University Of California Los Angeles

NIH Research Projects · FY 2025 · 2023-05

In response to RFA-AI22-024 Limited Interaction Targeted Epidemiology: Viral Suppression (LITE-VS), we propose “Exploring, Predicting, and Intervening on Long-term Viral suppression Electronically (EPI-LoVE)” with a cross-cutting, interdisciplinary scientific team with strong expertise in longitudinal cohorts to enroll a large, digitally maintained cohort of people living with HIV (PLWH) in the US who are not adequately virally suppressed (>200 copies/mL), report prior gaps in HIV care engagement, or lack of sustained viral suppression (VS). The cohort will investigate trajectories of HIV care engagement and VS applying a theoretical approach and analytic strategies that recognize the cyclical nature of retention in HIV care and VS. We will examine the syndemics underlying these outcomes including substance use, mental health, and barriers to HIV care including stigma and rural isolation. Our strategy includes multiple recruitment methods such as a) social media recruitment in partnership with digital advertising companies employing unique tools, websites/apps and artificial intelligence (AI)-based models to optimize outreach/recruitment; and b) a partnership with AIDS Healthcare Foundation (AHF), the largest HIV medical provider in the country. We will enroll a diverse cohort of PLWH enriched with those living in rural areas, Black, under 25 years of age and experiencing substance use challenges. An evidence-based digital platform (HealthMpowerment, HMP) deployed in 10 studies, including other limited interaction targeted epidemiology (LITE) initiatives, will be used for data collection, real-time analysis and participant communication and will be supplemented with semi-annual blood specimens collected with a multi-pronged strategy (i.e. local laboratory, clinics, and home- based collection options) to facilitate participation. We will develop a sophisticated risk assessment tool to optimize when PLWH in our cohort are most at risk for VNS and deliver tailored, real-time intervention components based on their personalized needs at the time they need them most. Our investigative team from three leading institutions The University of California at Los Angeles and Irvine, and University of North Carolina, Chapel Hill has decades of experience with recruitment, engagement, and care of PLHW and large-scale longitudinal cohort studies, as well as long-standing expertise developing digital and AI-based tools in collaboration with HIV stakeholders. We capitalize upon productive partnerships and expertise to articulate the drivers of the ongoing HIV epidemic among the most vulnerable populations in the US and to identify the most effective, expeditious and scalable digital strategies to address this ongoing public health crisis.

NIH Research Projects · FY 2026 · 2023-05

ABSTRACT A major goal of our laboratory is to delineate regulatory mechanisms that control adipocyte development and systemic physiology in obesity and diabetes. This proposal will address a new regulatory pathway involved in adipose tissue adipose depot-specific energy expenditure. Understanding how metabolic tissues store and utilize lipids is of central relevance to normal physiology, obesity and diabetes. Excess neutral lipids are stored in lipid droplets (LDs)–dynamic organelles that expand and shrink depending on the metabolic needs of the cell. The molecular mechanisms that link lipid LD dynamics and function to tissue metabolism are incompletely understood. Defining the molecular pathways that govern fuel utilization in tissues is important for understanding systemic homeostasis and the underlying causes of pathological lipid accumulation in the setting of metabolic disease. We have identified Clstn3, an adipose tissue- and liver-selective product of the Clstn3 gene, as a key determinant of multilocular LD morphology and function. Clstn3 is an integral ER membrane protein that localizes to ER-LD contact sites via conserved hairpin-like domains. Loss of Clstn3 in mouse brown adipose tissue (BAT) increases LD size, reduces triglyceride utilization, and leads to cold- induced hypothermia. Conversely, ectopic expression of Clstn3 in adipocytes is sufficient to reduce LD size and enforce a multilocular LD phenotype. Collectively, these initial discoveries have revealed a previously unrecognized molecular mechanism that maximizes LD surface area and facilitates lipid utilization in thermogenic adipocytes and potentially other cells. The overall goal of this proposal is to further define the mechanisms of Clstn3 action and its contributions to metabolic physiology. Specific Aim 1 will elucidate mechanisms by which Clstn3 regulates LD structure and function. Specific Aim 2 will investigate the ability of Clstn3 to modify white adipocyte function. Specific Aim 3 will define the role of Clstn3 in lipid metabolism in other tissues. These studies are expected to provide fundamental insight into pathways regulating LD function and may suggest opportunities for modulating lipid utilization in the setting of metabolic disease.

