Univ Of North Carolina Chapel Hill

NIH Research Projects · FY 2024 · 2024-09

For millions of patients who suffer from a variety of painful conditions, opioid analgesics can provide decisive pain relief in part by decreasing the aversion normally associated with pain perception (i.e., the characteristic unpleasant quality of pain experience, regardless of etiology). Mechanistically, this analgesia against pain unpleasantness is associated with the binding of opioids to specific G protein-coupled receptors (GPCRs), the mu opioid receptors, particularly in brain pathways that contribute to the affective-motivational dimension of pain. However, mu opioid receptors are also broadly expressed outside of pain circuits, where opioids produce unacceptably dangerous side effects including addiction and potentially fatal respiratory depression. Crucially, the human genome contains hundreds of other GPCRs with distinct expression profiles. Thus, because GPCRs are highly druggable proteins, developing small molecules that engage non-opioid, non-addictive GPCRs in affective-motivational pain circuits is an attractive strategy to develop safer analgesics that reduce pain unpleasantness more safely and across all pain conditions. We have assembled a multidisciplinary team comprising pain biologists, neuroscientists, physicians, GPCR pharmacologists, and medicinal chemists; advisors with pharmaceutical industry, drug development, intellectual property, and commercialization experience; and representatives from patient advocacy groups. In our previous work, we discovered an ensemble of neurons in the amygdala that encodes pain unpleasantness and demonstrated that interfering with amygdalar neural activity using artificially expressed GPCRs (DREADDs) significantly diminished pain affective- motivational behaviors in mice. We next launched an analgesic target discovery project combining mouse genetic tools, single-cell RNA sequencing, and bioinformatics methods to catalog GPCRs present in the amygdalar neurons active during pain. After generating this catalog, we histologically validated expression of these GPCRs and conducted preliminary antinociceptive efficacy tests, using known GPCR ligands. This work identified an amygdalar GPCR with antinociceptive properties. Furthermore, engagement of this target is not reinforcing in rodents. Although existing ligands were sufficient to demonstrate the antinociceptive potential of this GPCR, our next objective is to develop small molecules with optimized physical, PD, and PK properties. Toward this aim, our team proposes to use medicinal chemistry and computational docking techniques as in our previous study based on the recent resolution of several cryo-EM structures. Further, given that translational efforts can fail due to insufficient understanding of the target biology and its conservation in humans, we will expand our understanding of this GPCR biology by investigating signaling and its distribution in human tissues.

NIH Research Projects · FY 2024 · 2024-09

Chronic musculoskeletal pain (cMSP), including fibromyalgia, affects over 14% of the population, is a leading cause of disability worldwide, and is often refractory to available treatments. New, non-addictive treatment options are urgently needed to improve the management of cMSP and reduce reliance on opioids. Light therapy delivered to the retina promises to be a powerful, non-pharmacologic therapy to ameliorate cMSP. Evidence is mounting for the analgesic effect of light in common cMSP conditions (e.g., fibromyalgia, chronic low back pain). Despite the incredible promise, the neural mechanisms and properties of light that drive analgesia remain poorly understood. Elucidating these details of the underlying neural mechanisms will unlock the full potential of light therapy for treating cMSP. These details include discovering how activation of specific visual system circuitry modulates pain, including identifying the neurons in the retina involved and tracing out the distribution of their signals in the brain and their interactions with pain pathways. We hypothesize that light-driven analgesia operates through specific visual pathways originating at the level of color-sensitive ganglion cells in the retina. Color-sensitive ganglion cells receive excitatory and/or inhibitory input from short (S-), middle (M-), and long (L-) wavelength-sensitive cone photoreceptors (e.g. S vs L/M). Green light has been recently implicated as a color of light that drives analgesic pathways far greater than white light of equal brightness, a hallmark of a color-sensitive retinal mechanism. This proposal brings together an integrated team with demonstrated expertise in vision neuroscience, optoelectrical engineering, neuroimaging, and translational pain research to comprehensively evaluate the retinal, subcortical, and cortical color-opponent mechanisms involved in light-driven analgesia. The specific aims will be done in parallel using homologous model systems that translate to humans. In this proposal, we will (1) Identify color-sensitive retinal ganglion cells that mediate analgesia and characterize their light responses using extracellular and whole-cell voltage-clamp recordings in the primate and rat retina to determine the optimal stimulus paradigms (spatial/temporal frequency, wavelength) to drive analgesic circuits, (2) Evaluate the cortical and subcortical responses to retinal stimuli that drive these color-sensitive ganglion cells to elucidate the brain mechanisms of light-driven analgesia in humans with cMSP, and (3) Map the analgesic circuit that carries signals from color-sensitive ganglion cells to the rat central nervous system and behaviorally link circuits activated by colored-light to pain circuits by trapping circuits driven by color-sensitive ganglion cells in a validated rat model of cMSP. Together, these aims will provide critical mechanistic insights into the interplay between retinal and pain circuits that carry chromatic information and will allow future translation of these mechanistic findings into practical, non-opioid, non-addictive light treatments to manage cMSP.

NIH Research Projects · FY 2024 · 2024-09

ABSTRACT The NIH has declared that developing new non-addictive treatments for chronic pain is one of its top priorities. Certain polyunsaturated fatty acids are precursors to oxylipins that regulate pain pathways. Oxylipins derived from omega-6 (n-6) linoleic acid tend to have pro-nociceptive properties, while oxylipins derived from omega-3 eicosapentaenoic acid (n-3 EPA) and docosahexaenoic acid (DHA) tend to have anti-nociceptive properties. Because humans cannot synthesize n-3 and n-6 fatty acids de novo, the levels of these fatty acids—and their oxylipin derivatives—can be altered by diet. We have published results of two randomized controlled trials testing targeted dietary modification of n-3 and n-6 fatty acids (H3L6 diet) among adults with chronic headache (n=67) and migraine (n=182) reporting reductions in headache of 25-40% and reduction in NSAID use. The H3L6 diet altered the concentration of circulating n-6 and n-3 fatty acids and their oxylipin derivatives, and these changes predicted improvement in headache. These results suggest that the H3L6 diet is a promising adjunct treatment for reducing headache and a useful model for investigating mechanisms of pain reduction. Preclinical studies suggest that oxylipin modification could be efficacious in other chronic pain conditions characterized by neuronal sensitization and inflammation, but this has not been demonstrated in humans. We have pilot data (n=40) supporting feasibility and reduced pain intensity in adults with chronic lumbosacral radiculopathy randomized to the H3L6 vs control diet. We propose to conduct a 16-week randomized controlled trial testing the efficacy and biochemical mechanisms of the H3L6 diet among adults receiving usual care for chronic axial low back pain. We hypothesize that increasing dietary n-3 EPA+DHA while lowering n-6 linoleic acid will alter nociceptive oxylipins in a manner that decreases the intensity of back pain as well as pain medication use. The goal of this R34 planning grant is to develop all the necessary documents and procedures to conduct that trial. In Aim 1, we will update the H3L6 and control interventions to current nutrient values since the food supply has changed since they were developed. In Aim 2, we will complete all the planning activities (e.g., preparation of the manual of operating procedures, development of informed consent forms, and develop safety and data management plan) that are critical prior to implementing a clinical trial. Completion of this aim will take care of all requirements in the NIAMS Clinical Trial Planning Milestone Checklist and will facilitate the launching of a trial that is hypothesis-driven and milestone- defined. The proposed project is part of a series of studies designed to translate the preclinical and clinical research on oxylipin-pain pathways into accessible, effective, non-addictive treatments for chronic pain. Based on our previous work, this approach of using dietary modifications to alter biochemical regulators of chronic pain is a low-risk, high-reward endeavor potentially leading to new treatment options and biomarkers of treatment response.

