University Of Rhode Island

NIH Research Projects · FY 2025 · 2024-05

Project Summary/Abstract Adolescence is the developmental period most strongly associated with the initiation and escalation of substance use, making it an ideal time to identify protective factors against substance use. Alcohol and cannabis are among the most used substances in adolescence and their use is associated with negative consequences. Solidifying emotion regulation strategies and healthful behaviors in adolescence may protect against later deleterious substance use outcomes. Yet research on the mechanisms underlying substance use behavior change in adolescents is limited. Consistent with NIDA priorities on prevention targets, there is a need to focus on the developmental trajectory and elucidation of protective mediators (e.g., happiness, pleasurable activities) associated with alcohol and cannabis outcomes (e.g., alcohol use, binge drinking, cannabis use, alcohol-related consequences, cannabis-related consequences) across adolescence. This study addresses a critical gap in the literature by conducting longitudinal mediation analyses with secondary data using a large sample of adolescents from the Happiness and Health study (5U54CA180905). This project is significant in its positive psychological approach of examining positive emotions and pleasurable experiences rather than solely substance reduction, and in filling a research gap on mediators of substance use in adolescents. This project is innovative in its integration of the broaden-and-build theory with behavioral theories of choice by examining how happiness and pleasurable activities are associated. The broaden-and-build theory posits that experiencing happiness may increase one’s personal resources, allowing one to come up with a wider range of novel behavioral activities. These expanded behavioral activities may include novel healthful activities, such as spending time with family or exercising, which are associated with reduced substance use. Behavioral theories of choice suggest that pleasurable activities may substitute and protect against substance use and related consequences. The innovative integration of the broaden-and-build theory and behavioral theories of choice suggests that experiencing happiness may be associated with improved alcohol and cannabis outcomes through the pathway of pleasurable activities. The proposed study will examine whether changes in happiness and changes in pleasurable activities are associated with changes in alcohol and cannabis outcomes (Aim 1), and whether pleasurable activities work as a mechanism to explain the relationship between changes in happiness and changes in alcohol and cannabis outcomes (Aim 2). The goal of this proposal is to provide the Applicant with training experiences that will improve her content area knowledge, analytic skills, grantsmanship and manuscript development, and network, which are vital to flourishing as an independent researcher. The environment at the University of Rhode Island, including data analysis software, grant support, and an excellent mentorship team with expertise in relevant areas, provide the ideal setting for the successful completion of the proposed project.

NIH Research Projects · FY 2025 · 2024-05

Project Summary/Abstract Research targeting substance use and its comorbidities in Native Hawaiian/Pacific Islander (NHPI) communities often focuses on youth participants or aggregates small samples of NHPIs with the data of Asian Americans. This has created a significant gap in the field’s understanding of substance use and suicidal ideation in this underserved population. Further, NHPI advocacy groups cite both substance use and historical trauma as primary targets for research. Therefore, the specific aims of this project are to (1) conduct qualitative focus groups to understand the relationships between substance use, suicidal ideation, and historical trauma in NHPI adults and (2) conduct a subsequent quantitative analysis to develop a model of these associations. This project is significant because we will be building the first model of substance use and suicidal ideation in NHPI adults, a community that has been largely underserved by academic research. This project is innovative because it will utilize a mixed-methods research design with community based participatory research principles, including the formation of a NHPI community advisory board, to inform this model. The proposed study will be completed over the course of two years and two studies; the first is qualitative, the second quantitative. Study 1 will conduct 3–5 focus groups with 4–8 NHPI adults per group (n = 20–30) who will explore the impact of historical trauma on substance use and suicidal ideation using semi-structured interviews that will mirror traditional NHPI talking circles. Study 2 will translate the themes revealed in the qualitative analysis from Study 1 to inform measure selection in a quantitative analysis, with the goal of testing a model of the relationships between historical trauma, substance use, and suicidal ideation in NHPI adults (n = 120–168). Findings will be among the first to conceptualize these relationships in NHPI adults, where research is desperately needed. This project is aligned with NIDA’s 2022-2026 Strategic Plan as it explores the social and contextual factors that manifest and maintain substance use behavior by exploring comorbidities and improving the implementation of evidence-based practice for clinicians who seek to reduce substance use in NHPI communities through the development of the model. Further, this project will provide the Principal Investigator with the grantsmanship, networking, and methodological tools to establish a career serving the needs of NHPI communities. The research environment at University of Rhode Island including office space, technology, and grant support, along with excellent sponsors and consultants with expertise in relevant content areas and mixed methodology research, provide the ideal setting and mentorship to successfully conduct the proposed project. This project will create vital research training opportunities for the applicant’s future career as an independent researcher working within NHPI communities to alleviate health disparities, a role which is necessary for improved health among this population.

NIH Research Projects · FY 2025 · 2024-05

PROJECT SUMMARY/ABSTRACT Adolescents currently engaged in substance use often co-use (e.g., both alcohol and cannabis; AC co-use), yet few have systematically examined how youth AC co-use patterns change over time (e.g., additive or substitution effects) in differing recreational cannabis policy contexts. Particularly as it relates to environmental opportunity and social inequality, factors like socioeconomic status (SES) and may play a critical role. This project will inform prevention intervention strategies, specifically for young people engaged in alcohol use, by examining the intersection of comprehensive socioenvironmental opportunity and state- level cannabis policy, and their associations with adolescent AC co-use transitions. The aims are to identify latent profiles and longitudinal transition patterns of AC co-use, and to examine how AC profiles and transition probabilities are associated with multidimensional SES (mSES) and state-level recreational cannabis law (RCL) in two different policy environments. Disaggregating patterns of AC co-use in young people is essential to informing public health and clinical practice, as each year more states enact RCLs, and on-the-ground providers largely operate without information about how to navigate changes in use patterns among this age group. An exploratory aim will evaluate sociodemographic characteristics in these highly diverse samples (Mage=16.8; 55% Hispanic/Latino; 10.6% sexual and gender minority status). Here, the applicant will maximize data from two of her primary mentor's NIAAA-funded longitudinal R01s of underage youth engaged in alcohol use (N=710) collected across two regions with differing RCLs. The training plan is designed to provide a rich program of training in advanced longitudinal modeling, adolescent development, contemporary issues in addiction, and an initial exploration into how patterns may differ for underrepresented and underserved youth. The proposed project is a natural extension of the applicant’s current program of research, and critically, would provide essential protected research and training time to develop requisite skills and hone expertise to launch a career as an independent NIH-funded scientist. Without the F31 support, the applicant will need to take on teaching obligations in her department, rendering it far more difficult to achieve this same degree of crucial breadth and depth in training, particularly around writing and dissemination efforts. The applicant will be mentored by Dr. Feldstein Ewing (Sponsor, University of Rhode Island; URI), an expert in adolescent addiction and its prevention and treatment. Drs. Manshu Yang (URI) and Tammy Chung (Rutgers University) will also provide training in AC co-use, latent variable modeling, and longitudinal methods. Drs. Feldstein Ewing, Yang, and Chung have an over decade of work successfully collaborating, even while housed at different institutions, supporting a synergistic training environment that will work closely with the applicant to ensure that she meets and achieves all proposed research and training aims.

