents (age 13-17) presenting to the ED for any medical or injury complaint in a 6-month cohort study. Using recruitment, sampling, and follow-up methods similar to our prior work, we will intensively collect online social messaging (“OSM”), in-person interactions (using the Electronically Activated Recorder, or “EAR”, which collects snippets of codable audio), and self-perceived mood, loneliness, and peer victimization (using ecological momentary assessments, or “EMA”) for 1 month. We will administer validated self-report surveys at 0, 1, 3, and 6 months. Finally, we will collect continuous OSM data from 2 weeks prior to recruitment to the end of the 6-month study. We will use advanced computational modeling, as previously piloted by our group, to align and integrate OSM, EAR, and EMA data, and develop nuanced descriptions of at-risk youth’s social connection and isolation. We will then examine the relationship between their social connectedness, peer victimization, and future psychological well-being, and will explore how demographic and other vulnerability factors influence this relationship. SIGNIFICANCE: Consistent with the NICHD strategic plan, our methodology as well as the unique composition of our research team ensures that our research is aimed at identification of “targets for behavioral intervention.” Our findings will inform future in-person and population-level interventions to improve patterns of social connectedness, reduce peer victimization, and improve well-being among at-risk adolescents.

NIH Research Projects · FY 2024 · 2020-09

PROJECT SUMMARY/ABSTRACT The failure to find any effective treatment for Alzheimer’s disease (AD) despite over four decades of research underscores the critical need for new strategies to prevent or delay disease onset. The proposed investigation aims to examine mechanisms of risk and resilience to age-related cognitive decline by leveraging recent advances in cognitive neuroscience and a unique 60-year longitudinal prenatal cohort. The concept of reserve has been developed to account for the large individual differences in cognitive aging trajectories, with nascent understanding of potential modifiable determinants of reserve. However, fundamental questions remain regarding, for instance, the impact of education, cognitively stimulating activities in adulthood, or early childhood enrichment on reserve mechanisms and cognitive decline. Previous investigations have been hampered by a number of limitations, including the lack of: 1) prospective measures of early childhood cognition, needed to address critical issues of reverse causation plaguing this field; 2) indices of adult cognitive decline over a large time window; and 3) measures of relevant sociobehavioral factors across the entire lifespan. This proposal addresses these limitations by extending our continued study of the Providence RI cohort of the US Collaborative Perinatal Project (CPP). The original CPP involved systematic data collection from pregnancy through age 7 years, including measures of three key early life factors thought to influence cognitive trajectories in later life: early childhood IQ, family SES, and childhood adversity. We conducted a comprehensive cognitive assessment of 720 members of this cohort at age 35. We propose to reassess these participants (now approaching age 60) with a detailed neuropsychological battery to examine cognitive decline over a 25-year period. We will also assess engagement in cognitively stimulating activities, physical activity, occupational complexity, income, and health status. Participants will provide biosamples for plasma beta-amyloid (Aβ) 42/40 ratio and apolipoprotein E (APOE) genotype, and will undergo structural and functional MRI, providing operationally-defined brain measures of reserve. Finally, we propose a novel conceptual framework linking lifespan factors to cognitive outcomes through distinct brain mechanisms. This framework drives our aims which are: (1) Determine the relative influence of educational attainment, early life, and adult lifestyle factors on cognitive level and decline in late middle-aged adults; (2) Determine the relative contributions of specific brain reserve mechanisms to cognitive decline; and (3) Identify major determinants of brain reserve mechanisms in later life. A projected doubling of the elderly population by 2050 will place tremendous AD-related burden on the U.S. healthcare system. By providing novel insights into mechanisms of risk and resilience, findings may lead to new strategies to significantly reduce this burden by delaying cognitive decline and the onset of Alzheimer’s Disease.

