University Of Washington

NIH Research Projects · FY 2024 · 2023-07

PROJECT SUMMARY Research: Lower respiratory infections such as community-acquired pneumonia (CAP) are the leading cause of infection-related deaths worldwide. Emerging evidence suggests that adverse long-term health outcomes are more common in CAP survivors compared with patients hospitalized for other reasons, challenging the concept of CAP as solely an acute disease. The mechanisms underlying adverse long-term CAP sequelae are unknown, although dysregulation of the host immune response during acute infection has been postulated to be a contributing factor. Moreover, the clinical and biological heterogeneity of CAP serves as a major barrier to identification of individualized and targeted therapies, which may impede prevention of adverse long-term outcomes. In Thailand, the burden of CAP is high and in the northeastern region of the country the Gram- negative bacterium Burkholderia pseudomallei is the most common and deadly etiology. Studying CAP due to this single pathogen (Bp-CAP) may help to disentangle CAP heterogeneity and host-mediated determinants of long-term outcomes. Utilizing a uniquely large multicenter prospective cohort of patients hospitalized with Bp- CAP in Northeast Thailand, Dr. Coston will address the following Aims: (1) Determine if admission CAP severity is associated with adverse outcomes after discharge; (2) Identify pro-inflammatory cytokines associated with adverse outcomes after discharge; (3) Identify novel subgroups of Bp-CAP by applying clustering strategies to routinely collected clinical and laboratory data. The proposed work will yield insight into determinants of long-term outcomes and heterogeneity in Bp-CAP, which could facilitate identification of modifiable factors and host-focused tailored therapeutics in the future. Such findings may be generalizable to other CAP etiologies and are an important area of future study. Candidate/Environment: The candidate, Dr. Coston, is a promising junior investigator who is beginning his career as a clinical-translational physician-scientist focused on the global threats pneumonia and severe infections. He has assembled a team of accomplished faculty to provide him with mentorship and training throughout the award. He will avail of the University of Washington’s rich academic environment, pulmonary and global health expertise, and track record of training successful physician-scientists in pulmonary and critical care medicine. Through the proposed research, he will develop fundamental skills for analysis of longitudinal cohort data, cluster analysis, study of biomarkers in the host response to infection, and ethical conduct of research in global settings. The research and training proposed in this project will further Dr. Coston’s development as a physician-scientist and will prepare him to compete successfully for a K23 career development award.

NIH Research Projects · FY 2025 · 2023-07

Addiction is a growing, ubiquitous threat to health and society. A global pandemic and other large social changes in society have highlighted the importance of culture, strategies, and systems in patterning both addiction and its treatment in the U.S. Policies (e.g., Nixon’s “War on Drugs”) have fundamentally shaped responses to substance use in the U.S. Other structures like education, housing, criminal justice, and healthcare have also contributed to addictions and addictions treatment, as well as differences in both across populations in the U.S. However, structural factors in addictions have received less attention. A new generation of addictions health services scholars is needed to address challenges rooted in structures. Consistent with the goals of NIDA’s mission to advance science on drug use and addiction, next generation scholars will need strong training in policy, structural determinants of health, and related research methods and fields that can alter structures (e.g., critical theory, policy research, and implementation science) in addition to training in traditional health services and addictions-specific content and methodology. As the nation’s premier public university for research—home to a leading doctoral program in health services research, a top-ten medical school, and nationally-recognized programs in implementation science and health policy—the University of Washington (UW) is well positioned to address these training needs. Thus, UW’s Department of Health Systems and Population and Division of General Internal Medicine seek NIDA funding to found the Training in Enhancing Structural Solutions in Addictions (TESSA) Program to: 1) recruit 11 pre- and post-doctoral scholars with interest in addictions , 2) deliver a specialized curriculum fostering a multidisciplinary understanding of addictions and their care, theory, policy, and implementation science; 3) provide TESSA scholars mentored research opportunities focused on addictions and related structures in multidisciplinary research teams, 4) support TESSA scholars in developing research career training plans to enhance their skills and prepare them for research careers; and 5) evaluate the success of the program using explicit benchmarks and pre-defined outcomes. We have developed the TESSA program to train scholars in 17 core competencies addressing critical theory, policy, and implementation science in addition to traditional health services and addictions content and methodology. If we continue to train addictions scholars without such a direct multidisciplinary approach, we are likely to see slow progress and missed opportunities to improve access to care across groups and reduce morbidity, mortality, and suffering associated with addictions. Investment in TESSA will result in a new generation of multidisciplinary and structurally-focused addictions research scholars who are optimally prepared to develop and test novel strategies for prevention, treatment, and recovery, and implement effective strategies and policies into real-world settings, advancing NIDA’s cross-cutting strategic goals to increase access to treatments and reduce stigma and gaps in addictions treatment.

NIH Research Projects · FY 2025 · 2023-06

PROJECT SUMMARY Sexual and gender minority (SGM) populations are disproportionately impacted by mental health concerns relative to their heterosexual and cisgender peers. SGM populations, however, continue to report unmet mental health needs because they cannot or do not access mental health services. Digital Mental Health (DMH) has been recognized as a feasible, economical, and effective approach to broaden the availability of mental health care to consumers who face barriers to mental health help-seeking. SGM consumers cite a preference for DMH resources, and this delivery format holds promise to attend to major access barriers experienced by this consumer group. Yet, the availability of DMH content tailored to the needs of SGM consumers is limited, and a dearth of research examines SGM populations' actual engagement with DMH services. A potential solution to fully understand how SGM populations utilize DMH services would be to characterize their engagement within a natural setting. Leveraging an established partnership with Mental Health America (MHA), a non-profit mental health advocacy group offering free, evidence-based screenings and self-guided DMH resources, this study will follow a large, naturalistic sample of SGM DMH consumers with the aims to: 1) characterize consumers' current and predictive patterns of engagement with MHA's DMH resources and examine consumer characteristics associated with these different engagement patterns (Aim 1); 2) employ human-centered design approaches to gain insights related to group-specific processes not captured by MHA's meta-data that impact DMH engagement among SGM consumers and integrate data to design and build prototype engagement strategies for consumer evaluation (Aim 2), and; 3) test the tailored engagement strategies with MHA's SGM consumers using a micro-randomized trial (MRT) design (Aim 3). To accomplish these aims and prepare for a larger R01 trial, the Principal Investigator will receive training in: 1) the theoretical, substantive, and methodological underpinnings of DMH; 2) big data management and analytic methods, specifically supervised machine learning; 3) human-centered design approaches for designing tailored DMH interventions, and; 4) experimental design and data analysis for evaluating adaptive DMH interventions. The candidate is an Assistant Professor of Social Work at the University of Washington whose long-term career goal is to become an expert in the field of mental health services research, specializing in digital interventions to improve service access for SGM consumers through increased availability and enhanced acceptability. The proposed study advances this objective by aligning with the care preferences of SGM consumers, leveraging the infrastructure of an existing DMH platform at minimal burden to consumers, and contributing evidence towards optimized engagement outcomes for SGM consumers through the use of tailored strategies.