NIH Research Projects · FY 2026 · 2023-05

PROJECT SUMMARY/ABSTRACT Bioinformatics, computational biology, and omics are important areas that have the potential to uncover new discoveries in the molecular/cellular mechanisms and gene networks that lead to congenital birth defects, metabolic and genetic disorders, organ dysfunction, disorders of the immune system, and cancer in Pediatric patients. The Department of Pediatrics, David Geffen School of Medicine at UCLA proposes to fill the gap for much needed specialized education and in-depth training of pediatric graduate medical education (GME) clinical trainees in biomedical big data analysis, promote the establishment of multidisciplinary networks and opportunities for collaboration in these specialized areas, and provide a bridge for trainees towards successful participation as clinicians or clinician-scientists in multi-disciplinary team science towards obtaining future funding for the discovery and amelioration of childhood disorders (i.e. T32, K23, K12, K08) and academic careers in diverse research pathways. This program will focus on recruiting pediatric GME trainees from diverse backgrounds, with an interest in clinician researcher or physician-scientist careers, and who have a desire to build foundational skills in big data analysis. Specifically, the program will target Pediatric residents in their 2nd or 3rd year of training and Pediatric subspecialty fellows at the start of their 2nd year of training. The 12-week program, set to occur at the start of the academic year, will include weekly didactic lectures, taught by UCLA faculty with expertise in bioinformatics, biostatistics, computational biology, and omics, covering key areas of big data science and omics, accompanied by workshops linked to the specific topic presented in the didactic lectures, and interactive journal club sessions. The interactive workshops, conducted by faculty and UCLA Quantitative and Computational Biosciences Collaboratory postdoctoral PhD fellows, will reinforce concepts from the didactic lectures through hands-on application of the knowledge via analysis of actual experimental datasets and use of statistical techniques. The journal club sessions will be in a flipped classroom format and will reinforce concepts covered in the didactic lectures and workshops to demonstrate the application of bioinformatics and computational biology technology that lead to new discovery and advancement of Pediatric patient care. The program will allow for remote access by pediatric trainees beyond the institution through virtual learning (hybrid format) and availability of educational content online. Key areas of skills building will include next generation whole genome sequencing, transcriptome, proteome, and metabolome analysis, single cell RNA sequencing, DNA methylation analysis, microbiome analysis, and gene network analysis. This program will provide a unique opportunity for pediatric GME trainees to receive more formal instruction and training in the very important areas of big data analysis and directly interact with the faculty on campus, beyond the Department of Pediatrics, with expertise in these areas who could potentially serve as research and career mentors, thus facilitating their successful academic journey.