NIH Research Projects · FY 2024 · 2020-09

PROJECT SUMMARY Young men who have sex with men (YMSM; age 18-34) are disproportionately burdened by HIV. Minority stress and its “downstream” effects in YMSM, including mental health issues, sexual risk behaviors, and suboptimal HIV testing, contribute to the syndemic risks surrounding HIV. Mindfulness-based interventions (MBIs), adapted for HIV prevention among YMSM and internet-based delivery to maximize reach and engagement, could offer an innovative and scalable method to address this public health issue. Consistent with NCCIH’s scientific priority in Disease Prevention and Health Promotion across Lifespan, the current project aims to develop an internet-delivered MBI for HIV prevention among distressed, high-risk YMSM. Specifically, this K23 will provide support for an early phase, exploratory clinical trial by adapting mindfulness-based stress reduction (MBSR) and conducting a feasibility trial among YMSM. Candidate: Dr. Sun is a clinical scientist with a research background in HIV prevention and mental health concerning minority populations and marginalized communities. In recent years, she has pursued clinical and research development in mindfulness. Building on her prior work, she is applying for a five-year K23 Career Development Award to obtain training, mentorship, and research experience to become an expert in adapting and evaluating internet-delivered MBI to address HIV-related health disparities and an independent investigator capable of R01 funding. Mentoring: A stellar team of senior investigators serve on the advisory panel. Drs. Don Operario and Judson Brewer are co-primary mentors, who have complimentary expertise in HIV prevention for MSM and internet-based MBI for behavioral health. Three co-mentors bring expertise in internet-based HIV intervention with young adults (Dr. Larry Brown), mindfulness for population health (Dr. Eric Loucks), and stress physiology (Dr. Audrey Tyrka). Research: Guided by the ADAPT-ITT model, the proposed project aims to (1) adapt MBSR for distressed, high risk YMSM and internet-delivery using focus groups with YMSM (n=30) and stakeholders (n=16), (2) refine the intervention protocol by administering adapted materials to distressed, high risk YMSM (n=18) and stakeholders (n=16) via theatre testing, and (3) examine the feasibility and acceptability of the adapted iMBI for HIV prevention by randomizing 40 distressed, high-risk YMSM to the iMBI (n=20) and a Health Education condition (n=20). The study will examine recruitment and retention, intervention adherence (e.g., attendance, at-home practice), completion of assessment (HIV testing, sexual risk behaviors, hair sample collection, mental health, minority stress and coping), and acceptability of the intervention. Trainings: Dr. Sun will receive training in MBSR, intervention adaptation and implementation for YMSM and internet-delivery, and a biopsychosocial-based understanding of stress through coursework, seminars, workshops, directed readings, and mentored research. Guided by an excellent mentorship team, these training and research experiences will establish the candidate’s career as an expert in HIV-related behavioral health and iMBI for minority health. The candidate is institutionally supported by Brown University School of Public Health.

NIH Research Projects · FY 2025 · 2020-08

The spleen clears the blood by removing the altered red blood cells (RBCs) at the cost of splenic congestion and anemia in sickle cell disease (SCD). In infants with SCD, accumulation of normal and sickled RBCs in the spleen is central in acute splenic sequestration or subacute hypersplenism (ASSC/HS), major complications that often require splenectomy. Even without splenectomy, the spleen in SCD patients has been thought to become non-functional (autosplenectomy) early in childhood. However, our recent results indicated that approximately half of adult patients with SCD in France still retain some extent of splenic function. Further, in SCD children with ASSC/HS, swollen spleens clear stiff RBCs from the circulation so effectively that poorly deformable RBCs in circulation are as rare as in control subjects with a normal spleen. These recent findings strongly suggest that ASSC/HS may be managed by improving the deformability or reducing sickling of RBCs. This hypothesis, if confirmed, is expected to reduce the indication of splenectomy, preserve splenic function, mitigate anemia, and improve the quality of life for children with SCD. Curative treatments involving stem cell and gene therapy have made significant progress recently, but their implementation will not be universal. Four more affordable medications have been approved by the FDA for treating SCD, but none has a fully curative effect. Herein, we propose to conduct a comprehensive and integrated clinical, microfluidics, and computational investigation to explore the effects and mechanisms of voxelotor, one of the FDA-approved SCD drugs, and its equivalents, with the main aims of reducing spleen congestion, alleviating anemia and preserving splenic function in pediatric and adult SCD patients. While the clinical studies will assess the efficacy of voxelotor in protecting the organ function in vivo, phenotypic screening, microfluidics, and computational studies based on digital twins will identify new drugs and provide the mechanistic rationale to support the clinical and screening findings. Specifically, we propose to achieve our goal through three Aims. In Aim 1, we will assess the ability of the voxelotor to decongest the spleen and screen new drugs displaying this effect. In Aim 2, we will perform an in vitro investigation of the efficacy of voxelotor, its successor GBT601, and newly identified drugs through spleen-mimetic microfluidic chips to unravel the potential mechanisms of these drugs for protecting the splenic function. In Aim 3, we will build digital twins of the spleen to efficiently predict the patient-specific efficacy of voxelotor, GBT601, and newly identified drugs in preserving the spleen function. In summary, we will develop a new integrated clinical-microfluidics-computational framework to explore the impact of existing and new drugs in preserving the splenic function with the promise of improving the quality of life for the majority of SCD patients. This framework will have a broader impact as the filtering function of the spleen likely impacts hemolysis and vaso-occlusion in other organs, such as liver and lungs.