NIH Research Projects · FY 2026 · 2024-05

Zinc binding metalloproteins and metalloenzymes constitute ::::10% of the vertebrate metalloproteome and are essential for many cellular processes. Due to the critical importance of zinc to vertebrate physiology, zinc deficiency leads to numerous pathologies and is involved in the pathogenesis of many neurological disorders. In fact, zinc is one of the most prevalent metal ions in the brain where it serves important roles in neurogenesis, neuronal migration, and differentiation. Zinc deficiency constitutes a pervasive public health problem considering that approximately half of the world's population suffers from dietary zinc deficiency, now the fifth most important risk factor for mortality in developing countries. Despite the known importance of zinc cofactors to cellular function, the mechanisms by which zinc levels regulate tissue homeostasis remains poorly defined. Cellular zinc homeostasis is modulated by a specialized family of zinc trafficking proteins called metallochaperones. It is speculated that metallochaperones facilitate the hierarchical delivery of metals to their client proteins thereby regulating cellular and organismal homeostasis. We have identified the first vertebrate zinc metallochaperone, which we named Zinc regulated GTPase metalloprotein activator 1 (ZNG1). We demonstrated that vertebrate ZNG 1 binds to and transfers zinc to metalloproteins to promote their enzymatic activity. Further, we identified numerous candidate ZNG1 client zinc metalloproteins that are associated with neurogenesis and brain function, including the zinc-finger transcription factors, ZFHX3 and ZFHX4. Collectively these findings suggest that ZNG1 is a regulator of brain development and function via interactions with specific zinc-requiring transcription factors, which will be tested by experiments proposed in this application. This work is expected to determine the impact of ZNG1 mediated zinc transfer on transcription factor activity in the brain (Aim 1) while defining the ZNG1-dependent ZFHX3 and ZFHX4 signaling pathways important for neuronal development, neuronal response to stress, and behavior (Aim 2). Completion of these aims has the potential to identify ZNG1 as a factor that modulates signaling in the brain in a manner that is dependent upon zinc bioavailability. These findings will shed light on the in vivo role of the first discovered zinc metallochaperone and will vertically advance our understanding of zinc homeostasis and contributions to the progression of human neurological disorders.

NIH Research Projects · FY 2026 · 2024-05

PROJECT SUMMARY/ABSTRACT More than four million U.S. residents seek treatment for substance use disorder (SUD) each year. Community reintegration following residential SUD treatment is an especially vulnerable time, withmost people who return to use following residential SUD treatment doing so in the 30 days immediately following discharge. D during information aily monitoring methods such as ecological momentary assessment (EMA) can identify higher risk periods community reintegration as well as clarify time-sensitive proximal predictors of return to use. This can help tailor the type, amount, and timing of interventions to prevent and/or delay return to use. of substance use afterEscape from and avoidance of negative affect are leading motives for re-initiation periods of abstinence. These data underscore affect dysregulation—a widely regarded transdiagnostic risk factor—as a key target for interventions to be delivered during community reintegration of SUD inpatients. Yet, knowledge/methodological/population gaps limit our understanding of affect dysregulation in SUD. (1) Virtually all research on return to use during community reintegration has used cross-sectional or traditional longitudinal designs. Pinpointing real-time proximal predictors of return to use is necessary to inform interventions that can be delivered when dysregulation and use of Studies in this area have exclusively focused on dysregulation stemming from negative affect. Positive dysregulation SUD individuals are most in need or may most benefit from them. (2) Our understanding of affect in risk for return to use i s limited. Intensive longitudina l data methods (e.g., EMA) capture within- between-person affect dynamics, which may improve detection of individuals a greatest risk for return to as well as pinpoint risk states to intervene on in momentary interventions. They also allow for examination potential clinical targets for momentary interventions, such as engagement in affect regulation strategies. 3) affec may also increase risk for return to use during community reintegration. (4) Individuals in early recovery exhibit autonomic dysfunction; thus, HRV may be an important bio-signal for detecting t ( t risk for return to use during community reintegration. (5) Community reintegration is a period of unique/intense stress for people with SUD. Research during this period is severely limited. Studies must examine whether findings to inform interventions for this population will be useful for most people who experience community reintegration. Addressing these critical gaps, we propose integration of subjective data from EMA with physiology from the Empatica Embrace2, collected in individuals' (N=300) natural settings during the 30 days after residential SUD treatment. Aim 1 identifies features of negative and positive affect dynamics that predict return to use outcomes during community reintegration of SUD inpatients. Aim 2 tests theutility of physiology from a wearablebiosensor in detecting return to use. Aim 3assesses the extent to which features of affect dynamics and physiology proximally predict return to use across diverse demographic and clinical groups. Findings will inform evidence-based tools to prevent/delay return to use during community reintegration.

NIH Research Projects · FY 2026 · 2024-03

Abstract The goal of this FOA is “to improve our understanding of how vaccines against infectious agents lead to durable protective immunity.” This project seeks to address this objective through a detailed characterization of immune responses in the early phase post-vaccination to identify components that distinguish durable from non-durable responses to vaccination with a live attenuated vaccine against dengue virus (DENV). To date, a single dengue vaccine (CYD-TDV) has reached licensure and others have shown promising efficacy data, but there remain important gaps in the safety and efficacy of these vaccines, particularly around the issue of the durability of protective immunity. This project leverages blood samples available from dengue vaccine trials, in particular a longitudinal study of participants from a phase III trial of CYD-TDV that has been ongoing since 2011. The project addresses the overall hypothesis that functional, transcriptomic, and epigenetic profiles of DENV-specific T and B lymphocytes early post-vaccination predict the establishment of long-lasting DENV-specific serologic immunity through the following Specific Aims: 1) Identify T and B cell functional responses to DENV associated with the long-term persistence of binding and neutralizing antibodies after receipt of CYD-TDV; 2) Identify gene expression and epigenetic profile(s) in DENV-specific T and B lymphocytes associated with the persistence of antibodies after receipt of CYD-TDV; and 3) Validate the immunological signature of durable antibody responses in recipients of CYD-TDV and compare this signature to other dengue vaccines and to natural and experimental DENV infection.

NIH Research Projects · FY 2026 · 2024-03

As an organ responsible for nutritional and energy metabolism, liver plays important roles in maintaining normal pregnancy. Liver diseases during pregnancy is relatively poorly studied and represents one of the gaps for liver research. Approximately 3-5% of pregnant women are affected by liver diseases during pregnancy. When severe, those liver diseases are associated with significant morbidity and mortality for both mother and infant. Intrahepatic cholestasis of pregnancy (ICP) is the most common liver disease unique to pregnancy while non- alcoholic fatty liver disease (NAFLD) is the most prevalent primary liver disease occurring during pregnancy. Recent clinical and our preliminary studies have revealed that women with ICP and NAFLD have an increased risk for developing pregnancy complications of preterm birth (PTB) and stillbirth. However, the etiological link and underlying mechanisms remain to be determined. Currently there are limited intervention options to prevent or reduce pregnancy complications of PTB and stillbirth for pregnant women with liver diseases. In our recent and preliminary study with 36,755 pregnant women, we found that serum total bile acid (sTBA) levels directly correlate with the pregnancy complications of PTB and stillbirth and both ICP and NAFLD patients had markedly elevated sTBA levels. Bile acid cholic acid (CA) dose-dependently induced pregnancy complications of PTB and stillbirth and restoring bile acid homeostasis markedly reduced PTB and dramatically improved newborn survival rates. So, it was concluded that elevated bile acids are the etiological linker between liver diseases ICP and NAFLD and pregnancy complications of PTB and stillbirth. The overall objective of this proposal is to understand the mechanistic linkages among ICP, NAFLD, bile acids and pregnancy complications as well as the underlying mechanisms. The central hypothesis, built on our extensive preliminary results, is that elevated bile acids in pregnant women with liver disorders such as ICP and NAFLD induce pregnancy complications of PTB and stillbirth through activating the Takeda G protein-coupled receptor 5 (TGR5) signaling pathway, and restoring bile acid homeostasis by drugs will reduce or prevent bile acids-mediated pregnancy complications of PTB and stillbirth. Three specific aims will be conducted. Specific Aim 1 is to investigate the roles of TGR5 signaling pathway in the induction of pregnancy complications by elevated bile acids. Specific Aim 2 is to investigate increased risk and underlying mechanisms for NAFLD subjects to develop ICP and its associated pregnancy complications. Specific Aim 3 is to investigate the therapeutic potentials of four types of FDA-approved drugs that modulate bile acid homeostasis on pregnancy complications. The experiments proposed are built on our extensive, robust and novel preliminary findings, animal models established as well as our long- standing experience in studying bile acid regulation and associated liver diseases. our team is thus uniquely poised to investigate the underlying mechanisms and develop potential therapies for liver diseases-associated and bile acids-induced pregnancy complications of PTB and stillbirth.

