University Of California Los Angeles

NIH Research Projects · FY 2025 · 2022-05

Overall Component Abstract Community colleges (CCs) are primary engines for economic advancement for persons from lower socio- economic backgrounds, but the promise of higher education is often thwarted by untreated mental health problems, especially among racial/ethnic minority students. Alarmingly high rates of depression and anxiety on community college campuses collide with daunting life challenges (such as early adversity, housing and food insecurity) and inadequate mental health resources. Untreated depression and anxiety can have dire consequences, extending from poor academic performance to suicide. To address the enormous mental health gap in a low income, highly diverse sample of CC students at East Los Angeles College (ELAC), we propose to evaluate a scalable, efficient, and evidence-based system of care called STAND for screening, tracking and treating anxiety and depression. STAND uses a stratified stepped care model, ranging from self-guided online cognitive behavioral prevention, to online cognitive behavioral therapy with coaching, to clinician-delivered care. Continuous tracking enables treatment adaptation as needs evolve plus rapid detection and management of suicidality. The STAND system was implemented on the UCLA campus from late 2017- early 2020. Since Fall 2019, we have been collaborating with ELAC administrators and students to adapt STAND for their needs, and have an ongoing pilot project funded through the Los Angeles County Department of Mental Health (2020-2022). This pilot lays the groundwork for ALACRITY in which we will optimize STAND at ELAC (n=1000) with continuing support from DMH and we will explore sustainability and spread to other CCs. The ALACRITY center focuses upon (1) optimizing effectiveness through multivariate predictive models, including social determinants of mental health, for improving stepped care triaging, adaptation, and risk detection, which will simultaneously advance the science of personalized mental health, (2) optimizing implementation through exploratory projects, pilot trials and Methods Scientific Area hubs that primarily target uptake and engagement as well as integration and cultural competency to meet the needs of this underserved, diverse student population, and (3) exploring sustainability via centralized state-wide data-streams, cost-effectiveness and return-on-investment projections for STAND implementation, investigation of generalizability, and exploration of barriers and facilitators of implementation across geographically diverse CCCs, that inform discussions with policy makers and stakeholders. The overall approach is guided by the Accelerated Creation to Sustainment implementation framework which allows for continuous evaluation and redesign over each annual cohort. The Administrative Core will oversee operations of the Center, pilot study program, training of junior investigators, and sustainability planning. The Methods Core will support research projects, implementation efforts, and innovative and synergistic collaborations that focus on increasing engagement of stakeholders. Our long-term goal is to optimize STAND through personalization tools and facilitate expansion of STAND’s reach across CCs statewide and ultimately nationwide.

NIH Research Projects · FY 2026 · 2022-04

Project Summary/Abstract This career development award will establish me (Dr. Estelle Everett MD, MHS), as an independent investigator focused on evaluating and addressing disparities in management and outcomes in vulnerable patient populations with type 1 diabetes (T1D). This K23 award will provide the support I need to develop expertise in three key areas: 1) EMR-based retrospective data analysis and natural language processing (NLP) methods, 2) clinical trial design, implementation, and analysis, and 3) qualitative study development, data collection and analysis. After receiving my medical and research training in at Johns Hopkins and publishing a series of general diabetes papers, my research interests have increasingly focused on patients with poorly controlled T1D. I am committed to improving care and outcomes in this complex group of patients whose long duration of T1D increases their risk of developing complications early in their lifetime. Although diabetes technology has revolutionized T1D management, disparities in technology access are evident among racial-ethnic minorities, patients with lower socioeconomic status and those with poorly controlled T1D. To help address these gaps, it is critical to leverage electronic health record (EHR) data to readily identify patients experiencing diabetes technology disparities. In order to examine whether diabetes technology can reduce diabetes care burdens and enhance outcomes among some of highest need patients, we need to expand diabetes technology clinical trials beyond the very select populations included thus far (ie., mostly White, higher SES). Therefore, I propose to: 1) To develop and validate a novel electronic medical record (EMR) algorithm using natural language processing (NLP) to identify insulin pump and/or CGM use among patients with type 1 diabetes; 2) To perform a pilot RCT of hybrid closed-loop insulin pump therapy (HCL) in 40 diverse adult patients with poorly controlled T1D (HbA1c >9%) from the largest academic and safety net health systems in the Los Angeles region; and 3) To identify facilitators and barriers of effective use of closed loop insulin pump therapy in patients with poorly controlled T1D. Findings from Aim 1 can be readily used to support T1D care in other settings and findings from Aims 2 and 3 will also be used to inform a future RCT as part of a future NIDDK R01 application. This K23 award will provide the support to complete these aims and my educational objectives, which will provide me with the training and skills needed to become a national leader and independent clinician-investigator aimed to improve outcomes in vulnerable populations with T1D.

NIH Research Projects · FY 2026 · 2022-04

Project Summary Child obesity disproportionately impacts young Latino children. Obesity interventions focusing on 2- to 5- year-olds are critical as excessive weight gain during this period increases the risk of adolescent and adult overweight and has important implications for later health problems. Moreover, many obesogenic behaviors in adulthood, like television viewing and consumption of sugary drinks, begin at this age. The most effective childhood obesity interventions are those rooted in behavior and family systems theories. Both of these theories provide approaches to support lifestyle changes with an understanding that family is the major mediator of social influences on a child’s development. To date, however, most family-based interventions: (1) focus on one parent, typically mothers; (2) miss the opportunity to leverage the Latino cultural value of familism (i.e. family connectedness) to impact childhood obesity outcomes; and (3) include lengthy curricula requiring weekly in-person sessions over a 2- to 6-month time period. The rationale for the proposed study is to address these shortcomings by evaluating the effectiveness of a community-based intervention that is shorter and involves multiple family caregivers. The intervention will include in-person and mobile phone components focusing on Latino caregivers of young children, to support evidence-based and age appropriate dietary, media-viewing, and physical activity practices among 2- to 5-year old children, in order to decrease ethnic disparities in childhood obesity. The study will also explore the intervention’s potential to multiply the public health benefit by reducing obesity risk for adult caregivers. A prospective randomized study design will be used to evaluate the effectiveness of the family-based childhood obesity intervention on child BMI at 6- months (primary outcome) and at 12 months (secondary outcome), compared to a usual WIC care group. The study will randomize approximately 260 adult Latino caregivers of 2- to 5-year old children (2 caregivers per child) and half will be assigned to the intervention, and the other half will serve as the control group. All families will be recruited from four WIC Centers in Los Angeles County. Primary and secondary outcomes will include: (1) changes in child BMI outcomes at 6- and 12 months; (2) changes in child dietary, media-viewing, and physical activity practices; (3) whether familism attenuates or amplifies the intervention’s effect on differences in child BMI change between intervention and WIC usual care group; and (4) changes in caregiver’s dietary, physical activity, and weight. Pre- and post-intervention anthropometric and survey data will be collected at baseline, 1-, 6-, and 12-months post-baseline to estimate the intervention effect size on child BMI and weight-related practices, and explore whether familial mechanisms moderate the intervention’s effect on child BMI.