NIH Research Projects · FY 2025 · 2020-08

Project Summary Understanding molecular mechanisms that govern the aging process is critical in the face of the ever-increasing incidence of age-related diseases. Loss of epigenetic regulation with age has emerged as a hallmark of aging, but little is known about the mechanisms linking chromatin alterations to longevity. Recently, in collaboration with the Brunet lab at Stanford University, we demonstrated that chromatin changes in the Caenorhabditis elegans germline, specifically a deficiency in trimethylation of lysine 4 on histone H3 (H3K4me3) via the Complex Proteins Associated with Set1 (COMPASS), induce changes in expression of mTOR targets which orchestrate a metabolic shift in somatic tissues to extend lifespan via a specific enrichment of mono-unsaturated fatty acids (MUFAs). This effect is mediated by the SREBP1/SBP-1 transcription factor, which is activated through COPII- mediated ER-to-Golgi transport. Recent data in mammals highlighted a critical role for CREB regulated transcriptional coactivator (CRTC)2 in COPII trafficking, while we have shown that the sole C. elegans CRTC modulates aging and energetic metabolism. Excitingly, my preliminary data indicate that CRTC-1 specifically regulates lifespan extension in H3K4me3-deficient animals, establishing a novel role of CRTC-1 in the epigenetic regulation of aging. My long-term goal is to understand how epigenetic regulation integrates environmental and internal signals to influence gene expression and downstream cellular processes to promote longevity and transgenerational benefits. This proposal will use a combination of genetics, microscopy, metabolomics, and genomic approaches to uncover the molecular mechanisms that mediate H3K4me3-dependent longevity. Aim 1 will define the spatiotemporal requirements of the COMPASS chromatin complex to mediate longevity and its effectors such as CRTC-1, SREBP1/SBP-1 and mTOR targets. To complement these studies, Aim 2 will identify the downstream molecular mechanisms and metabolic changes that a specific function of CRTC-1 regulates to promote H3K4me3-dependent longevity. The independent R00 phase will focus on studying transgenerational mechanisms downstream of the COMPASS-mTOR-CRTC pathway to promote longevity. The conservation of all these components will allow me here to translate these findings into mammalian systems to identify the cellular and physiological responses that epigenetic modifications control to promote longevity. Together, these findings will serve as the foundation of my research program and will launch the beginning of my independent research career. My primary mentor, Dr. William Mair will provide important scientific and career guidance to ensure my success. My advisors and collaborators complement Dr. Mair’s expertise and will help me reach my career and research goals. The K99/R00 award constitutes a unique opportunity for my advance in the academic track. It will help me to consolidate an innovative niche in the study of epigenetics of aging and provide me with the necessary academic and technical training to launch my career as an independent investigator.

NIH Research Projects · FY 2024 · 2020-07

PROJECT SUMMARY Neurons, the basic processing and communicating units of the brain, typically use action potentials to transmit messages from a site near the cell body to neurotransmitter releasing terminals via axons. Action potentials can, in some cases, also travel backwards along the axon towards the cell body and dendrites; I refer to these here as ‘ectopics.’ Ectopics have been recorded in models of epilepsy, as well as in a small group of inhibitory interneurons under normal conditions. Recently, I discovered that nearly all parvalbumin positive (PV+) cells of the brain, which account for about half of neocortical inhibitory cells, can fire ectopics. We do not yet know exactly where in the axon ectopics are generated. In addition to not knowing where in the axon they come from, we also do not know what mechanism generates them. Finally, we do not know what conditions lead to ectopics in vivo. Here, I propose a series of experiments designed to answer these questions. In Aim 1, I will test whether receptors, ion channels, and cotransporters capable of depolarizing the presynaptic terminal are involved in ectopic generation. I will also use an ultra-rapid imaging technique to track action potentials as they travel through the axons of PV+ cells to directly confirm both where ectopics are generated and the number of synapses they trigger. In Aim 2 I will determine whether astrocytes, which envelop and modulate PV+ cell terminals, help elicit ectopics by blocking astrocyte-specific transporters and receptors, as well as by modulating intracellular astrocytic calcium stores and optogenetically depolarizing astrocytes. Finally, in Aim 3, I will undertake a series of experiments to detect ectopics in PV+ cells while mice are under anesthesia, and in various awake, behaving conditions. These experiments will discern both how, and in what contexts, ectopics are generated. Understanding the mechanisms of ectopic action potential initiation will yield new insights into the function of an important population of inhibitory interneurons. It may also reveal mechanisms that relate to brain disorders involving cortical hyperexcitability, providing novel targets for future investigations of circuit-level changes related to these brain disorders and, potentially, new approaches to treatment. This mentored award will support the training I need to establish an independent career as an academic physician-scientist. I will develop technical expertise in voltage-sensitive dye imaging and in vivo recording techniques under the direction of my mentor, Dr. Barry Connors, Ph.D., with input from advisory committee members Drs. Judy Liu, M.D., Ph.D. and Christopher Moore, Ph.D., who are leading experts in their fields. I will supplement this training with courses in the responsible conduct of research, molecular neuroscience techniques, and grant writing, along with attendance at local seminars and national meetings to disseminate my findings and foster collaborations. This training will help me achieve my goal of becoming an independent investigator exploring the neurocircuitry underlying neuropsychiatric disorders using cutting edge techniques.