NIH Research Projects · FY 2025 · 2023-06

PROJECT SUMMARY/ABSTRACT Stabilized HIV-1 envelope gp140 trimers such as BG505 SOSIP provide a viable platform to elicit protective neutralizing antibodies that can be improved upon through various approaches to induce heterologous neutralizing breadth. BG505 SOSIP trimer immunization elicits protective neutralizing antibodies in rhesus macaques and is now being tested in several phase I clinical trials, including HVTN 137. Here we will perform in-depth studies to determine how antibodies that neutralize only the autologous virus and those that also have activity against heterologous viral variants developed in parallel during BG505 SOSIP immunization of rhesus macaques using cryopreserved samples. We will then track the antibody germline precursors for these neutralizing antibodies in other immunized rhesus macaques that share the allele to understand why they sometimes failed to develop these activities. We will also compare the targets of the neutralizing antibody responses in BG505 SOSIP immunized human subjects to those recognized in the rhesus macaque model. The HVTN 137 trial is also administering BG505 SOSIP with different adjuvants and we will investigate how these impact neutralizing antibody specificities in the human volunteers. Finally, we will isolate neutralizing monoclonal antibodies from selected BG505 SOSIP immunized rhesus macaques and human subjects to compare the structural and biophysical properties of antigen recognition. These extensive pre-clinical and clinical resources combined with our multidisciplinary expertise provides a novel setting in which to address barriers that impede the development of effective HIV vaccination strategies. If successful, these studies will illuminate new strategies to improve upon HIV-1 trimer envelope immunogens and adjuvants.

NIH Research Projects · FY 2025 · 2023-06

PROJECT SUMMARY/ABSTRACT Black Americans bear a disproportionately greater burden of alcohol-related health problems when compared to their White counterparts,1 representing a significant public health concern. Accordingly, eliminating health disparities and achieving health equity is one of the leading goals of the NIH Healthy People Initiative.2 Although existing research has made progress in understanding broad contributors to health inequities, existing models of substance use fail to adequately explain disparities in alcohol-related consequences among Black adults.3 One promising approach to explaining these disparities is the examination of one’s neighborhood environment and its relation to alcohol use and related consequences.4,5 Extant literature has linked specific neighborhood characteristics (e.g., alcohol outlet and liquor store density6,7 and neighborhood disadvantage5) as important contributors to alcohol use. Yet, existing research on the relationship between neighborhood context and substance use among Black adults provides conflicting evidence on which neighborhood characteristics are most important,8,9 highlighting the necessity of using novel approaches to identify salient factors within individuals’ environments that may contribute to differential alcohol-related outcomes. Moreover, more research is needed to identify mechanisms of action that associate environmental characteristics with alcohol outcomes, and drinking motives are often theorized as a potential pathway. Adults living in different neighborhoods may drink for different reasons, which may differentially influence their alcohol consumption and consequences experienced. Thus, the current proposal seeks to use both qualitative and quantitative approaches to identify neighborhood- and community-level factors that may influence alcohol outcomes among Black adults. Specific aims include (1) identifying neighborhood characteristics (e.g., neighborhood disorganization and deprivation) that serve as protective or risk factors for alcohol outcomes (i.e., alcohol consumption and alcohol-related consequences) among Black adults and (2) investigating the association between neighborhood characteristics and alcohol use outcomes and how alcohol motives may explain this relationship. Study findings will have important implications for future health disparities research and are crucial for the development of effective, mechanistically driven public health strategies, prevention and intervention efforts, and policy implications. The applicant will gain training in (1) understanding the etiology of and treatment approaches for race-related disparities for alcohol and substance use, (2) qualitative, quantitative, and analytical methodology, (3) scientific writing and research dissemination, and (4) community-engaged and interdisciplinary approaches. Ultimately, through the proposed research and training plan, the applicant will develop the skills and expertise necessary to make a substantive contribution to the field of racial health disparities, aligning with the applicant’s strong desire to become an independent clinical scientist addressing health inequities in the substance use field.

NIH Research Projects · FY 2024 · 2023-06

ABSTRACT Targeting IL-18 in Thymic Regeneration The thymus, the organ responsible for T cell development, is both highly sensitive to acute injury and capable of regeneration. However, the thymus progressively loses its function with age such that there is markedly reduced capacity for T cell production and recovery from damage even early in adulthood. The thymus is particularly sensitive to pre-hematopoietic stem cell transplant (HCT) cytoreductive conditioning. Therefore, transplant recipients are at increased risk of opportunistic infection as well as relapse of malignancy during a prolonged period of T cell deficiency. No clinically approved strategies currently exist to improve thymic function and treat lymphopenia. Better understanding endogenous pathways of thymic damage and regeneration may inform therapeutic strategies to this end. Here, we provide evidence supporting the involvement of pyroptosis induced interleukin-18 (IL-18) as a negative regulator of thymopoieisis following acute injury and propose its targeting for improving organ function in settings of lymphopenia. Aim 1 of this study investigates the source of this suppressive IL-18 following acute damage by sublethal irradiation (SL-TBI) and its downstream cellular effectors. Specifically, we investigate thymic epithelial cells (TECs) and innate lymphoid cells within the thymus as effectors of IL-18’s mechanism of action. Aim 2 of this study proposes the temporal attenuation of IL-18 signaling using anti IL-18 monoclonal antibody as a novel therapeutic strategy to improve thymic recovery, and subsequently, peripheral T cell reconstitution and function. I put forward clinically relevant transplant models to assess its potential for improving regeneration post-HCT. Additionally, I will assess the potential of blocking IL-18 signaling in aged models of thymic involution. Together, these studies will not only provide insight into the biological mechanisms of tissue injury and repair, but also will offer an innovative therapeutic strategy to boost immune function especially in recipients of HCT.

NIH Research Projects · FY 2025 · 2023-06

Autism Spectrum Disorder (ASD) is a prevalent, lifelong condition that manifests early in life and is associated with significant social communication challenges1–3 and economic needs1 for children with ASD and their families. Access to early, ASD-specific services can profoundly improve long-term outcomes for children with ASD4–9 and depends on timely detection of the condition. However, the predictive accuracy of ASD screening is well below recommended standards for screening tools10,15,21. As a result, a formal ASD diagnosis is often not conferred until preschool or school-age22,23. Critically, these delays impede access to ASD-specialized care within the time-period of increased brain plasticity25 during which services are most likely to attenuate developmental challenges, thereby reducing the need for more costly and restrictive services later in life8. Screening tools, which typically rely on parental report, may lack predictive accuracy because they do not sufficiently account for heterogeneity in social communication expression across individuals. Variation in the expression of ASD-specific social communication behaviors have been widely noted29,46–51, and some social communication behaviors used in ASD screening perform significantly differently across a range of individuals31,32,36–38. Additionally, existing phenomenological heterogeneity has been observed via clinicians in the development of social communication emergence across prodromal individuals over time44, 53–58. However, current screeners employ methods that do not sufficiently capture this existing heterogeneity, and this heterogeneity has not been precisely characterized as prospectively observed and reported by caregivers. The primary objective of this proposal is to generate a framework for developing highly predictive parental- report screening measures to improve the accuracy of autism screening. This will be achieved by i) developing ASD screening items that reflect the heterogeneity in social communication expression across individuals; ii) using these items in data collection via ecological momentary assessment (EMA); and iii) employing Machine Learning (ML) to develop prototype algorithms that maximize ASD prediction across individuals. EMA provides real-time in-context monitoring at time-periods proximal to target dynamics60–62. EMA is therefore an ideal choice to capture the heterogeneity in developmental trajectories of social-communication behaviors over time as observed and reported by caregivers. ML develops prediction algorithms that can differentially weigh and combine ASD indicators based on individual differences and temporal specificity and is an optimal approach for algorithm development in the presence of developmental heterogeneity76 but is underutilized in ASD screening efforts77. Through the proposed research and training plan, the applicant will develop the skills and expertise needed to make a substantive contribution to ASD research as an independent clinical scientist.

