University Of California Los Angeles

NSF Awards · FY 2025 · 2025-04

This I-Corps project is based on the development of a tool to assess mental health conditions using wearable sensors to monitor stress. Currently, insurance companies and clinicians rely on patient self-reports, psychological assessments, and limited physiological monitoring such as pulse, heart and respiratory rate, and the electrical activity of the brain to assess mental health conditions. However, these methods are often inconsistent and prone to error. This technology is based on the use of a sensor to measure cortisol levels in the body, which is the primary stress hormone. Alterations in cortisol levels have been shown to correspond to stress and mental state. This technology may fill the critical gap in how mental health is measured and treated. The goal is to improve outcomes for patients with mental health conditions. This I-Corps project utilizes experiential learning coupled with a first-hand investigation of the industry ecosystem to assess the translation potential of a quantitative cortisol measurement tool based on acoustic wave sensors and molecularly imprinted polymers (MIPs). This solution is a wearable technology that aims to provide a continuous assessment of the mental state of a patient based on cortisol levels in the body. This sensor technology combines MIPs with acoustic wave devices to provide continuous cortisol monitoring. Cortisol is targeted using a MIPs bioreceptor that is capable of operating in situ continuously. The binding of cortisol in the MIP leads to a shift in the resonant frequency of the acoustic wave devices made of piezoelectric materials. The frequency shift can be electrically read by applying voltages to the acoustic wave devices. This innovation may enable better assessment of mental health conditions, better treatment decisions, and improved patient outcomes. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2025 · 2025-03

The objective of this Grants for Rapid Response Research (RAPID) project is to collect ephemeral data to better understand the evacuation experience of households affected by fast-moving urban wildfires in Pacific Palisades and Altadena, California. The project examines how people evacuate (travel mode, time, routes), where they find immediate shelter, and the effect of the evacuation experience on evacuees and their future housing decisions. Cities continue to develop in wildland-adjacent areas, greatly increasing community exposure to wildfires. The findings from this study provide the data to improve how households, emergency responders, and management agencies prepare for and respond to this growing threat. The increase in urban wildfires highlights the need to better understand human behavioral responses to them, an area of research with significant gaps. This RAPID project focuses on wildfire evacuation and collects survey data from a heterogeneous set of households affected by the two recent urban wildfires in Pacific Palisades and Altadena, California. The data are collected using a random sample of households in the most affected neighborhoods and a convenience sample collected through non-profit and community partners. The survey instruments include questions on evacuation (mode, routes, and experience), the evacuation experience, and shelter or housing destinations and type. The survey data are paired with information on the built environment in the evacuated neighborhoods and the location and timing of official evacuation notices. The survey, combined with other supplementary data, provide the foundation for improved behavioral models and serve as the basis for strengthening evacuation procedures in urban wildfires and other disasters. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2025 · 2025-03

This project will examine ion-neutral coupling processes at high latitudes to understand how the thermospheric dynamics affect the electron density structures and associated ion outflow. The upper atmosphere above 100 km altitude consists of electrically neutral gases as well as electrically charged ions and free electrons. The neutral component is called the thermosphere, and the charged components are called the ionosphere. The ionosphere significantly alters the propagation of radio waves passing through it, including communication and navigation signals transmitted from satellites. Because of their impacts on radio propagation, understanding the processes creating structures in the ionosphere is a critical part of space weather research. This research will be conducted with numerical models of the coupled thermosphere and ionosphere as well as analysis of ionospheric data from radars and the global positioning system. The project will support a graduate student and the models will be open-source to the community. Results of the project will be used to create classroom examples of ionospheric phenomena for use in undergraduate and graduate classes at UCLA. The polar cap ionosphere contains a variety of mesoscale (100-1000 km) electron density structures, including polar cap patches and tongues of ionization. The electron density gradients associated with these structures can drive plasma instabilities and severely affect radio propagation at high latitudes. The polar cap ionosphere is also the source of significant ion outflow to the magnetosphere, and the polar wind reflects the structuring of the high-latitude ionosphere. Magnetospheric energy inputs drive significant variations in the high-latitude neutral thermosphere. This project will examine ion-neutral coupling processes at high latitudes to understand how the thermospheric dynamics affect the electron density structures and associated ion outflow. The specific science questions to be addressed are (1) How do thermospheric density and composition changes during geomagnetic storms affect the formation and evolution of high-latitude electron density structures? and (2) How do thermospheric variations modulate the supply of ion upflow and outflow? These questions will be addressed with controlled numerical experiments coupling the Thermosphere Ionosphere Electrodynamics General Circulation Model 3.0 (TIEGCM 3.0) model of the neutral thermosphere to the High-latitude Ionospheric Dynamics for Research Applications (HIDRA) model of the high-latitude ionosphere and polar wind. The team will contrast simulations using the coupled model to simulations using a static thermosphere to isolate ion neutral coupling effects. They will compare the simulation results to observations of high-latitude density structures from incoherent scatter radars (e.g. RISR) and GPS total electron content observations. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2025 · 2025-03

This RAPID project will provide important information on the local air quality associated with recent fires in Los Angeles. The Eaton and Palisades fires that broke out in early January have been labeled the second and third most destructive fires on record in California. Residents in these areas continue to face uncertainty as to how air quality during and after these fires has impacted their health. The work will provide timely information to the residents of these areas on their air quality during the fires and offer general insight into the potential health impacts of fires like these that occur at the wildland urban interface. The objectives of this project are to: (1) Investigate the impact of the Palisades and Eaton Fires on the concentrations of volatile organic compounds (VOC) in the Los Angeles area, and (2) Develop a process-level understanding of VOC persistence in indoor spaces following a wildland urban interface fire. A suite of research-grade instrumentation was deployed on the roof of UCLA’s Young Hall from January 11-30, 2025, during an intense phase of the Eaton and Palisades fires. The site is approximately 6 miles from the Palisades fire and 20 miles from the Eaton Fire. These data will be used to identify signatures of emissions from fires and burn areas, examine differences as compared to typical biomass burning emissions, assess correlations between VOC concentrations and more typical metrics of air quality, and use a photochemical box model to assess potential impacts on ozone production during and after the fires. A set of follow-up measurements will be performed 1 year later in the same location with the same instrumentation to serve as a baseline for comparison of smoke-impacted measurements. Samples of common household materials will be collected from several smoke-impacted homes in the Pacific Palisades and Altadena neighborhoods of Los Angeles, as well as similar materials from homes in less-impacted areas of Los Angeles. VOC off-gassing will be measured under controlled conditions to assess how individual materials and surfaces contribute to the lingering effects of VOC partitioning on indoor air after a fire. The project will provide full support for a graduate student. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2026 · 2025-03