NIH Research Projects · FY 2026 · 2023-05

PROJECT SUMMARY/ABSTRACT The World Health Organization has set goals for cervical cancer (CC) elimination through global HPV vaccination and cervical cancer screening (CCS). Unfortunately, neither real-world HPV vaccine effectiveness nor efficient CCS have been established for women living with HIV (WWH) who are disproportionately affected by CC. Our group reported that HPV-vaccinated young women living with perinatal HIV infection (WWPHIV) had very high rates of abnormal cervical cytologic compared with HIV [-] women suggesting reduced vaccine effectiveness. While primary HPV testing used for screening (PHS) with a triage test is the preferred method for CCS in the general population in the U.S., the CDC has not recommended it for WWH because of the lack of scientific support. A recent study by our group showed that PHS with triage 16/18 genotyping in WWH cut the number of unnecessary colposcopies in half without reducing sensitivity (vs HPV/cytology co-testing); however, the positive predictive value remained low. Furthermore, the recently FDA-approved dual immunocytochemistry staining for p16/ki67 as well as novel biomarkers using extended HPV genotyping and DNA methylation show great promise but are vastly understudied in WWH. We have an exceptional opportunity to examine both HPV vaccine effectiveness and PHS screening triage strategies in WWH by partnering with the Pediatric HIV/AIDS Cohort Study (PHACS) led, in part, by our investigative team. PHACS includes a cohort of over 2400 WWH, including WWPHIV and WWH, horizontally (WWHH) infected, who are enrolled along with their HIV exposed children. We estimated that 90% of the WWPHIV and 50% of the WWHH <41 years of age have received at least one HPV dose. Among WWH, we aim to: 1) examine the effectiveness of the HPV vaccine defined by the 3-year cumulative risk of i) vaccine-HPV types that persist 12 months or longer and, ii) histologic (h) cervical intraepithelial neoplasia (CIN)-2+; 2a) examine and compare the sensitivity (Se), specificity (Sp), positive (PPV) and negative predictive values (NPV) to detect hCIN-2+ immediately or in 3 years in PHS[+] women using 4 reflex strategies: (i) cytology, (ii) HPV extended genotyping, (iii) p16/Ki-67 dual staining cytology, and (iv) HPV/host methylation levels; 2b) examine the Se, Sp, PPV, and NPV in self-collected PHS[+} samples for hCIN2+ detection focusing on methylation and HPV genotyping triage tests since these 2 tests are suitable for self-collected samples. We plan to screen ~810 WWH using a self-sampling kit--now a well-accepted mode for screening-- for PHS testing (Roche Cobas) and those who PHS[+] (~570) will attend a clinical visit to have colposcopy/biopsy and the 4 triage tests. WWH with <CIN 2+ are asked to return annually for colposcopy and HPV genotyping for up to 3 yrs. WWH with CIN 2+ are exited. WWH PHS[-] will be asked to return in Year 2 for rescreening. Those PHS[+] will be followed as above and PHS[-] will be asked to obtain self-collected vaginal samples for HPV genotyping annually for 3 years. Impact. Understanding HPV vaccine effectiveness and optimal CCS strategies in WHH will make a significant contribution to decreasing the worldwide burden of CC.

NIH Research Projects · FY 2026 · 2023-05

Project Summary/Abstract Atherosclerotic cardiovascular disease (CVD), a chronic lipoprotein-driven inflammatory disorder, is the leading cause of death worldwide. Conventional lipid-lowering therapies only modestly lower cardiovascular risk in the population due to “residual risk,” thought to be caused by excessive inflammation. Emerging evidence shows that the interruption of inflammation resolution, an active tissue repair process, is a key mechanism that contributes to atherosclerotic plaque progression. Therefore, identifying novel targets that mediate both inflammation and resolution is crucial for developing cardiovascular therapeutic strategies that can both boost resolution and prevent inflammation. As endocytic trafficking is an essential cellular process that regulates macrophage function, we have focused on the role of C-terminal Eps15 homology domain-containing (EHD) family proteins, the key conductors of endocytic trafficking in the immune response of macrophages. The publicly available single-cell RNA sequencing (scRNA-seq) data of macrophage populations in both human and murine atherosclerotic plaques reveal that EHD1 is selectively expressed in inflammatory lesional macrophages compared with other EHD proteins, and our new study shows that EHD1 levels are increased in lesional macrophages from both human and murine plaques as atherosclerosis progresses. These data support an overall proatherogenic role for EHD1 and underscore its relevance to human disease. The overall objective of this proposal is to study the role and the underlying mechanisms of EHD1 in inflammation and resolution in the context of atherosclerosis. Our data suggest that EHD1 impairs inflammation resolution by inducing the ectodomain cleavage of MerTK, an efferocytosis receptor required for timely resolution of inflammation, and aids inflammation by promoting macrophage polarization toward a proinflammatory phenotype. Moreover, we have established a novel link between EHD1 and sortilin, a human genetic risk factor for CVD, by showing that EHD1 silencing decreases sortilin protein levels. The ectodomain of MerTK is cleaved by the metalloproteinase ADAM17, and our preliminary data show that EHD1 enhances ADAM17 on the cell surface, where shedding takes place. Hence, we will test our hypothesis that EHD1 promotes ADAM17 recycling to the cell surface, which leads to MerTK cleavage, defective efferocytosis, impaired inflammation resolution, and plaque necrosis (Aim 1). As autophagy is well known to suppress polarization of proinflammatory macrophages and we found that EHD1 suppresses autophagy, we hypothesize that EHD1 promotes proinflammatory macrophage polarization by suppressing autophagy, leading to inflammatory plaque progression (Aim 2). Finally, we will investigate whether EHD1 stabilizes sortilin and induces inflammatory cytokine secretion by facilitating retrograde transport of sortilin (Aim 3). By exploring the role of EHD1 in atherosclerosis, we hope to bring to the forefront an important new concept regarding EHD1-mediated intracellular trafficking in plaque progression, one that could provide the basis for novel therapeutic strategies to prevent CVD.