NIH Research Projects · FY 2024 · 2023-06

PROJECT SUMMARY: Chronic stress contributes to the pathogenesis and exacerbation of numerous disorders that frequently present with atypical motivation during reward-seeking behavior including substance use disorder (SUD), major depressive disorder (MDD), and anxiety. The extent to which motivation is disrupted by stress can depend on the form of stress exposure. Hence, it is critical to understand the neural circuitry regulating motivated behaviors become disrupted under diverse chronic stress states to improve our understanding of how these disorders develop, what makes some individuals more susceptible, and to identify more effective molecular therapeutic targets. Our laboratory previously reported that neurons producing the endogenous opioid peptide nociceptin in the paranigral ventral tegmental area (pnVTAPnoc neurons) act locally on nociceptin receptor (NOPR) to limit motivation for reward (Parker et al, Cell, 2019), while others have identified a role for nociceptin signaling in the orchestrated stress response. Preliminary data show that pnVTA nociceptin neurons are dynamically engaged to different extents by distinct stressors. The central hypothesis of this proposal is that stress differentially engages pnVTA nociceptin signaling to regulate the expression of motivated behaviors such as approach-avoidance. This proposal is in direct response to NIDA’s Strategic Goal 1 which aims to investigate circuitry contributing to brain functions “such as reward, motivation, decision-making…and stress reactivity, ” alongside examining a NIDA high priority target for SUD. Aim 1 will determine how diverse physical and psychological stressors alter the VTA nociceptin opioid system on a molecular and functional level. Aim 1A will evaluate how various stressors acutely and chronically alter VTA nociceptin/NOPR expression and neuron activity. Aim 1B uses a new genetically encoded biosensor for the nociceptin peptide (NOPLight), and head- fixed approach-avoidance (Ap-Av) behavioral models to determine how nociceptin release in the VTA is altered during Ap-Av decision making following stress exposure. Aim 1C uses prepronociceptin (Pnoc) conditional knockout line created in-house and optogenetics to manipulate VTA nociceptin peptide expression and activity following stress. Aim 2 will determine the anatomical and functional involvement of the lateral hypothalamus (LH) as an afferent input regulating pnVTAPnoc neuron activity in naïve and stressed states using electrophysiology and fiber photometry to simultaneously record LH terminal activity and nociceptin release in the VTA following chronic stress exposure. Leveraging these new approaches will enable us to provide brand new insight into this poorly understood system. During my training period I will learn to utilize cutting-edge techniques in order to perform powerful, high-resolution investigations of neuropeptide circuitry, and gain valuable career development training across a host of scientific, intellectual, and mentored programming. This F31 mechanism will allow me to pursue my individual development plan and prepare me for a career as an independent neuroscientist.

NIH Research Projects · FY 2024 · 2023-06

This F31 project seeks to advance the evidence on the violence prevention potential of early childhood education programs and examine the interactive effects of such programs with multi-level social, economic, and environmental factors on violence across the life course. In 2020, there were 4.6 million nonfatal violent victimizations and almost 25,000 homicides in the United States (US).1,2 That year 15.2 million people aged 12 and older reported serious thoughts of suicide, and over 45,000 people died by suicide.1,3 While firearm access is a significant determinant of violent death,4 risk is also profoundly determined by social and structural conditions across the life course and inter-generationally, including poverty, early life adversity, and economic opportunity.5 Despite evidence that sources of risk and resilience begin early in life and accumulate over the life course and across generations, and that early childhood education can address shared developmental etiologies of multiple forms of violence, there are critical gaps in our understanding of the long-term effects of large-scale early childhood education programs on violence.6 This F31 project examines the long-term effects of Head Start—one of the oldest and largest preschool programs for vulnerable children in the US—on inter- personal violence perpetration and suicidal ideation, and the social and structural factors that modify those effects. In Aim 1, we will examine inter-generational effects of Head Start on the second generation’s suicidal ideation and inter-personal violence perpetration in adolescence and adulthood using a quasi-random variation in Head Start roll-out over time and place and inter-generationally linked nationally-representative data from the National Longitudinal Survey of Youth 1979 and Child & Young Adult cohorts. In Aim 2, we will examine whether Aim 1 effects are modified by offspring sex and race/ethnicity, community disadvantage, and state policies related to economic opportunity and structural racism. In Aim 3, we will examine the intra-generational effects of Head Start on handgun carrying and inter-personal violence perpetration in adolescence and adulthood using data from the National Longitudinal Survey of Youth 1997. In Aim 4 will examine whether Aim 3 effects are modified by participant sex and race/ethnicity, community disadvantage, and state policies related to economic opportunity and structural racism. All Aims will use targeted maximum likelihood estimation, a doubly-robust estimator for causal inference with observational data. This project provides the opportunity to evaluate the effects of a widely implemented program to reduce the toll of violence in the nation. It will contribute to scholarship on both early childhood education and violence prevention at a time when policy conversations about violence and its social determinants are increasing in prominence and urgency. This project will provide the F31 candidate rigorous training in 1) causal inference methods for observational data, 2) quasi-experimental methods for policy evaluation, 3) content expertise in life-course theories of violence and early childhood education, and 4) social epidemiologic theories for macrosocial conditions and policies.