Project Summary The goal of this study is to evaluate mitochondrial networks as a critical determinant of response to antibody drug conjugates (ADCs) in advanced/metastatic (adv/met) non-small cell lung cancer (NSCLC). Recent advances with immune checkpoint inhibitors and targeted therapy have revolutionized the treatment of adv/met NSCLC, but most patients eventually develop therapy resistance. As such, novel approaches to the management of adv/met NSCLC are emerging, including three promising ADCs with the topoisomerase I (topo I) payload deruxtecan (DXd) that target HER2 (T-DXd), HER3 (HER3-DXd), and TROP2 (Dato-DXd). Importantly, recent data suggest that these three DXd-ADCs are effective in adv/met NSCLC after failure of standard therapies. Upon target receptor binding (HER2/HER3/TROP2), DXd-ADCs are internalized via receptor-mediated endocytosis, leading to cleavage of a plasma stable linker, selective delivery of the DXd payload, and DXd mediated tumor cell apoptosis. As such, it would be predicted that the efficacy of DXd-ADCs would be reliant upon high tumor target receptor expression assessed by IHC and expressed as an H-score. However, published data suggest that H-scores are unreliable predictors of patient response to DXd-ADCs and no clear understanding of the biological principles underlying NSCLC tumor response to these emerging agents exists. Apoptosis is the cytotoxic endpoint of the DXd payload, a process that is governed by mitochondria, and our preliminary data, generated via the novel structural/functional analysis that integrates positron emission tomography (PET) imaging with ultra-resolution microscopy, suggest that the structure and function of mitochondrial networks is mechanistically linked to DXd-ADC induced apoptosis. As such, we hypothesize that tumor intrinsic mitochondrial network structure and function dictate response/resistance to DXd-ADCs in NSCLC. To test this, Aim 1 will investigate baseline mitochondrial network architecture as a critical determinant of DXd- ADC response in NSCLC by profiling mitochondrial networks and cristae in cell lines, xenografts, patient-derived xenografts (PDXs), and tumor samples from DXd-ADC treated patients. In Aim 2, we will investigate mitochondrial network remodeling as a critical mechanism of DXd-ADC adaptive resistance, by quantitatively measuring changes in mitochondrial networks in cell lines, xenografts, PDXs, and primary patient tumors as DXd-ADC resistance occurs. Since most NSCLC patients do not respond to DXd-ADCs, quantitative profiling of mitochondrial networks has the potential to improve DXd-ADC patient outcomes by identifying conserved biological principles underlying treatment response.

NIH Research Projects · FY 2026 · 2025-03

PROJECT SUMMARY & ABSTRACT Poverty drives inequities in parent health, birth outcomes, and child development, but financial interventions in health care are rare. Low income and financial stress increase mental and physical health risks, chronic illness, preterm birth, child developmental delay, and unmet medical needs. Given that half of Americans report living paycheck-to-paycheck, financial stress is common, especially in pregnancy and infancy, with disproportionate impacts on marginalized communities and population-wide consequences for adult health and child development. While the National Academy of Medicine recommends health systems address poverty-related social needs in clinical settings, some medical professional organizations have gone further to recommend anti-poverty income and financial supports as health interventions. This has led to growth of Medical-Financial Partnerships (MFPs), which are cross-sector service collaborations of medical and financial professionals to reduce poverty and financial hardship directly as an upstream cause of health risks. Financial coaching improves income, savings, debt, and financial stress using standard tools and techniques similar to motivational interviewing applied to supporting clients’ financial goals, but its reach could be much greater if integrated with clinical care, which nearly all infants and parents routinely access. Our team, including the national nonprofit financial coaching organization LIFT, completed a community-partnered pilot randomized trial of clinically-integrated financial coaching in a single pediatric clinic that improved parent mental health, preventive visit adherence, and income, as well as potentially reducing child developmental delay risk. Because financial stability in pregnancy protects maternal mental health and child development, the pediatric MFP intervention’s health impact could be even more effective if begun during prenatal care. We propose a multi-clinic randomized clinical evaluation of the impact of clinically-integrated financial coaching on perinatal and postnatal parent mental health and health-related quality of life, infant low birthweight, child developmental delay, health care adherence, family income, and public benefits use. We will examine the MFP intervention’s mechanisms by exploring timing and mediation effects across the pregnancy and newborn periods while assessing implementation factors influencing its success. We will partner with clinics in the Los Angeles County Department of Health Services network, the second largest public health care system in the US. This community-partnered study will continue our collaboration with LIFT, a national nonprofit financial coaching organization, to inform the intervention, as well as a national external advisory MFP Learning Community for insights on implementation and dissemination. We anticipate this study will advance the field of clinical interventions addressing social and economic drivers of health, providing evidence on an innovative approach to reduce inequities in mental health and child development.

NIH Research Projects · FY 2026 · 2025-03

PROJECT SUMMARY/ABSTRACT Cancer immunotherapy with T-cells expressing a transgenic T-cell receptor (TCR) or chimeric antigen receptor (CAR) can generate dramatic clinical responses in a variety of solid tumors. However, a significant number of patients do not respond to therapy. We have previously shown that increased secretion activity of tumor necrosis factor alpha (TNF-alpha) is associated with superior clinical responses to TCR-T cell therapy. Furthermore, we have shown that increased TNF-alpha activity reduces immunosuppressive T helper 2 (Th2) cell activity, which is associated with inferior response to therapy due to their anti-effector functionality. We have generated novel lentiviral vectors which simultaneously encode for TNF-alpha along with a tumor antigen-specific TCR or CAR (which we have termed a TNF-alpha-“armed” TCR/CAR vector). Treatment with TNF-alpha-armed TCR-T cells results in enhanced anti-tumor activity in vitro and in vivo in preliminary humanized mouse xenograft studies. Importantly, the improved antitumor functionality was not associated with increased systemic toxicity, due to the antigen-dependent nature of the increased TNF-alpha secretion. We hypothesize that utilizing TNF-alpha-armed TCR/CAR-T cells will result in superior antitumor efficacy of the transgenic T-cells compared to conventional TCR/CAR-T cells. We will explore our hypothesis in a wide variety of TCRs and CARs and associated tumor types via two related but independent aims. Aim 1 will evaluate the impact of transgenic TNF-alpha co-delivery with a transgenic TCR or CAR on T-cell anti- tumor functionality and toxicology in humanized murine xenografts, as well as T-cell infiltration into the tumor microenvironment and gene expression patterns of the tumor tissue in response to the increased TNF-alpha activity via spatial transcriptomics/proteomics. We hypothesize that TNF-alpha-armed TCR/CARs will result in superior anti-tumor functionality in vivo compared to conventional TCR/CAR-T cells without increased toxicity. Aim 2 will explore the T-cell intrinsic impact of increased TNF-alpha activity on T-cell functional phenotype and the underlying signaling mechanisms in the face of chronic antigen stimulation. Tumor-infiltrating lymphocytes obtained from the same humanized mouse xenografts obtained in Aim 1 will be interrogated with mass cytometry, single-cell cytokinetic polyfunctionality assays, and single-cell phospho-proteomics. Repetitive tumor cell stimulation assays in vitro, as well as TNF-receptor-2 knockouts will serve as confirmatory experiments. We hypothesize that the addition of transgenic TNF-alpha to TCR/CAR-T cell therapeutics will augment TNF- alpha/TNF-receptor 2 signaling, leading to inhibition of Th2 immunosuppressive cytokinetic activity. This project represents an innovative approach to improve transgenic T-cell therapeutics and further elucidate the role of TNF-alpha in T-cell biology. Our findings will set the stage for the translation of TNF-alpha-armed TCR/CAR T-cells into the next generation of adoptive T-cell therapies for solid tumors.