NIH Research Projects · FY 2025 · 2024-02

Apolipoprotein E4 (ApoE4) is recognized as a strong risk factor for the development of late-onset Alzheimer’s disease (LOAD). To better understand the impact of ApoE genotype on the emergence and progression of LOAD and to effectively evaluate therapeutic interventions for this condition appropriate experimental animal models are needed. To date, most animal model studies designed to address the contributions of ApoE genotype to AD have largely centered around the use of transgenic mice. Typically, most transgenic lines for AD rely on highly artificial over-expression of transgenes and largely incorporate one or more early-onset FAD mutations in AbPP or presenilin. Moreover, transgenic animals are prone to developmental and insertional effects on the host genome and are susceptible to loss of transgene expression and genetic drift in subsequent generations. In addition to these caveats, another major shortcoming of transgenic lines is that any AD pathology that develops typically is from a ‘sole source’ of transgene expression. In most cases, the ‘sole source’ of transgenic proteins results from strong over-expression in neuronal cells. With regards to AD, it is known that besides neurons neighboring astrocytes and microglia can express AbPP, produce Ab peptides and participate in AD pathogenesis. In addition, vascular cell types including endothelial cells, smooth muscle cells and pericytes all express AbPP, produce Ab peptides and reside at the site of CAA, a common vascular co-morbidity of LOAD. Since the complexity of the cellular origins of Ab in AD are not captured in ‘sole source’ transgenic models they fail to reveal the true pathogenesis of this disorder and an accurate understanding of the impact of ApoE. This glaring shortcoming has prompted the quest to generate better experimental animal models for LOAD that more fully capture the pathogenesis of this condition and more accurately reflect human disease. The overall goal of this exploratory proposal is to study the impact of ApoE genotype on the emergence and progression of LOAD pathologies and cognitive impairment using a novel gene-edited rat model (CrHuAb) used to generate bigenic CrHuAb/hApoE3 and CrHuAb/hApoE4 rats. These novel and timely rats will provide superior, state-of-the-art preclinical models that will more realistically reflect the true pathogenesis of LOAD that develops in patients compared to transgenic mice commonly used in the field.

NIH Research Projects · FY 2026 · 2024-01

PROJECT SUMMARY/ABSTRACT Laband real-world validation of a system for monitoring ingestive behavior Project Summary: Population-based and short-term laboratory findings demonstrate eating behaviors linked to overeating and excess body weight can be modified to reduce energy intake and enhance satiety. These findings suggest that slowing specific ingestive behaviors (IB; bites, chews, oral processing) may thus be effective for healthy body weight management. However, no accurate automated methodology exists to measure these combined IB outside laboratories, in people's free-living, real-world settings. Thus, the central goal of the proposed project is to validate and test a wearable device assembly pairing two validated instruments that can provide these measurements with good accuracy and low participant burden. One is a wrist-worn bite counter, which detects the wrist-roll motion associated with placing food in the mouth, tracking bite number and bites per minute for each eating episode. The other is a discreet chewing sensor adhered to the skin over the condyle bone, to detect chewing frequency and duration, as well as oral processing. Combined, these sensors can provide data on chew-to-bite ratio (which has implications in energy intake and satiety) and can capture overall eating episodes and IB with more precision than a single device alone. The project includes laboratory aims, supported by two studies for device assembly validation across a range of foods, beverages, utensils and eating styles, along with real-world aims, supported by three studies that progress from semi-controlled to true free-living settings in people's everyday lives. These will include restaurants, cafeterias, work, school, and home lives. Device assembly data will be compared to multiple established ground truth measures such as video, the universal eating monitor, observation, and self-reports. Participants will represent a broad range of body mass index, adult ages, genders, and race/ethnicity, with over-representation from LatinX communities, who experience higher incidence of obesity and associated health conditions. Our multi-disciplinary team includes a nutritionist specializing in eating behaviors associated with obesity, a psychologist specializing in behavior monitoring through wearable technologies and longitudinal analysis, and a computer engineer specializing in wearable devices to detect IB. Scientific automated impacts f this project lie in developing a tool to enable long-term free-living data collection on behaviors vital for weight management. o Health impacts lie in potentially equipping people with a passive self-monitoring tool for improving eating behaviors and diet, with minimal participant burden, yet optimizing impact through targeting key IB. Thus, promising multi-disciplinary laboratory findings will be moved to free-living settings with a user-friendly non-invasive digital device assembly, allowing for self-monitoring. The management ultimate goal is t o facilitate evidence-based personalized weight programs leveraging real-world modification of eating behavior that are scalable to large populations.

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY Gender minority young adults (GMYA; 18-25 years old), who have a gender that is different than their assigned sex at birth, have 3-4 times greater risk of depression and anxiety than those whose gender is congruent with their assigned sex at birth (i.e., cisgender). The accumulation of gender minority stress (GM stress), stress due to stigma related to one’s gender identity and/or expression is one proposed cause of this disparity. GM stress can become internalized, and feelings of shame and repetitive thoughts (rumination) can make mental health worse. Despite the known associations between GM stress, mental health, shame and rumination, few interventions exist to address GM stress in GMYA. Self-compassion, treating oneself with kindness instead of self-criticism in painful or difficult times, has been identified as a useful strategy to alleviate GM stress among GM people, and is a trait that can be strengthened. Mindful self-compassion (MSC), an 8-week intervention, combining mindfulness and self-compassion skills is one way to increase self-compassion. However, MSC has not yet been tested with GYMA and it is not known whether gender dysphoria (distress due to body not matching identity) could make it difficult to fully engage with body-based practices. My long-term research goal is to improve the mental health and wellbeing of GMYA by identifying, and intervening on, modifiable risk and protective factors using community-engaged, trauma-informed interventions. The current project builds upon my prior cross-sectional research on GMYA’ mental health by exploring the feasibility of an existing intervention with a new population. The objective for this proposal is to obtain training and certification as an MSC teacher as well as additional skills in trauma-informed mindfulness and embodied practice, intervention science (implementation, evaluation, and adaptation), advanced data analysis, and community engaged research. With guidance from my mentors, I will pursue the following specific aims: 1) evaluate the feasibility of an 8-week MSC intervention and data collection plan (pre-, post-, 3-month follow-up) with 5 consecutive groups of GMYA, 2) evaluate the usability of MSC intervention activities by GMYA and determine whether MSC activities need to be tailored for GMYA, and 3) explore GMYA’s pre- and post- intervention and 3-month follow-up data to examine whether shame, rumination, self-compassion, depression, and anxiety are sensitive to change. The goals of this project are consistent with NCCIH’s interest in mind-body interventions to help reduce stress, anxiety, and depression among sexual and gender minority populations (NOT-MD-22-012), objectives to advance science on health promotion, resilience, and symptom management (Obj. 3), and commitment to research with diverse populations and a diverse scientific workforce (Obj. 4). Under the guidance of expert mentors in the population, methods, approaches, and with a strong history of research funding- the proposed project will provide me with the necessary skills to independently conduct rigorous complementary and integrative health research to improve mental health and wellbeing among GMYA.