NIH Research Projects · FY 2026 · 2023-05

Project Summary/Abstract Non-alcoholic steatohepatitis (NASH) has emerged as the leading cause of chronic liver disease worldwide, with liver fibrosis as the most important predictor of morbidity and mortality in NASH. However, due to the major gaps in understanding the mechanisms of NASH progression, particularly fibrosis, there are no FDA-approved drugs to treat NASH and halt the progression of NASH to cirrhosis and hepatocellular carcinoma. Emerging evidence shows that excessive cholesterol accumulation in hepatocytes promotes liver fibrosis in NASH, but how hepatic cholesterol homeostasis is disrupted during NASH is not completely understood. Human genome-wide association studies (GWAS) have indicated that EH domain binding protein 1 (EHBP1) is associated with low- density lipoprotein (LDL) cholesterol levels, and single-cell RNA sequencing (scRNA-seq) of human livers has revealed that EHBP1 expression is dramatically reduced in hepatocytes from cirrhotic livers with advanced fibrosis, indicating that hepatocyte EHBP1 may play a role in liver fibrosis through modulating cholesterol metabolism. The overall objective of this proposal is to study the role and the regulation of EHBP1 in NASH. Our studies with primary human and mouse hepatocytes showed that EHBP1 deficiency enhances LDL receptor (LDLR), cellular cholesterol, and the Hippo pathway effector TAZ, a novel cholesterol sensor that can induce liver fibrosis in NASH. We further found that hepatocyte-specific silencing of EHBP1 induces liver LDLR, cholesterol, TAZ, and liver fibrosis in NASH mice. We recently published that hepatic cholesterol stabilizes TAZ, and therefore propose that hepatocyte EHBP1 reduces liver fibrosis by preventing cholesterol accumulation and suppressing TAZ in NASH (Aim 1). Our study supports a role of EHBP1 in cholesterol homeostasis to prevent liver fibrosis in NASH. However, as NASH progresses, EHBP1 expression is reduced. Surprisingly, we found that the NASH-relevant inflammatory cytokine TNFa significantly suppresses the expression of EHBP1 and PPARa, a predicted transcriptional regulator of EHBP1, in primary hepatocytes. Hence, we propose that inflammatory stress caused by TNFa disturbs cholesterol homeostasis by suppressing PPARa/EHBP1 expression in hepatocytes during NASH (Aim 2). We further found that TNFa-suppressed EHBP1 can be blocked by treatment with resolvin D1 (RvD1), a docosahexaenoic acid (DHA)–derived specialized pro-resolving mediator (SPM) that can trigger resolution of inflammation. As RvD1 is produced by macrophages, we propose that macrophage-derived RvD1 blocks TNFa-mediated EHBP1 suppression in hepatocytes and this RvD1- mediated cellular crosstalk maintains cholesterol homeostasis and prevents fibrosis in NASH (Aim 3). As the beneficial effects of SPM analogues have been tested in clinical trials for other inflammatory diseases, our study elucidating the crosstalk between inflammation resolution and cholesterol homeostasis will provide insights on the potential use of RvD1 analogues as an innovative therapeutic strategy for NASH.