NIH Research Projects · FY 2024 · 2023-06

ABSTRACT This F31 proposal aims to evaluate pregnant and postpartum women’s preferences for different pre-exposure prophylaxis (PrEP) methods and identify early process indicators for implementing these options in maternal and child health (MCH) systems. HIV incidence remains unacceptability high among adolescent girls and young women (AGYW) in East and Southern Africa and evidence suggests a two-fold higher risk of HIV acquisition during pregnancy. Daily oral PrEP is scaling up for pregnant/postpartum women in Kenya but despite appreciable uptake of oral PrEP by pregnant/postpartum women, >50% discontinue within 30 days of initiation. Unique attributes of pregnancy and postpartum may influence discontinuation, including co-occurring side effects (e.g., nausea) and demands of motherhood. New long-acting (LA)-PrEP methods (e.g., vaginal rings and injectables) have recently been approved and may address some barriers to PrEP persistence during pregnancy/postpartum, though no systemic evaluation has been conducted to date. Early implementation studies for LA-PrEP can accelerate its integration into maternal and child health (MCH) systems. Kenya, as one of the first countries to implement PrEP at scale, is an ideal setting to study expanding access and uptake among pregnant women. This proposal leverages data collected in an ongoing RCT (MR01NR019220, MPI: Pintye, Kinuthia) among 600 Kenyan women who initiate daily oral PrEP during pregnancy and are followed through nine months postpartum. The study includes longitudinal assessments of preferences for PrEP methods (pills, vaginal rings, injectables). Interviews and focus-groups are also conducted among PrEP users, providers, and PrEP stakeholders to ascertain implementation outcomes. In Aim 1, we will determine pregnant and postpartum women’s preferred PrEP attributes for HIV prevention-effective use applying discrete choice experiment analysis methods to identify preferred PrEP method. In Aim 2, we will identify profiles of pregnant/postpartum women who would prefer novel PrEP methods using latent class models to identify distinct profiles of study participants with different preferences for several PrEP methods (daily oral, vaginal ring, injectable) and the driving predictors of preference within these classes. In Aim 3, we will evaluate implementation determinants for integration of LA-PrEP formulations into MCH systems using qualitative research informed by an implementation science process framework. The proposed research plan will provide the F31 candidate rigorous predoctoral training in 1) analytic techniques in discrete choice experiments and latent class modeling, 2) measurement of social and structural determinants of HIV risk for pregnant/postpartum women, and 3) application of a process framework for implementation of LA- PrEP. This study will be the first evaluation of user-preferences for new PrEP methods among pregnant and postpartum women and findings will help inform messaging and introduction of novel PrEP agents tailored to this important population. This F31 will provide rigorous implementation science training, expertise in maternal HIV prevention, and opportunities for future implementation research in this unique and understudied population.

NIH Research Projects · FY 2026 · 2023-06

Project Summary Co-use of opioids (fentanyl, heroin) and methamphetamine is now highly prevalent across the U.S., and is associated with severe health risks, including HIV infection and overdose, and poorer treatment outcomes. Yet, the neural circuit alterations and accompanying behavioral changes associated with this polysubstance use are poorly defined, as are the similarities/differences between distinct patterns of opioid/methamphetamine co-use. Notably, the patterning of drug use can have enormous impacts on both circuit-wide brain adaptations and the development of addiction behaviors. Accordingly, delineating whether the outcomes that occur following distinct patterns of polysubstance use reflect the summation of each drug or are synergistic or distinct is particularly important, and likely critical for designing appropriate and long-lasting therapeutic interventions. To address this, we will use rat self-administration models of sequential (use of each substance on separate occasions) and simultaneous (use of both substances at the same time) polysubstance use of fentanyl and methamphetamine that mimic patterns of human consumption. Comparisons will also be made to groups that undergo self- administration of each substance singly. We will combine behavioral analysis with in vivo fiber photometry, ex vivo slice electrophysiology and targeted chemogenetic cellular manipulations to comprehensively map how striatal circuit activity is associated with addiction behaviors following different patterns of fentanyl and/or methamphetamine use. Striatal circuits (i.e., the NAc and its glutamate afferents from the PFC and its dopamine afferents from the VTA) will be examined as they are a key node of the cortico-basal ganglia-thalamic circuit that is well-established to regulate addiction-related behaviors of both opioids and stimulants. The overarching hypothesis of this work is that neural alterations in striatal circuitry will differ between sequential and simultaneous patterns of fentanyl and methamphetamine polysubstance use. In addition, we hypothesize that polysubstance use will produce synergistic and/or distinct circuit changes rather than summative changes compared to single substance use. Collectively, these results would support the idea that the patterning of substance use is particularly important for conferring the development of addiction-related behaviors. This work is significant as polysubstance use of opioids and methamphetamine is common and riskier, but vastly understudied. Our studies will help to address this gap and will provide an important and necessary foundation for ultimately understanding why polysubstance use drives continued drug use, and what neural cells and adaptations may be particularly relevant targets for therapies aimed at addressing polysubstance use.

NIH Research Projects · FY 2026 · 2023-06

ABSTRACT The severe acute respiratory syndrome coronavirus 2 (denoted COVID-19) pandemic has shaken the foundation of services delivered to vulnerable families involved with or monitored by the child protective/welfare system. COVID-19 has changed the landscape of how children and families interact with the vital services provided by the child welfare system. Home visitation, which includes a bedrock of essential and transformative parenting support services for families involved with child welfare, was no longer safe or viable in the presence of COVID-19. The pandemic shredded safety nets. It made evident to providers, administrators, and policymakers how fragile our child protective system is. Under this strained state, child welfare agencies and mental health providers innovated service delivery systems. In Washington State, the Department of Children, Youth, and Families (DCYF) worked with local service agencies providing evidence-based programs to revise program protocols. Provider teams and program developers worked together to transition in-person services to remote platforms by developing and delivering telehealth services to families. The pandemic created the conditions for a natural experiment in service delivery in Washington State. The natural experiment proved that telehealth services are a viable service delivery system; thousands of child welfare involved families were served via telehealth. We do not know, however, if these services were effective, or which families had the technological capacity to engage, or for those who did engage were they able to complete the program. Did online home visiting produce the expected outcomes? While online delivery was an innovation driven by the necessity in response to COVID-19, many questions remain. The potential is high, but little is known about telehealth in child welfare. This proposal is a three-arm effectiveness trail of an evidence-based home visiting program: 1) delivered online, 2) delivered in-person, and 3) usual care. We will assess the effectiveness of Promoting First Relationships (PFR: a 10-week model) to improve observed parent-child interaction and caregivers’ knowledge of social and emotional development in a sample of 358 caregivers with children under age 18 months at enrollment. We will also assess if PFR reduces child externalizing behavior and reduces out of home placements of the child into foster care. We will assess the cost-effectiveness of providing PFR via telehealth. We will address the degree to which families in Child Protective Services (CPS) have the technology needed to engage with telehealth services, as well as family satisfaction and compliance. Finally, we will measure service providers’ fidelity to the PFR model and their adherence to delivering PFR via telehealth. The proposed study leverages a longstanding partnership between the University of Washington and Washington State DCYF, overseeing services in child welfare to answer these questions.