NIH Research Projects · FY 2024 · 2024-09

(PLEASE KEEP IN WORD, DO NOT PDF) Kidney failure impacts many, with 750,000 cases annually in the US and 2 million globally. Treatment options include kidney transplant or dialysis. Hemodialysis requires vascular access, often through arteriovenous fistulae (AVF) for improved long-term survival and reduced infection risk when compared to grafts and catheters. Nevertheless, AVFs frequently mature inadequately, exceeding 50% within 6 months, leading to interventions and complications due to neointimal hyperplasia (NH) and inadequate outward remodeling. Vascular injury results in the phenotypic modulation of vascular smooth muscle cells (VSMCs), pathognomonic of NH. Oxidative stress emerges as a pivotal contributor to these downstream processes. Consequently, interventions aimed at mitigating oxidative stress through antioxidant therapies have the potential to enhance AVF maturation, especially since patients with kidney failure have elevated levels of oxidative stress. Our hypothesis posits that Nrf-2 activation in VSMCs and in an in vivo mouse AVF stenosis model, particularly in uremia, can inhibit VSMC phenotypic changes, and reduce NH while promoting outward remodeling, thus improving AVF maturation. We will investigate this through: Studying the effect of Nrf2 activation on the phenotype of VSMC Assessing a new local therapeutic approach that activates Nrf2 in a mouse AVF stenosis model. Successful completion of this proposal holds the potential to alleviate clinical morbidity associated with AVF failure, which remains our foremost objective, driven by the pressing needs of our patients.

NIH Research Projects · FY 2025 · 2024-09

Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. Work-related stressors take a heavy toll on individuals’ health and well-being as made even more evident by the increased awareness of essential workers during the pandemic and its still lingering impact on workplace settings. Resilience programs have arisen as a promising workplace strategy to improve mental health and well-being for those at greatest risk; however, emerging programs are limited by time- and resource-intensive in-person strategies limiting scalability and practicality for the most marginalized of the workforce. Additionally, the literature on resilience programs are largely from preliminary studies that lack a priori sample size calculations, representative participants, and long-term maintenance following the intervention, as well as inadequate control groups, which limits translation prompting calls for more rigorous designs to evaluate the efficacy of these programs. Consistent with the aim of PAR-24-086 to test a fully remotely delivered clinical trial with no in-person contact, this team has developed and translated the Stress Management and Resilience Training (SMART) program for web-based delivery. Our pilot work demonstrates feasibility, usability, satisfaction, and initial efficacy of the brief self-paced web-based learning sessions (1 hour per week) with only 5-10 minutes of daily practice suggesting a fully powered study is timely and warranted. An adequately powered, cluster randomized controlled trial to test the efficacy of the web-based SMART program compared to a matched attention control in a high-need, representative, under-resourced, and under-studied segment of essential workers – childcare workers - will be conducted. Participants (640 workers from 80 childcare centers) will be randomly assigned to either SMART or a matched attention control condition with the primary outcome of mean change in resilience assets and resources (Connor-Davison Resilience Scale). Measures will be collected at four timepoints: baseline (0 months), post-intervention (3 months), and long-term maintenance (9 and 15 months). Secondary outcomes will include changes in overall mental health, negative and positive mental health indicators, social support, and organizational assets and resources. We will also explore potential moderators’ (e.g., demographics, social determinants of health) influence on treatment effects. The RE-AIM Framework will be used to determine reach and representativeness, and potential for organizational level adoption, implementation, and maintenance of the SMART program. This study fills key gaps of previous resilience research in an underserved population in critical need of mental health and well-being resources with implications for the feasibility and impact of remote programming in other segments of the workforce.

NIH Research Projects · FY 2025 · 2024-09

ABSTRACT The main goal of this project is to assess the contribution of epigenetics to cardiovascular risk in African American women. Cardiovascular disease substantially impacts African American women, who are at high-risk for mortality and complications. Genome-wide association studies have identified several genetic loci for coronary heart disease and stroke, but the epigenetic contribution to cardiovascular disease has been less studied, especially in African Americans and women. Epigenetic modification such as DNA methylation may better reflect lifestyle and environmentally induced risks, including risk due to lifestyle and behavioral factors, biological aging and environmental toxins. We propose to study epigenetic biomarkers of cardiovascular disease in a large sample of African American participants the Women's Health Initiative, a cohort of postmenopausal women with comprehensive clinical and lifestyle data, and large numbers of adjudicated clinical outcomes. We will identify epigenetic biomarkers of cardiovascular disease and its environmental determinants, and evaluate if epigenetic biomarkers contribute to risk prediction assessments of cardiovascular disease. The proposal aligns to goals set forth in the 2019-2023 Trans-NIH Strategy Plan for Women's Health Research and the NHLBI mission to reduce the burden of cardiovascular disease in populations with disparities in disease risk.