NIH Research Projects · FY 2026 · 2025-03

Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. Modern healthcare data, e.g., electronic medical records (EHRs) and biobanks, provide massive multi-level and multi-scale information over a long period. These datasets offer a unique opportunity to quantify disease progression and the associated time-varying risk factors. However, existing statistical algorithms and tools that can effectively analyze exposure trajectories and disease onset at this scale and complexity lag behind. This proposal aims to fill these gaps by delivering novel statistical methods, computational algorithms, and user-friendly software to study individual health trajectories relevant to disease onset and progression for biobank scale real-world data. It is motivated by our team’s recent experiences analyzing the UK Biobank, VA EHRs, NIH All of US, and other complex data sources. The proposed work will push forward several frontiers in biostatistics, optimization, and clinical medicine (i.e., personalized diabetes management, dynamic prediction, and early detection of disease progression).

NIH Research Projects · FY 2026 · 2025-03

PROJECT SUMMARY/ABSTRACT Anxiety disorders, including generalized anxiety disorder (GAD) and post-traumatic stress disorder (PTSD), are the most prevalent mental health conditions globally with a high rate of treatment resistance and substantial healthcare costs. These disorders are believed to stem from fear responses that are excessive and disproportionate to the situation. Therefore, understanding how the human brain processes fear and how this may go awry in anxiety disorders is crucial for developing effective therapies. Research using rodent models of anxiety suggests that the formation and regulation of fear responses to the environment require a complex interplay between two brain structures, the amygdala and hippocampus. However, it is unknown whether these findings can be translated to the human brain, and whether modulating neural activity associated with maladaptive fear responses can be used as a therapeutic tool to treat anxiety disorders. This project aims to 1) elucidate the neural mechanisms governing the acquisition, extinction, and renewal of fear and anxiety responses within the hippocampal-amygdala circuit in humans, 2) investigate whether targeted stimulation of the amygdala, aimed at dampening its role in maintaining fear responses to innocuous stimuli, can facilitate recovery from maladaptive fear responses, and 3) explore potential differences in outcomes based on individuals’ baseline anxiety levels. To address these questions, we will work with participants who have previously undergone surgical implantation of a responsive neurostimulation (RNS) device in the amygdala and hippocampus for the treatment of epilepsy or PTSD. The RNS is a chronically implanted intracranial recording and stimulation device that provides a unique opportunity to directly record from the hippocampal- amygdala circuit and deliver targeted stimulation. To simulate real-world fear responses and assess the impact of environmental context on fear learning, we designed a virtual reality (VR) experiment where participants acquire and subsequently extinguish fear responses to various stimuli within different virtual environments (e.g., library, grocery store), providing insights into how contextual cues influence fear responses. This award will allow me to complete a multifaceted career development plan under a world-class mentoring team. Building upon my prior experience with acutely implanted intracranial electrodes, I will broaden my skill set to encompass mobile (chronic) intracranial electrophysiology and targeted electrical stimulation. I will also develop expertise in the implementation of immersive, ambulatory VR experiments in human neuroscience research. Lastly, through seminars, coursework, and conferences, I will develop both as an experimental scientist and scientific communicator. Taken together, this will allow me to grow into an independent physician- scientist who effectively leverages innovative technologies to study the mechanisms of anxiety disorders.

NIH Research Projects · FY 2025 · 2025-03

PROJECT SUMMARY Youth in custody face significant health challenges, including high rates of sexual and reproductive health issues, substance use disorders, chronic medical conditions, and poor quality of care, leading to preventable morbidity and mortality. These issues are exacerbated by substandard healthcare and a lack of evidence- based guidelines. The proposed “American Pediatric Society: Building the Evidence Base to Improve Pediatric Care for Youth in Custody Conference” aims to address these gaps by establishing a research network focused on improving healthcare for youth in custody. Aim 1 will identify barriers to evidence-based care for youth in custody, focusing on behavioral health and chronic diseases such as asthma and sickle cell disease. Aim 2 activities will result in the development of collaborative multi-center investigator teams that close research gaps in youth carceral healthcare, utilizing a mentorship model to support early career researchers. The conference is scheduled for April 2025 in Honolulu, Hawaii, adjacent to the Pediatric Academic Societies Annual Meeting, leveraging a pre-existing meeting. The conference grant will include pre-workshop activities to identify key barriers and workshop sessions to further illuminate key barriers and develop priority strategies to support early initiation of a research network. The conference will leverage recent initiatives by the American Pediatric Society (APS) and partnerships with organizations like the Equal Justice Initiative. The main impact of the conference is that it will lay the groundwork for the establishment of the APS-KIDS (Kids in Detention Services) Pediatric Research Network, aimed at improving health outcomes for youth in custody. Expected outcomes include published recommendations, development of research teams, and establishment of infrastructure for future NIH grant submissions. The conference activities will also support the careers of diverse early career researchers.