NIH Research Projects · FY 2025 · 2020-07

Solving complex problems in human health and modern biology represent a major challenge for those who will lead biomedical research in the near and long-term future. The core disciplines of our training program—molecular biology, cell biology, and biochemistry—have led the way in innovations that are driving life sciences research and applications today. It is imperative that US life scientist training programs evolve to meet the demand for leaders who are trained in rigorous and transparent implementation and reporting of quantitative analysis of biological data. We recognize that this demand will require a change in training culture that focuses on a high standard of professional development for trainers and trainees. The objectives of this predoctoral training program are to: (1) Build and sustain a training environment for an outstanding group of PhD students. (2) Integrate training in the design and implementation of rigorous and transparently reported experimentation throughout the program. (3) Integrate training in quantitative and computational approaches throughout the training program. (4) Integrate career exploration and student professional development throughout the program. Faculty trainers in the Molecular Biology, Cell Biology, and Biochemistry Graduate Program (MCBGP) are accomplished scientists who are drawn from 11 Departments at Brown University and the Warren Alpert Medical School. The mission of the MCBGP is to build and sustain a training environment in which all PhD students will successfully gain quantitative, conceptual, technical, and professional skills that will allow them to conduct rigorous, reproducible and innovative interdisciplinary life science research. The MCBGP admits 9-14 students each year using a holistic review and interview process that emphasizes research, academic, and leadership potential. Each year we will select four trainees from the group of 8-12 eligible first-year students. In most cases, these students will be reappointed in their second year. So, each year, four first-year and four second-year predoctoral students will be supported; funds to support eight trainees per year are requested.

NIH Research Projects · FY 2024 · 2020-06

PROJECT SUMMARY Given the growing complexity of healthcare, continued problems related to quality and cost, and a widely- recognized 17-year evidence to practice gap, there is an urgent need for a rehabilitation resource center that supports the conduct of learning health systems (LHS) rehabilitation research and develops LHS researchers to advance the field of rehabilitation care. Brown University, the University of Pittsburgh (Pitt) and Boston University (BU), together with health system/health organization partners, are combining expertise and resources to create LeaRRN: the Learning Health Systems Rehabilitation Research Network. LeaRRN’s mission is to improve the quality, outcomes and value of rehabilitation care by fostering stakeholder-partnered research within and across LHSs. LeaRRN will build upon a well-established infrastructure and collaborative relationships at Brown, Pitt, and BU; faculty expertise in health services research, implementation science, stakeholder engagement, and informatics; and established and emerging partnerships with a diverse group of LHSs. LeaRRN’s overarching objective is to establish a national resource network to advance stakeholder- partnered, rehabilitation LHS research to improve quality of care, demonstrate value, and enhance patient and system outcomes. LeaRRN will include training to promote seven core LHS research competencies, including (1) using a system science approach, (2) asking meaningful questions, (3) applying appropriate research methods, (4) capitalizing on informatics, (5) championing research ethics, (6) optimizing quality improvement and implementation science, and (7) engagement, leadership and research management. LeaRNN will also support research innovation by convening health system stakeholders to identify priority topics to address through mentored collaborations (i.e., LHS Scholar opportunities and pilot studies). Finally, through techniques development, we will assess the needs of the rehabilitation research community, prioritize and design our resources and activities to respond to those needs, and evaluate our impact. LeaRRN’s specific aims are to: 1) create a LHS Innovation Hub that partners researchers with healthcare systems and engages stakeholders, including patients, providers, administrators, payers, and policymakers, to develop rehabilitation-focused LHS research questions; 2) provide funding and methodological/technical support for LHS Scholars and Pilot Study Awardees to transform research ideas into full-scale studies conducted in real-world practice; and 3) develop a knowledge repository, tailor LHS resources for rehabilitation and disseminate materials to advance best practices in rehabilitation LHS research. LeaRRN will serve as a resource and incubator for rehabilitation researchers interested in LHS research. The knowledge repository, investigative experience, collaborations, and evidence generated by LeaRRN will transform the delivery, quality, and outcomes of rehabilitation care.

NIH Research Projects · FY 2026 · 2020-05

Program Summary Progressive Multifocal Leukoencephalopathy (PML) is a major life threatening complication in patients with AIDS and in patients undergoing immunotherapy for autoimmune diseases such as multiple sclerosis, Crohn's disease, severe plaque psoriasis, systemic lupus erythematosis, hematologic malignancies, and rheumatoid arthritis. The disease is paradoxically caused by a common human polyomavirus following the loss of normal immune surveillance of the central nervous system (CNS). There are several major gaps in our understanding of the basic biology that underpins the development of PML. First, the anatomical site of virus persistence is not known but kidney, bone marrow, and brain have all been postulated to be involved. Second, the mechanisms that govern viral persistence are not well defined but changes in the viral promoter (archetype to PML-type) and regulation of a viral microRNA are thought to be critical for transition to the lytic phase. Third, the mechanisms of viral spread to the CNS and within the CNS are not known. Based on our recent work we hypothesize that free virus as well as virus enclosed in extracellular vesicles spreads from the kidney to the choroid plexus and meningeal compartments where replication in CPE cells provides the means for EV mediated invasion of brain parenchyma. Once in the brain extracellular vesicle mediated spread is likely to play the major role in spreading the infection because macroglia lack the principle cellular receptors to support infection by free virus. Our vision for the R35 application is to further our understanding of these basic mechanisms of infectious spread of virus and to use the information to identify biomarkers that can predict PML early and in easily accessible compartments well before the virus has a chance to spread to the CNS. The work should also lead to the development of novel strategies to treat and prevent PML.