NIH Research Projects · FY 2024 · 2024-09

Abstract Members of the Armed Services deployed in the Middle East were exposed to numerous environmental toxicants, including emissions from open-air burn pits. Burn pits are designated areas on military sites for open air combustion of trash and other unwanted items. Large amounts of waste are destroyed through burn pits. The contents of burn pits are highly variable temporally within the same location and between locations, but at least three components are present in most; plastics, military plywood and military cardboard. Burn pits contain both smoldering and flaming combustion. In collaboration with colleagues at the EPA, we utilize a controlled furnace to burn plastics and military plywood and cardboard at either smoldering or flaming temperatures. These three components are burned either individually or as a mixture, and the complex combustion products are analyzed in detail. Our studies show that single exposures of flaming combustion products of any component or the mixture induce lung inflammation, whereas smoldering combustion products do not. Repeated exposure to flaming combustion products of the mixture, which commonly occurs among military personnel, induce a small increase in neutrophils compared to a single exposure when both were studied 24 hours after the final exposure, but no change in lung injury. Importantly, the nature of the immune response changes after repeated exposures, as measured both by mRNA of selected immune mediators and by multiplex assay of cytokines, chemokines and other mediators. Unbiased analysis of the proteome present in the BAL fluid also reveals differences between single and multiple exposures. Evidence of a change in the lung microenvironment toward Th1 immune responses and a greater anti-oxidant capacity is present. The proposed study thus tests the hypothesis that the lung's response to multiple exposures takes on a different nature than to a single exposure, reflecting adaptation and resiliency by the lungs. Studies proposed in Aim 1 will characterize both the immune cell infiltrate in bronchoalveolar lavage and lung tissue and the lung injury following a single exposure and multiple exposures to burn pit combustion products. Mice will receive either a single exposure or five or ten exposures, 2 or 3 days apart, of either combustion products of the mixture or saline (controls) and will be studied at 24 hours after the final exposure. The number of epithelial and immune cells (neutrophils, macrophage subpopulations, T and B lymphocytes, NK cells and their activation states) will be measured using flow cytometry. Markers of acute inflammation, Th1 immune responses, anti-oxidant capacity, and lung injury and repair will be measured. Studies in Aim 2 will determine the transcriptomes of lung bronchial and alveolar epithelial cells, neutrophils and macrophage subpopulations following single compared to multiple exposures to burn pit combustion products. These studies will use single cell RNAseq/CITE-seq of lung digests obtained 24 hours after the single or the fifth exposure. Thus, studies will provide an understanding of the lungs' response to burn pit combustion products experienced by members of our Armed Services and may suggest interventions to be pursued.

NIH Research Projects · FY 2024 · 2024-09

PROJECT SUMMARY/ ABSTRACT Aspirin is one of the most used drugs in the world. Unfortunately, many older adults will consume aspirin without an established indication, a scenario in which risks (i.e., bleeding) likely outweigh benefits (i.e., primary stroke/myocardial infarction prevention). Furthermore, many patients use aspirin in the presence of drug-drug interactions that increase bleeding risk and in the presence of relative contraindications (i.e., history of recurrent falls). Deprescribing - the purposeful discontinuation or dose reduction of potentially inappropriate drugs – of chronic aspirin use should be considered after the manifestation of a bleeding event resulting in an emergency department (ED) visit. Yet, little is known if older adults on chronic aspirin will discuss the possibility of deprescribing with their primary provider/aspirin prescriber after an ED bleeding event. The objective of this proposal is to conduct foundational research, guided by Intervention Mapping Theory (IMT), to inform the development of a novel ED-based deprescribing intervention to address aspirin use among older adults with bleeding. Aim 1 is to determine the frequency with which older adults receive counseling on the benefits and risks of chronic aspirin use 14 days after a bleeding event requiring ED care. Aim 2a is to identify patient and provider factors associated with absence of counseling on the benefits/risks of aspirin within 14 days of an ED visit for bleeding. Aim 2b is to conduct qualitative interviews to understand the patients’ perspective on the decision-making process in continuing (or discontinuing) aspirin use after a bleeding event. In applying IMT, we will demonstrate the need and theoretical framework for a paradigm shifting ED-based intervention to facilitate supervised deprescribing of aspirin after an ED encounter for bleeding. This study will be led by an ED physician (Martin Casey MD MPH) who seeks to build a career in leveraging the ED to promote deprescribing and medication optimization in older adults. His work will be completed under the guidance of a diverse mentorship team with expertise in aging epidemiology (Michelle Meyer PhD), geriatric cardiology (Parag Goyal MD MSc), geriatrics and deprescribing (Jan Busby-Whitehead MD), and geriatric ED care processes (Ula Hwang MD). In completing this work with his mentorship team, Dr. Casey will move towards becoming a pioneering emergency medicine physician with expertise in deprescribing.

NIH Research Projects · FY 2024 · 2024-09

Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia that is associated with disseminated intravascular coagulation and fatal bleeding. Although chemotherapy and differentiation therapies are quite effective, APL is still associated with a high incidence of early death (4-26%) that typically occurs within 30 days of diagnosis. Notably, severe bleeding, particularly intracranial bleeding, is the leading cause of the early deaths in APL. The precise mechanisms of APL-induced bleeding are unknown. However, observational studies indicate that it is characterized by thrombocytopenia, hyperfibrinolysis and coagulation activation. The goal of the proposal is to determine the mechanisms of bleeding in APL. We have recently established two new mouse models of APL (xenograft and allograft models) that reproduce many of the hemostatic abnormalities of APL patients. Podoplanin (PDPN) activates platelets via C-type lectin-like receptor 2 (CLEC-2) on platelets. Blast cells from APL patients express high levels of PDPN suggesting a role of PDPN in thrombocytopenia. Consistently, we observed high plasma PDPN levels in our allograft model. Increased levels of plasmin- antiplasmin complexes (PAP) and D-dimer are observed in APL patients. We observed high levels of PAP and D-dimer in our mouse models of APL. The S100A10 (S100)/annexin A2 (AA2) and the urokinase-type plasminogen activator (uPA)/ uPA receptor (uPAR) complexes are expressed on APL cells and may play a role in hyperfibrinolysis. APL patients have high levels of thrombin-antithrombin complex (TAT). We observed high levels of TAT in our mouse models of APL. Peripheral blood mononuclear cells (PBMC), which includes blast cells, from APL patients have high levels of tissue factor (TF) activity. Importantly, we recently found that inhibition of APL cell-derived TF reduced TAT levels in the xenograft model. Similarly, inhibition of both APL cell- derived and host cell-derived TF reduced TAT levels in the allograft model. To date, no studies have evaluated the roles of the PDPN-CLEC-2 pathway, the S100/AA2/tPA and uPA/uPAR pathways in the coagulopathy and bleeding in APL using mouse models. In addition, our study is the only study that shows the role of TF in the activation of coagulation in mouse models of APL. Our central hypothesis is that bleeding in APL patients is driven by simultaneous reduction of platelets and activation of fibrinolysis, and coagulation which collectively impose a catastrophic failure of the hemostatic system. We will test this hypothesis by determining the individual contributions of the PDPN-CLEC-2 pathway, the S100/AA2/tPA and the uPA/uPAR pathways, and TF to the coagulopathy and bleeding in mouse models of APL. Our study will provide a better understanding of mechanisms of APL-associated coagulopathy and bleeding. We will also have explored new treatments for APL- associated bleeding and APL itself. In addition, our study may find new biomarkers to identify APL patients at high risk of bleeding using omics techniques.