NIH Research Projects · FY 2026 · 2023-06

Coordinating the timing of responses both within and between cells is critical for multicellular behaviors like development. One way to evolve (or engineer) a molecular pacer is via induced turnover of transcriptional repressors acting at multiple loci—a solution observed in diverse eukaryotes. Yet we know remarkably little about how protein degradation kinetics translate into downstream transcriptional responses that lead to outcomes like changes in cell fate. One possible reason is the lack of available models for high-resolution structure-function analysis of degradation-linked transcriptional activation. We have leveraged the auxin response, at the heart of nearly every aspect of plant biology, as a model to investigate general principles underlying ubiquitin-mediated degradation and its connection to transcriptional activation and morphogenesis. The small-molecule triggered degradation in the auxin pathway offers a unique advantage for these studies, and has facilitated our engineering of auxin-induced degradation and transcriptional activation in yeast. Our extensive work with our ‘AuxInYeast’ system has led to a central hypothesis: the auxin system functions as a developmental timer in plants, and similar logic circuits act in many eukaryotes. One recent insight into the molecular mechanism underlying the auxin timer was our discovery that transcriptional repression in the auxin circuit, conferred by a Groucho/Tup1/TLE-type corepressor called TPL, requires interaction with the Mediator complex. Our results suggest a new model of transcriptional regulation where corepressors can stabilize the Pre-Initiation Complex in the absence of RNA Polymerase II, priming loci for rapid activation. In addition, we have shown in transgenic plants that the rate of degradation-triggered removal of the TPL corepressor sets the pace of de novo organogenesis in the root. Here, we will rigorously test the emergent model that corepressor- based priming facilitates coordination of rapid transcriptional bursts at multiple loci across the genome, and facilitates cell-cell synchrony during morphogenesis. Specific research projects will: (1) Deliver a high spatiotemporal resolution, integrated, functional map of a single synthetic yeast locus transitioning from repressed to active state, including composition/placement of protein complexes and chromatin modifications; (2) Dissect the mechanism of a novel autonomous TPL repression domain we have identified that is found in thousands of proteins, and quantify the impacts on repressive function of cancer-associated variants in select proteins; (3) Build an in vivo cell fate tracker to probe the connection between synchrony in transcription and morphogenesis. Together, the proposed work will provide a mechanistic framework for degradation-initiated transcriptional activation in the auxin response, and potentially provide insights into fundamental properties in common with many corepressor-primed systems. These insights can inform our understanding of degradation- and transcription-associated human disease, as well as guiding future design of synthetic circuits using auxin components for therapeutic applications.

NIH Research Projects · FY 2026 · 2023-06

Project Summary/Abstract With the introduction of antiretroviral therapy (ART), the prevalence of severe manifestations of HIV-associated neurocognitive disorders has improved over the past few decades. However, in the context of viral suppression, new pressing questions have emerged regarding the etiology of the persistent cognitive sequalae in PLWH on ART. Up to 40% of individuals living with virally suppressed HIV experience cognitive impairment and the mechanisms underlying neurologic injury in these individuals remain poorly understood. A hallmark finding of HIV associated neurocognitive disorder (HAND), white matter injury, has primarily been evaluated indirectly through non-specific markers of myelination on neuroimaging in PLWH or pathologic markers in animal studies. Our team has developed an MRI sequence, myelin water imaging, to directly measure myelin content, a component of white matter, in vivo. We will apply this novel sequence to longitudinally evaluate if reduced myelination rates occur in young adults living with virally suppressed HIV (YLWH) compared to demographic and antiretroviral therapy risk factor matched, HIV-uninfected controls. Additionally, we will evaluate the independent correlation between changes in myelin content and cognitive trajectories, accounting for social determinants of health, to determine if loss of myelin may contribute to the development of cognitive disorders in YLWH. The premise of this application is based on our preliminary data, which demonstrate decreased global and regional myelin content in young adults living with virally suppressed HIV compared to age and sex matched HIV-uninfected controls and that myelin loss mediates the relationship between immune activation and lower domain specific cognitive scores in young adults living with virally suppressed HIV. We will combine our novel imaging methodology assessing myelin content with established imaging techniques, such as diffusion tensor imaging, longitudinally acquired cognitive data and standardized measures of social determinants of health to determine predictors of the latent cognitive phenotypes within our cohort of virally suppressed YLWH using an unbiased statistical modeling approach, group-based trajectory analyses. The information provided by our proposed study will not only improve our understanding of changes in myelin content in YLWH in relation to cognitive outcomes, but also provide the basis for evaluating myelin water imaging as a biomarker to identify PLWH of all ages at risk for cognitive impairment. This work may provide the preliminary data needed to support early intervention trials of myelin preservation or remyelination therapies to improve cognition in a broader population of PLWH.

NIH Research Projects · FY 2026 · 2023-06

SUMMARY One of the major challenges limiting the potential of genomic medicine to revolutionize clinical care is the current lack of knowledge about the function of most human genetic variants. Consequently, the majority of clinically encountered genetic variants are classified as variants of uncertain significance (VUS), which cannot be used for clinical decision making given their unknown relationship to disease. The VUS problem is particularly acute for individuals from populations historically excluded from research, compounding existing healthcare inequities when implementing genomic medicine. Variant-level functional data has the potential to overcome many of these challenges by providing pathogenicity information for variants from diverse populations. For example, we and others have demonstrated that multiplexed assays of variant effect (MAVEs) can resolve a large fraction of VUS in clinically important genes (e.g., 49% of BRCA1 VUS, 69% of TP53 VUS, and 93% of DDX3X VUS), and several U.S. and international consortia are currently using MAVEs to produce functional data for all possible coding and non-coding variants associated with all genes that have been linked to human disease. Given the potential of functional information to augment the implementation of genomic medicine, clinical guidelines have recently been updated to recommend the use of variant-level functional data when interpreting variant pathogenicity. However, despite the potential clinical utility of large-scale functional datasets, how best to implement them such that clinicians can appropriately incorporate variant functional data into clinical practice remains unknown. In this proposal we aim to address this unmet need in genomic medicine using the following approach: ● First, we will generate a framework for standardizing and disseminating curated large-scale functional data into clinician-facing resources, and implement this framework into ClinVar (Aim 1) ● Second, we will perform a proof-of-concept integration of variant level functional data in ClinVar into two large clinical practices to evaluate the clinical uptake and impact of variant-level functional data (Aim 2). ● Finally, we will build and disseminate resources for training clinicians on best practices for integrating functional data into clinical practice (Aim 3). Overall, this proposal has the potential to significantly advance the implementation of genomic data into clinical practice by enabling clinicians to appropriately leverage emerging variant-level functional data to resolve VUS, thereby making genomic medicine more equitable and impactful.