NIH Research Projects · FY 2026 · 2020-03

PROJECT SUMMARY/ABSTRACT Nervous system development and function demands tight regulation of gene expression. Post-transcriptional modification of RNA regulates gene expression at multiple levels and tRNA modifying enzymes are emerging as important regulators of nervous system development and function. Here, we build on our in vivo studies of ALKBH8 in Drosophila. ALKBH8 is a wobble uridine tRNA methyltransferase recently identified as the causative gene for intellectual disability in a growing number of families. Our findings support the model that ALKBH8-dependent methylation of tRNA-Sec promotes selenoprotein synthesis and the regulation of oxidative stress to restrain synapse formation and promote learning and memory. In Aim 1, we build on these findings to determine the contribution of selenoproteins to memory deficits in ALKBH8 null animals and investigate approaches for circumventing ALKBH8-dependent tRNA-Sec methylation in the nervous system. We will also leverage whole brain transcriptomic and proteomic datasets we have generated to identify additional ALKBH8- dependent proteins. In Aim 2, we define the spatio-temporal requirements for ALKBH8 in nervous system development and function and characterize the dynamic regulation of ALKBH8-dependent tRNA modifications during neurodevelopment and in response to neuronal activity or oxidative stress. In Aim 3, we expand our investigations to complementary human iPSC-derived neurons and brain organoids to understand the impact of intellectual-disability associated variants. Through this integrative approach we will gain deep mechanistic understanding of ALKBH’s role in nervous system development and function and how it goes awry in disease states while identifying critical windows and targets for therapeutic intervention. More broadly, our studies will reveal fundamental insights into the critical, yet understudied, role of tRNA modification in the dynamic regulation of gene expression in the nervous system.

NIH Research Projects · FY 2025 · 2019-09

PROJECT SUMMARY Endolysosomal dysfunction is a convergent mechanism in many brain disorders. We are studying genetic con- ditions caused by mutations in the endosomal Na+/H+ Exchanger 6 (NHE6). Through our work with affected families in the International Christianson Syndrome and NHE6 Gene Network Study, we have found three phe- notypes associated with NHE6 mutations: 1) Christianson Syndrome (CS), a profound intellectual disability af- fecting males with loss-of-function mutations; 2) the Female-specific NHE6 Mutation Carrier Syndrome (FCS); and 3) Non-Syndromic ID/Autism (NS-ID/ASD) which occurs in males who carry putative hypomorphic muta- tions in NHE6. The objective of this R01 renewal proposal is to define pathogenic mechanisms that cause NHE6-related disease, as well as to develop mechanistic linkages to other related developmental and degen- erative disorders. We find a high degree of relevance to Lysosome Disorders, as well as, Alzheimer’s Disease (AD) and AD-Related Dementias (ADRD). Our central hypothesis is that loss of NHE6 leads to abnormal endo- some-lysosome fusion, thereby causing: 1) cell-autonomous defects, such as aberrant retrograde axonal transport and lysosomal deficiency; and 2) cell non-autonomous pathology, such as toxic exosome release, and activation of disease-associated glial. Our research team is in an excellent position to study NHE6-related disease bench-to-bedside. We have unique resources, including: NHE6 mutant mice and human stem cells; as well as an NHE6-null rat that shows endogenous tauopathy. We also have a long-standing relationship with the family-led Christianson Syndrome Association, as we lead the natural history studies. There are four Aims: Aim 1 focuses on defining the molecular mechanism whereby loss of NHE6 leads to an endosome-lysosome fusion defect. In Aim 2, we define molecular mechanisms governing the emergence of disease-associated astrocytes and microglia in NHE6-mutant brains. The impact of this Aim, in part, involves the strong overlap of disease- associated glial states with AD/ADRD. In Aim 3, we will define the mechanism whereby putative hypomorphic NHE6 mutations in patients with NS-ID/ASD cause developmental delays and behavioral regressions. In this Aim, we will dissect biological mechanisms in developmental regression, which are common but have re- mained largely undefined. In Aim 4, we will focus on FCS, and define potential cell non-autonomous disease mechanisms in female NHE6 mutation carriers, including assessment of tau toxicity. In this Aim, through study of patient-derived iPSCs and the female carrier rat, we will contribute to knowledge of the understudied female carrier syndrome, and also to elucidating disease mechanisms related to X-chromosome inactivation in female brain. Overall, this research will define mechanisms in new genetic diseases in males and females, and will establish linkages with more common disorders, including AD/ADRD, potentially identifying new therapeutic targets. Additionally, our research uses a powerful integrated translational approach, bridging patient-oriented studies to experimental models, thereby contributing to robust research outcomes with high societal impact.