NIH Research Projects · FY 2025 · 2024-09

ABSTRACT Autoimmune diseases affect 1 in 10 people. Commonly, patients needlessly suffer for years due to delays in diagnosis and referral delays to specialists. Systemic lupus erythematosus is a classic example due to its nonspecific symptoms and potential to mimic other diseases. It affects women 9 to 1 with average diagnostic delays of over 5 years, increasing the chances of life-limiting end-organ damage. A diagnosis typically requires an experienced rheumatologist to carefully consider and integrate various data sources. This need for a specialist creates health equity concerns which are further compounded by the disproportionately higher prevalence of lupus in Black and Hispanic women. This project will develop a unified multimodal representation learning technology that will allow 1) using many different datatypes (e.g., electronic health records, omics-data, full-body imaging, clinical measures, tabular data, and data from activity monitors); 2) adding data sources to the multimodal model as needed; 3) supporting missing modalities by cross-modal generative learning; 4) providing inherent end-to-end interpretable results; and 5) patient-specific disease predictions and patient-personalized multimodal information acquisition plans. The project will use a holistic design approach where a model will account for population imbalances during training and model design and will incorporate debiasing approaches directly into the modeling. Our approaches will be generally applicable to multimodal learning. They target significantly earlier diagnoses for autoimmune diseases, strategies to recommend suitable additional diagnostic tests, and the ability to identify patients at greatest risk for the worst outcomes for which more aggressive treatments may be recommended.

NIH Research Projects · FY 2024 · 2024-09

Project Summary The sharp increase in mental health symptoms among adolescents has triggered alarm regarding possible sources for this increase, with much public concern focused on the high consumption of social media by youth. Although numerous studies have examined linkages between adolescent social media use and mental health outcomes, much of this research uses self-report assessments and cross-sectional designs, which are limited by inaccuracy and inability to determine temporality in associations. Moreover, less research attention is dedicated to the early adolescent period (ages 10–12). This developmental period marks the first entry into the digital world for many youth and is a critical window during which to understand the effects of social media. Body image concerns is an element of mental health that is especially relevant for social media use, and early adolescents are developmentally at risk for negative body image perceptions and subsequent mental health challenges. This study will examine how early adolescents use social media with a focus on how this use relates to body image concerns, as well as how visual attention biases to highly visual self-focused digital content relates to both social media use and body image concerns. We will also examine the role that parents play in these associations. Parents are known sources of influence on adolescents’ body image concerns and can also shape how adolescents select, interact with, and interpret social media content. For example, a parent who demonstrates visual attention biases to appearance-oriented stimuli may intergenerationally transmit these biases to their adolescent. This longitudinal study will examine an early adolescent sample (N = 200) at two time points: first, when adolescents are entering the 6th grade, and second, when adolescents are entering the 7th grade. Adolescents and their parents will complete measures of their social media experiences, as well as their body image concerns, at both time points. Self-reports will be supplemented with objective measures of adolescent social media use via a) recordings of smartphone app usage, and b) recordings of accounts followed on major social media platforms, with public accounts coded for appearance-oriented content. Adolescents and their parents will also complete an eye-tracking task assessing self-focused visual attention during a video chatting task. By collecting these data over time, we can examine how body image concerns and visual attention to digital stimuli may change in concert with changes in social media use, with a special focus on appearance-oriented social media use. Specifically, we can examine bidirectional associations between early adolescent social media use, visual attention biases to self-focused digital content, and body image concerns, with an additional focus on how parent body image concerns and self-focused visual attention biases may predict these attitudes and behaviors. The information gained can inform prevention and intervention efforts targeting unhealthy social media use during adolescence, such as by testing parents as a source of influence and identifying visual attention biases as a risk factor.

NIH Research Projects · FY 2025 · 2024-09

Studying Mitochondrial Dynamics and Energetics During Cardiac Reprogramming Abstract: Direct reprogramming of cardiac fibroblasts (CFs) to induced cardiomyocytes (iCMs) shows promise for the treatment of cardiac injury, such as a myocardial infarction (MI). Barriers to clinical application include low reprogramming efficiency and relative immaturity of iCMs. A metabolic shift from glycolysis to mitochondrial respiration is required to transdifferentiate CFs to mature iCMs, but this aspect of cardiac reprogramming remains understudied. In preliminary experiments, mitochondria in native CMs showed higher fusion activity, more organizational complexity and higher trans-membrane potential than native CFs. By day 15 of standard cardiac reprogramming, only some of these changes are observable in reprogrammed cells. Knockdown of the mitochondrial fission regulator Mtfr1l led to improved reprogramming efficiency and iCM maturation. I therefore propose to characterize a time course of mitochondrial structural and functional changes during cardiac reprogramming. Additionally, I will investigate the molecular mechanisms of Mtfr1l as a barrier to cardiac reprogramming and evaluate other mitochondrial perturbations for impact on reprogramming efficiency and iCM maturation. This work will offer insights into the mitochondrial regulation of cardiac reprogramming and how mitochondria can be harnessed to improve reprogramming strategies. These insights will bring us closer to clinical translation of these strategies to benefit patients after MI.

NIH Research Projects · FY 2025 · 2024-09

Project Summary Common genetic variants identified through genome-wide association studies have been reproducibly associated with risk for Alzheimer’s disease (AD), but the function of many risk variants are unknown and likely context-specific. At the same time, several environmental exposures have been implicated in AD and dementia, including particulate matter air pollution (PM2.5), heavy metals (especially lead (Pb)), and infections. We posit that the genetic architecture of AD includes gene-environment interactions (GxE) between common, non-coding variants and environmental exposure. Here, we propose to identify these GxE using an in vitro model, "GxE in a dish", using the inherent genetic diversity in a population of neural cells exposed to AD-relevant environmental exposures. We will test the context-specific function of common genetic variation in 100 induced pluripotent stem cell donors differentiated to cortical organoids. We will expose the organoids to PM2.5, Pb, infection mimics (LPS + IFNγ), or vehicle. We will collect scRNA-seq data from each exposed organoid, allowing inference of context- specific single cell expression quantitative trait loci (QTL). To find genetic variants associated with neural cell survival, we will additionally generate chimeric brain organoids composed of cells derived from multiple independent donors. We will use the Census-seq approach to determine the proportion of each donor within the chimeric organoids in response to the exposures described above. We will then conduct a genetic association study to find common variants associated with differential survival response to these environmental exposures. To complement our in vitro cell culture model, we will also identify GxE effects on brain structure in vivo using a large population scale database. We will then colocalize context-specific eQTLs, survival QTLs, and in vivo brain QTLs with each other and AD GWAS loci. In all, our results will reveal new mechanisms underlying AD GWAS loci by exploring the context-specific nature of genetic variant function using both in vitro and in vivo systems.