NIH Research Projects · FY 2026 · 2023-06

PROJECT SUMMARY/ABSTRACT The scope of the problem is that 50% of patients with focal segmental glomerulosclerosis (FSGS), the leading cause of primary proteinuric glomerular disease in adults, progress to chronic kidney disease. Thus, developing new treatment strategies to improve FSGS patient outcomes is of utmost importance. Yet, there is a large unmet need in our mechanistic understanding of disease progression. The traditional view in FSGS is that podocytes are central to its pathology and that they are the first cell type to be injured. A more contemporary view is an expansion of this paradigm and includes injury to neighboring glomerular cells. This grant will focus on glomerular endothelial cells (GEnCs). The rationale is that (1) in FSGS, GEnCs decrease in number, loose their glycocalyx and their fenestrae widen; (2) patients with GEnC damage have the highest rates of disease progression; (3) GEnC injury scores for all glomerular diseases are highest in FSGS; (4) GEnC genes/biomarkers are linked to the lowest remission rates and poor long-term outcomes of FSGS. Yet the understanding of how podocytes cause secondary GEnC injury is very incomplete. To begin to close the knowledge gap, we undertook an in silico approach to identify paracrine ligand-receptor signaling networks between podocytes and GEnCs. Surprisingly, we discovered that experimental and human FSGS results in a senescence associated secretory phenotype (SASP) and an activated inflammasome phenotype in non-aged podocytes, both of which are characterized by the secretion of distinct classes of signaling mediators. Our preliminary data shows that inhibiting the NLRP3 inflammasome in podocytes improves GEnC health. Our specific aims will test two hypotheses: Specific Aim #1 tests the hypothesis that SASP and inflammasome activation from injured podocytes are responsible for GEnC damage. Specific Aim #2 tests the hypothesis that interfering with the paracrine injury signals from injured podocytes is a therapeutic target to prevent GEnC dys- function in FSGS. The innovative experimental approaches we will use include: (i) In vivo loss-of-function validation using mutant mice, in which we can reduce/inhibit the SASP or inflammasome phenotypes in podocytes in the setting of experimental FSGS, and then measure the impact on GEnC health; (ii) in vivo gain- of-function validation using transgenic mice, in which we can forcibly induce either a SASP or inflammasome phenotype in podocytes to understand the impact on GEnCs; (iii) Quality-by-Design utilizing a systematic, high complexity approach based on the Design-of-Experiment theory and Multivariate Data Analysis to address the contribution of the podocyte secretome on GEnC health and function. As such, this proposal is highly significant for its short-term impact on understanding the crosstalk between podocytes and GEnCs in FSGS, and for its long-term impact in developing new therapeutic strategies to lower the risk and magnitude for secondary GEnC damage in patients with FSGS.

NIH Research Projects · FY 2025 · 2023-06

Project Summary Although there has been substantial progress in the development of medications to lower pulmonary vascular resistance in pulmonary arterial hypertension (PAH), there are no therapies that are known to benefit the right heart in the absence of changes in right ventricular afterload in patients with PAH. Right heart failure is the key driver for morbidity and mortality in patients with PAH, but also complicates a range of other common diseases such as emphysema, interstitial lung disease, and left heart failure. We are pursuing a novel approach that targets angiotensin receptors in patients with PAH and right heart failure. Previous animal studies suggest angiotensin signaling may contribute to myocardial fibrosis and could also be important in the pathogenesis of PAH and pulmonary vascular remodeling. Angiotensin receptor blockers are well established in left heart failure where their benefit is not merely a result of improvement in left heart afterload. Our work has shown a substantially lower all-cause mortality in veterans with pulmonary hypertension who use angiotensin converting enzyme inhibitors or angiotensin receptor blockers. These mechanistic and observational results raise the strong possibility that angiotensin receptor blockade might be an effective treatment for right heart failure. Angiotensin receptor blockade is an appealing therapeutic target that is well aligned with current NIH priorities of repurposing existing, inexpensive, and well-tolerated medications for novel use in other disease states. Medications for PAH are particularly expensive. If adjunctive therapy with an angiotensin receptor blockers are efficacious, this would benefit PAH patients and society at-large. We propose a Phase 2, single-center, randomized placebo-controlled trial of valsartan (an angiotensin receptor blocker) in adults with PAH. The study will evaluate the safety and clinical efficacy of a 24- week course of valsartan. The primary endpoint is change in six-minute walk distance at 24 weeks. Secondary endpoints include differences in right ventricular function, biochemical markers of right heart failure (NT-proBNP), New York Heart Association Functional Class, health related quality of life (as assessed by the disease specific emPHasis-10 instrument), and the frequency with which routine therapies for patients with PAH are escalated during the trial.

NIH Research Projects · FY 2026 · 2023-06

PROJECT SUMMARY/ABSTRACT Cancer cachexia (CC) is a wasting syndrome characterized by decreased appetite, weight loss, and muscle wasting in cancer patients leading to decreased physical function and poor quality of life, shortened lifespan, and higher medical costs. To this date, there is no approved treatment for CC. Paradoxically, muscle wasting and weakness are also very common side effects of some chemotherapeutic agents such as cisplatin, a first-line therapy for several cancer types. Since current interventions for preventing or treating cachexia associated with cancer or cisplatin are suboptimal, there is an urgent need to develop new therapies to improve muscle mass and function in these conditions. 5’-adenosine monophosphate-activated protein kinase (AMPK) is an intracellular energy sensor that plays a central role in skeletal muscle physiology through the regulation of mitochondrial biogenesis and metabolism. It has also been shown to decrease inflammation in a variety of cell types. AMPK is of particular interest in the context of CC because, although the mechanisms underlying cancer cachexia are not fully understood, one of the primary triggers of CC is increased inflammation and oxidative stress. Impaired mitochondrial function is also thought to be one of the main contributors to muscle dysfunction in CC. However, the function of AMPK in CC, as well as its potential therapeutic role in preventing muscle wasting and weakness are not known. This study aims to characterize the role of AMPK in cisplatin- and lung cancer tumor (Lewis Lung Carcinoma, LLC)- induced CC, and evaluate the potential for modulating AMPK as a therapeutic target for these conditions. Specific Aim 1A will investigate if genetic (AMPKα2 activity inhibited) or pharmacological inhibition of AMPK (Compound C) exacerbates cisplatin-induced muscle wasting and dysfunction in mice; whereas promoting AMPK activation by its agonist AICAR attenuates this myopathy. Specific Aim 1B will determine whether activating AMPK attenuates cisplatin-induced myopathy in C2C12 myotubes and characterize the signaling pathways involved. Specific Aim 2A will determine if AICAR attenuates LLC tumor-induced muscle wasting and dysfunction and Compound C exacerbates these deficits, and Specific Aim 2B will determine the same effects of AMPK modification on LLC media-cocultured C2C12 myotubes and elucidate the underlying molecular pathways. The overall hypothesis is that AMPK is essential for maintaining muscle function during cachexia; promoting AMPK activation by AICAR counteracts cisplatin- or tumor-induced muscle wasting and weakness, whereas inhibiting AMPK activation will exacerbate this myopathy. We postulate that the effects of AMPK are mediated by suppressing inflammation and oxidative stress while promoting mitochondrial function. Ultimately, our findings from this study will provide evidence of the potential therapeutic role of AMPK in CC, and benefit cancer patients by improving their quality of life and longevity. This project will also allow me to transit to an independent investigator in cancer cachexia and muscle research.

NIH Research Projects · FY 2026 · 2023-06

PROJECT SUMMARY Cell therapies are living drugs that can access a multifaceted biological response and can therefore potentially provide not only therapeutic but also regenerative outcomes. However, these beneficial attributes of cell therapeutics are accompanied by significantly more complex, variable, and costly production logistics. Major advances in biomanufacturing are required for cell therapies to have broad and widespread use. In this application, we propose to develop aptamer-based technologies for cell separation that will provide an impactful improvement over current technology, resulting in superior product at a fraction of the cost. Our main objectives are to 1) establish a novel SELEX method for membrane proteins and identify new aptamers for cell isolation applications, 2) develop methods for traceless isolation of monocytes and generation of macrophage and dendritic cell products for immunotherapy, 3) demonstrate multiplexed selection and T cell subset selection for CAR T cell immunotherapy applications, and 4) enable efficient collection and expansion of urine stem cells as a source for regenerative medicine therapies. Successful completion of these aims will lead to a platform technology for scalable and more affordable production of CAR T cell immunotherapy, monocyte-based cell therapies and stem cell treatments.