NSF Awards · FY 2025 · 2025-03

This project brings together two scientific fields: distributed computing and descriptive set theory. Distributed computing is the area of computer science that studies distributed systems, i.e., decentralized networks of computers that communicate with each other by passing messages. Distributed computing is especially relevant in the modern era of large networks, such as the Internet, where millions of machines are interconnected. On the other hand, descriptive set theory investigates the structure of subsets of the real line and other well-behaved spaces. It is used to understand the complexity of various sets defined by mathematical formulas and to classify them according to their complexity. Surprisingly, it turns out that these two areas are closely related, and that ideas and results from one can often be applied in the other. As this relationship has only recently been discovered, it is still poorly understood. This project will explore it in depth with the ultimate aim of developing a unified theory that integrates the two subjects. The educational component of this project is focused on creating opportunities for junior researchers to enter this rapidly developing field. Specifically, it will support training of graduate students and designing a suite of materials (textbooks and lecture notes, instructional videos, workshops, and courses) aimed at students and scholars with background in combinatorics or computer science but no prior exposure to descriptive set theory. Known interactions between descriptive combinatorics and distributed computing take place in the framework of locally checkable labeling (LCL) problems, where the objective is to assign labels to the vertices of a given graph subject to some "local" constraints. Part of the project is to investigate the following general question: Given an LCL problem that can be solved with some degree of regularity (e.g., Borel, measurable, etc.) on Borel graphs, when can we find an efficient algorithm for this problem in some model of distributed computation? Currently, the answer is only known in a few special cases, and this project aims to extend it to a much wider context. Another goal of this project is to develop an effective classification of the complexity of LCL problems from the perspective of descriptive set theory and distributed computing, or to prove that such classification is impossible. Thirdly, this project will study specific problems of particular interest, such as graph coloring and perfect matchings. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2025 · 2025-03

Wildfires pose a severe threat to civil infrastructure, especially in high-density wildland-urban interface (WUI) communities. The January 2025 Los Angeles wildfires, including the Palisades and Eaton Fires, were among the most destructive in California's history and resulted in extensive infrastructure damage. This Grant for Rapid Response Research (RAPID) award supports research to analyze wildfire impacts on infrastructure resilience in highly dense WUI communities by collecting and analyzing perishable field data on the performance of infrastructure in areas impacted by the Eaton and Palisades Fires. This data collection will support advancements in predictive modeling for infrastructure performance, the design of fire-resilient infrastructure, and the formulation of guidelines for wildfire mitigation. The objectives of this RAPID project are to (a) collect high-resolution aerial and ground-based data on fire-impacted structures and communities; (b) analyze structure-to-structure fire spread patterns and key resilience factors; (c) evaluate the effectiveness of firebreaks and mitigation strategies; and (d) enhance fire propagation modeling based on observed data. This data will include (a) high-resolution aerial scans of regions impacted by both fires; (b) ground-based inspections of characteristics of building clusters, including structural features, defensible spaces, and layout of the neighborhood in selected areas; (c) attributes of standing and lightly damaged buildings (separation distance to nearby structures, construction material, defensible spaces, windows, vents, roofing types, and attached deck or fences are among factors to be studied); (d) ground-based inspections of schools including property layout, distance to nearest structures, and orientation of the school with respect to the fire front and wind direction; and (e) damage indicators for reinforced concrete bridges such as cracking, crazing, spalling, and color change, and non-destructive testing to evaluate material change in strength. The data collection will use the Unmanned Aerial Systems and LiDAR equipment provided by the NSF-supported Natural Hazards Engineering Research Infrastructure (NHERI) Natural Hazards and Disaster Reconnaissance (RAPID) facility at the University of Washington. The data collected from this project will be archived and made publicly available through the NHERI Data Depot (https://www.DesignSafe-ci.org). This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2026 · 2025-02

PROJECT SUMMARY Over 20 million individuals in the United States live with an autoimmune disease, resulting in significant disability and mortality. The increasing prevalence of autoimmune diseases raises the stakes to develop new therapies. Harnessing Tregs as a cellular therapy is a promising and attractive treatment approach for autoimmunity. However, Tregs represent a rare cell subset and can exhibit unstable suppressive function due to the unstable expression of master transcription factor FOXP3. We propose a novel approach to study the role of endogenous and exogenous FOXP3 expression in thymic-like Treg development from a self-renewing source: induced pluripotent stem cells (iPSC). Pilot data demonstrate the ability of artificial thymic organoids (ATOs) – developed in the Crooks’s Lab – to support the differentiation of CD4+FOXP3+ T cells from iPSC (henceforth “iPSC-Tregs”). In Aim 1, Dr. Yiu will test methods to enhance endogenous FOXP3 expression in iPSC and compare iPSC-Tregs to Tregs isolated from the thymus (tTregs) and peripheral blood (pTregs) based on their immunophenotype, transcriptional pattern, hypomethylation, and suppressive function. Because constitutive FOXP3 expression blocks T cell development, in Aim 2, Dr. Yiu will link exogenous FOXP3 transgene expression to endogenous genes that are only expressed at mature T cell stages, via CRISPR/Cas9. In Aim 3, Dr. Yiu will transduce iPSC with exogenous T cell receptors (TCRs) isolated from either a non-Treg or Treg cell, to determine the effect of TCR expression and identity on Treg fate and antigen-specific suppressive function. This proposal is a five-year research career development plan for the Principal Investigator, Dr. Gloria Yiu, M.D., Ph.D., a physician-scientist and Assistant Professor of Medicine in Rheumatology at the University of California, Los Angeles (UCLA). During the award period, Dr. Yiu will be mentored by Dr. Gay Crooks, M.D., an expert in stem and T cell development, distinguished physician-scientist, and accomplished mentor with a productive track record of mentoring physician-scientists. Dr. Yiu will also obtain Treg expertise from co-mentor Dr. Maureen Su, M.D., a leading physician-scientist at the forefront of mouse and human autoimmunity. The goal of this proposal is to build upon Dr. Yiu’s rigorous background in cellular immunology and gain new training in gene editing, advanced transcriptomic and proteomic techniques, and bioinformatics. This will be accomplished through high- yield didactic coursework and guidance from advisory committee members, who were carefully selected for their relevant scientific expertise and impressive records of mentorship. UCLA’s Department of Medicine and Division of Rheumatology will provide the resources, support, and infrastructure to assist Dr. Yiu in achieving the aims described in this proposal and her long-term goal of developing into an independent physician-scientist studying Treg development for the treatment of autoimmunity.