NIH Research Projects · FY 2025 · 2022-04

Project Summary/Abstract High prevalence rates of attention-deficit/ hyperactivity disorder (ADHD) (5-11% of children 4-17 years), combined with its high societal cost, strong persistence and pernicious effects on quality of life, warrant continued efforts to understand its underlying neural mechanisms and find efficacious treatments. Clinical heterogeneity is a major challenge, likely related to multiple causal paths, and contributes to variability in clinical presentation, underlying neural mechanisms, and treatment response. Although psychostimulants are the gold standard of treatment for ADHD, problems with suboptimal response, adverse side effects and non-compliance occur for a significant minority of those with ADHD. As a result, there is a critical need for empirically supported non- pharmacological interventions for ADHD. In addition, a reliable method for predicting response to treatment interventions in ADHD (and psychiatry in general), both medication and non-pharmacological approaches alike, remains elusive. This inability to prospectively predict whether a treatment approach will be effective for a given individual is costly and time consuming for professionals and patients, and often inconclusive due to disagreement between informants. In this project, we will conduct a large, multisite randomized clinical trial to test the efficacy of external trigeminal nerve stimulation (TNS), a novel, minimal risk, non-invasive neuromodulation treatment, for ADHD in children ages 7-12 years old (N=180). This high impact project will contribute significantly to the literature for empirically-supported nonpharmacological interventions for ADHD, identify underlying neural mechanisms, and test clinically useful behavioral and cognitive predictors of treatment response. Confirming the efficacy of TNS for ADHD could provide millions of families a viable non- pharmacological treatment option, and in some cases, as first-line treatment strategy for patients with ADHD, if supported by this research. The validation of a behavioral profile that is significantly predictive of treatment response will make identification of patients appropriate for TNS treatment simple and extremely cost effective as well as enhance dissemination of treatment into the community. This proposal is consistent with several NIMH priorities, including the development of innovative interventions, assessment of the mechanisms of action of efficacious interventions in the brain and identification of behavioral and cognitive characteristics to guide treatment approaches.

NIH Research Projects · FY 2025 · 2022-04

This application is a resubmission for a new CFAR that is a partnership between UCLA and CDU. Our overarching goal is to create a nimble multi-institutional infrastructure that will connect, and support investigators affiliated with both institutions to advance critical HIV science. The UCLA-CDU CFAR will strengthen and amplify the impact of existing research activities and launch new partnerships across Los Angeles and globally through our focus on three themes: we will STOP HIV by preventing new HIV infections (Prevention), reducing morbidity among people living with HIV (Treatment) and developing strategies for eradication (ART-free Remission). This grant will fund AIDS-related activities and programs conducted by investigators at UCLA, CDU and our Affiliated institutions, which include Harbor-UCLA Medical Center in Torrance; the UCLA CARE Clinic and the VA Greater Los Angeles Healthcare System in Westwood; the UCLA Vine Street Clinic in West Hollywood; and the Drew CARES, the CDU PUSH coalition and the MLK OASIS Clinic at CDU. These facilities are at ground zero for the AIDS epidemic in Los Angeles County, with the greatest number of persons living with HIV residing in the neighborhoods directly served by our hospitals and clinics. In addition to the facilities and programs based in Los Angeles, researchers at UCLA and CDU have extensive partnerships with HIV programs around the globe that are aimed at building global capacity. The CFAR will enhance our ability to deliver research at the interface of community by reaching communities most in need and by bringing to bear the talent of CDU and UCLA researchers to address problems from a multi-disciplinary perspective while mentoring the next generation who better reflect the communities being served. The overall organization of the UCLA-CDU CFAR will allow us to efficiently and effectively manage AIDS research activities by harnessing the wide-ranging expertise in our CFAR, and by including linkages to community-based clinician investigators and communities. The action plan for the first year of requested support includes 6 cores and 1 scientific working group (SWG): the Administrative Core, Developmental Core, Centralized Laboratory Support Core, Humanized Mouse and Gene Therapy Core, Community Engagement and Clinical Informatics Core, Clinical Science Core, and a Translational Research in Substance Use SWG. RELEVANCE: Research into the pathogenesis, treatment and social aspects of HIV disease is required to end the epidemic. The UCLA-CDU CFAR seeks to catalyze and expand HIV research by providing the infrastructure to connect, support and enhance the capacity of investigators affiliated with UCLA and CDU. This will be accomplished by stimulating the conduct and dissemination of high impact multidisciplinary research aimed at the NIH priorities of preventing new HIV infections (Prevention), reducing morbidity among people living with HIV (Treatment) and developing strategies for eradication (ART-free Remission).

NIH Research Projects · FY 2026 · 2022-04

PROJECT SUMMARY Major Depressive Disorder (MDD) and fibromyalgia (FM) are highly comorbid, disabling and resistant to treatment. More than half of MDD patients present with pain symptoms, and the comorbidity is associated with reduced quality of life, poor pharmacological treatment outcomes, and opioid use disorders. New approaches to help comorbid patients are urgently needed. Repetitive Transcranial Magnetic Stimulation (rTMS) treatment may ameliorate both pain and mood symptoms, possibly through modulation of shared underlying pathophysiological brain networks. Preliminary data indicate rTMS applied to the left dorsolateral prefrontal cortex (lDLPFC) significantly improved both depressive and moderate pain symptoms but failed to improve more severe comorbid pain. In this application, we propose to test the efficacy of a multi-target rTMS protocol that may be more successful in treating both mood and pain symptoms in comorbid MDD/FM. This includes two complementary objectives: 1) to test the effects of a novel rTMS protocol for comorbid MDD and FM, and 2) to provide critical additional training to the candidate that will facilitate her transition into independence as a researcher specializing in the comorbidity of mood disorders with chronic pain and their treatment with rTMS. This will be achieved through a randomized, sham-controlled study with two experimental conditions: A) Active rTMS to lDLPFC (established target for MDD) and sham rTMS to the primary motor cortex (M1, established pain target); and B) Active rTMS to both, lDLPFC and M1. We anticipate that multi-site rTMS will be more efficacious to treat both MDD and FM symptoms than the single site rTMS protocol. Additionally, we will determine the differences and similarities of neural signatures of MDD and FM and how these interact in the comorbid condition using machine learning techniques. The K01 project will take place at UCLA with the mentoring support from the director of the Neuromodulation Division, two co-mentors and four other collaborators with expertise in rTMS, depression, chronic pain, multimodal imaging, and machine learning analysis. This approach will achieve the project’s specific aims to: 1. Evaluate the effect of multi-site vs. single site rTMS on clinical symptoms; 2. Determine the interaction of networks affected in MDD and chronic pain and how they are modulated by rTMS; and 3. Examine the interaction between analgesic and antidepressant effects of rTMS. If these aims are achieved, the short-term outcome of this project will help determine the efficacy of multi-site rTMS for comorbid MDD and FM, identify the overlap of the neural signature of MDD and FM and how it is modulated by rTMS, and characterize the relationship between rTMS-induced antidepressant and analgesic effects. In the long-term, current rTMS procedures may be significantly improved for the treatment of MDD with comorbid chronic pain.