NIH Research Projects · FY 2024 · 2023-09

Project Summary One in five undergraduate women experience sexual assault (SA) during their college career, most commonly under the influence of acute alcohol intoxication. One critical mechanism through which intoxication increases risk for SA is a reduced ability to perceive SA risk cues due, in part, to the diminished attentional capacity that occurs during intoxication. While laboratory studies have consistently observed greater reductions in SA risk perception among intoxicated versus non-intoxicated women, the potential influence of state emotion on SA risk perception during acute alcohol intoxication remains unexplored. This is a critical gap given theoretical evidence to suggest that SA risk perception may be influenced by both negative and positive state emotions. Accordingly, the proposed study will assess the roles of negative and positive emotion states and acute alcohol intoxication on SA risk perception (Aim 1) as well as identify subjective (e.g., self-report) and objective (e.g., electrodermal response [EDA], heart rate variability [HRV]) indices of emotion states that underlie changes in SA risk perception during acute alcohol intoxication (Aim 2). In a single experimental session, participants (i.e., undergraduate women aged 21 and older who use alcohol) will be randomly assigned to one of two alcohol conditions (i.e., alcohol or no-alcohol) and one of three idiographic emotion induction conditions (i.e., positive, negative, or neutral) prior to completing a SA risk perception task. Participants assigned to the acute alcohol intoxication condition will be administered alcohol to achieve a target BAC of .08 (i.e., a dose of alcohol equivalent to approximately four standard alcohol drinks). Positive, negative, or neutral emotion state will be achieved using a validated idiographic emotion induction task. SA risk perception will be measured using a hypothetical SA vignette designed to assess instances of discomfort and decision of when to leave the hypothetical scenario. Subjective intensity and regulation of state emotion will be assessed via self-report measures administered pre- and post- emotion induction as well as post-SA risk perception task. EDA and HRV will capture objective arousal and regulation of state emotion, respectively, and will be measured continuously during the experimental session with the BIOPAC MP36. This study is the first to utilize a laboratory-based, multi-method approach to explicate the roles of state emotion and acute alcohol intoxication on SA risk perception. In alignment with the NIAAA strategic plan, findings will help develop and improve strategies to reduce and prevent alcohol-related harm, such as SA among undergraduate women. Additionally, the proposed project would provide the Applicant with training that will inform her future research on the intersection of SA and alcohol, including via the development of skills necessary for conducting sophisticated experimental paradigms relevant to the study of state emotions (e.g., use of biomarkers), acute effects of alcohol (e.g., alcohol administration), and SA risk perception (e.g., vignette methodology). 2

NIH Research Projects · FY 2025 · 2023-08

Project Summary: Serotonin based therapeutics in cerebral palsy Cerebral palsy (CP) is a relatively common nonprogressive disorder causing lifelong motor dysfunction. The most prevalent type, spastic cerebral palsy, is characterized by muscle hypertonia, weakness, hyperreflexia, less voluntary (and more involuntary) activation of motor units, thinning of the corticospinal tract, and decreased numbers of motor units. While weakness and hypertonia in muscles have been well documented in spastic cerebral palsy, the etiopathogenesis is almost completely unknown. Previous work and our preliminary data from preclinical models of CP show that motoneurons (MNs) show excessive activity after perinatal injury, particularly in response to serotonin (5HT). This is likely causing or contributing to hypertonia since blocking 5HT receptors can alleviate hypertonia. During development, spontaneous neural activity is largely responsible for establishing connectivity within spinal circuits and between spinal MNs and developing muscles and establishing numbers of MNs that survive past natural developmental cell death. This proposal focuses on blockade of spinal 5HT receptors at a critical developmental time point in order to restore normal MN activity / motor unit function, and alleviate weakness, hypertonia, and hyperreflexia. In this study we will utilize a larger animal model of CP (prenatal hypoxia-ischemia [HI] at 70-80% gestation in rabbits), which shows robust motor dysfunction and has recently been demonstrated to have clinical features of CP including thinning of CST and cortical damage, hyperreflexia, muscle pathology, and reduced numbers of MNs. Aim 1: Identify postnatal milestones in motor units following prenatal HI injury. From birth to 31 days of age in rabbit kits of both sexes, we will quantify aberrant development of motor units, specifically 1) motor behavior in awake kits, including joint torque, 2) in vivo recording of motoneuron / motor unit firing patterns, motor unit contraction force, and H reflex and 3) anatomical development of motor units. Significance: Timing of treatment (Aim 3) will be delivered motor unit maturation, either perinatally or postnatally. Aim 2: Identify 5HT receptor(s) mediating hypertonia. In newborn rabbit kits of both sexes (sham and HI), we will assess receptor pharmacology and dose dependency in vitro and in vivo using a variety 5HT receptor agonists and antagonists. Significance: Findings will guide choice of drug treatment in Aim 3. Aim 3: Evaluate treatment with a 5HT antagonist. We will compare effects of perinatal and postnatal treatment with a serotonergic antagonist and agonist on sham and HI kits based on results of Aim 2. Treatment coincides with maturation of motor units. We will examine the outcome in kits as described in Aim 1. Significance: This aim provides a preclinical evaluation of novel therapeutic for reduction of spasticity in CP. We will use the rabbit model of CP to evaluate potential therapies to reduce spasticity after prenatal injury. Several FDA-approved serotonergic drugs could be investigated to improve outcomes in kids at risk of CP.

NIH Research Projects · FY 2025 · 2023-07

PROJECT SUMMARY/ABSTRACT Life-long education and learning in science, technology, engineering, and math (STEM) is necessary for society at large to adapt to a 21st century world and beyond. This is especially true at the high school level, where students begin to translate the imagination, discovery, and curiosity of middle school science to higher-level science and analysis, which will then advance further when university studies begin. Enhancing STEM literacy requires that science, technology, engineering, and math training be accessible and engaging to high school studies, well before university studies even begin. Faculty in the College of Pharmacy at the University of Rhode Island train upper-division undergraduate students in course-based undergraduate research experiences or CUREs in medicinal chemistry. Course participants become more than just learners; they become motivated researchers involved in a genuine scientific effort designed to enable future biomedical discoveries. One deliverable that students create during their medicinal chemistry course is a plant extract library from specimens in the Heber W. Youngken Jr. Medicinal Garden. This library is named PRISM - the Principal Rhode Island Secondary Metabolite library. We propose to extend the concept of a medicinal chemistry CURE and authentic research experiences to the high school level (9-12 grades) by developing HERBAL: Hands-on Education and Research for Biomedical and Analytical Learning. HERBAL will pair research in the laboratory with game-based online classroom modules to teach theory and methods of medicinal plant and herbal product analysis during the academic year. Summer sessions will allow students in the HERBAL program to analyze samples they themselves have generated on cutting-edge instrumentation available in the University of Rhode Island’s teaching laboratories. Additionally, we will focus on the beneficial wellness aspects of herbals and their integrated role in our biomedicine along with artistic and creative opportunities connecting medicinal plant research to drawing and illustration. The HERBAL program will consist of 1) teacher training workshops to educate instructors on how to deliver the HERBAL academic year program. 2) Teacher training will be followed by an academic laboratory course for students with game-based learning modules to train students in theory and application. 3) Following completion of the academic year, students will attend a summer course in chromatography, mass spectrometry, and informatics analysis. This summer course will be complemented with mentorship, career enhancement activities, guest speakers on herbal medicine, and artistic and wellness events. HERBAL’s focus on curricular and method development activities augmented with interactive digital-media based learning modules will shift the paradigm in how these students traditionally learn science, which will increase student interest in STEM topics and enhance their STEM identity.