NIH Research Projects · FY 2026 · 2025-02

Overall-Project Summary/Abstract The NIH Human Microbiome Project has redefined our understanding of the human bacteriome, opening new avenues of research in the biomedical and behavioral sciences and improving healthcare delivery. However, the human virome remains largely unexplored. In response to this gap, the NIH Human Virome Program (HVP) offers the opportunity to uncover the spectrum of “healthy” viromes across the lifespan, facilitating identification of alterations associated with disease and further advancing biomedical research and healthcare delivery. Toward this goal, we propose to establish this Human Virome Characterization Center (HVCC) for the Oral–Gut–Brain Axis, a known functional unit with a central role in human health. Informed by our team’s long-standing expertise studying these organs and their interconnected physiology, we will create an organizational hub for virome study, leveraging multiple unique and diverse cohorts. Our goal is to identify and characterize the viruses comprising the human virome across the oral–gut–brain axis, providing accurate estimates of its richness and complexity in healthy cohorts across the life/healthspan. In support of this goal, we bring together investigators at several institutions, including UCLA, Baylor College of Medicine, Mayo Clinic, Penn State, USC, UCSD, NIH/NIDCR, with broad experience successfully guiding large NIH programs. We will establish five interacting Cores— Administrative, Biospecimen Collection, Biospecimen Analysis, Data Analysis and Submission, and Ethical, Legal, and Social Implications (ELSI)—that will work together to identify the viromes in numerous patient cohorts diverse in age, race/ethnicity, each derived from the three target organs. Our Cores have interdisciplinary expertise across key areas, including virome/microbiome sequencing, biomedical informatics/data science, and patient recruitment/tissue banking, and will be tasked with handling multiple data types (virome/microbiome, genomic, neuroimaging) to support the broad aims of our HVCC. The Biospecimen Collection Core will leverage prospective cohorts and retrospective biospecimen banks at UCLA, Mayo Clinic, and NIH/NIDCR, as well as several future cohort opportunities (All of US, Together for Change, AIIMS/India). Our Biospecimen Analysis Core will use cutting-edge technologies to sequence the viromes in our biospecimens, and our Data Analysis and Submission Core will analyze the data we collect using innovative bioinformatics, data science, and machine- learning tools to uncover clinical, physiologic, and genetic interactions that shape the human virome. The ELSI Core will provide policies and guidance and conduct original research to explore the ELSI of this work. The Administrative Core will bridge the patient cohort teams with the supporting Cores to ensure seamless operation and coordination with the broader HVP. Our Cores are designed to maximize the integration and sharing of ideas through dynamic, contemporary communication methods, promoting refinement and dissemination of best practices between our group and the wider scientific community. In doing so, this HVCC will provide a unified framework to broadly advance our understanding of the oral–gut–brain virome toward improving human health.

NIH Research Projects · FY 2025 · 2025-02

Project Summary/Abstract Poor sleep is common among Asian Americans. Untreated sleep problems increase the risk of chronic diseases, cognitive decline, and mortality. Cognitive behavioral therapy for insomnia (CBTI) is considered the first-line treatment for chronic sleep problems and has demonstrated significant improvement in sleep health among older adults. However, existing CBTI is built upon Western culture, making it challenging to apply for Asian immigrants who maintain close ties to their native cultures that shape and influence their sleep habits. Addressing the lack of availability of a culturally adapted sleep intervention program is the first step to filling the gap in sleep health disparity among Asian immigrants. The current proposal aims to develop a culturally adapted sleep intervention program for older Korean immigrants with poor sleep and to evaluate its feasibility and preliminary efficacy. In Year 1 of the project, using the cultural adaptation strategies guided by Barrera and colleagues and prior studies, we will refine an existing behavioral sleep intervention program built upon the core components of CBTI with input and feedback from key stakeholders and older Korean immigrants in a community setting. Next, we will train a sleep educator to deliver the intervention at a community-based agency serving older Korean immigrants. In Year 2 of the study, we will conduct a pilot randomized clinical trial in which the study participant (N=32) will be randomized to either (a) our culturally adapted sleep intervention group or (b) the control group (general sleep education only). We will evaluate the feasibility of the intervention and the preliminary effects of the intervention on sleep health outcomes among Korean immigrants. The knowledge gained from this study can potentially improve the lives of Asian immigrants with poor sleep. If our sleep intervention program is acceptable and feasible for delivery in the community setting and shows superior clinical outcomes compared to the control group, the preliminary findings will pave the way for a larger clinical trial to examine the efficacy of the sleep intervention in the long term. The intervention manual is scalable and can be easily delivered by staff in various community settings. It also has the potential to increase its accessibility and adherence to the intervention recommendation.

NSF Awards · FY 2025 · 2025-02

This award supports a meeting on mathematical logic, titled a Very Informal Gathering of Logicians, from Friday February 7, to Sunday February 9, 2025, at the University of California Los Angeles. This is the twenty-second in a series of biennial logic meetings at UCLA which, starting in the mid 1970s, has been one of the most important forums for mathematical logic on the West Coast. The meeting is a key opportunity for logicians to learn about and discuss important advances in research, to exchange ideas, and to collaborate on scientific projects. About half the grant funds are dedicated to travel awards for graduate students and early career researchers, to allow them to come to the meeting. Most of the participants will be research mathematicians and university teachers. What they learn at the meeting will have a positive impact on their research and teaching. The meeting is scheduled to have eleven talks, on a wide range of topics within mathematical logic, including set theory, descriptive set theory, model theory, recursion theory, and philosophical logic, with speakers at all career stages who have obtained outstanding results in these fields. There is particular emphasis on descriptive set theory, in honor of Alekos Kechris, on the occasion of his formal retirement from Caltech. One of the talks is a named lecture in honor of Greg Hjorth. The 2025 Hjorth speaker is Grigor Sargsyan. The meeting's webpage is at http://www.math.ucla.edu/~ineeman/Conf/VIG2025/ This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2025 · 2025-02

Experiences of early-life adversity (ELA) are associated with a range of physiological and behavioral changes. However, the pathways through which these effects occur and their relationship to survival and reproduction remain unclear. This Doctoral Dissertation project addresses key questions regarding how ELA shape adult features in ways that increase survival and reproduction under conditions of adversity. Information obtained in this study is of interest to the fields of evolutionary medicine, sociology, developmental psychology, and public policy. This project investigates connections between ELA, developmental plasticity of the hypothalamic-pituitary-adrenal axis (HPAA), life-history strategies, and behavior in a non-human primate species. The research takes advantage of a pre-existing longitudinal dataset containing fine-grained detail on the early lives, hormones, and behavior. The study tests a theory of facultative calibration of life-history strategies by assessing whether plasticity of the HPAA moderates the relationship between ELA and behaviors such as risk-taking and aggression. These behaviors have been theorized to both increase the risk of mortality and accelerate reproductive timing in the males of this species. This project provides training opportunities for undergraduate and graduate students to prepare for a career in the sciences. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2025-02