NIH Research Projects · FY 2026 · 2023-05

Project Summary A major target of retinal output is the superior colliculus (SC). In fact, more retinal ganglion cell (RGC) types may project to the SC than any other retinal target including the lateral geniculate nucleus (LGN). Understanding retinal input to SC is important because SC plays a major role in a range of attentional and decision-making processes in both rodents and primates – two major model systems used in biomedical research supported by the National Institutes of Health. However, the functional diversity of retinal input to SC, and ultimately how it impacts SC signaling, remains poorly understood in mammals. This gap is particularly pronounced in primates. The overarching goal of this proposal is to determine the diversity of cell types and the visual signals they transmit from the retina to SC in rats and rhesus monkeys. The rationale for this proposal is that to understand the role of SC in visually guided behaviors, we must determine how retinal signals converge and are processed in SC. The first step toward achieving this goal is to determine which RGC types project to SC and what visual signals they carry. Performing these experiments in both rodents and macaques is critical not just for understanding which specific visual pathways are conserved (or diverge) from rodent to the primate brain, but also what evolutionary advantages such specializations endow to each species. In Aim 1 of this proposal, we will use and optimize viral methods for retrogradely infecting RGCs that project directly to SC in rats. We will determine the morphological diversity of these RGCs. We will also determine their receptive fields and other visual response properties, ex vivo, using large-scale multi-electrode arrays. The outcome will be a complete catalog of the morphological and functional types of RGCs that project to SC in the rat brain. In Aim 2, we will use the most effective viral approaches from Aim 1 to dissect the diversity of RGC types that project to SC in monkeys. As with rats, we will determine the morphological diversity of these RGCs in macaques and determine their receptive fields and other visual response properties using large-scale, high throughput electrophysiology. In Aim 3, we will determine the overlap of RGC projections to SC and LGN, separately for rats and primates. Retrograde viruses injected into SC and LGN will carry genes for different fluorescent proteins that will allow us to determine the types and functions of RGCs that project to one versus both brain areas. The overall outcome of this project will be a functional and morphological catalog of RGCs that project to SC in rats and primates, allowing for detailed cross-species comparison of this key visual circuit. This comparison is important given how much research is dedicated to the rodent visual system with the ultimate aim of understanding the human visual system. The data will be critical for designing next-stage studies that will measure and manipulate the functions of specific populations of SC-projecting RGCs in order to determine their contributions to visual processing and behavior and their potential impairments in ADHD and other attentional and visuomotor disorders.