NIH Research Projects · FY 2026 · 2022-04

Project Summary/Abstract Monica Kelly, PhD is an Adjunct Assistant Professor at the David Geffen School of Medicine at UCLA. She is fully committed to becoming an independently funded investigator specializing in the study and treatment of sleep, cardiometabolic health and posttraumatic stress disorder (PTSD) in older adults. Dr. Kelly is an ideal candidate for this field of research with over 10 years of sleep and PTSD research experience, advanced geriatrics fellowship training, and licensure in clinical psychology. This K23 award will provide foundational career development skills for achieving her long-term goal of understanding and improving mental and physical health outcomes for older adults with insomnia and PTSD. Data collected will provide the basis of a larger, randomized controlled trial designed to examine the most effective treatment sequencing for mental health and cardiometabolic disease risk outcomes among older adults with comorbid insomnia disorder and PTSD. Career Development and Training Plan: The proposed work will be carried out at the UCLA and take advantage of available resources within the VAGLAHS, providing a rich training environment and the ability to conduct the proposed research and training plans. Dr. Kelly's team of nationally renowned mentors include Drs. Jennifer Martin (primary mentor; behavioral sleep interventions expert; K24 awardee), Cathy Alessi (geriatric sleep and health expert), Peter Liu (cardiometabolic health and sleep expert; K24 awardee), and Thomas Neylan (PTSD and sleep expert). Available resources include UCLA's Clinical and Translational Science Institute (CTSI), Multicampus Program in Geriatric Medicine and Gerontology (MPGMG), and the Geriatric Research, Education and Clinical Center (GRECC). Her training plan features carefully curated didactic and experiential training aligning her research and training goals in 1) clinical trials, 2) cardiometabolic health, 3) circadian rhythms, and 4) career skills necessary to become an independent clinical investigator. Research Plan: The proposed pilot randomized controlled trial will address a gap in knowledge related to addressing modifiable risk factors for cardiometabolic disease through treating residual insomnia in the context of PTSD in older adults. This project utilizes evidence-based interventions and standard clinical care measures. The study will evaluate the benefits of 5 sessions of Cognitive Behavioral Therapy for Insomnia (CBT-I) versus control, following 12 sessions of Cognitive Processing Therapy (CPT) for PTSD in older Veterans, an expanding group of individuals at elevated risk for PTSD, insomnia and cardiometabolic disease morbidity and mortality. The aims of this project are to 1) Evaluate the added benefits of CBT-I versus control on sleep, PTSD, and cardiometabolic risk biomarkers; 2) Evaluate CBT-I versus control following CPT on cardiometabolic risk biomarkers and quality of life; and 3) Evaluate the durability of the sleep, cardiometabolic and quality of life benefits of CBT-I following CPT versus control following CPT at 6-month follow-up.

NIH Research Projects · FY 2026 · 2022-04

Project Summary Effective utilization of somatic stem cells to repair injured tissues or to bioengineer organs is an important goal in regenerative medicine. However, clinically-proven application of stem cells in therapies remains limited in medicine today. The translational hurdles are in large part due to our lack of ability to precisely control stem cell proliferation and differentiation, which is critical for safe and effective clinical use. To overcome this challenge, we must first deepen our knowledge of normal stem cell regulation in organs. In addition to biochemical signals, tissue mechanical forces exerted by cell pulling and pushing can in theory serve as a signaling mechanism to regulate gene expression and various cellular processes in adult stem cells. However, the modulation and influence of these force signals within a 3D tissue are dramatically understudied, leaving open questions around how stem cells sense and interpret forces. We and others have demonstrated the mouse incisor as a powerful model system to study adult epithelial stem cells and we have previously shown that the transcription co-factor Yes-associated protein (YAP) and chromatin repression are important for regulating incisor epithelial stem cells. Our initial studies indicate that both mechanical deformation of cells and the cell geometry associated with dense packing can influence the expression of YAP and repressive chromatin marks in the incisor stem cell niche. The mouse incisor thus provides a valuable in vivo platform to study how cellular organizations coordinate mechanical signals to control stem cell functions via YAP and chromatin. In this application, we propose to test the hypothesis that dense cell packing modulates the effect of tissue forces on nuclear deformations, which in turn regulate YAP nuclear entry and H3K27me3-mediated transcriptional repression in the dental epithelial stem cells. To test this: Aim 1 will characterize the force patterns, magnitude, and nuclear stiffness in wild type incisors, specifically in the densely packed dental epithelial stem cells and the more loosely packed transit amplifying cells. Aim 2 will study how changes in the cell geometry and packing affect tissue force patterns, nuclear deformations, YAP localization, and chromatin states. We will perform mechanical rescue experiments to test the role of forces. Aim 3 will address the functional role of lamin A in regulating nuclear stiffness and heterochromatin formation in the dental epithelial stem cells, as well as its scaling response to cell packing. Together, these studies will deliver a mechanistic understanding of how tissue forces control dental stem cells and yield findings that will be of general interest to both dental researchers and to the stem cell and regenerative medicine communities.

NIH Research Projects · FY 2026 · 2022-04

PROJECT SUMMARY/ABSTRACT Glioblastoma (GBM) is a uniformly fatal disease with very few clinical options. Despite modest advancements in surgical procedures, radiation and chemotherapy, median survival from diagnosis is only around 14 months. Upon recurrence, few effective treatment options exist. Bevacizumab, a humanized monoclonal antibody that inhibits VEGF-A, received accelerated FDA approval in May 2009 for use in recurrent GBM and quickly became the standard of care for recurrent GBM in the United States. Almost all patients receive bevacizumab at some point in their treatment. Because bevacizumab plays such an important role in the management of GBM, the development of imaging biomarkers to improve risk stratification and predict patient benefit is highly desired. Such a biomarker would be clinically useful for identifying patients that will benefit from bevacizumab as well as scientifically useful for cohort enrichment in the next phase of combination therapies or exploratory studies aimed at high-risk patients, where conventional therapies like bevacizumab are likely to fail. Extensive preliminary data (>7 trials in >400 patients) suggests diffusion MRI characteristics are a strong, independent predictor of anti-VEGF therapeutic efficacy in recurrent GBM, with patients exhibiting a significant survival benefit if they present with a high apparent diffusion coefficient (ADC) within contrast enhancing tumor. Data also suggests these diffusion MR signatures may result from an elevated expression of decorin (DCN), a glycoprotein with a variety of functions. We hypothesize that the survival advantage and imaging signatures arise from the multifaceted functions of DCN, which include anti-angiogenic characteristics and softening of the extracellular matrix, which we theorize would result in increased effectiveness of anti-VEGF therapies and an increase in ADC. The current study will explore the causal, mechanistic links between DCN expression, diffusion MRI, and anti-VEGF treatment efficacy. First, Aim 1 will involve a deep exploration into the association between diffusion MR phenotypes and DCN expression in human GBM using image-guided biopsies and examining DCN protein expression using immunohistochemistry and gene expression using in-situ hybridization. The relationship between diffusion MRI, DCN expression, and corresponding genotypes using whole exome analysis, genetic subtypes using bulk RNA sequencing, cellular states using single-cell RNA sequencing, and blood plasma levels of circulating DCN will also be performed. Concurrently, Aim 2 will establish the causal, mechanistic links between DCN expression, diffusion MRI measurements, and anti-VEGF treatment in GBM through ca complex, genetically modified patient-derived orthotopic xenograft (PDX) preclinical trial. To accomplish this, a series of patient-derived cell lines will be edited to silence of overexpress DCN within PDX models using a tetracycline-controlled gene expression system. The direct role of DCN expression in changing diffusion MRI measurements and increasing survival following anti-VEGF therapy by turning on or off DCN expression using doxycycline will be determined.