NIH Research Projects · FY 2025 · 2023-06

Project Summary: Impairments in visual processing and perceptual decision-making are a significant cause of morbidity in neuropsychiatric disorders such as Alzheimer’s disease and schizophrenia. The primary goal of this training proposal is to characterize a potentially novel node in the distributed network underlying visual perceptual decision-making - the midbrain reticular nucleus (MRN). Classical models of perceptual decision-making ascribe decision formation to forebrain sensorimotor regions, with the midbrain existing at the end of a feedforward pathway to relay motor commands. However, there is substantial evidence that the midbrain, especially the superior colliculus (SC), participates in the visual decision process. Additionally, our recent work has shown that a variety of coding, from movements, to action selection, to even abstract cognitive representations such as cue valuation, is simultaneously distributed in multiple regions throughout the brain. We hypothesize that this coding scheme applies to visual decisions as well, with midbrain regions including MRN and SC participating in a network with regions in the cortex and basal ganglia to form the decision. The MRN has traditionally been thought of as a purely motor-related region. Challenging this notion, we recently found visual and action selection signals in MRN during a visual decision-making task. Questions remain however regarding how the diverse coding in MRN is organized topographically, whether visual responses are a result of task learning, the encoding of abstract decision signals in MRN, and how MRN interacts with the broader perceptual decision-making circuitry. This training proposal addresses each of these questions by leveraging the scale of Neuropixels 2.0 probes and a novel visual reverse contingency task I have designed and implemented to distinguish sensory, motor, and decision signals. Aim 1A uses Neuropixels 2.0 recordings across MRN in mice viewing a variety of stimuli to build a topographic map of sensory and motor coding, and Aim 1B uses similar recordings in task-naive and trained mice passively perceiving task stimuli to assess visual plasticity in MRN. Aim 2A uses recordings across MRN during task performance to establish the presence of abstract decision signals, and Aim 2B uses multi-probe recordings throughout the visual decision network to establish inter-area interactions during decision formation. Together these aims will advance our understanding of the distributed regions and the complex computations that give rise to visual decision-making, thereby improving our ability to precisely target key circuits in disorders where this process goes awry. During my tailored training period, I will learn Neuropixels electrophysiology, rodent behavioral task design and implementation, whole-brain histological processing and imaging, and advanced computational analysis techniques under the guidance of experts in a supportive training environment. These skills, combined with clinical training in a world-leading medical institution, will ideally prepare me for an independent career as a physician-scientist working to advance the understanding and treatment of neurological disorders.

NIH Research Projects · FY 2025 · 2023-05

PROJECT SUMMARY Patients with chronic pain on opioids frequently experience loneliness, which is associated with poorer health outcomes and higher risks for opioid misuse and opioid use disorder. Given that almost half of opioids are prescribed in primary care, a critical need exists for the development and testing of interventions to reduce loneliness in primary care patients at risk for opioid misuse. The long-term goal of our study is to reduce opioid misuse and opioid use disorder by addressing loneliness in primary care patients on chronic opioids. Interventions addressing maladaptive social cognition through cognitive behavioral therapy and improving social support through social navigation have been shown to be effective in reducing loneliness and improving outcomes in other fields but have not been tested in patients at risk for substance use disorder. In our study, which responds to RFA-DA-23-010 (Enhancing Social Connectedness and Ameliorating Loneliness to Prevent and Treat SUD and Support Recovery), we propose a pilot 3-arm randomized clinical effectiveness trial that will adapt and test the feasibility of implementing two efficacious interventions: (1) a psychological intervention using cognitive behavioral therapy to address maladaptive thought patterns around social connection and (2) a social navigation intervention to connect participants with social opportunities and develop supportive social networks. Our proposed study would take place in primary care practices from the Washington, Wyoming, Alaska, Montana and Idaho region Practice and Research Network, a practice-based research network of over 100 practices. Our specific aims are: (1) to refine and adapt both the social navigation and psychological loneliness interventions for primary care patients on chronic opioids by engaging patients and clinicians in a series of stakeholder group meetings, (2) to assess the feasibility of implementing a 3-arm randomized clinical effectiveness trial with 102 patients using the RE-AIM framework, and (3) to determine the distribution and variability in the mediating outcome (loneliness), the primary outcome (opioid misuse) and secondary outcomes including opioid dose, functional status and patient-reported pain at three time points -- baseline, post-intervention and 3 months post-intervention. Our study is innovative because we are testing evidence-based interventions for loneliness in patients at high risk for opioid misuse where they are already receiving care and where most patients with chronic pain receive their pain related care. We expect that, consistent with the purpose of the R34 mechanism, this project will prepare us for larger scale pragmatic trial, where we can leverage embedded or remote behavioral health professionals within a diverse set of primary care practices, that tests patient outcomes, clinic-level feasibility, and sustainability. The project is expected to have a positive impact in reducing opioid misuse and potentially development of substance use disorder, as well as improve health outcomes, functionality, and quality of life.

NIH Research Projects · FY 2026 · 2023-05

PROJECT SUMMARY/ABSTRACT Preventive genomic medicine, particularly identification of individuals with inherited cancer risk, provides health systems with the opportunity to improve longevity and quality of life for their patients. The ability to uncover substantially elevated risk of disease through genomic testing, act to reduce that risk, and improve outcomes while lowering costs has been the longstanding promise of genomic medicine. In the case of inherited cancer, however, adherence to recommended risk management following genomic testing is low. Further, our pilot data suggests that health systems are reluctant to expand cancer genomic testing without a clearer idea of how to manage tested patients over time. Our goal in this application is to address this roadblock to genomic medicine implementation. Specifically, we will demonstrate the benefits that adopting population management interventions following genomic testing can provide health systems, using hereditary cancer as a case example. We will revise and rigorously evaluate two population management interventions (web resources and personalized outreach) that improve timely patient outreach and end-to-end tracking without burdening providers. Web resources is a low-touch intervention that links patients with existing educational resources (e.g., the Facing Our Risk of Cancer Empowered website). Personalized outreach is a high-touch intervention that connects patients with a dedicated care manager to discuss risk management and provide care reminders. Both interventions are highly scalable and mirror population management programs that health systems have used to support cancer screening, diabetes management, and other evidence-based care for decades. We will compare web resources and personalized outreach to usual care in a pragmatic hybrid type-1 randomized trial that engages patients captured in hereditary cancer registries within two health systems, Kaiser Permanente Northwest (KPNW) and Denver Health (DH). KPNW is a vertically integrated health system and DH is a federally qualified health center, providing two highly unique evaluation settings. Our primary effectiveness outcome is the proportion of registry patients up to date with recommended cancer screening over two years. We will collect secondary implementation outcomes, including the acceptability, appropriateness, feasibility, sustainability, and costs of high- and low-touch intervention approaches. By providing clinical champions with essential data and tools to select and implement population management interventions that address critical gaps in post-testing quality and patient safety, this innovative project will advance preventive genomic medicine.