NIH Research Projects · FY 2026 · 2023-06

Project Summary/Abstract The proposed K01 Mentored Research Scientist Development Award will prepare Manshu Yang, Ph.D. to become an independent researcher in developing cutting-edge and practical statistical methodology to address the timely issue of missing data in drug use and addiction (DUA) research. Dr. Yang is currently an Assistant Professor of Quantitative Health Psychology at the University of Rhode Island. The outlined proposal builds upon her training and research experience in statistics and psychology and will facilitate her path to become a scholar dedicated to bridging state-of-the-art methodologies and substantive theory to advance knowledge of DUA etiology and intervention strategies. DUA has a myriad of deleterious impacts and continues to raise public health concerns in the US. In the past two decades, ecological momentary assessment (EMA) has been increasingly used to help researchers understand the influence of psychosocial and contextual factors on substance use in the real world and nearly in real time, so that more efficacious interventions can be developed accordingly. However, along with the opportunity of using EMA comes a significant methodological challenge: missing responses are inevitable, often substantial, and not properly handled in data analysis, hence significantly increasing researchers’ risks of reaching incorrect conclusions and developing ineffective or even unsafe interventions. Current methods cannot address all the unique methodological challenges in DUA EMA studies due to their complex missing data patterns and untestable missing data assumptions. On the other hand, EMA brings a unique opportunity to address these challenges by re-prompting participants shortly after they missed an EMA survey to retrieve their data. Such later-retrieved data are readily available from existing data (e.g., morning reports capturing missed DUA consequences in the prior day) or can be easily added to an automated EMA system without altering EMA schedule. The outlined proposal includes a comprehensive mentorship and didactic plan to support Dr. Yang’s career development and advance her knowledge and skills in DUA etiology/intervention, EMA design, data management, and analysis, Bayesian missing data analysis, and statistical programming. Specifically, the aims of the proposed research study are (1) to use all available data (initially observed and later retrieved) to characterize missing data mechanisms in DUA EMA, (2) to develop a novel Bayesian method for handling missing data and making valid inference on DUA etiology, (3) to develop a Bayesian sensitivity analysis method to test the robustness of findings to possible departures from missing data assumptions. The proposed study will investigate missing data issues and develop analysis methods using empirical EMA datasets from three NIDA-funded projects and computer- simulated data in a cost-effective way. Statistical methods developed from the study will greatly help researchers elucidate the real-world mechanisms of DUA and develop tailored, effective interventions.

NIH Research Projects · FY 2026 · 2023-05

Title: Development of personalized healthy food incentives to improve diet and cardiovascular risk ABSTRACT It is imperative to address the complex factors that drive food decisions and promote unhealthy dietary patterns. This mentored career award will support a rigorous training and research plan that will apply mixed methods to promote healthier grocery purchases and improve dietary intake and cardiovascular (CV) health. Through strong mentorship and training opportunities, I will adapt and test the novel automated machine- learning based Smart Cart 2.0 platform to deliver personalized recommendations and incentives for healthier grocery purchases among Rhode Island adults with CV risk factors (i.e., Body Mass Index (BMI) > 30 kg/m2 and/or hypertension). To date, interdisciplinary research from my Big Data and Eating Decisions lab has focused on investigating determinants of food choice and diet quality in large population cohorts and using those insights to develop dietary interventions. I previously developed and pilot tested a semi-automated personalized healthy food incentive platform using decision tree logic and found that it significantly improved grocery purchase quality among healthy adults in the 9-month randomized controlled Smart Cart Study. The proposed project extends this research by using novel applications of grocery sales data to adapt and evaluate the automated `Smart Cart 2.0' platform to encourage healthier food purchases and dietary quality. To adapt and scale this platform to adults at high CV risk, it is essential to understand its's feasibility, acceptability, and preliminary effectiveness to facilitate adoption of a healthier diet among adults with CV risk factors. This project also advances methodology to leverage technology and machine learning to automatically evaluate sales data and deliver personalized dietary recommendations in real time. The proposed research will use the Obesity- Related Behavioral Intervention Trials (ORBIT) framework to determine whether the Smart Cart 2.0 platform adapted and tested with input from adults with CV risk factors promotes a clinically significant change in diet quality and CV risk factors. In Aim 1, I will evaluate how well the Smart Cart 2.0 content and function meet the needs of adults at CV risk using focus groups and surveys. In Aim 2, I will conduct a 1-week 3-arm mock shopping trial in a simulated online grocery store to see how much the platform affects willingness to purchase (WTP) recommended foods relative to control using a discrete choice task comparing a) personalized recommendations b) personalized recommendations plus incentives to c) generic education and incentives (control). In Aim 3, I will conduct a pilot 6-month randomized controlled trial to test the acceptability, feasibility, and preliminary effectiveness of the Smart Cart 2.0 platform for improving real-world dietary behaviors, diet quality, BMI, and blood pressure. Results of this project will provide critical pilot data to support a larger randomized controlled trial. The training plan and collaborations established through this award will position me to pioneer a policy-relevant translational research program focused on promoting healthier dietary patterns and CV health.

NIH Research Projects · FY 2026 · 2023-05

PROJECT SUMMARY The University of Rhode Island proposes to establish the URI ESTEEMED program to provide a diverse cohort of students from underrepresented backgrounds with the skills and resources necessary to pursue advanced education and degree programs in bioengineering and related disciplines. The goals of URI ESTEEMED program are (1) to develop a cohort of scholars from underrepresented backgrounds who embody critical thinking, engineering design, and fundamental research skills that enable them to develop an early scientific inquiry and research mindset, and (2) to support the development of Scholars’ STEM identity and self-efficacy through self-exploration, faculty and near-peer mentoring, academic and professional development advising, academic support and preparation, and positive research experiences. Scholars selected for URI ESTEEMED will participate in the program through their first two years of college, which involves intentionally designed activities, including a summer bridge program, academic year training and research activities, early exposure to biomedical research, and strong mentoring by faculty and peers. Participants will advance through increasingly sophisticated activities to provide them with a chance to engage in mentored bioengineering research, develop and hone technical skills, and fully realize their scientific identity. Together with numerous community-building activities, this progressive program will instill students with a sense of personal belonging and engagement within the STEM community and promote participation towards advanced degree programs. We hypothesize that the development of scholar identity and self-efficacy will result in improved academic and research performance and deeper engagement with scientific fundamentals. The PI of URI ESTEEMED – a tenured female professor in engineering with strong leadership and training skills – will oversee program design and implementation with support from a professor in engineering (Co-I) who has extensive experience in the LGBTQ+ community and curriculum development. In achieving the URI ESTEEMED goals, it is anticipated that 100% of ESTEEMED Scholars will be prepared to enter an advanced honors program, at least 90% will enroll in an advanced program after their sophomore year, and 90% of scholars will self-identify as a bioengineering or biomedical scientist. Overall, through the URI ESTEEMED program, we will create a robust and inclusive environment to support underrepresented students early in their academic careers, who possess the technical and soft skills necessary to excel in advanced research programs and ultimately pursue Ph.D. or M.D./Ph.D. degrees.