NIH Research Projects · FY 2025 · 2024-09

Postoperative pain (POP) affects millions of Americans and incurs significant costs to the US healthcare system. Poorly managed acute POP can lead to increased morbidity, mortality, and complications such as chronic POP and opioid overuse. Accurate prediction of POP outcomes and in-depth understanding of POP causal mechanisms are crucial for developing effective management strategies to achieve timely POP control and reduce the risk of opioid overuse. Furthermore, POP studies have shown the heterogeneity of responses to anesthesia methods and postoperative substance use, suggesting an urgent need for effective methods to identify the optimal individualized POP management strategy. However, achieving these goals is challenging due to the complex POP mechanisms and limited data from ideal large randomized controlled trials. On the other hand, abundant observational POP data found in surgery patients’ electronic health records (EHRs) are readily available, and they can serve as cost-effective alternatives to address these fundamental knowledge gaps in POP management. However, the etiology of POP can be intricate due to their observational nature, i.e., many factors may interweave together and impact POP phenotypes in complex fashions, introducing daunting modeling and analytical challenges. In particular, confounding, a major concern associated with observational data, represents a critical challenge for conducting solid causal inference on POP data. Further, POP outcomes, e.g., POP intensity, are often irregularly and repeatedly measured, and distributed non-normally with two distinct data processes, requiring more advanced analysis methods. This proposal aims to overcome these analytic and modeling challenges by developing robust deep learning-based computational tools to improve POP management. Specifically, we will 1) establish robust deep learning models for more accurate predictions of both acute and chronic POP to achieve timely POP control and care, and reduce the risk of opioid overuse; 2) develop efficient deep learning-based semi-parametric methods to identify POP causal mechanisms for designing more effective interventions; and 3) propose powerful analytical methods to conduct robust hidden subgroup analysis to achieve the optimal individualized POP management. Methods developed in this proposal are motivated and will be tested by two unique data sets: a large EHR data from the University of North Carolina at Chapel Hill’s Carolina Data Warehouse for Health (CDW-H), and a high-quality cohort data from NIH-funded TEMporal PostOperative Pain Signatures study, which complements the CDW-H in scale and scope. Ultimately, the project aims to uncover fundamental clinical mechanisms of POP and improve clinical decision-making and POP management.

NIH Research Projects · FY 2024 · 2024-09

1) We will build a robust, dynamic Translator Standards and Reference Implementations Component (SRI) that integrates the collaborations and investments that the NCATS Translator has made to date. This component will consist of a suite of standards and products, a model for their governance, and processes to coordinate integration and shared implementation: ● Community governance coordination will be developed with community buy-in to ensure an effective collaborative environment, and drive consortium-wide consensus on the other components. ● Architecture and API specifications will drive community efforts to define details of project architecture and communication protocols across Translator Knowledge Providers (KPs), Autonomous Relay Agents (ARAs), and the Autonomous Relay System (ARS). ● The BioLink model will define the standard entity types, relationship types, and a schema shared by all Translator components. This includes related utility libraries and a novel approach to accommodate multiple alternate data modeling perspectives. ● Integrated reference ontologies will provide BioLink-compliant terms and relationships. We will draw on the ROBOKOP Ubergraph framework [1] , the Monarch integrated ontologies, and other ontologies from Open Biological and Biomedical Ontologies (OBO) [2] . ● A continually-updated knowledge graph and data lake will provide Translator with a standardized and integrated global view of the whole information landscape. ● Next-generation Shared Translator Services will integrate features of ROBOKOP [3] , Monarch [4] , BioLink [5] , and the reasoner APIs to remove integration barriers. These services will provide validation, lookup, and mapping functionality for use across Translator. ● A registry of Translator KPs, ARAs, and shared services will increase efficiency, eliminate duplication of effort, and promote collaboration. 2) Our proposed SRI will address the problem of connecting together different components and data/information sources at scale, with community buy-in, and with a plan for sustainability. 3) For the development of the standards component of the SRI, our plan will begin with accepted Translator standards, and we will work with the ARS, ARAs, and KPs to identify gaps. We will have a community process for contributing to the standards, making use of GitHub pull requests and voting, to help everyone contribute effectively and fairly with clear attribution. We will ensure rigorous documentation and testing. For the reference implementation component, we will stand up core Translator services, and will include additional services if they are useful to more than one Translator component rather than used by only one. 4) Consensus-building is hard. Our team has proven expertise and resources to identify needs, refine solutions, and find agreement , thereby successfully bringing infrastructure to fruition. Our team also has the technical and biological expertise to design and test the necessary standards, having been at the forefront of multiple ontology, data standards, and large enterprise software initiatives. 5) The Translator infrastructure is by nature heterogeneous, distributed, and growing; consequently, the most significant data and infrastructure challenge is managing the validity, currency, equivalency, and typing of entities (diseases, phenotypes, drugs, etc.). Our group has developed several innovative algorithms for managing this and related problems; these algorithms are in use for other integration projects and will be modified to suit Translator needs.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY Significance. Pulmonary inflammation, which contributes toward the severity of lung diseases, is markedly exacerbated by obesity. Thus, there is a need for novel therapeutic approaches for targeting pulmonary inflammation in obesity. One promising strategy involves increased dietary consumption of docosahexaenoic acid (DHA), an omega-3 polyunsaturated fatty acid, which exerts anti-inflammatory properties. The first step toward developing DHA as a therapeutic for pulmonary inflammation in obesity is to establish the cellular targets and mechanisms of this unique fatty acid. One key target of DHA is alveolar macrophages (AMs), which are critical for maintaining respiratory homeostasis and drive pulmonary inflammation in obesity. Based on strong preliminary data, we propose the central hypothesis that DHA targets AMs to improve the inflammatory response through two key mechanisms. The first mechanism, tested in Aim 1, involves DHA esterification into plasma membrane phospholipids of AMs and thereby controlling the biophysical organization of sphingolipid/cholesterol-enriched lipid rafts to lower inflammatory signaling in obese mice. The second mechanism, tested in Aim 2, involves DHA displacing arachidonic acid (AA) in the phospholipidome. AA is an omega-6 PUFA which exerts pro-inflammatory effects through its conversion to hydroxylated derivatives such as prostaglandins. Displacing AA with DHA would shift the balance from pro-inflammatory AA derivatives in obesity to anti-inflammatory and pro-resolution DHA derivatives. One such DHA derivative is resolvin D1 (RvD1). RvD1 binds the G-protein coupled receptor ALX/FPR2 and decreases inflammation by driving macrophages to have an anti-inflammatory phenotype. To test the central hypothesis, the applicant will rely on advanced imaging tools, biochemical assays, and knockout mouse models including the innovative use of a newly generated myeloid specific DHA-deficient mouse. Impact: The proposed studies will establish mechanisms by which DHA improves pulmonary inflammation in obese mice and inform future clinical studies. This research will provide the applicant with skills in developing and implementing rigorous study design, use of advanced laboratory techniques (cutting-edge biophysical microscopy methods, flow cytometry, and biochemical assays), foster interdisciplinary collaboration, and enhance leadership skills through writing, project management, and mentoring. Ultimately, this will build the foundation for a successful biomedical research career.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY Glioblastoma multiforme (GBM) is the most aggressive form of brain cancer and ~90% of GBM patients die within 24 months after diagnosis.1 Treatment options for GBM include surgery and chemoradiation however, recurrence is common, and the disease is universally fatal.2,3 Over the past 20 years, induced neural stem cells (iNSCs) have been investigated as a novel modality for the treatment of brain cancer. The ability of iNSCs to home to tumors and kill cancer cells are makes them attractive as a new approach for the treatment of GBM. Other potential challenges include the need for repeated invasive surgery for redosing or to remove the biomaterial if it is not biodegradable in nature. To address these limitations, we propose to develop a combination therapy that harnesses long-acting delivery (>90 days) of NSCs using a novel injectable and biodegradable biomaterial and a non-invasive and efficient redosing of NSCs across the blood brain barrier (BBB) using state- of-the-art focused ultrasound (FUS) technology for enhanced treatment of GBM. The Scientific Premise of these studies is that A) an injectable biodegradable hydrogel scaffold can be developed that: 1) implements a tunable/scalable manufacturing process, 2) can accommodate high concentrations of NSCs (≥106 cells/mL) with initial targeted sustained delivery of ≥3 months, and 3) is biodegradable and does not require surgical removal post administration; B) a non-invasive systemic redosing regimen of NSCs to recurring GBM using FUS to delivery NSCs across the BBB. Our central hypothesis is that sustained local delivery of NSCs ( 3 months) alone or in combination with non-invasive redosing using FUS will improve access to residual or recurring tumor cells and survival outcomes in preclinical models. This cutting-edge combined approach will be utilized to evaluate the scientific premise of our proposal in preclinical mouse models to investigate the safety and efficacy of a unique and highly innovative combinatorial technology and treatment approach to improve treatment of GBM.