NIH Research Projects · FY 2026 · 2023-05

Project Summary/Abstract Human genetic studies have identified hundreds of genes contributing to Neuropsychiatric and Neurodevelop- mental Disease (NPD) risk. But for most genes, their normal function or the consequences of their absence or reduction on neurodevelopment and neural function are not known. Here, we propose to address the substantial challenges of discerning potential functions of hundreds of NPD genes through the development of a High Throughput Neuropsychiatric Disease Phenotyping Center (UCLA HT-NPC), driven by the activity of 9 highly collaborative investigators (Aharoni, Bhaduri, Damoiseaux, Geschwind, Golshani, Kitai, Luo, Novich, and Wells) and two substantial core facilities (UCLA Molecular Screening Shared Resource and the Human Stem Cell and Genome Engineering Center). Through a tiered approach, we combine high throughput and high value, quantitative phenotyping with stem cell engineering to characterize the functional consequences of NPD gene knockouts (null alleles), a key initial step that will inform our understanding of disease pathways. In the first step, we will rapidly generate null alleles for 250 genes chosen by the Consortium using a rapid, high throughput lentiviral based system in hESCs. Viability and neural induction potential will be assessed, and quantitative phenotyping conducted using RNA-seq on all lines. Those genes passing viability and neural induction tests will be used in the production of clonal null hiPSC lines (male and female) for downstream phenotyping and wider distribution to the community. Subsequently, we will perform high throughput, quantitative, multi-scale phenotyping at the molecular, morphological, and physiological levels in both 2D and 3D hiPSC-based models of human cortical development. We leverage the relative strengths and scalability of each model to enable us to perform both snRNA and bulk RNA-seq, measure the maturation, morphology, and synaptic density of neural cells using automated imaging, including the multiplexed, protein-based CODEX (Phenocycler) platform, and characterize neuronal activity and synchronization through optical recordings using custom-built mini-scope arrays (STIMscope). By using multiple systems (e.g. hESC/hiPSC; gene editing, 2D and 3D cultures), we test biological reproducibility across systems and technical reproducibility through replication. The use of experimentally validated, quantitative phenotypes across multiple scales of analysis facilitates data sharing and comparisons with other SSPsyGene investigators and provides a template for the field more broadly.

NIH Research Projects · FY 2026 · 2023-05

ABSTRACT This R01 confirmatory efficacy clinical trial application involves telehealth delivery of a treatment approach to improving core cognitive deficits in schizophrenia, using an experimental therapeutic design that NIMH has advocated. Our telehealth intervention approach combines neurotrophin-releasing aerobic exercise training with neuroplasticity-based cognitive training to enhance the impact of cognitive training on cognition. Telehealth cognitive training and telehealth physical exercise training address the NIMH strategic research priorities for creating innovative interventions that can be “disseminated broadly” and “readily taught to the existing workforce with minimal cost.” Cognitive training and physical exercise have each been shown separately to improve cognitive deficits in schizophrenia to some degree, and our previous research has shown that when combined they show promise of improving cognition and work/school functioning more than either treatment alone. In our preliminary studies, comparing the combined treatment with cognitive training without aerobic exercise, we find evidence of brain-derived neurotrophic factor (BDNF) target engagement, differential improvement in cognition, and prediction of later cognitive outcome from initial BDNF gain. The portability of the proposed intervention outside of academic research programs will be demonstrated by providing the interventions via videoconferencing. The proposed study will incorporate additional methods, such as Fitbit wrist-worn fitness trackers, web-based motivational support, and personalized text messages to encourage motivation and to maximize participation in the exercise condition. We will use Mature BDNF as our primary target and cognition as our primary outcome. We hypothesize that the increases in Mature BDNF associated with regular aerobic exercise provide a platform which allows neuroplasticity-based cognitive training to enhance cognition more quickly than is typically observed in studies of cognitive training alone. We hypothesize that combining aerobic exercise with cognitive training will produce larger cognitive improvements, relative to cognitive training without exercise, with all interventions conducted remotely via videoconferencing. Further, we hypothesize that a greater proportion of exercise sessions completed will be associated with greater cognitive improvement. The research will also test whether intrinsic motivation at baseline and increases in intrinsic motivation over time predict the extent of participation in the telehealth physical exercise program. Cognitive deficits in persons with schizophrenia are a major influence on their everyday functioning in the community. We target the period shortly after a first episode of schizophrenia to maximize the generalization of cognitive improvement to real-world functional outcome, before chronic disability is established. This telehealth cognitive training plus aerobic exercise clinical trial has the potential to test a hypothesized mechanism of action and to make a meaningful difference in the lives of individuals with severe mental illness.