NIH Research Projects · FY 2025 · 2022-04

Project Summary Prolonged Crohn’s disease leads to intestinal fibrosis, which is difficult to prevent or treat. The surgical resection may negatively impact a patient’s quality of life. Thus, new therapeutic approaches are actively sought after. We have recently shown that intestinal expression of antimicrobial peptide and protease inhibitor elafin is reduced in stricturing CD patients. Its potential protective effect in intestinal fibrosis has never been reported in the literature. Our preliminary data showed that elafin- overexpression inhibited preexisting colonic fibrosis in TNBS-mediated mice, Salmonella-infected mice, and SAMP1/YitFc mice. We generated an orally active elafin-Eudragit formulation for potential therapeutic applications. The elafin-Eudragit formulation reversed preexisting colonic fibrosis in TNBS-treated mice. We also discovered that elafin inhibits collagen expression in the intestinal fibroblasts by modulating several stricture-specific genes. We hypothesize that oral administration of modified elafin may be useful for treating colitis-associated intestinal fibrosis by affecting a stricture- specific pathway. We propose to (1) establish oral therapeutic regimens of modified elafin for treating intestinal fibrosis in a mouse model of preexisting intestinal fibrosis and (2) determine the cathepsin S- PAR2-miR205-ZEB1-mediated anti-fibrogenic mechanism of elafin in intestinal fibroblasts. The overall impact of this study will produce a comprehensive assessment of optimized oral elafin delivery approaches for intestinal fibrosis. This mechanistic study will reveal how and why elafin inhibits intestinal fibrosis.

NIH Research Projects · FY 2026 · 2022-04

SUMMARY Cortical circuit dysfunction is a primary pathophysiology that underlies prominent neurological symptoms of Fragile X Syndrome (FXS). Yet the precise way in which circuit development in the cortex is altered in FXS has not been fully elucidated. Recent work by us, and others, has established that local circuit interneurons (INs) may be a key to understanding cortical circuits in FXS. We demonstrated that the density, maturity and activity of parvalbumin (PV) cortical INs are all reduced in the Fmr1 knockout (KO) mouse model of FXS. Here we propose to address outstanding questions in the field by determining how the birth, migration and connectivity of PV INs are disrupted in Fmr1 KO mice, and how this leads to sensory hypersensitivity and tactile defensiveness. We will incorporate a detailed analysis of PV INs using birth dating, neuroanatomical and functional studies to define how the abnormal integration of PV INs into feedforward circuits in the primary somatosensory cortex (S1) contributes to atypical sensory processing. In preliminary studies, we demonstrate that, in response to repetitive whisker stimulation, Fmr1 KO mice display maladaptive avoidance behaviors that correlate with a lack of neuronal adaptation of layer (L) 2/3 pyramidal neurons in S1. We also show that PV INs and their precursors from the medial ganglionic eminence (MGE) are hypoactive in S1 of Fmr1 KO mice by postnatal day (P) 6, and that increasing their activity for a few days using excitatory DREADDs significantly increases their density by P15. We will now determine whether similar early activity manipulations of MGE-derived INs, or later on in more mature PV INs, can restore the loss of sensory adaptation of L2/3 neurons and ameliorate tactile defensiveness in Fmr1 KO mice. We will address the following important questions: 1. What are the contributions of neurogenesis, migration, connectivity and developmental apoptosis to the reduced density of PV INs in FXS? 2. How do MGE-derived INs and pyramidal neurons interact during the early postnatal critical period and how is their ‘handshake’ different in FXS? 3. Is the hypoactivity of PV INs or their precursors causal to the circuit and behavior deficits of Fmr1 KO mice? The mechanistic experimental design employs cell type-specific intersectional genetics, in vivo calcium imaging, chemogenetics, and ex vivo circuit channel-rhodopsin connectivity mapping, among others. An important goal of this grant is to identify whether targeting INs is a viable path for therapeutics in FXS. As such a novel class of allosteric modulating drugs of Kv3.1 channels (responsible for fast-spiking characteristics of PV INs) will be tested in Fmr1 KO mice. Overall, the collaboration between the laboratories of Dr. Carlos Portera-Cailliau (co-PI, PL) at UCLA and Dr. Anis Contractor (co-PI) at Northwestern University will enable a comprehensive approach to understanding the developmental and functional contributions of INs to the pathophysiology of FXS.

NIH Research Projects · FY 2025 · 2022-04

PROJECT SUMMARY Therapeutic advances in vascular disease may have far-reaching public benefits. Arteriovenous malformations (AVMs) are the common feature of hereditary hemorrhagic telangiectasia (HHT) and cause the high risk of life- threatening complications. Advanced studies have shown that loss function of mutations in activin receptor-like kinase 1 (ALK1) are linked to HHT type 2 (HHT2) and ALK1 gene deletion in mice causes AVMs. Previous studies also reveal that ALK1 is predominantly expressed in arterial endothelial cells (ECs). However, it is unknown if ALK1 deficiency allows arterial ECs to acquire ill characteristics resulting in AVMs. In present proposal, we have obtained preliminary data to suggest that the emerging lymphatic endothelial characteristics in arterial ECs through the induction of mouse double minute 2 (MDM2) is previously unknown mechanism of AVMs in endothelial ALK1 deficiency, and we show that the approaches of erasing these undesired characteristics reduce AVMs. Therefore, we hypothesize that ALK1 deficiency elevates MDM2 to cause AVMs through the induction of lymphatic endothelial characteristics in arterial ECs, and MDM2 inhibition abolishes these characteristics to reduce AVMs. In specific Aim 1, we will elucidate the mechanism underlying arterial MDM2 induction as a causative factor of AVMs in endothelial ALK1 deficiency. In specific Aim 2, we will determine the contribution of arterial MDM2 induction to human HHT2. In specific Aim 3, we will determine if limiting MDM2 reduces AVMs in endothelial ALK1-deficient mice. There is no primary medical treatment to prevent or reduce the AVMs of HHT2 patients. In this proposal, we discover a novel mechanism that reveals the unwanted characteristics emerging in arterial ECs driven by ALK1 deficiency, and arterial ECs with these characteristics cause AVMs. We identify a compound and propose a novel treatment paradigm aiming to ameliorate AVMs by erasing these ill characteristics from arterial ECs. If succussed, our proposed studies would reveal the mechanistic underpinnings of alterations in arterial ECs of HHT2 and provide insight into new opportunities for therapeutic interventions.

NIH Research Projects · FY 2026 · 2022-04

Project Summary/Abstract This K01 Mentored Research Scientist Development Award is designed to prepare the candidate to become an independent investigator in the emerging field of the gut microbiome in alcohol use disorder (AUD). AUD is a chronic relapsing disease with a major public health impact. While substantial research has been done to understand the neural circuitry underlying AUD, the role of the periphery and the connections between the periphery and the central nervous system have been understudied. One promising avenue of study is the gut microbiome and the microbiota-gut-brain axis, which have only recently been recognized as contributing to the pathogenesis of AUD. Despite the promise of the microbiota-gut-brain axis as an important contributor to AUD, there have been no comprehensive investigations of the microbiota-gut-brain axis in a single sample of individuals with AUD. Therefore, this proposal seeks to evaluate the relationship between gut dysbiosis, clinical phenomenology of AUD, and a brain-based biomarker in individuals with AUD and matched controls. The research objective of this K01 application is to characterize the microbiome-gut-brain axis across different levels of analysis. Specifically, 64 individuals with AUD and 64 matched healthy controls will provide a fecal sample to localize the effects of chronic alcohol use on the gut microbiome. Participants will also provide a blood sample to evaluate gut permeability through serum biomarkers. Participants will also complete an in- depth neuroscience-informed clinical assessment battery, which will allow for phenotyping individuals into the three domains of the Addiction Neuroclinical Assessment (ANA): incentive salience, negative emotionality, and executive dysfunction. Finally, participants with AUD will complete an alcohol cue-reactivity neuroimaging task to obtain a brain-based biomarker of AUD. The specific aims of the proposed project are: (1) to identify the gut microbiota discriminating individuals with AUD from controls; (2) to evaluate the relationship between the gut microbiome and AUD phenomenology; and (3) to test the relationship between gut microbiota and a brain- based biomarker for AUD. The successful completion of the above aims will provide the first data linking the microbiome-gut-brain axis to AUD in a clinical sample. This K01 award will position the candidate to be at the forefront of the AUD microbiome-gut-brain axis field. The training goals for Dr. Grodin are to gain expertise in (1) the gut-microbiome applied to AUD phenomenology, (2) quantitative methods in machine learning and big data, and (3) professional development as an independent scientist.