NIH Research Projects · FY 2025 · 2019-09

Over 6 million Americans have Alzheimer's disease (AD) or an AD-related dementia (AD/ADRD). Health care systems (HCS) in all settings (e.g., nursing homes (NHs), community, hospitals, assisted living) struggle to provide high quality, coordinated care that meets the needs of people living with dementia (PLWD) and their care partners (CPs). Scalable and adoptable non-pharmacological interventions that are effective in improving the care delivered to this population are desperately needed. Meeting this challenge demands innovative approaches and robust infrastructures that bring together HCS, researchers, community partners, funders, and regulators focused on this common purpose. Established in September 2019, the National Institute on Aging (NIA) IMbedded Pragmatic Alzheimer's disease (AD) and AD-Related Dementias (AD/ADRD) Clinical Trials (IMPACT) Collaboratory’s mission is to build the nation’s capacity to conduct embedded pragmatic clinical trials (ePCTs) of interventions for PLWD and their CPs. Since its inception, IMPACT has actualized its original Aims to advance the conduct of ePCTs, develop and disseminate knowledge, build investigator capacity, and catalyze stakeholder collaboration. IMPACT also established an interdisciplinary and collaborative community of over 150 investigators at all career stages, contributing to its mission. IMPACT proved to be nimble; novel programs were conceived and launched during its initial years to address unanticipated needs to advance the field. These accomplishments and challenges inform its next steps and provide the rationale for its continuation. The overriding objective of this renewal proposal is to achieve IMPACT’s mission by building on the many successes established in IMPACT’s first funding cycle through 4 fundamental aims; Aim 1. Maintaining and enhancing the highly functional established infrastructure; Aim 2. Supporting the conduct of ePCTs to identify effective interventions that improve dementia care within HCS through grant funding and providing guidance and resources to investigators; Aim 3. Building investigator capacity to rigorously conduct this research by providing trainees with opportunities for career development funding, mentorship, scholarly projects, training workshops, and on-line learning curricula; and Aim 4. Advancing knowledge and methodology in the field. Central to IMPACTs mission is that its work will include, apply to, and strive to improve dementia care for all Americans. IMPACT: IMPACT’s bold vision is to transform the delivery, quality, and outcomes of care provided to PLWD and their CPs by accelerating the testing and adoption of evidence-based interventions within HCS. Its accomplishments to date provide a strong foundation for this vision, but realizing it will require more time, investment, and innovative approaches. Support for a 5-year renewal period is necessary to achieve the full potential of this remarkable national infrastructure and ultimately translate its resources to meaningfully improve the quality of care delivered to Americans living with dementia and their CPs.

NIH Research Projects · FY 2025 · 2019-08

Substance use (SU) negatively affects the risk, management, progression, and outcomes of chronic disease and contributes to socioeconomic and racial/ethnic health disparities. Although linkages between SU and chronic disease are well documented, biopsychosocial mechanisms underlying these linkages are poorly understood. Prospective, longitudinal studies that investigate links between SU and chronic disease are needed to inform the development of targeted prevention and intervention efforts. In Phase I, the Center for Addiction and Disease Risk Exacerbation (CADRE) made considerable progress toward establishing a multidisciplinary research center of excellence. With support from our Administrative and Clinical Laboratory Cores, we provided 11 early-stage investigators (ESI) with research funding and career development to support their transition to research independence. Our CADRE team published 612 peer-reviewed articles, 147 of which were directly CADRE-supported, and 4 (of 6) of our initial cohort of Project Leaders (PL) obtained R01s. In Phase II of the CADRE, we propose to continue to support ESIs leading thematically and technically linked studies. Our three initial Phase II PLs will (1) examine effects of alternative nicotine delivery products on smoking, obesity, and relevant clinical outcomes among people with obesity who smoke (Murphy); (2) investigate how sleep and negative affect may mediate the short-and long-term relationship between cannabis use and depression in young adults (Sokolovsky); and (3) investigate the intergenerational effects of parental alcohol use on child externalizing disorders, a predictor of health problems over the life course (Micalizzi). CADRE PLs and Pilot Project Leaders (PPLs) will benefit from mentorship by faculty mentors who will provide guidance on research, publication, and grant writing. The Administrative Core will continue to provide organizational structure and state-of-the-art mentoring; administer the Pilot Projects Program; and lead evaluation of all RPs and center components. The Clinical Laboratory Core will continue to provide research infrastructure and resources to the PLs and PPLs, thereby enhancing investigator productivity and promoting research rigor and reproducibility. Our Recruitment, Engagement, and Community Health (REACH) Core will provide direct support for local, face-to-face and digital recruitment, to help CADRE ESIs meet their enrollment and inclusion goals. Through innovative and interdisciplinary research, the CADRE will contribute new knowledge and continue to serve as the nexus and path toward independence for the next generation of scientists.