NIH Research Projects · FY 2026 · 2023-04

PROJECT SUMMARY The applicant seeks this K01 award to gain expertise on integrating social factors and neuropsychological assessments to examine within race heterogeneity for cognitive decline risk factors in the Black community. To achieve these goals, the applicant plans to leverage her strength is quantitative methodology for biomarker data to gain expertise in four critical areas of training: (1) research neuropsychological testing and community engagement; (2) health disparities and lifecourse factors; (3) genetics; and (4) professional training. With the guidance from her expert mentorship team and through a detailed training plan, the applicant will develop an in-depth knowledge in these training areas and enable the applicant to be well positioned to successfully complete the proposed aims of the K01. The overall research goal of this K01 application is to determine how social, neuroimaging markers, and genetic risk factors contribute to cognitive decline in non-demented older Black individuals. Research suggests current “well-established” risk factors for cognitive decline and Alzheimer’s disease (AD), which have been identified primarily in the white community, do not behave the same in Black individuals. Thus, it is critical to explore potential heterogeneity in risk factors within the Black community in order to accurately predict risk for cognitive decline. The first part of aim 1 examines the effect of early and current social factors on neuroimaging measures that have previously been associated with cognition (e.g. structural magnetic resonance imaging measures and vascular burden measured as white matter hyperintensities) in self-identified non-Hispanic Black participants. The second part of aim 1 will determine if these neuroimaging markers mediate the association of social factors and cognitive decline. We hypothesize that more social disadvantage will be inversely associated with AD-specific brain regions and faster rates of cognitive decline. We also hypothesize that neuroimaging measures will partially mediate the association of social factors on cognitive decline. Differences in racial groups may be due to social factors, which members of the Black community are disproportionately impacted. Finally, it is important to remember that race is a social construct and is dependent on self-identification, with no biological root. Moreover, recent studies suggest that genetic ancestry may influence risk for AD and impact pathological features of aging. It is unclear if genetic ancestry and social factors correlate, or if they have unique contributions to cognitive decline. Thus, our final aim will determine if genetic ancestry and/or social factors differentially influence the effect of APOE4 on cognitive decline. The primary hypothesis is that Black participants with more social disadvantage throughout life, will inversely effect these risk factors and have a faster rate of cognitive decline. We will also investigate if this association impacts conversion from mild cognitive impairment to AD dementia. Completion of these aims, along with the training from an experienced multidisciplinary mentoring team, will generate data and support for a future R01 application collecting data from members of the Black community in Los Angeles County.

NIH Research Projects · FY 2025 · 2023-04

PROJECT SUMMARY Model-based learning affords individuals the ability to contemplate the specific outcomes of actions or events. This facilitates flexible decision making. While we know of brain regions that contribute to model-based learning, the wider pathways and circuits that facilitate development of these flexible representations in these regions are less explored. Given that substance use disorders are characterized by deficits in model-based decision making, a gap in the knowledge of the neural circuits contributing to model-based learning prevents us from making clinical advances in the treatment of these deficits. The overarching goal of this proposal is, thus, to expose the neural circuits that mediate model-based decision making. Recent evidence from our team and others has implicated ventral tegmental area dopamine neurons (VTADA) as critical to driving model-based learning. This was surprising because phasic VTADA activity was typically restricted to assigning general value to cues, which prevents this signal from contributing to more flexible associative relationships characterizing model-based learning. This work acts as our catalyst to investigate how this dopamine signal is used in the circuits necessary for model-based learning. We are particularly interested in the dopamine pathways to the basolateral amygdala (VTADABLA) and lateral hypothalamus (VTADALH). We have shown that BLA and LH are important for the development of model-based associations. However, while the BLA and LH both contribute to model-based learning about cues proximal to rewards, the function of these regions diverge when it comes to more distal predictors. Specifically, the BLA remains important for using distal predictors to predict rewards, while the LH opposes learning about distal predictors. It is unknown how VTADA projections to BLA or LH facilitate reinforcement learning generally, or model-based learning specifically. Thus, we hypothesize that midbrain dopamine projections to the BLA and LH mediate the encoding of detailed model-based associative memories that allow prioritization of information most relevant to rewards. Capitalizing on the overlapping and complementary expertise and perspectives from two labs, we will uncover the function of these two non-canonical dopamine circuits in model-based learning. We will use a symmetrical and multifaceted approach using modern cell-type and projection-specific manipulation and recording techniques in the context of sophistical behavioral tasks to reveal the function VTADA projections to BLA and LH in proximal and distal learning. We will use cell-type and projection-specific optogenetic inhibition, stimulation, and recording of the VTADABLA and VTADALH pathways to expose the role of these pathways. We will use next-generation dopamine sensors to provide novel measurements of dopamine release in BLA and LH. Finally, we chemogenetically inhibit VTADA projections to BLA or LH while optically imaging BLA or LH neuronal activity to elucidate the contribution of dopamine input to learning- and decision-related activity.