NIH Research Projects · FY 2026 · 2022-04

PROJECT SUMMARY Medications for opioid use disorder (MOUD) have the potential to improve the health and well-being of more than 2.1 million Americans with OUD, however, long-term adherence particularly to buprenorphine is alarmingly poor. Pain, mental health, and substance use disorders are increasingly recognized as risk factors for inadequate treatment adherence and often co-occur in families due to shared genetic and environmental factors. Understanding comorbidities in patients with OUD and their family members, and the impact of these comorbidities on poor opioid use outcomes, can help identify patients at risk for inadequate treatment adherence and serious adverse events. Further, information on the costs associated with buprenorphine non-adherence and family comorbidities can inform health insurance reimbursement policies. The overall career goal of the recipient is to become a leading pharmacoepidemiologist focused on improving treatment for substance use disorders, particularly opioid use disorders. The goal of this K01 is to train the recipient to investigate associations between family comorbidities and/or prescription medications with a high risk of misuse and buprenorphine treatment adherence, opioid use outcomes, and costs to the family unit and health insurer. Research aims of this project are to: (1) develop a clinically relevant prediction model to identify patients prescribed buprenorphine at risk of inadequate adherence; (2) determine whether other prescriptions in the family are associated with poor buprenorphine adherence and opioid-related adverse events; and (3) compare overall healthcare costs to the family and health insurer across varying levels of buprenorphine adherence. The training aims of this project are to: (1) gain understanding of the clinical assessment and diagnosis of opioid use disorders and comorbid mental health conditions; (2) learn and apply innovative methods for dyadic data analyses; (3) learn and apply methods for conducting economic evaluations of substance use treatment; (4) hone professional skills in research, publishing, and project administration; and (5) responsible conduct of research. Training aims will be pursued through tutorials with world-renowned experts forming the recipient's mentorship team, graduate-level coursework, workshops and seminars, participation in scientific meetings, and mentored research. Research aims will be accomplished using the OptumLabs Data Warehouse, a large integrated commercial healthcare insurance claims database that tracks beneficiaries, spouses, and dependents across health plans and over time. This project will fill an important gap in our understanding of how family comorbidities and medication use by family members influence MOUD treatment adherence, outcomes, and costs, and will provide evidence to support interventions by clinicians and health insurers to improve MOUD adherence outcomes.

NIH Research Projects · FY 2025 · 2022-04

PROJECT SUMMARY / ABSTRACT Translation of eukaryotic mRNAs is highly regulated, and mutations that prematurely halt translation cause 11% of all heritable human diseases. Yet, it is unknown how ribosomes rapidly and accurately identify stop codons to halt protein synthesis and release the nascent polypeptide. It is also unclear how ribosomes trapped on an aberrant mRNA, such as those devoid of a stop codon, are liberated by decay machinery. An understanding of these fundamental processes could facilitate the discovery of novel therapeutics for diseases such as Cystic Fibrosis, Duchenne Muscular Dystrophy, and hereditary cancer syndromes. My central hypothesis is that the slow rate at which aberrant mRNAs are translated by ribosomes is exploited by slowly-acting decay factors to specifically degrade aberrant mRNAs and leave normal ones untouched. Examination of this hypothesis will require real-time tracking of ribosomes translating normal or aberrant mRNAs, capturing intricacies of pathway dynamics that are critical for regulation. As a postdoc in Joseph Puglisi’s lab at Stanford, I established single- molecule assays to directly track individual eukaryotic ribosomes throughout termination using an in vitro- reconstituted system. Co-mentored by Rachel Green, an expert in eukaryotic translation and mRNA decay, I will extend these assays to monitor other key events in termination, recycling, and mRNA decay. I will further assess the architecture of unique sub-states in translation and mRNA decay using cryo-EM. I propose the following specific aims: (I) Decipher the mechanisms that ensure fidelity in eukaryotic termination; (II) Define the dynamics that liberate ribosomes from normal and aberrant mRNAs; (III) Determine how termination, recycling, and mRNA decay are regulated in humans. Together, the proposed aims will reveal how eukaryotic cells distinguish between normal and aberrant mRNAs. Supported by my mentoring team, I will obtain expertise in cryo-EM, and the additional training necessary to expand beyond my initial studies of translational control into related mRNA decay mechanisms in yeast and humans. I will also become conversant in the language of genome-wide techniques such as CRISPR screening and ribosome profiling. The proposed research and training activities will provide me with the skills needed to establish an independent research program focused on the dynamic interplay of eukaryotic translation and mRNA decay, and reveal fundamental facets of gene expression with relevance to human health to be built upon in a future R01.

NIH Research Projects · FY 2025 · 2022-04

PROJECT SUMMARY/ABSTRACT Cardiac injury predisposes patients to heart failure (HF), and ventricular tachycardia/fibrillation (VT/VF). Development of HF and VT/VF after cardiac injury is tightly linked to sympathetic neural remodeling. Although several medications targeting cardiac sympathetic excess reduce mortality following cardiac injury, significant shortcomings of these drugs include off-target effects, limited efficacy, and focus on downstream consequences of neural remodeling such as excess catecholamine release, rather than preventing it upstream. In this proposal, we build on strong preliminary data from humans, porcine, and murine models demonstrating that satellite glial cell (SGC) activation is a central feature of chronic cardiac injury. Activated glia release inflammatory cytokines, ATP, and other factors that modulate neuronal function. Chemogenetic upregulation of glial calcium signaling (as observed in activated glia) increase cardiac sympathetic neuronal excitability, synaptic efficacy, and tonic firing. Based on these novel findings, the goal of this proposal is to test the hypothesis that satellite glial activation and enhanced glial-neuronal signaling is a primary driver of cardiac sympathetic neuronal dysfunction, heart failure and VT/VF after cardiac injury. We will test our hypotheses using novel tools from a multidisciplinary team of investigators in 3 specific aims in two murine models of cardiac injury (ischemia-reperfusion and dilated cardiomyopathy). We will test whether following cardiac injury, satellite glial cell activation within stellate ganglia exacerbates neuronal and cardiac remodeling (structural and functional) to promote LV dysfunction and VT/VF (Aim 1). We will investigate the mechanisms by which cardiac injury activates SGCs in stellate ganglia after injury (Aim 2). Finally, we will determine whether targeting glial Gq-GPCR Ca2+ signaling or Cx43-mediated glia-neuron/glial- glial communication mitigates adverse remodeling and arrhythmogenesis following cardiac injury (Aim 3). The results of this proposal will 1) indicate whether and how satellite glial cell activation contributes to sympathetic imbalance after cardiac injury; and 2) determine whether targeting satellite glial cell activation offers therapeutic potential in chronic cardiac injury.