NIH Research Projects · FY 2026 · 2023-04

PROJECT SUMMARY Chronic inflammation and persistent infection conditions have long been associated with increased risk of cancer. Growing evidence suggests that cancer-associated inflammatory processes, such as lipid peroxidation, cause genomic instability that can be linked to the development of carcinogenesis. Reactive species from lipid peroxidation are known to damage DNA and form etheno-type adducts. Previously, four etheno DNA adducts have been reported: 1,N6-ethenoadenine (εA), 3,N4-ethenocytosine (εC), 1,N2-ethenoguanine (1,N2-εG), and N2,3-ethenoguanine (N2,3-εG). These etheno lesions are also generated by metabolites of the human carcinogen vinyl chloride. Recently, a new etheno adduct, 3,N4-etheno-5-methylcytosine (ε5mC), was identified. It bears the etheno damage on 5-methylcytosine, an important epigenetic marker in humans. Thus far, no information on the repair and mutagenicity of ε5mC has been reported. Replication of the etheno lesions is known to cause mutations and may constitute a critical step in the pathway leading to neoplastic transformation. Importantly for cells, DNA repair pathways are the guardians of genomic integrity and function to return damaged DNA to its canonical state. This research project focuses on two key repair pathways: base excision repair (BER) and direct reversal repair (DRR). Most of the experiments that give rise to our current understanding of BER and DRR were conducted using DNA oligomers. There is a fundamental gap in knowledge of how repair occurs in the context of chromatin, where eukaryotic DNA is compacted in a complex hierarchy of DNA-protein interactions. At the most fundamental level of chromatin organization, the nucleosome core particle (NCP) is the basic packaging unit that is comprised of ds-DNA wrapped around a histone protein core. The overarching goal of the proposed research is to understand how DNA sequence context and the packaging of DNA into chromatin influence repair of the etheno adductome. The central hypothesis of this proposal is that BER and DRR enzymes repair etheno lesions with different efficiencies, and these distinctive repair profiles are the result of 1) sequence context of the lesion and interactions with the enzyme and 2) modulation of repair by the protein component of chromatin, the histones. Guided by this novel hypothesis, strong preliminary data, and innovative techniques, the proposal investigates three aims that: (1) define the sequence context effects (by considering the 5’ and 3’ neighboring bases) of BER and DRR enzymes in unpackaged DNA oligomers; (2) characterize the repair profiles of the five etheno adducts in NCPs; and (3) determine the extent to which tailless and variant histone proteins provide a mechanism of modulating repair in chromatin. The proposed research is significant because it will reveal key mechanisms and critical differences that influence repair of the etheno adductome and how cells minimize the harmful consequences of these lesions. The results obtained in this work will explain in vivo observations of alkylation damage profiles and contribute to our understanding of mutational hotspots and mutational signatures. Therefore, the research has considerable translational potential to enhance our understanding of DNA repair and the results can assist in the development of future therapeutic treatments that improve cellular defenses against genomic instability.

NIH Research Projects · FY 2025 · 2022-09

Borrelia burgdorferi (Bb), transmitted via the blacklegged tick (Ixodes scapularis), is of growing public health importance as the etiologic agent of the most prevalent vector-borne disease in North America, Lyme disease (LD), which continues to increase in incidence. Although often framed as a pathogen in the Enzootic Transmission Cycle (ETC), there is no evidence that Bb elicits disease in either the reservoir or tick hosts between which it cycles. Here, we conceptualize Bb-infection in I. scapularis ticks as a facultative mutualism that is influenced by microbial dynamics within ticks and the broader context of ecological interactions between ticks and vertebrate hosts comprising the ETC. Ixodes scapularis is a valuable candidate to study networks of ecological interactions, as its microbiome encompasses the spectrum of relationships in which microbes can engage with arthropod hosts from transitory, commensal environmentally-acquired microbes to heritable obligate, intracellular endosymbionts, the most predominant of which is Rickettsia buchneri (Rb). Focusing on interactions hypothesized to influence the Bb-ETC, the proposed study will characterize Bb colonization in ticks, evaluating changes in Bb abundance and gene expression as a function of the presence of the putative nutritional endosymbiont Rb and the tick microbiome as characterized by 1) the relative abundance of bacterial taxa (16S ribosomal RNA) and 2) manipulated, categorical microbiome assemblages (i.e., natural-field collected ticks; artificial-lab reared; and disrupted-lab reared in sterile-containers (SA1). Bb effects on tick life-history traits, survival, metabolism and behavior and associated gene expression (of Bb and tick) will be measured, estimating the benefits/costs of Bb-tick associations, and testing potential mechanisms (SA2). Finally, the cumulative impacts of within-ticks, tick-microbe, and tick-microbiome interactions (Bb-Rb interactions and categorical assemblages) will be estimated and evaluated for the Bb-ETC using two modeling frameworks. An agent based model will focus on microbe-mediated differences in tick bloodmeal engorgement, development, survival, behavior, and fecundity (SA3.1). A compartmental model of Bb-ETC dynamics over a broader time scale will also consider seasonality across multiple cycles. Models, developed in parallel with and informed by field and lab experiments and empirical data will be leveraged to develop a formal tick vectorial capacity definition inclusive of important components and effects of the tick microbiome (SA3.2). These results then will be leveraged to improve understanding of Bb-ETC and prediction of LD risk indicators.

NIH Research Projects · FY 2026 · 2022-09

Project Summary/Abstract Alzheimer’s disease (AD) is a gradually progressive neurodegenerative disorder that results in total cognitive and functional loss. To date, disease-modifying therapeutics and secondary prevention efforts have proven ineffective in combating this public health burden, which impacts over 5.8 million individuals, and is the 6th leading cause of death in the United States. The proposed study addresses the critical need for minimally invasive, cost-efficient, scalable, and accessible AD risk screening biomarkers capable of detecting AD in the earliest pathologic stages (preclinical AD) before clinical symptoms are evident. We target biomarkers in the human retina, a part of the central nervous system (CNS), as they can be visualized non-invasively using standard ophthalmologic techniques and show promise for early AD risk detection and disease monitoring. The Atlas of Retinal Imaging in Alzheimer’s Study (ARIAS) is a longitudinal, observational cohort study to identify sensitive and specific retinal biomarkers of preclinical AD and define their context of use. The objective of the proposed project is to leverage the existing ARIAS infrastructure, adding reference standard brain imaging biomarkers (3T MRI, Ab PET) and novel plasma biomarkers (ptau231, ptau181) to test the central hypothesis that retinal biomarker alterations will predict cerebral biomarker changes and mirror longitudinal cerebral biomarker changes in preclinical AD. Four specific aims will be pursued: (1) identify retinal biomarker differences between preclinical AD participants and cognitively unimpaired (CU) older adults; (2) validate candidate retinal biomarkers cross-sectionally against cerebral biomarkers using Ab PET as a measure of cerebral amyloidosis and MRI as a measure of neurodegeneration; (3) determine the longitudinal relationship between retinal and brain imaging biomarkers, and the ability of baseline retinal biomarkers to predict cognitive and/or brain imaging biomarker changes over 3-year follow-up; and (4) (exploratory) assess the combined sensitivity and specificity of candidate retinal biomarkers with emergent plasma biomarkers in AD risk prediction. Work will be carried out at one existing ARIAS site and two high performing AD research sites. CU participants will complete 5 study visits: screening, baseline, year (Y) 1, Y2, and Y3 follow-up. Brain imaging (MRI and Ab PET) and plasma analysis will occur at baseline and Y3 follow-up. Retinal imaging and cognitive evaluation will occur at baseline and Y1, Y2, and Y3 follow-up. Brain imaging, retinal imaging, cognitive evaluation, and plasma analysis will be supported by four respective cores. Validating retinal biomarkers in preclinical AD is expected to shift focus in AD retinal biomarker development towards systemic, quantitative characterization of retinal risk biomarkers scalable for population-based AD risk screening. Combining plasma biomarkers with sensitive and specific retinal biomarkers could transform AD risk assessment, allowing identification of AD-related changes decades before clinical onset, which may offer the best chance of therapeutic success. Clinical applications include population-based screening for ideal candidates for emerging secondary prevention therapeutics.