ABSTRACT Glioblastoma (GBM) is the most common and aggressive form of malignant glioma, carrying a dismal prognosis of a median survival of around 14-20 months; while brain metastases (BMs) affect 10-25% of all adult patients with cancer, with an annual incidence of 98,000-170,000 new cases and rising. The dismal prognosis of malignant brain tumors along with lack of effective therapies emphasizes the need for comprehensive and multi- disciplinary training programs that prepare the next generation of brain cancer scientists. Neuro-oncology is multidisciplinary field involving coordinated research and clinical activities between oncology, neurology, neurosurgery, radiation oncology, radiology, immunology, pharmacology, pathology, computational biology, neuroscience, biochemistry, and biostatistics. As such, there is tremendous need for translational research training programs that can cross these broad disciplines and provide mentoring and support for young investigators who will become future leaders in neuro-oncology research. The Neuro- Oncology Translational Research Training Program (NOTR-TP) at University of California Los Angeles (UCLA) will establish a new multidisciplinary translational research program within Southern California with the goal of considerably expanding and significantly impacting brain tumor research and clinical care. The UCLA NOTR-TP will support a total of 4 trainees: 1 predoctoral and 3 postdoctoral trainees, including 1 basic scientist (PhD) postdoctoral trainee and 2 clinician-scientist (MD or MD/PhD) postdoctoral trainees, over 2-3 years. Twenty-two expert senior investigators spanning more than 10 different departments and 6 training programs will form the core faculty mentor group. These investigators have unique experience in mentoring pre- and post-doctoral fellows, have a remarkable publication record in neuro-oncology research, and have extensive NIH and extramural support. Outstanding applicants with a PhD, MD, or MD/PhD will be recruited with emphasis on identifying trainees from underrepresented backgrounds to promote diversity. The UCLA NOTR-TP Training Program is an comprehensive, multidisciplinary translational research program consisting of (1) a core curriculum of educational courses across a broad range of disciplines and scientific programs at UCLA; (2) research rotations and training in 2 or more neuro-oncology focused laboratories at UCLA; (3) participation in weekly brain tumor board meetings; (4) attendance and presentation at regular intramural (e.g. SPORE) and extramural scientific and educational meetings (e.g. SNO, ASCO, AACR, etc.); and (5) immersive and concentrated research in a laboratory or laboratories focused on translational neuro-oncology research. Trainees will learn critical thinking skills related to solving clinical and biological problems in neuro- oncology, gain an understanding of diverse areas in neuro-oncology research, as well as master experimental methods and proficiencies related to specific sub-disciplines within in the neuro-oncology research field.

CIHR Grants and Awards · FY 202526 · 2025-02

Pain is a the most common reason people seek health care, and many North Americans live with chronic pain. Opioids used in the treatment of pain can be harmful when misused creating a need for safer treatments. Medical cannabis is often used to relieve pain, and there's evidence that certain compounds in cannabis, called terpenes, may play a role in this. Terpenes are safe and have potential for medical use. One terpene in cannabis, B-caryophyllene (BCP), has been shown to reduce pain in animals, but we do not fully understand how it works and have not tested it in people. Our research has two main goals: 1) determine if BCP can reduce pain in men and women, and 2) understand how BCP affects pain in mice. We will give different dosages of BCP or placebo in a controlled setting in humans and measure intoxication, abuse risk, pharmacology, pain perception, and general mood. We will also use regular and genetically modified mice to examine similar outcomes, as well as use special neural sensors to determine BCP's mechanism of action. This research will help us understand not only whether BCP can be used to manage pain but also how it is involved in pain management. Ultimately, this work may lead to new and improved ways to help people living with pain as we determine efficacy and safety in both preclinical and clinical studies. Keywords: CANNABINOIDS; TERPENES; BETA-CARYOPHYLLENE; PAIN; ANALGESIA; SEX DIFFERENCES; NEUROIMMUNE; DRUG PHARMACOKINETICS; CLINICAL; PRECLINICAL

NIH Research Projects · FY 2026 · 2025-02

Project Summary Posttraumatic stress disorder (PTSD) is an often chronic and disabling mental disorder that can have adverse consequences for health. Indeed, PTSD has been linked to heightened incidence of cardiovascular disease (CVD) and mortality. Fortunately, there are highly effective treatments for PTSD, including evidence-based psychotherapies (EBPs) and evidence-based antidepressants (EBAs). However, it is not yet known if these evidence-based treatments for PTSD can reduce incidence of CVD or mortality, likely due to limitations of existing epidemiologic datasets and the infeasibility of answering these questions in a randomized controlled trial framework. The proposed project is distinctively poised to address these questions by harnessing a unique data resource: the world’s most comprehensive PTSD treatment database, with up to 20 years of data on over 2 million veterans with PTSD receiving care in the United States Department of Veterans Affairs healthcare system. Not only does this data resource have electronic health record (EHR) documentation of pharmacotherapy for identifying EBA receipt, but we trained Natural Language Processing algorithms to identify EBPs for PTSD, as well as changes in PTSD symptoms on a validated self-report measure. By analyzing these comprehensive EHR data, including treatment receipt, PTSD symptom severity, CVD diagnoses, and mortality, in a large, diverse sample of veterans, the proposed project is thus uniquely positioned to address the impact of evidence-based treatment for PTSD on CVD outcomes. In Aim 1, we will examine whether incidence of CVD and mortality (cardiovascular and all-cause) vary by evidence-based PTSD treatment received (EBP, EBA, both EBP/EBA, no evidence-based treatment). We hypothesize that receipt of evidence-based PTSD treatment will be associated with reduced incidence of CVD (e.g., myocardial infarction, stroke, as documented with diagnostic codes in the EHR) and mortality, with variability by treatment type (e.g., EBPs may have more CVD benefit than EBAs given some findings of heightened CVD incidence with EBAs). In Aim 2, we will investigate whether clinically significant improvement in PTSD symptoms, as well as symptomatic remission, are associated with reduced CVD incidence and mortality, within type of treatment received. Although treatment receipt alone may have implications for cardiovascular health, we predict that treatment accompanied by clinically significant PTSD symptom improvement or symptomatic remission will be more strongly associated with reduced CVD incidence and mortality. In Exploratory Aims, we will examine these associations in models stratified by relevant patient characteristics, namely sex, race, and ethnicity. This project brings together an interdisciplinary team of experts, a cost-effective use of an existing data resource, and innovative questions to identify potential interventions for a leading cause of death and disability. Findings have the potential to guide treatment decisions for patients with PTSD to best promote cardiovascular health and inform new approaches to prevent and treat CVD in broader patient samples.