NIH Research Projects · FY 2025 · 2024-09

Optimized High-Resolution Fast Magnetic Resonance Fingerprinting with Cloud- Based Reconstruction Abstract Magnetic resonance imaging (MRI), despite its wide utility, is inherently limited due to its inability to measure tissue properties quantitatively, which is critical for objective and scanner-independent diagnosis and treatment monitoring. MR Fingerprinting (MRF) is a relatively new quantitative MRI framework for simultaneous quantification of multiple tissue properties. While MRF outperforms most conventional methods in quantitative imaging, existing MRF techniques are still handicapped by limited spatial resolution and coverage, long acquisition times, suboptimal acquisition parameters, long data reconstruction times, and complicated post- processing workflows, hindering large-scale clinical validation and translation. In this project, we will leverage the expertise of our team in MRF, machine learning, and pulse sequence optimization to develop and optimize a rapid and robust quantitative MR technique, applicable to high-resolution volumetric brain imaging. Our team has recently developed a new B1-insensitive MRF method using low flip angles and multiple magnetization preparations for improved accuracy and precision in tissue quantification compared with existing MRF methods. We will first develop and optimize this new MRF method for 3D high- resolution brain imaging, using our newly developed pulse sequence design framework. Novel fat navigator will be incorporated to improve motion robustness (Aim 1). We will leverage state-of-the-art deep learning techniques to accelerate both acquisition and post-processing (Aim 2). Finally, a complete MRF post-processing pipeline empowered by GPU cloud computing will be developed to significantly simplify the post-processing workflow and facilitate efficient clinical translation and validation of the proposed methods for patients with neurological diseases (Aim 3).

NIH Research Projects · FY 2024 · 2024-09

Project Summary Maternal morbidity and mortality in the United States (US) is driven by health disparities along axes of race, poverty, disability, socio-economic and sexual gender minority status. Such structural inequities also influence career choices of underrepresented early-stage investigators, who may pragmatically avoid studying health conditions that are hard to measure or difficult to fund. Intimate partner violence (IPV) is one such ethically and logistically complex condition. Perinatal IPV has marked effects on incident hypertension, common mental disorders, obstetric complications, and adverse birth outcomes. IPV was present in 57% of pregnancy- associated homicides, and homicide is now the leading cause of US maternal death. Despite these preventable deaths and years lost to disability, perinatal IPV remains underexamined in observational, interventional, and population-based studies. Training a broad spectrum of early-stage investigators on measurement rigor and ethical practice has strong potential to narrow this evidence gap. “Restoring equity to measuring and preventing perinatal intimate partner violence” (Remap-IPV) is a comprehensive, hybrid cohort training with tailored mentorship. The training approach uses constructivist, adult learning techniques to facilitate dialogue and skills application. Trainees are matched with established IPV investigators to co-produce a peer-reviewed manuscript or specific aims and outline for a research proposal. Throughout the 18-month traineeship, Remap-IPV will build skills in ethical measurement of perinatal IPV and extend the professional network of both new and established faculty in this field. The project leverages the resources of two leading public universities: University of North Carolina and University of California, San Diego. Our team of 20 core faculty have a demonstrated commitment to mentoring excellence and expertise in IPV assessment across various disciplines: public health, nursing, medical ethics, obstetrics, clinical forensics, psychology, psychiatry, social epidemiology, criminology, sociology, and health economics. The longevity and scalability of the Remap-IPV training will be steered by a Translational Impact Group consisting of experts in educational design, innovation, maternal health, and community engagement. The Remap-IPV training model will be replicable for future cohorts and through a freely-licensed online curriculum that includes comprehensive lectures, skill-development activities, mentorship approaches, and well-defined learning objectives. Remap-IPV is designed to lay a strong foundation for ESIs in methodological rigor, ethical considerations, and scientific perseverance necessary to conduct IPV research. This program will contribute to the NIH IMPROVE initiative's aim to promote diversity within the next generation of maternal health scientists and reduce preventable maternal deaths.