NIH Research Projects · FY 2025 · 2022-09

We aim to uncover metabolic and protein signaling pathways contributing to the regional vulnerability of neocortical pyramidal neurons in Alzheimer's disease and to identify novel targets for detection and intervention. We will compare the prefrontal cortex, a neocortical brain area afflicted by neuropathology early in Alzheimer's disease, with the primary visual cortex, a brain area that is relatively spared. We will use mass spectrometric imaging in combination with segmentation analyses, to identify spatial changes of small molecules and proteins in postmortem brain sections prepared from these neocortical areas from donors at various clinical and pathological stages of Alzheimer's disease compared to controls. Then, we will apply multiplexed immunofluorescence imaging on sequential sections from the same specimens, to obtain information on cellular and microenvironment changes in and around vulnerable neocortical neurons during disease progression, correlated with the clinical severity, degree and location of neuropathological changes, and the risk genotype. Further, we will register the data from both imaging techniques to identify metabolic pathways and protein signaling changes at the regional, laminar and cellular level and to locate covariation in molecular and cellular phenotypes contributing to Alzheimer's disease vulnerability. In addition to generating a comprehensive dataset of the cellular and molecular changes at various stages of Alzheimer's disease, these studies will involve the development, validation, and dissemination of novel tools for analysis of large datasets generated using two powerful imaging tools, one that detects hundreds of analytes with the possibility of detecting previously unknown contributors to disease and the other that provides higher resolution with a select set of known markers. In the long term, the data generated from these studies could provide the basis for testing novel disease- modifying treatments by cell-type specific targeting of identified metabolic pathways using experimental models, such as brain organoids to replicate cortical lamination with human neurons or humanized mouse chimeras to model interactions between neurons and non-neuronal cell types.

NIH Research Projects · FY 2025 · 2022-09

PROJECT SUMMARY The proposed Mentored Research Scientist Development Award (K01) will launch Dr. Amy Stamates’ program of research as an independent scientist focusing on the etiology of alcohol problems among young adults. This goal will be achieved through a 5-year parallel research and tailored training plan. Training goals include building expertise in (1) clinical knowledge of alcohol use; (2) executive functioning (EF) and attention- deficit/hyperactivity disorder (ADHD); (3) ecological momentary assessment (EMA); (4) advanced longitudinal data analyses; and (5) grantsmanship. Training goals will be met through a comprehensive training plan involving meetings with Drs. Lynda Stein (expert in alcohol interventions), Lisa Weyandt (expert in ADHD), Kristina Jackson (expert in EMA methods and analyses), and Timothy Wilens (expert in ADHD and substance use disorders); workshops; conferences; coursework; and experiential activities. Skills gained through the training plan will be put into action through a complementary research plan aimed to understand the alcohol- risk process of young adult drinkers with ADHD. Young adults with ADHD are at greater risk for experiencing alcohol problems (e.g., risky sex, driving after drinking) and developing alcohol use disorder (AUD) compared to those without ADHD. However, it is unclear why those with ADHD are at greater risk because research supports that they drink less than or equivalent to their non-ADHD peers. The proposed project will study this discrepancy by utilizing a measurement-burst design pairing laboratory and EMA to examine controlled (EF) and automatic (craving) processes in relation to alcohol use among those with and without ADHD. Participants (stratified by ADHD and gender) will be 141 young adult drinkers who complete three bursts over a one-year period (baseline, 6-months, and 12-months). Each timepoint will include a laboratory session assessing EF followed by 17 days of EMA assessing craving, alcohol use, alcohol problems, context, and social setting. The proposed project has three specific aims: (1) examine the impact of ADHD on EF and alcohol outcomes (craving, alcohol use, and alcohol problems) at baseline; (2) determine within-person changes between EF and alcohol outcomes over one year for those with and without ADHD; (3) identify event-level predictors (context, social setting) that heighten craving, alcohol use, and alcohol problems for those with ADHD. Findings from the proposal will provide preliminary data for a R01 application to be completed by Dr. Stamates during the award period. The proposed research seeks to address knowledge gaps of etiological factors underlying ADHD and AUD, with the ultimate goal to identify opportunities to tailor prevention and intervention approaches for young adults with ADHD. Thus, this proposal is in line with NIAAA’s 2017-2021 Strategic Plan for Research to investigate mechanisms underlying comorbid alcohol and psychiatric disorders. Completion of the K01 will provide Dr. Stamates with the expertise to conduct innovative, high-impact research focusing on the etiology of alcohol-related problems, particularly young adults with ADHD who may be most vulnerable.

NIH Research Projects · FY 2025 · 2021-06

Project Summary/Abstract Women disproportionately experience violence compared to men;21-23 however, violence against women is not distributed randomly. Due, in part, to their stigmatized identity, sexual minority women (SMW) are 2-3 times more likely to face violence than heterosexual women.21, 24-26 Many women use alcohol to cope with the negative sequelae of violence (e.g., PTSD).28 This comorbidity may be exacerbated among SMW given their experiences of psychosocial stressors (i.e., violence and minority stressors such as discrimination).11 Despite the public health necessity of developing targeted alcohol treatment approaches for victimized SMW, current alcohol treatment models do not specify unique stressors and clinical needs of this population. Consistent with the NIAAA’s research priorities,11, 14 the K01 will provide major advances in understanding biopsychosocial mechanisms (e.g., minority stressors, physiological reactivity, PTSD) and moderators (e.g., race/ethnicity) influencing the heterogeneity in hazardous drinking among SMW as well as the role that these core factors play in SMW’s differential need for and response to treatment. The project will include: 1) an epidemiologic assessment that uncovers distinct combinations of psychosocial stressors among SMW, identifies racial/ethnic differences in classes of psychosocial stressors, and determines how these patterns of psychosocial stressors predict comorbid PTSD and hazardous drinking over 11 years (n = 450-600); 2) a lab-based study that advances knowledge of the influence of minority stressors on allostatic load (e.g., salivary cortisol, heart rate, heart rate variability, and skin conductance) among victimized SMW (n = 125); and, 3) a once-daily ecological momentary assessment (EMA) approach over 21 days that determines the role of minority stressors as antecedents to daily fluctuations in PTSD and hazardous drinking using the same sample of SMW from the lab-based study. The proposed training plan in this K01 application will provide essential knowledge and skills that the principal investigator, Jillian R. Scheer, PhD, needs to become an independent, interdisciplinary alcohol scientist. The advanced training acquired by Dr. Scheer via this timely and innovative project will target 3 objectives: (1) rigorous alcohol research methodology and its application to studying determinants of hazardous drinking patterns; (2) physiological measurement of stress reactivity as a tool to assess biological mechanisms underlying the influence of minority stressors on comorbid PTSD and hazardous drinking; and, (3) EMA approaches to assess the proximal effects of minority stressors on daily comorbid PTSD and hazardous drinking among racially diverse SMW. Dr. Scheer will be primarily mentored by John Pachankis, PhD, at Yale University, with additional mentoring from Tonda Hughes, PhD (Columbia University), Rajita Sinha, PhD (Yale University), Tami Sullivan, PhD (Yale University), Joshua Warren, PhD (Yale University), and Robert Pietrzak, PhD, MPH (Yale University). Dr. Scheer’s training through the K01 award will ensure her success as an independent scientist whose work informs public health and clinical efforts to reduce alcohol use among SMW.