NIH Research Projects · FY 2026 · 2025-02

ABSTRACT The goal of this research is to discover novel regulators of cellular deformability that block cancer cell spread; to achieve this goal we will use a high throughput cell filtration platform that is unique to the Rowat Laboratory at UCLA. While most treatments for high grade serous ovarian cancer (HGSOC) are initially effective in reducing tumor growth and spread, cancer recurs in over 80% of ovarian cancer patients because cells become resistant to common, platinum-resistant chemotherapy drugs. There is a critical need for new therapeutics to block the spread of chemoresistant tumor cells. While much research focuses on characterizing the genetic and biochemical differences in chemoresistance, our proposed research will establish a new paradigm for screening in drug discovery. Our previous research demonstrates that platinum-resistant ovarian cancer cells are more compliant, or more deformable, than their drug-sensitive counterparts. These drug-resistant cells also showed characteristics of mesenchymal cells; epithelial-to-mesenchymal transition is implicated in disease progression. Using the novel High Throughput Filtration (HTF) screening technology that we recently invented, we can distinguish platinum-resistant and platinum-sensitive cells on the basis of their deformability. In the proposed research, we will use our HTF technology to screen platinum-resistant cell lines against large libraries of small molecules to identify novel compounds and targets that reverse the deformability of platinum-resistant cells to levels of the drug-sensitive controls. We hypothesize that the altered mechanical phenotype (or ‘mechanotype’) of platinum-resistant cancer cells is a hallmark feature that can be used to inform novel therapeutic strategies for ovarian cancer. Specifically, we postulate that we can identify novel molecules and targets that modulate cancer cell mechanotype by conducting a high throughput screen on the basis of cell deformability; the lead candidates that we discover will cause platinum-resistant cancer cells to become stiffer and reduce cell invasion. We will test this hypothesis through the following specific aims: 1) Identify molecules and targets with potential for anti-cancer treatment strategies using deformability screening; we will validate using functional assays as well as patient expression data and tumor microarrays. 2) Discover novel targets for anti-cancer therapeutics in platinum-resistant cancer cells using an unbiased genome-wide CRISPR-Cas9 screen with cellular deformability as a readout. Taken together, our findings could address the lack of treatment options for HGSOC. Ultimately the compounds that we discover could be used in combination with platinum-based therapies to target platinum- resistant cells and thereby prevent disease recurrence and improve patient outcome.

NIH Research Projects · FY 2026 · 2025-02

Project Summary/Abstract Visual attention is a universal ability by which an individual’s focus is directed upon a selected visual stimulus in preparation for action. It is (i) a phenomenon that we experience constantly, (ii) a process that has long been studied, and (iii) the target of many neurological disorders such as hemispatial neglect, schizophrenia, and ADHD. Yet, we still do not have a mechanistic understanding of where and how visual selective attention is generated by the brain. Here, I propose to reveal fundamental mechanisms of visual selection by leveraging the rich behavioral repertoire of an invertebrate model that provides connectome-based functional predictions, precise genetic targeting and manipulation at circuit and single-cell levels, and overt orientation behavior toward select objects – an elemental form of attention-like selectivity. I recently showed that a class of visual columnar neurons that send input to the third neuropil of the fly optic lobe detect texture features of visual objects and are imperative for saccadic object tracking behavior. The saccadic tracking pathway resides in the same neuropil as a well-characterized pathway for avoidance responses. Evidence is accumulating that this neuropil is homologous to the optic tectum in vertebrates or superior colliculus in mammals, and thereby can inform general mechanistic principles the neural basis of selective visual attention. In Aim 1 (K99 phase), I will identify the neural components of the object detection and saccadic control, and formalize their computations by means of behavioral, connectomic and opto-physiological studies. I hypothesize that the selection mechanisms underlying this pathway are implemented by inhibitory circuit motifs within and between visual lobes. These studies will further our understanding of simple bottom-up attentional phenomena. Innovative approaches include “read- write” of neural activity with an ‘all-optical’ microscope in flies inside a virtual reality flight simulator. Co-mentors, Dr. Hartenstein and Dr. Huk, will help me dig into connectivity motifs and computational models of neural circuit for orienting behavior. My primary mentor, Dr. Mark Frye, will provide me the necessary guidance to transition to the independent phase. The vibrant and interactive research environment at UCLA represents a key factor for my career development and for the phylogenetic aspect of my research proposal. In Aim 2 (R00), I will bring with me all apparatus necessary to carry out behavioral and physiological investigation of top-down modulation of selective attention by targeting a central structure of the fly brain that coordinates goal-directed actions. I hypothesize that dopamine signaling determines the strength of goal attention, while also modulating the saccade control pathway to reduce distractibility from the goal. These experiments will disclose circuits and algorithms for visual selection-for-action. My long-term career goal as a principal investigator is to pursue how selective visuomotor mechanisms give rise to attentional phenomena.