NIH Research Projects · FY 2026 · 2022-04

Project Summary / Abstract The overall goal of this proposal is to reveal central regulators of microglial attributes that can impact synapses. Synaptic dysfunction is tightly linked to declining cognition and neuronal health during aging. A long- standing mystery in neuroscience is why some CNS neurons are more vulnerable to age-associated synapse loss and neurodegenerative disease. Microglia are well-positioned to influence synapses throughout the lifespan, being equipped to induce synapse formation, synapse elimination and alter synapse composition through multiple mechanisms. Moreover, synapse-relevant attributes of microglia change during aging, including their cell process motility, phagocytic behaviors, and production of inflammatory factors. We and others recently discovered that microglia exhibit region-specific phenotypes, raising the possibility that microglial regulation of synaptic health varies. In addition, our preliminary data indicate that ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) microglia begin to proliferate and produce inflammatory factors during midlife in mice, and months before microglia in other basal ganglia nuclei. These “pockets” of early inflammation are likely detrimental to synaptic function of nearby dopamine neurons, which are highly vulnerable to functional decline and degenerative disease during aging. Here, we will investigate the possibility that microglial lysosomes can simultaneously regulate multiple synapse-relevant attributes of these cells, and that regional differences in lysosome function give rise to regional variation in microglial aging and synapse vulnerability. Lysosomes are typically viewed as purely degradative organelles, but new data show that they are intimately involved in membrane recycling and intracellular signaling that can shape cell properties. Indeed, lysosomes play a central role in regulating macrophage phenotype, including their inflammatory profiles, phagocytosis, and responses to aging. Our findings suggest that lysosomes play similar regulatory roles within microglia; the region-specific phenotypes and responses to aging that we observe within VTA/SNc microglia were accompanied by prominent differences in lysosome abundance, expression of lysosome component genes, and rates of lysosome overload with protein-lipid aggregates, compared to microglia in other basal ganglia nuclei. Nonetheless, surprising little is known about microglial lysosomes in vivo. Focusing on the basal ganglia and working in mice, we will use multidisciplinary approaches to define the composition and functional status of microglial lysosomes across brain regions and lifespan (Aim 1). We developed novel methods to manipulate microglial lysosome overload and will determine how this shapes synapse-relevant microglial attributes during aging (Aim 2). Finally, we will directly measure how microglial lysosome overload affects lifespan synaptic integrity and function in distinct brain regions (Aim 3). These studies will reveal whether these organelles are central orchestrators of microglial phenotype and will identify molecular targets for promoting neuroprotective microglial phenotypes to preserve synaptic function in vulnerable populations of neurons.

NIH Research Projects · FY 2026 · 2022-04

Project Summary Rodent models remain an important in preclinical studies of brain disease and disorders, as well as basic neuroscience investigations. Rodent imaging data, acquired through techniques including MRI and microscopy, play a critical role in many of these studies. While a great deal of effort has gone into the development of software tools for analyzing MRI of the brain, much of this work has been focused largely on human data, and investigators studying animal models of disease must often resort to adapting these tools for their research. In this project, we will address this need by developing a dedicated suite of open source software tools for processing, analyzing, and visualizing neuroimaging data acquired from rodent brains. These tools will operate on structural diffusion, and functional MRI, as well as optical microscopy of optically cleared serially sectioned tissue samples. These tools will build upon our decades of experience developing software for analyzing human and mouse imaging data, our experience in developing multimodal atlases of the mouse brain, and our active efforts in community engagement and dissemination while applying these resources in neuroscientific studies. Where suitable, we will make use of deep learning methods to produce powerful segmentation and registration networks trained on manually annotated and delineated data. We will also develop easy-to-use interfaces that will facilitate data processing and provide advanced visualization capabilities of datasets with sizes on the order of one terapixel. The project has five specific aims. Aim 1 will develop MRI processing tools, which will include intrasubject co- registration of MRI modalities, extraction of brain tissue from whole head scans, tissue classification, and processing of diffusion and functional MRI data. Aim 2 will develop tools for processing microscopy of cleared and sectioned tissue, with the major goal of aligning these data to a reference atlas generated from either optical microscopy or MRI. These tools will perform cell counting in automatically segmented regions; axon following; dendritic arborization; and dendritic spine counting. In Aim 3, we will develop a statistical analysis toolbox, which will perform statistical inference for neuroimaging measures from microscopy and MRI data analyzed using methods from Aims 1 and 2. In Aim 4, we will integrate the components from Aims 1-3 into an informatics platform that will provide command line tools for easy scripting, interoperability with related imaging tools, and a graphical interface for visualizing data across different scales. In Aim 5, we will perform evaluation of our software tools using two studies: imaging an experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis; and imaging a mouse model of normative aging. We will also work with a network of small animal imaging experts external to the project, who will use and evaluate the software. These driving projects will serve as testbeds to ensure the practical utility of the software in a research setting, providing direction for the development of our research platform. We will distribute the software freely under an open source license, and provide user support through our website.

NIH Research Projects · FY 2026 · 2022-03

Project Summary The SARS-CoV-2/COVID-19 pandemic has disproportionately impacted older socioeconomically disadvantaged African-Americans. This research will test whether a recently developed community-based intervention program known as Generation Exchange (GenX) can enhance a key biological mediator of antiviral resistance (Type I interferon response) in this disadvantaged population. Our previous research has identified a stress-triggered genomic program known as the “Conserved Transcriptional Response to Adversity” (CTRA). The CTRA is activated by fight-or-flight stress responses and causes immune cells to reduce antiviral activity and stimulate inflammation, both of which are detrimental in the context of COVID- 19. Our previous research on biological resilience in the face of adversity has also found that the CTRA is reduced in people with high levels of eudaimonic well-being, which includes purpose in life, generativity, and pro-social engagement. In the present study, we will conduct a randomized controlled intervention trial (n=160) to test whether a eudaimonia-promoting intergenerational mentoring program known as Generation Xchange (GenX) can enhance Type I interferon responses and reduce hyper-inflammatory responses in older African-American women and men living in a socioeconomically disadvantaged urban community. Our hypotheses are that GenX will, 1) increase Type I interferon antiviral responses, 2) reduce hyper-inflammatory bias, and 3) reduce rates of clinical respiratory virus infection and symptomatic disease (COVID, influenzas, and colds). To identify the biological mechanisms of antiviral resistance in this specific population, we will also analyze specific antiviral cell types (e.g., plasmacytoid dendritic cells, monocytes) and gene regulatory processes (e.g., transcription factor activity and single-cell gene expression). These measures will be used to determine 4) which biological factors are most important in protecting older African-Americans from respiratory virus infection, 5) how those biological risk factors are linked to other established respiratory virus risk factors (e.g., overweight/obesity, pre-existing chronic disease, low physical activity, poor sleep, social isolation/loneliness), and 6) which biological factors are impacted by GenX. Finally, we test the hypothesis that 7) GenX will show positive effects for both women and men, for those with low or high education level, and for those with low or high levels of background risk factors (e.g., overweight/obesity, chronic disease, low physical activity, social isolation/loneliness). Our overarching goal is to establish a community-based biobehavioral intervention program that is broadly scalable, involves defined biological mechanisms of antiviral resistance, and leverages social support and eudaimonic well-being to mitigate the detrimental effects of age and social disadvantage on host resistance to respiratory virus infection among COVID-vulnerable older African-Americans.