NIH Research Projects · FY 2024 · 2024-09

ABSTRACT This application proposes to adapt a Formerly Incarcerated Transitions (FIT) program for mostly African American women, often with health disparities, who are released from incarceration and at high risk for HIV acquisition. We propose to refer eligible incarcerated women for HIV pre-exposure prophylaxis (PrEP), a highly effective biomedical prevention strategy. Our novel HIV prevention program, FIT for PrEP (F4P), will leverage the infrastructure of a successful FIT program, revise and adapt it to link these at-risk women post- release to PrEP services with adjunctive social services. Guided by the 5-steps of the Centers for Disease Control and Prevention’s ADAPT framework (Assess, Select, Prepare, Pilot, Implement), F4P is modified specifically to address the barriers that women face during community re-entry preventing post- release PrEP use. Previously, we completed steps 1 (Assess the target population’s needs) and 2 (Select the intervention to adapt). This application targets step 3 (Prepare) by pre-testing and refining the intervention to address the needs of the target population, and step 4 (Pilot) by testing the adapted intervention. We propose to refine our novel F4P program, which increases access to HIV PrEP to women experiencing incarceration (WEI). Peer Community Health Workers (CHW) with incarceration histories will begin meeting with WEI before their release to provide PrEP education, needed social support, serve as role models, and link WEI to post- release health care including PrEP. CHW will also address WEI’s social determinants of health during the community re-entry period. We will refine our novel F4P program based upon feedback from WEI, CHWs, and FIT clinicians using iterative Plan-Do-Study-Act (PDSA) cycles. We plan to randomize sixty WEI to either the F4P program or Stay Healthy cardiovascular prevention (attention) control arm and use quantitative and qualitative approaches to assess the acceptability and feasibility of the F4P program. To gain preliminary evidence for efficacy, PrEP initiation will be compared between the two groups at week 12 in aim 3. In addition, the other PrEP care continuum steps will be measured to inform the future efficacy trial. The PI and Co- I’s are experienced and have long-standing collaborations conducting research and implementing programs within the NC women’s prison, FIT programs and NC community health centers. This application is both innovative and highly significant because F4P expands the current HIV correctional prevention paradigm to biomedical prevention (PrEP). F4P builds on the successful FIT model to target WEI, a high- risk yet understudied US population. The resulting data on F4P’s acceptability, feasibility, and preliminary effect will inform a R01 application to evaluate the intervention’s efficacy in increasing WEI’s post- release PrEP adherence and retention in care.

NIH Research Projects · FY 2025 · 2024-09

Abstract Almost a third of the US population is exposed to ozone (O3) levels that are unsafe according to US EPA standards. These levels are deemed unsafe primarily because O3 has been shown to cause inflammation and negatively impact the respiratory system. One mechanism by which O3 contributes to health complications is by forming oxysterols, a result of oxidizing cholesterol and cholesterol-like precursors. These oxysterols can cause endothelial cell stress and dysfunction, as well as contribute to the formation of atherogenic plaques in the vasculature. These effects of oxysterols have inspired the investigation of how oxysterols might also negatively impact the cardiovascular system. This interest is partially driven by the 30% increase in cardiovascular disease observed in the US over the last 30 years without an understanding of all the contributing mechanisms to this trend. A potential way O3-induced oxysterols could be impacting cardiovascular disease is by increasing risk of thrombosis. Oxysterols form protein adducts (particularly at lysine residues) that can disrupt the functions of other proteins, with an example being the oxysterol adduction of the liver X receptor (LXR). This also suggests that oxysterols in plasma could be forming protein adducts with coagulation factors. Interestingly, prothrombotic changes in plasma have been identified after O3 exposure via unbiased proteomics. This evidence supports our hypothesis that ozone exposure and oxysterol generation can increase risk of thrombosis. We will test this hypothesis through the following specific aims (SA): In SA1, to investigate the mechanisms by O3 oxysterols might contribute to thrombotic risk, we will investigate if O3-induced oxysterols induce prothrombotic endothelial activation. Culturing endothelial cells in vitro, we will expose them to various concentrations of O3-induced oxysterols and proinflammatory cytokines. Subsequently, we will perform RNA-seq to determine if any of the differentially expressed genes might exacerbate thrombotic risk. Additionally, we will assess endothelial barrier integrity using trans-endothelial electrical resistance (TEER). In SA2, we will use mass spectrometry and “click” cycloaddition chemistry to determine if any coagulation factors have adducted to any oxysterols in samples from O3-exposed participants. We will also determine how controlled O3-exposure affects in vitro thrombin generation (TG) and plasmin generation (PG) assays. We expect that we will observe more prothrombotic TG and/or PG parameters from the plasma of O3-exposed participants compared to controls. The specific regions of adduction on any coagulation factors will allow us to evaluate potential mechanistic consequences to protein function, and thrombotic risk by extension. Together, data from these experiments will inform how O3 exposure and O3- induced oxysterols might impact cardiovascular disease by identifying specific biomarkers and mechanisms to clearly link oxidant air pollutant exposure with thrombotic risk.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY/ABSTRACT Chemotherapy-related cognitive decline (CRCD) is common and consequential to quality of life and function, but there is no standard of care to prevent or treat CRCD. Three major barriers to developing effective interventions include: 1) interindividual variability in pre-systemic risk factors; 2) multiple mechanisms of CRCD; and 3) a lack of investigators capable of developing mechanism-driven interventions and deploying them in complex medical settings (e.g., concurrent with chemotherapy). Memantine is a promising medication for CRCD, as it modulates pathways involving brain-derived neurotrophic factor (BDNF) and inflammation, two interrelated mechanisms of CRCD and of cognitive aging broadly. Exercise is an optimal behavioral augmentation strategy, as it also targets BDNF and inflammation, improves frailty, and is recommended for mood, fatigue, and physical function in cancer patients undergoing treatment. In the proposed K23 study, we will conduct a three-arm randomized controlled trial (RCT) of MEM+EX (combined memantine and an established cancer exercise program [Get Real & Heel]), memantine, or placebo to mitigate CRCD in 90 patients with breast cancer. Specific research aims are to: determine the feasibility and acceptability of MEM+EX during breast cancer chemotherapy (Aim 1); evaluate the preliminary efficacy of MEM+EX and memantine to mitigate cognitive decline (Aim 2) and changes in CRCD biomarkers (Aim 3); and explore the impact of frailty on changes in cognitive function and CRCD biomarkers (Exploratory Aim 4). We hypothesize that 1) our RCT will be a) feasible (≥ 40% recruitment rate; ≥85% retention rate; ≥75% adherence to ≥90% medication doses and ≥75% exercise sessions) and b) acceptable; MEM+EX and memantine will 2) exhibit lesser decline in objective and patient-reported cognition; and 3) mitigate BDNF decline and inflammation; and 4) treatment changes in cognition and CRCD biomarkers will be moderated by baseline frailty levels. The primary outcomes are feasibility and acceptability. Secondary outcomes are a composite of objective measures of attention and executive function, patient-reported cognition, BDNF, and an inflammatory composite measure. Outcomes will be assessed at baseline, 4 weeks, post-intervention (primary endpoint), and 6 month follow-up. Dr. Nakamura’s long-term goal is to become an independent investigator who develops and tests effective, mechanistically-based cognitive interventions for patients with cancer. His short- term goals for this award are to obtain training in: 1) design, conduct, and analysis of clinical trials; 2) cognitive measurement; and 3) mechanisms of CRCD. The mentorship and resources at the University of North Carolina at Chapel Hill create an ideal environment for this K23 award. The proposed research and training aims are consistent with the NIA’s goal to develop effective interventions to maintain well-being and function and reduce the burden of age-related diseases. This award provides Dr. Nakamura with the necessary education, training, and pilot data to prepare him to conduct a future definitive trial of MEM+EX and lead other large-scale RCTs of interventions targeting the pathophysiology of cognitive decline induced by cancer and its treatments.