NIH Research Projects · FY 2026 · 2023-05

Project Summary/Abstract Sexual minority women (SMW) experience disproportionately high risk of sexual assault (SA) and resulting mental health sequelae (e.g., depression, PTSD), and these sequelae appear to be especially pronounced among Black SMW. The main theoretical model of sexual minority mental health disparities (i.e., the minority stress model) attributes this elevated risk to climate-level factors (e.g., laws, policies, and other conditions that afford risk or protection to minoritized groups) that vary across municipalities and states. Indeed, evidence suggests that climate-level factors are associated with risk for PTSD and other disorders in sexual minorities. However, nearly all studies to date have relied exclusively on assessments of individual-level perceptions of climate-level factors, and no studies have directly tested these climate-level factors in relation to SMW’s mental health following SA. This proposal therefore aims to test the minority stress model in relation to SMW’s SA recovery, including the first-ever direct test of the role of climate-level factors, to inform novel interventions and policy change efforts. We will recruit a geographically-stratified sample of 2400 SMW aged 18-35 (oversampling Black SMW) to complete self-report surveys every 6 months for 2.5 years, and use publicly- available population-level data on SMW and Black-relevant policies/laws and community presence to characterize the climates of participants’ municipalities and states. Aim 1 will involve testing cross-sectional baseline differences in mental health as a function of history of adolescent/adult SA and climate-level variables. Because the mental health effects of SA are most evident in the first 6 months following SA, Aims 2 & 3 will focus on the subsample of SMW (approximately 33%) who experience a prospective SA during the study. Aim 2 will test mediated relationships between climate-level variables, individual-level SMW minority stress, and rates of mental health symptom change in prospectively-assaulted SMW. Aim 3 will apply a critically-needed intersectional lens to these questions by testing the relationship of anti-Black climates to rates of recovery in prospectively-assaulted Black SMW. Combining these self-report and population-level datasets over multiple years provides an unprecedented opportunity to evaluate how sociopolitical environments influence health disparities while the disparities are emerging. Given persistent health disparities among SMW, identifying contributing factors across varying levels of causation is important for public health, both for SMW, and also for other minoritized groups. We will draw upon our team’s extensive expertise in SMW research and practice and utilize SMW advisory to carry out this study. Results of this study will immediately inform clinical interventions to improve recovery from SA among this highly vulnerable group and help to prioritize and justify public policy changes to reduce this mental health disparity.

NIH Research Projects · FY 2025 · 2023-05

ABSTRACT Both genetic and environmental factors influence the risk of developing autism spectrum disorder. Environmental contributions in particular, are estimated to account for ~40% of autism risk, yet we know very little about the identities of these environmental risk factors for autism. To bridge this gap in knowledge through an experimental approach, I developed a zebrafish-based high-throughput behavioral assay of sociality during my postdoctoral training. Social deficit is one of the two core symptoms of autism and a hallmark of this disease, so I hypothesized that environmental inhibitors of sociality are also likely risk factors for autism. Using this assay, I conducted a large-scale screening of 1120 compounds and discovered topoisomerase II (Top2) inhibitors as a class of environmental chemicals that inhibit the development of sociality and likely contribute to autism risk. The main objective of this proposal is to characterize the role of Top2 in the development of social behavior. During the K99 award period, I demonstrated that between the two isoforms of Top2, Top2a but not Top2b is required for the normal development of sociality. In addition, I discovered that Top2a likely functions by interacting with the polycomb repressive complex 2 (PRC2) and regulating H3K27 trimethylation (H3K27me3) in specific genomic loci. I also gained skills and knowledge in mouse genetics, mouse behavioral science, genomics, and bioinformatics. With the new training and mechanistic insights acquired in the K99 phase, I will extend the scope of my research in the R00 phase to: 1) establish and characterize a genetic mouse model of Top2a depletion through conditional knockout; 2) examine genome-wide changes in H3K27me3 distribution following Top2a inhibition; and 3) systematically discover environmental factors that affect the development of social behavior by screening the ToxCast library. Together, the proposed research will greatly facilitate environmental risk factor discovery for autism and may reveal novel therapeutic targets to prevent or treat autism. The support that the R00 award provides will help me achieve my long-term goal of establishing a successful independent research program to investigate environmental impacts on mental illnesses.

NIH Research Projects · FY 2026 · 2023-05

Mitochondria play a central role in age-related pathologies, loss of resilience, and the decline in quality of life in older adults. As we age changes in mitochondrial function lead to disruption of redox and energy homeostasis, altered metabolite levels, impaired calcium regulation, and increased sensitivity to permeability transition, all of which contribute to tissue dysfunction. Mitochondria are dynamic organelles that continuously adapt to changing cellular demands by altering protein assembly and interactions to modify their function. Despite the obvious importance little is known about how age-related changes in mitochondrial protein interactions underlie changes in function. To address this fundamental question we propose to apply a state of the art novel quantitative chemical cross-linking with mass spectrometry approach (XL-MS) to quantify the changes in the mitochondrial interactome in heart and skeletal muscles with age. By combining this innovative XL-MS approach with targeted functional assays and interventions developed over the last several years to manipulate mitochondria in vivo and in vitro we are uniquely positioned to identify the changes in mitochondrial protein interactions that underlie age- related mitochondrial dysfunction. Our preliminary data indicate specific disruption of multiple protein interaction networks involved in ADP transport, ATP synthesis, glutamate metabolism, and complexes of the electron transport system with age. Many of these protein complexes that XL-MS indicates are disrupted in aging directly interact with the mitochondrial targeted peptide SS-31 that we have shown reverses mitochondrial dysfunction in heart and skeletal muscle. Our overall hypothesis is that changes in the mitochondrial interactome driven by elevated mitochondrial redox stress underlie decreased ATP production and altered metabolite levels in mitochondria from aged heart and skeletal muscle. In aim 1 we will apply XL-MS and site-specific assays to measure the link between the interactome and function in mitochondria from aged mouse heart and skeletal muscle. As a specific test of new mechanistic insights available from this approach we will use gene-edited iPSC derived cardiomyocytes to test the causal relationship between altered interactions in the glutamate dehydrogenase regulatory region, the largest change identified in the aged mitochondrial interactome, and impaired glutamate and α-ketoglutarate metabolism. In aim 2 we will use mitochondrial targeted interventions to reverse mitochondrial dysfunction, SS-31 and AAV-mitochondrial targeted catalase, and induce mitochondrial redox stress to identify the most functionally important changes in the mitochondrial interactome from aim 1. In aim 3 we use human muscle biopsies to test whether changes in the mitochondrial interactome identified in aims 1 and 2 translate into aged human skeletal muscle. We will separate older adults into low and high performing groups to compare the mitochondrial interactomes and function with those of young adults. Results from these experiments will have a transformative impact on the field by providing the first window into the links between the mitochondrial protein interaction network and age-related mitochondrial dysfunction. 1