NIH Research Projects · FY 2025 · 2022-03

PROJECT SUMMARY/ABSTRACT Depression in late life is prevalent, affects nearly one fifth of older adults, and exacts an enormous burden on public health. One hallmark of late-life depression is a loss in the ability to experience pleasure and reduced motivation to seek rewarding experiences. Loss of pleasure and motivation limits engagement in activities that could improve physical and mental health, leads to social isolation, and increases risk of suicide and early mortality. These devastating impairments in reward function are also notoriously difficult to detect and treat, due in part to a limited understanding of the mechanisms that contribute to impaired reward function. Elevated inflammation, which is closely linked to depression, has been implicated as a biological mechanism of reward dysregulation in preclinical models. Translational work has shown that pro-inflammatory challenges, such as endotoxin administration, also alter reward behavior and reward neurocircuitry in healthy human adults. Our laboratory has extended this line of inquiry to older adults, and preliminary data show that endotoxin administration reduces motivational behavior in non-depressed older adults with elevated, but not low, anxiety. Anxiety is prevalent in older adults, a risk factor for depression, and increases vulnerability to inflammation- induced negative mood; moreover, aging increases exposure to inflammation (e.g., higher susceptibility to infection, chronic disease, inflammaging). As such, anxiety and inflammation are risk factors that may comprise “two hits” to impair reward behavior in older adults. Yet, no studies have tested whether such behavioral effects are driven by alterations in reward neurocircuitry to help clarify mechanistic pathways and identify intervention targets. The objective of the current study is to use multilevel analysis of reward function and an experimental design to test effects of experimentally induced inflammation on reward behavior (Aim 1) and reward neurocircuitry (Aim 2) as a function of anxiety in older adults. A double-blind, placebo-controlled, inflammatory challenge with endotoxin in older adults (60-80 y) with (n=40) and without (n=40) anxiety symptoms will evaluate whether anxious older adults are especially vulnerable to inflammation-induced deficits in reward function and should be prioritized for monitoring and intervention. Insights from multilevel analysis of reward can be used to inform the development of precision-based and personalized medicine strategies for the prevention and treatment of late-life depression. With the support of the K01 Award, I will use this study to launch an independent research program that uses experimental methods to identify mechanisms of late-life depression to improve health and well-being in older adults. To this end, I am seeking 1) advanced training in experimental clinical trial methodology using the endotoxin model to accelerate my development as an independent investigator; 2) acquisition of skills in neuroimaging techniques and data analysis to evaluate neural mechanisms that may be sensitive to inflammation and drive aberrant behavior; and 3) expertise in late- life anxiety to broaden my research program and test new conceptual models of reward deficits.

NIH Research Projects · FY 2025 · 2022-03

Abstract Inflammation is a necessary biological response to injury, infection, and environmental exposures, and a well- orchestrated physiological process, which if unchecked produces undesirable toxicity. Unresolved inflammation contributes to the development of chronic diseases exacerbated by environmental exposures. The molecular mechanisms and players of resolution of inflammation are not well understood. In this application, we will examine two novel pathways that we hypothesize to play a critical role in the resolution of inflammation. 1. We previously reported that diesel exhaust particle extracts and associated polycyclic aromatic hydrocarbons inhibit COX2-dependent eicosanoid synthesis in murine macrophages. While COX2 is commonly thought to be pro- inflammatory, Cox2 macrophage-specific knock-out (Cox2MKO) mice develop intestinal inflammation when fed a high fat diet. Macrophage COX2 thus appears to provide an inhibitory molecular check on chronic inflammation mediated by dietary and environmental exposures. In preliminary experiments, we show that loss of COX2 impaired efferocytosis in mouse primary macrophages and COX2 modulated the production of efferocytosis- dependent lipid inflammatory mediators that not only affect secondary efferocytosis but also induce a tissue repair phenotype in intestinal epithelial organoids. Under specific aim 1, based on published and recent preliminary results, we will test the hypothesis that macrophage COX2-dependent eicosanoids play a critical role in chronic inflammatory diseases exacerbated by environmental pollutants. 2. Our laboratory pioneered the development of amphipathic peptides that mimic the antioxidant and anti-inflammatory properties of apolipoprotein A-I (apoA-I). ApoA-I mimetic peptides (4F) inhibit the development of inflammatory diseases that are exacerbated by dietary and environmental exposures including atherosclerosis and intestinal inflammation. We demonstrated that 4F attenuates ambient ultrafine particle (UFP)-mediated oxidative stress, lipid metabolism, atherosclerosis and intestinal inflammation. A common mechanism of protective action of 4F in all these disease models is by tilting the net balance of lipid mediators of inflammation to an anti-inflammatory state, in the circulation and tissues. In preliminary results, we demonstrated that apoA-I mimetic peptides enhance transintestinal lipid transport (TILT) ex vivo and in vivo. Under specific aim 2, we will test the hypothesis that TILT is a key mediator of resolution of inflammation and plays an important role in the development of chronic inflammatory diseases exacerbated by environmental exposures. Successful completion of the studies proposed in this new R01 application will not only advance our understanding of the biology and molecular mechanisms underlying the effects of environmental exposures on the resolution of inflammation but also provide novel therapeutic strategies in our fight against chronic inflammatory diseases exacerbated by air pollution.

NIH Research Projects · FY 2025 · 2022-02

PROJECT SUMMARY (ABSTRACT) Contact network epidemiology is a compelling epidemiologic framework that aims to model dynamic interactions of people over their social networks in order to track infection cascades, especially for communicable diseases. Network-based simulations in contact network epidemiology can incorporate variations in people’s attributes and behaviors (e.g. age, race/ethnicity, wearing a facial mask), their interaction patterns (e.g. homophily or assortativity), and social structures (e.g. social norms and policies including non-pharmaceutical interventions [NPIs]). Although obtaining precise network data is challenging, it can guide us to identify potential working network intervention strategies, which may prove beneficial in addressing the COVID-19 pandemic. Using the framework of network interventions, a pilot simulation study proposed alternative NPI strategies to the stay-at-home order, in which transmission is mitigated while people’s socioeconomic activities are sustained (Nishi et al, 2020, PNAS). In the most effective dividing + balancing groups strategy, a social group (e.g. employees of the same workplace and students of the same school) is divided randomly into two subgroups with an equal number to reduce the number of physical contacts. If it is operated in a spatial manner, additional space for the subgroups is prepared; if it is operated in a temporal manner, the two subgroups will engage in their activities during different business hours. Therefore, the strategy would allow people to engage in the same magnitude of economic activities. The strength of the proposed strategy is that it does not require actual network data, which is difficult to obtain in most cases. Following the pilot study, this research seeks to create other novel NPI strategies for infectious disease control (the targets are both COVID-19 and other emerging diseases) (Aim 1). This research also seeks to create novel network intervention strategies for vaccine allocation (Aim 2). The proposed strategies for mitigating an epidemic and optimizing vaccine allocation will not, in principle, require actual network data. Therefore, their potential effect needs to be examined using network-based simulations with realistic assumptions or using other approaches, including mathematical modeling. The utilized social network will be based on a sample city of 10,000 individuals (Nishi et al, 2020, PNAS) and various network structures that are publicly available (the use of secondary data). Moreover, this research will analyze the role of early warning signals (EWS), which has been developed in non-linear dynamical systems in the infectious disease control context. I plan to use the 76 California County COVID-19 data (Aim 3).