NIH Research Projects · FY 2025 · 2024-09

ABSTRACT Epstein-Barr Virus (EBV) is the etiological agent of several hematopoietic malignancies including multiple types of non-Hodgkin lymphoma (NHL). These EBV-positive NHL subtypes are comprised of post-transplant lymphoproliferative disease (PTLD), diffuse large B cell lymphomas (DLBCL), T cell lymphomas, Natural killer (NK)/T cell lymphoma (NKTL), and Burkitt's lymphoma (BL). Our studies have found that FAM72A is highly expressed in EBV-positive lymphomas and contributes to EBV-mediated lymphomagenesis, which gives rise to EBV-positive NHL. In response to PAR-21-348, we propose to address how EBV’s upregulation of FAM72A contributes to the development of EBV-driven NHL.

NIH Research Projects · FY 2025 · 2024-09

Project Summary/Abstract Metazoan replication-dependent histone mRNAs are the only eukaryotic mRNAs that lack a polyA tail ending instead in a conserved stemloop. In contrast mRNAs for histone variants, e.g. H3.3 and H2A.Z, are encoded by polyadenylated mRNAs. The genes for all five histone proteins are clustered in metazoan genomes, and factors required for histone gene expression are concentrated at the histone genes in a nuclear body, the histone locus body (HLB) which contains three factors (FLASH, Mxc (NPAT) and U7 snRNP) that only function in histone mRNA biosynthesis. Histone mRNAs are synthesized in the HLB. Our goal is to understand how the HLB is assembled and concentrates the factors required for histone mRNA biosynthesis, and activates expression only during S-phase. We have shown the core U7 snRNP is targeted to the HLB in G1, but the active U7 snRNP is only assembled in the HLB in S-phase cells, when the cleavage factor containing CPSF73, CPSF100 and symplekin is bound to U7 snRNP in the HLB. The HLB forms immediately after mitosis and is inactive until cells enter S-phase. Phosphorylation of Mxc (NPAT) by cyclin E/cdk2 activates histone gene expression. In this proposal we address how U7 snRNP is targeted to the HLB (aim 1), how U7 snRNP is activated inside the HLB (aim 2) and using the ability to remove specific factors from the nucleus during early embryogenesis to determine the role of other factors in histone mRNA biosynthesis (aim 3).

NIH Research Projects · FY 2025 · 2024-09

This K23 application requests funds to develop and test a set of behavioral economics and financial incentive- based strategies to improve patients' treatment engagement, medication adherence, and substance avoidance as they transition from Coordinated Specialty Care (CSC) for first-episode psychosis (FEP) to post-CSC care. While CSC was conceived as a means to improve short-term and long-term outcomes, evidence suggests that its short-term gains are lost after discharge. Improving treatment engagement, medication adherence, and substance avoidance during post-CSC care promises to mitigate this loss of gains. Behavioral economic and financial incentive-based behavior change strategies improve treatment plan adherence for people with other health conditions, including general psychosis. But these interventions have not been tested in the post-CSC period, where they face two obstacles: (1) frequent loss of contact in care transition and (2) concerns about the ethical acceptability of these interventions. Yet, preliminary research suggests that text messaging and emerging mHealth apps like mindLAMP will increase continued contact and that behavioral economic and financial incentive-based interventions will be acceptable when designed in participatory, ethically-informed ways. I will pursue 3 research aims to develop ethically-informed behavioral economics and financial incentive- based strategies to improve treatment plan adherence for people transitioning from CSC to post-CSC care. Guided by principles of community-based participatory research, a Steering Committee involving stakeholders, including CSC researchers, patients, family members, and clinicians, will oversee all aims. In Aim 1, I will assess facilitators of and barriers to using behavioral economic and financial incentive-based strategies in the post-CSC period. Using data from Aim 1, in Aim 2, I will adapt and sequentially improve these strategies while leveraging text messaging and mindLAMP to monitor and reinforce patients' adherence. In Aim 3, I will conduct a pilot RCT to examine preliminary effectiveness, utility of the measurement battery, success of recruitment and retention strategies, and feasibility and acceptability of the intervention developed in Aim 2. I will also pursue training goals in (1) decision science, (2) mHealth, (3) mixed methods analysis, and (4) field trials in order to become an independent clinician-scientist and psychosis a leader in the use of behavioral economics and financial incentives in treatment and an expert in the ethical application of these strategies. Successful completion of these aims will lead to an R01 application to conduct an RCT testing effectiveness, cost implications, and implementation issues. Related future research will apply similar methods to enhance engagement and monitoring in other domains of psychosis care. Ultimately, the research and training plans in this K23 will launch my career as an independent clinician-scientist and and leader in the use of behavioral economics financial incentives in psychosis treatment and an expert in the ethical application of these strategies.