NIH Research Projects · FY 2026 · 2025-02

Project Summary Activated cardiac fibroblasts (cFBs) are the primary source of extracellular matrix (ECM) following myocardial infarction (MI). However, studies suggest that cFBs also regulate neovascularization in the ischemic heart by expressing pro- and anti-angiogenic secreted ligands. We recently identified that fetal epicardial-derived fibroblasts express angiogenic factors that facilitate coronary angiogenesis during embryogenesis, which are also expressed in adult cFBs following myocardial infarction (MI). Specifically, we determined that collagen type XVIII (Col18a1) and slit guidance ligand 2 (Slit2) were enriched in cFBs compared to cardiomyocytes. Col18a1 sources the anti-angiogenic peptide endostatin, which was downregulated in the border zone of the damaged heart 7 days post-MI but upregulated in the mature scar at 28 days post-MI. Slit2, a secreted glycoprotein that binds to roundabout receptors expressed in endothelial cells and pericytes, has been shown to promote angiogenesis and vessel stabilization and limit fibrosis and inflammation. In the ischemic heart, Slit2 expression was activated in the border zone and infarct areas 7 days post-MI but quickly downregulated in the reparative and maturation phases of MI. These data suggest that cFBs coordinate the secretion of angiogenic cues in a temporal and spatial-specific manner to support cardiac repair; however, the investigation of anti- and pro- angiogenic factors in fibroblasts has yet to be elucidated. Our central hypothesis is that cardiac fibroblasts regulate neovascularization by expressing endogenous angiogenic-modifying factors following ischemia. Our overall objective for this study is to identify mechanisms that increase vascular perfusion and promote positive clinical outcomes for patients suffering from ischemic heart disease. The following two specific aims will address our hypothesis: Specific Aim 1. To evaluate the function of anti-angiogenic factors in cardiac fibroblasts following myocardial infarction. We will assess cFB activation and angiogenic functions in vitro with or without overexpression of Col18a1 using adenoviruses. For in vivo studies, we will analyze a Col18a1 knockout mouse following a time course of MI and measure cardiac function, fibrosis, angiogenesis, and coronary and collateral vasculature formation. Specific Aim 2: To determine if the expression of pro-angiogenic factors alters angiogenesis and repair following myocardial infarction. The fibroblast-specific Tcf21MCM mouse will be crossed to Slit2flox/flox mice. We will perform MI, measure cardiac function, and quantify angiogenesis. We will perform single-cell RNA sequencing on cFBs lacking Slit2 to identify fibroblast-directed programs to enhance neoangiogenesis. Additionally, we will utilize an AAV9-cTNT-mSlit2-eGFP to express Slit2 in the heart and evaluate cardiac functional recovery and vascular formation after MI. Overall, accomplishing these studies will provide an understanding of the cells and molecular signals that enhance vascular perfusion following MI and guide the development of novel vascular therapeutics.

NIH Research Projects · FY 2026 · 2025-01

PROJECT SUMMARY The overarching goal of the research presented in this application is to understand how environmental chemicals trigger a deregulation of the epigenome that can resist epigenetic reprogramming in germ cells and therefore can become heritable. Inorganic arsenic (iAs) is a model epigenetic toxicant owing to its well described impact on global DNA hypomethylation coinciding with a reduction in the levels of the universal methyl donor SAM, used towards DNA and histone methylation. iAs is also a chemical with well-established transgenerational epigenetic inheritance effects, producing heritable reproductive and metabolic dysfunctions and neurobehavioral outcomes for multiple generations. However, iAs shows remarkable complexity in its epigenetic impact since even in the context of global DNA hypomethylation, some loci show hypermethylation and the effect on histone methylation are non- uniform with many methylated histone marks showing increases while others show a decrease. It is unclear how iAs causes such varied epigenetic effect and how these effects are maintained during reprogramming. Here, we propose to leverage a unique model of germ cell reprogramming based on the step-wise differentiation of mouse Embryonic Stem Cells (ESCs) into Primordial Germ Cell-Like Cells (PGCLCs). PGCLCs undergo epigenetic reprogramming in vitro and are transcriptionally and functionally similar to in vivo PGCs since they generate viable offspring upon transplantation in vivo. We will build on compelling preliminary data showing that in mESCs, at levels where sodium arsenite does not cause a significant increase in ROS levels, a pronounced metabolic impact on the methionine cycle and on the transsulfuration pathways are observed concomitant with its epigenetic impact. We also show that two enzymes crucial for the one-carbon and iAs metabolism, MAT2A and AS3MT, respectively, are strongly upregulated in response to iAs and translocate to the nucleus where they associate with chromatin. Finally, we show that PGCLCs retain a transcriptional memory of prior exposure to arsenic. Thus, we hypothesize that the metabolic rewiring caused by iAs exposure causes the differential nuclear activity of reprogramming-resistant metabolic enzymes which locally modulate the availability of SAM for epigenetic modifications. To test this hypothesis, we will (1) assess the developmental reprogramming of iAs-induced epimutations by WGBS, CUT&Tag, ChIP-seq, RNA-seq, and Pandora-seq in PGCLC; (2) test whether iAs metabolic impact is required for the induction of these epimutations; and (3) examine whether iAs epimutations require the activity of MAT2A and AS3MT at locus-specific levels. At the completion of these aims, we will have determined how the metabolo-epigenetic crosstalks mediate locus-specific epigenetic alterations in response to arsenic and how these epimutations resist developmental reprogramming.

NIH Research Projects · FY 2026 · 2025-01

PROJECT SUMMARY Huntington's disease (HD) is an inherited neurodegenerative disorder caused by a CAG-repeat expansion encoding mutant Huntingtin (mHTT). Recent genome-wide association studies (GWAS) identified 10 genomic loci significantly modifying the age-of-onset or progression of HD. These loci are significantly enriched with DNA repair genes, including four DNA mismatch repair genes (Msh3, Mlh1, Pms1 and Pms2). Our mouse genetic study demonstrated that Msh3 deficiency significantly reduced mHtt aggregates and rescued mHtt-induced transcriptionopathy in Q140 knockin mouse model of HD. Our research initiative focuses on developing novel therapeutic strategies for HD by targeting the Msh3 protein. Leveraging a multi-faceted approach, we have established a robust screening pipeline utilizing a newly developed knockin mouse model expressing a luciferase-based reporter of endogenous Msh3, enabling high-throughput screening of small molecules that modulate Msh3 levels in cellular models. In the R61 phase, we aim to demonstrate the scalability, precision, and reproducibility of our primary mouse embryonic fibroblast (MEF)-based Msh3 reporter assay (Aim 1) and subsequently develop secondary assays to further interrogate and eliminate less desirable chemical hits (Aim 2). These assays include directly measuring endogenous MSH3 RNA and protein levels in human a human cell line, examining Msh3 lowering efficacy with a therapeutically relevant cell type (primary striatal neuron), and assessing the functional consequence of lowering MSH3 in cells. In the R33 phase, we will utilize the MEF- based Msh3 reporter assay optimized in Aim 1 to conduct a large-scale screening of 300,000 chemically diverse compounds to identify potential Msh3-lowering modulators. Subsequently, we will establish a testing funnel with the assays developed in Aim 1 and 2 to gradually eliminate and prioritize the hits and chemical scaffolds to identify potential leads. Throughout these endeavors, rigorous authentication of biological and chemical resources will be ensured, aligning with our commitment to scientific integrity. Through this comprehensive approach, we aim to identify lead compounds with therapeutic potential for HD and potentially other neurodegenerative diseases sharing similar MSH3-dependent, repeat-expansion related pathogenic mechanisms, ultimately advancing towards effective disease-modifying treatments.