NIH Research Projects · FY 2026 · 2022-02

PROJECT SUMMARY Neurodevelopmental and neuropsychiatric disorders are a global health problem; yet remarkably little is known about their neurological basis in humans. Consequently, treatment options remain limited. The advent of methods to direct the formation of neurons from human embryonic and induced pluripotent stem cells (collectively hPSCs) provides unprecedented opportunities to both investigate how the function of human neural circuits is subverted by neurological disease and screen for new therapies. A major step towards these goals has been realized by the development of organoid culture techniques through which hPSC can be directed to form spatially organized, brain-like structures. Thus far, brain organoids have been successfully employed to model the impact of genetic mutations and environmental pathogens that result in overt defects in brain growth. However, overall brain structure is preserved in most neurological disorders, and defects are primarily defined by alterations in neural activities. Major challenges thus remain in developing means for defining the organization and function of neural networks within organoids and using this approach to explore underlying disease mechanisms and therapeutic opportunities. In our recent work, we discovered that remarkably complex neural network activities can emerge through the creation of cortex-ganglionic eminence fusion organoids, which permits the intermixing and functional coupling of excitatory and inhibitory neurons. Using a combination of calcium sensor imaging and electrophysiological approaches, we identified that fusion organoids exhibit sustained multifrequency neural oscillations reminiscent of higher network functions seen in intact brain samples and slice cultures. We further developed a fusion organoid model for the neurodevelopmental disorder Rett syndrome and found that organoids harboring mutations in the MECP2 gene exhibit markedly abnormal neural network activities including episodes of hypersynchronous bursting, loss of low-to-mid frequency oscillatory rhythms, and abnormal appearance of epileptiform high frequency oscillations. Together, these studies illustrate the extraordinary potential for the fusion organoid platform to report both normal and dysfunctional neural network functions and recapitulate salient pathological features seen in Rett patients such as seizures. Here, we seek to address three central questions for elucidating the mechanisms underlying neural network dysfunction associated with Rett syndrome and other neurodevelopmental disorders. First, does neural network dysfunction seen in Rett syndrome organoids generated from patients harboring different mutations correlate with the nature of the mutation? Second, what is the impact of cellular mosaicism in MECP2 function on neural network activities? Third, do organoid models for different neurological diseases with a seizure component exhibit shared or distinct network dysfunction profiles? Through our studies, we will explore how brain organoids can be best utilized to determine the root causes of a range of human neuropathologies and work towards the goal of discovering new treatments.

NIH Research Projects · FY 2026 · 2022-02

Project Summary The goal of this project is to identify and characterize functional 3’ UTR genetic variants that alter post-transcriptional regulation of mRNA abundance, with a focus on variants relevant to Alzheimer’s disease (AD). Recently, an increasing number of genetic variants have been cataloged that confer risks to human diseases, including AD. However, it remains a great challenge to identify causal variants and elucidate their potential function relevant to disease pathogenesis and progression. Compared to the progress in pinpointing genetic variants that alter transcriptional regulation or protein-coding sequences, how genetic variants may affect post-transcriptional processes is poorly understood. Many of the newly identified AD-associated variants reside in non-coding regions, such as introns and 3’ UTRs, that may confer regulatory function to the related gene, especially at the level of post-transcriptional regulation. In particular, the 3’ UTRs of human genes are enriched with many cis-regulatory elements recognized by trans-factors, such as RNA-binding proteins (RBPs). Together, these cis-elements and trans-factors dictate many aspects of the mRNA that affect the final expression of a gene. mRNA abundance of a number of well-known AD-relevant genes are regulated by RBPs or microRNAs bound to their 3’ UTRs. Genetic variants that affect these regulatory mechanisms will lead to abnormal mRNA expression, thus significantly altering related functional pathways. In this project, we will leverage the large collection of public data sets on RBP-RNA interaction profiling, RNA-seq and genotyping data collected from AD and control subjects, and our in-house data generation. We will develop and apply novel methodologies to make full use of these data sets, complemented by further bioinformatic prediction and high-throughput experimental testing, to pinpoint 3’ UTR genetic variants that alter mRNA abundance in AD. This work will allow a previously unattained level of understanding of genetic variants in post-transcriptional regulation and provide new means to tackle the imperative task of functional interpretation of genetic variants in AD.

NIH Research Projects · FY 2026 · 2022-02

PROJECT SUMMARY/ABSTRACT (AD-focused Administrative Supplement) The estimated number of people with dementia is predicted to triple by 2050 worldwide. Together with the lack of effective treatments to stop, slow or prevent Alzheimer’s disease (AD) and its related dementias, the best strategy to limit the predicted incidence is to mitigate AD risk factors. Exposure to ambient particulate matter (PM) is emerging as a modifiable environmental risk factor for AD. However, the mechanism by which PM exposure contributes to the development of AD is not known. Our previous research has shown that exposures to ultrafine particles (UFP) and diesel exhaust (DE) in mice lead to chronic inflammation, increased lipid peroxidation in lung and systemic tissues, disturbances in lipid metabolism and plasma lipoproteins, and the development of liver steatosis and atherosclerosis, all components of the commonly called cardiometabolic syndrome. Recent studies suggest that cardiovascular and metabolic disorders may play a critical role in the development of AD. In fact, AD and cardiometabolic syndrome share major risk factors, in addition to cerebrovascular and cardiovascular changes occurring years before symptoms occur. We will augment the Parental R01 (ES033703, RESTORE RFA) by extending its focus on hepatic steatosis and atherosclerosis with the analyses of brain tissue in the same hyperlipidemic mouse model (low-density lipoprotein knockout, Ldlr KO), placed on a high fat diet (HFD). Importantly, Ldlr deficiency and HFD administration have been associated with worsened AD-related phenotypes and cognitive dysfunction in a transgenic mouse model of AD through impairment of antioxidant system defenses leading to oxidative stress and neuronal apoptosis. Therefore, while this is not a typical mouse model for the study of AD, we do expect significant neuroinflammatory and neurodegenerative effects. Our overall objective is to identify critical pathways in the Lung-Heart-Brain Axis that could be involved in the development of chronic inflammation in the brain. Our hypothesis for this AD- focused Research Supplement is that particulate matter inhalation exposure promotes proinflammatory and degenerative effects in the brain of Ldlr null mice fed a HFD, and retards the resolution of those effects after halting the feeding of the HFD. Our hypothesis will be tested via the following aims: Supplemental Specific Aim 1) Determine neuroinflammatory effects, AD-relevant changes in the brain and neurobehavioral alterations induced by diesel exhaust exposure and feeding of a HFD, and how such exposure affects resolution of those effects after cessation of the HFD; and Supplemental Specific Aim 2) Assess neuroinflammatory effects, AD- relevant changes in the brain and neurobehavioral alterations induced by UFP exposure and feeding of a HFD, and how such exposure affects resolution of those effects after cessation of the high fat diet. Results from this Supplement could provide convincing preliminary data for additional proposals to investigate environmental factors that may induce AD and other potential drivers of cognitive decline.