NIH Research Projects · FY 2024 · 2019-08

Abstract Individuals who have been previously incarcerated have a significantly higher risk of dying from overdose[4]; particularly in the first two weeks after release. More than 4.5 million people is the US are supervised in the community setting and nearly half have a substance use disorder but few receive services. There is a critical need for linkage to medication for opioid use disorder (MOUD) for individuals on community supervision. Providing medication for opioid use disorder (MOUD) to individuals on probation or parole decreases the rate of relapse and recidivism, and increases retention in substance abuse treatment. In 2016, RIDOC introduced the first correctional system-wide MOUD program in the country to initiate a comprehensive program to offer all three FDA approved medications (in all prison or jail settings) to all eligible individuals. As a result of the RIDOC program, we have expanded MOUD linkage to treatment in the community that is associated with a significant drop in statewide overdose deaths post-release. This work is the foundation from which we have built the current proposal. Our proposed research is to rigorously test a systems-change approach for increasing use of MOUD using a randomized type 1 hybrid implementation-effectiveness design in probation and parole sites. We propose a unique network of 7 geographically distinct community supervision (probation and parole) performance sites from Rhode Island, North Carolina, and Pennsylvania. After a 6-month period of baseline for comparison, the Exploration, Preparation, Implementation, Sustainability framework is used to guide system-change through facilitated local change teams consisting of justice and community service providers. A core set of implementation strategies is provided to all sites. The overall objective is to improve linkage to the continuum of evidence-based care for justice-involved individuals. Organizational assessments are timed with EPIS stages. At the end of Implementation, N=680 probation/parolee clients will be randomly assigned to receive peer support specialists vs. no peer support with follow-up at 3, 6 and 12 months. Implementation outcomes include program acceptability, adoption, penetration, sustainability and costs. Client- level effectiveness outcomes include retention, satisfaction, opioid use, opioid overdoses, recidivism, linkage to OUD treatment, and utilization of recovery services. This research team is uniquely poised to evaluate the implementation and impact of MOUD among justice-involved individuals, to answer questions of urgent public health significance, inform implementation science, and improve service delivery.

NIH Research Projects · FY 2025 · 2019-07

ABSTRACT Our training program for Interactionist Cognitive Neuroscience (ICoN) seeks to provide student-focused, interdisciplinary training in computational cognitive neuroscience that integrates multiple levels of computation and analysis with data across e scales and species. Such integration is key to making transformative gains in understanding the human brain and mental health. Prior to launching the ICoN Training Program, we argued that fulfilling this promise requires making direct links between circuit-level computation, often only testable in animal models, and the emergent function of the human system (Badre, Frank and Moore, 2015 Neuron). Bridging these levels does not happen spontaneously but demands a systematic approach that requires a new generation of scientists who can take full advantage of computational theory and data at multiple levels from cellular to systems to cognitive. Traditional neuroscience training relies on an apprenticeship model that limits students to a single lab, and usually, a single level of inquiry. Cross-disciplinary training in this traditional model comes with considerable risk and places an unusual burden on the individual student to forge a path. Thus, we developed a specialized ICoN Training Program that facilitates the broad-based computational and interdisciplinary training necessary to equip neuroscientists to be next generation leaders in the ‘Interactionist’ approach. ICoN program elements are based on two central tenets: 1. Computation is key to translating between levels. Students must be rigorously quantitatively trained and versed in formal theory. They must be skilled in the languages, tools, and approaches of the computational sciences, and fluent in advanced analysis methods necessary for cross-level integration. 2. Next-generation scholars must have expertise at multiple levels. Students must be trained to integrate multiple methods and data sources from animal to human, molecule to mind. They must have the skills (and courage) to pursue ideas to their next most logical step, to be question-driven and not technique-limited. Students must be versed in multiple scientific literatures, cultures, and vocabularies. To achieve these tenets, the ICoN program provides a variety of training opportunities that are tailored to individual student goals through team advising. Building on the success of the initial funding period, program elements include: cross-level research experiences bridging domains such as human cognitive, system, and computational neuroscience; weekly ICoN group meetings, with intensive discussion on merits and challenges of Interactionist science; formal coursework; intensive computational and experimental workshops; and career development training opportunities. The cross-disciplinary training and collaborations ICoN provides will accelerate the pace of discovery in mental health research and ultimate translation to real world impact.