NIH Research Projects · FY 2025 · 2021-04

PROJECT SUMMARY A detailed insight into the molecular defects leading to neuronal death in ALS/FTD is still missing, hindering the development of a cure. Defects in the nuclear pore complex (NPC) and nucleocytoplasmic transport (NCT) have been proposed to play a central role in ALS/FTD pathology. An outstanding knowledge gap is what are the mechanisms, consequences, and pathogenic relevance of impaired NCT on neuronal resilience in neurodegenerative diseases and during aging. The objective of this application is to identify at the mechanistic level the novel cellular and molecular pathways that are dysfunctional and cause the failure of the NCT ultimately leading to neurodegeneration. In particular, we will test the hypothesis that the actin cytoskeleton is a main modulator of nuclear stability and NPC function, and that changes to this pathway in ALS/FTD lead to a diminished ability of neurons to cope with stress and physiological stimulation. The specific aims of this proposal are to: 1) Define how actin regulates the function and dysfunction of the NPC. We will perform a systematic and in-depth investigation of the molecular interactions between actin and the NPC using pharmacological and genetic approaches in iPSC-derived neurons carrying the C9ORF72 mutation. 2) Identify the consequences of NCT defects on the nuclear and cytoplasmic proteome in response to cellular stimulation. By combining an “omics” approach with a candidate approach (i.e. CREB pathway), we will analyze changes in the nuclear and cytoplasmic proteome in iPSC-derived neuronal models of ALS/FTD following stimulations, and we will test the potentials of cytoskeleton modulation to rescue such defects. 3) Define how defects in nuclear import affect the transcriptional response to cellular stimulation. We will analyze changes in gene expression and splicing profile in ALS/FTD neurons following cell stimulation by RNA-Seq. Network analysis performed by integrating the results from the transcriptomic and proteomics approaches will identify ALS/FTD relevant altered pathways. Modulation of the cytoskeleton will be used to rescue the identified defects. At the completion of this research, we will have identified the molecular and cellular mechanisms that control the stability and function of the NPC, and the functional consequences that the disruption of NCT has on the resilience of neurons in ALS/FTD. Gaining insights on what pathways upstream and downstream of the NPC are affected in ALS/FTD will greatly expand our understanding of disease pathogenesis and will allow us to identify yet unexplored avenues for therapy in these diseases. Ultimately, we expect that our research will lead to more effective therapeutic strategies that take advantage of the crosstalk between NPC, RNA regulation, and cytoskeleton. This research will have a broad impact on a spectrum of diseases including but not limited to ALS/FTD.

NIH Research Projects · FY 2025 · 2017-09

Quinlan, Katharina Project Summary This project pursues the hypothesis that in individuals with spastic cerebral palsy (CP), primary afferent depolarization (PAD), a type of presynaptic modulation of Ia afferents, contributes to hypertonia, hyperreflexia and reflex irradiation. We have recently shown that spontaneous tonic activity of nociceptors contributes to PAD. Recent evidence from a large animal model of CP shows nociceptor sprouting is present along with more PAD and reflex irradiation. We propose parallel studies in people with and without CP and rabbits after prenatal hypoxia-ischemia (HI) at 70% gestation. The rabbit HI model shows hallmarks of spastic CP including cell death in the cortex, white matter injury, thinning of the corticospinal tracts, muscle stiffness, hyperreflexia, reflex irradiation, and changes in muscle architecture consistent with spastic CP. This study will investigate mechanisms by which nociceptive afferent expansion influences PAD in rabbits and humans and tests the effectiveness of transcutaneous nerve stimulation (TENS) to reduce spasticity in both rabbits and people. AIM 1: Compare nociceptive drive to GABAaxo neurons and PAD in HI/CP. Corticospinal innervation of spinal GABAaxo neurons is weakened by developmental injury. We hypothesize that this results in expanded nociceptor innervation of GABAaxo neurons and increased amplitude of nociceptor driven PAD, which then increases intersegmental Ia afferent conduction and reflex irradiation. Therefore, PAD will be measured in people with CP using conditioning of the H reflex by CST and other sensory pathways known to activate PAD, and using the in vitro rabbit spinal cord, stimulation of sensory and descending pathways and pharmacology. Expected outcome: Nociceptor-driven PAD and reflex irradiation will be larger in HI/CP. AIM 2: Quantify nociceptive synaptic contacts onto GABAaxo neurons in HI/CP. Nociceptive expansion occurs in CP/HI, potentially increasing synapses onto GABAaxo neurons, consistent with Aim 1. We hypothesize in HI/CP, additional synapses between nociceptors and GABAaxo neurons are concomitant with fewer CST contacts. We will quantify CGRP+ - GAD2+ contacts in rabbits and postmortem human tissue and CST-GAD2+ contacts using dye labeling and immunohistochemistry (IHC) in rabbits. Expected outcome: Nociceptor expansion in CP/HI will extend onto GABAaxo neurons driving aberrant PAD. AIM 3: Therapeutic blockade of nociceptors. TENS appears to reduce nociceptor neurotransmission, possibly via opioid and 5HT1D receptors. We hypothesize that in CP/ HI, use of lumbosacral TENS will reduce nociceptor-driven PAD, hyperreflexia, and reflex irradiation through a mechanism involving activation of spinal opioid and 5HT1D receptors, possibly through activation of a brainstem pathway. Lumbosacral TENS will be tested in rabbits and humans for its ability to reduce spasticity. In rabbits, mechanisms of action of TENS will be pharmacologically dissected in vivo intrathecally and in vitro to determine involvement of 1) 5HT1D 2) α5GABAA and 3) opioid receptors. Expected outcome: TENS will reduce reflex irradiation / spasticity.

NIH Research Projects · FY 2025 · 2017-09

PROJECT SUMMARY/ABSTRACT – OVERALL PFAS have emerged as national priority pollutants, and more than 2000 sites contaminated by PFAS have been identified across the U.S., including 180 EPA-identified Superfund sites. Elevated human exposures to PFAS have been associated with adverse health outcomes, including metabolic disruption, immunotoxicity, and endocrine disruption, although exposure-dependence and individual vulnerability need to be better understood. STEEP II builds on the successful collaborative it established within the first STEEP SRP Center (STEEP I) to further advance the science, training, engagement and outreach in support of SRP mandates. STEEP II will continue to collaborate with the RI and MA state and federal agencies, and will expand its reach to work with DE, ME, NJ, and MI state agencies in support of their needs for knowledge on PFAS. The environmental engineering and chemistry projects will focus on the transport and transformation of PFAS precursors, as well as legacy, novel, and total PFAS. Novel detection tools will be developed and used to support remediation of PFAS- contaminated groundwater, the atmospheric transport and fate of PFAS, and to predict bioaccumulation of PFAS relative to modeling predictions. The Center will build on its leading research on the critical effects of PFAS in children, with a focus on immunotoxicity and metabolism. Given the public health importance of breastfeeding, STEEP II will focus on understanding cellular mechanisms that dictate PFAS uptake and elimination into milk and accumulation in the infant, thereby advancing understanding of toxicokinetic mechanisms and potentials for preventing PFAS from reaching human milk. STEEP II research projects, working with the Community Engagement Core (CEC) and the Data Management and Analysis Core (DMAC), will perform a thorough human exposure assessment for PFAS and risk assessment. STEEP trainees and mentors will remain key to the ongoing growth as a unified Center, via cross-cutting collaboration fostered by the Research Experience and Training Coordination Core (RETCC), and joint mentorship. STEEP II will include an additional focus on Diversity, Equity, and Inclusion (DEI) training for trainees and mentors alike. The STEEP II goals will address the following Specific Aims: Specific Aim 1: Assess the distribution, transformations, and bioaccumulation of PFAS Specific Aim 2: Investigate the processes affecting PFAS distribution and uptake and assess critical adverse effects in humans Specific Aim 3: Engage new and established stakeholders across multiple sites Specific Aim 4: Integrate STEEP internally and execute effective outreach and collaboration with stakeholders