NIH Research Projects · FY 2025 · 2019-04

Project Summary Conventional augmentative and alternative communication (AAC) devices for people with severe speech and motor impairments (SSMI) rely on residual motor function, inherently limiting communication throughput. Commercially available AAC solutions require daily caregiver setup, need frequent recalibration often from a technically savvy caregiver, are often unable to be used in dark lighting conditions, and can encumber or fatigue important remaining physical abilities. Furthermore, for people with progressive motor dysfunction due to amyotrophic lateral sclerosis (ALS), even the most well-designed AAC devices will eventually fail as movements become unreliable. For people with brainstem stroke, ALS, and other disorders causing locked-in syndrome (LIS) or SSMI, brain-computer interfaces (BCIs) hold promise as a method of enabling communication that does not rely upon speech or voluntary movement. In prior NIDCD-supported research, our BrainGate research team provided early proofs of principle of a powerful intracortical brain-computer interface (iBCI) that decodes movement intentions directly from brain activity. This technology has allowed people to control a cursor on a computer screen for communication simply by imagining movements of their own arm. The proposed NIDCD U01 clinical research will further the development and testing of a fully implanted iBCI that could provide robust, intuitive control of industry-grade communication apps for people with LIS or SSMI. By leveraging the ongoing pilot clinical trials of the investigational BrainGate system, we aim to (1) improve the robustness and accuracy of neurally actuated point-and click, in part through the translation of neuronal activity from human premotor and motor cortex, (2) expand the number of input dimensions to tablet computers available via neural activity, allowing intended hand gesture commands to control communication apps on touch-screen tablet computers, and (3) rigorously compare the performance of the investigational BrainGate system to trial participants’ conventional AAC systems with respect to communication competence, information throughput, user preference and outcomes measures. By incorporating the feedback of six individual participants with paralysis, this feasibility trial will optimize a powerful iBCI for communication and will establish the metrics needed for a subsequent pivotal trial of a fully implanted, always-available iBCI communication system for people with SSMI.

NIH Research Projects · FY 2025 · 2018-09

Project Summary In the last thirteen years, analysis of ancient genomes suggests that population admixtures are a dominant feature of human history. Admixture between populations leads to genetic exchange between populations, and this provides an opportunity to introduce new genetic variation much more rapidly than waiting for mutations to occur naturally. Analysis of Neanderthal, Denisovan and ancient modern human genomes suggests that admixture has occurred at different time scales in the past. We are only beginning to understand how genetic variation that is introduced during an admixture event has been evolving in the recipient populations. Evolutionary forces like demographic history and natural selection will also affect the frequency distributions of these mutations in recipient populations. The goal of this research project is to develop statistical methods and computational approaches that can be applied to admixed genomes to investigate how admixture shapes patterns of genetic variation and how it facilitates adaptations. As admixed genomes are mosaics of different ancestries, we can study genetic variation in these genomes to gain insights into the histories of both recipient and donor populations. For example, we can identify genetic variation that help recipient populations adapt to new environments. We will also leverage genetic patterns of admixed genomes to characterize how natural selection acted on genetic variation after very recent admixture events. Finally, with our methods, we can also gain insight into the structure present in the donor populations even if only a handful of genomes exists for these populations. In summary, the methods and the empirical approaches proposed here will be useful to elucidate how different contributions from a complex web of population interactions has affected the evolution of our species.

NIH Research Projects · FY 2026 · 2018-09

With 6.6 billion episodes and 1.5 million deaths annually, diarrheal diseases remain one of the leading causes of death and disability in both children and adults worldwide. In the United States, diarrheal illness accounts for 1.7 million emergency department visits and 70,000 hospitalizations each year in children alone. While the vast majority of diarrheal episodes follow a relatively benign course, approximately 35% of cases in younger children and 5% of cases in older children and adults lead to moderate or severe disease requiring advanced medical management. Appropriate rehydration with either oral or intravenous fluids remains the most important step for treating acute diarrhea. Accurate assessment of dehydration status has been shown to reduce the morbidity and mortality that results from inappropriate rehydration of patients and can also improve the cost-effectiveness of diarrhea management. Yet no validated tools exist for estimating dehydration severity in patients with acute diarrhea across the lifespan. Using artificial intelligence, our prior research derived and internally validated new clinical diagnostic models for assessing dehydration severity both in children under five years of age (DHAKA models) and patients over five years of age (NIRUDAK models) and demonstrated that they were more accurate and reliable than the current World Health Organization guidelines. We then incorporated our new clinical diagnostic models into a simple mobile health application (mHealth) clinical decision support tool (CDST) that can be used by frontline providers to guide management for patients with acute diarrhea. Building upon the success of our prior work, the proposed R01 renewal award research will evaluate the transportability of our novel clinical diagnostic models to a variety of settings worldwide, including the United States, Africa, and South-East Asia. In addition, we will use an implementation science-based approach to better understand the barriers and facilitators to uptake and usage of the mHealth CDST by a variety of different types of healthcare providers in both Tanzania and the United States. Once validated, our new mHealth CDST has the potential to reduce both the morbidity and mortality that occurs as a result of missed diagnoses of dehydration, as well as the adverse events and inappropriate utilization of limited healthcare resources that can result from inaccurate diagnoses of dehydration. This can potentially improve treatment for the hundreds of millions of patients presenting to healthcare facilities worldwide with acute diarrhea each year, including millions of patients in the United States alone.