NIH Research Projects · FY 2026 · 2023-04

PROJECT SUMMARY (See instructions): Protein aggregation is a hallmark of neurodegenerative diseases, including Alzheimer's Disease, and these diseases lack effective therapeutics. We currently lack an understanding of the molecular and cellular mechanisms controlling protein aggregation in the human brain, which would enable new therapeutic strategies. The protein tau aggregates in the brain in many neurodegenerative diseases called tauopathies, including Alzheimer's Disease. In early stages of disease, tau aggregates only in specific neurons despite being expressed in every neuron in the brain, implying that specific factors in the cellular environment predispose tau to aggregation. Similarly, tau mutations are associated with the onset of only specific tauopathies. Together, these disease features imply that tau is exquisitely sensitive to both its sequence properties and its cellular environment. Post-translational modifications (PTM) are a mechanism by which the cellular environment can act on a protein primary sequence, similar to mutation. Tau is heavily post-translationally modified and changes to tau PTMs are correlated with progression of disease. Tau phosphorylation and proteolysis are proposed to be central events in the onset and progression of tauopathies. Similarly, mutations are correlated with early disease onset and are known to hasten in vitro tau aggregation. Mutations can also cause changes in PTMs by changing tau interaction partners. The function and causality of these changes to tau aggregation, however, is unknown. I hypothesize that PTMs and mutations license tau to access specific conformations to form aggregates. The goal of this proposal is to comprehensively identify (1) the biological basis of tau PTM changes and (2) how tau mutation and PTMs cause aggregation. I have shown that mitochondrial electron transport chain dysfunction causes remodeling of tau PTMs, including the accumulation of a tau proteolytic fragment. In Aim 1, I will acquire new training in mass spectrometry (MS)-based proteomics to determine the tau PTM changes that occur due to ETC dysfunction and how those control tau aggregation. In Aim 2, I will use deep mutational scanning (OMS) to comprehensively probe tau's sequence-structure relationship. As part of Aim 2, I will use cross-link MS to directly compare in vitro and in vivo tau states to reveal the structural mechanisms for the identified PTM and sequence changes. I am ideally positioned to complete

NIH Research Projects · FY 2026 · 2023-04

Summary/Abstract Acute pancreatitis (AP) is a disorder with significant morbidity and mortality that lacks treatments. The lysosomal/autophagy pathway – a key catabolic mechanism by which cells eliminate damaged cytoplasmic organelles – is impaired in both experimental and human pancreatitis. Further, genetic alterations specifically targeting autophagy or lysosomes cause spontaneous pancreatitis in mice. These findings implicate impaired lysosomal/autophagy pathways in initiating and driving pancreatitis. The mechanisms through which disordering of these pathways causes the disease remain, however, unknown. Studies in other organs and disease models showed a critical role for lysosomal/autophagy pathways in regulating cholesterol homeostasis, essential for cell viability and function. Moreover, recent studies indicate that use of cholesterol-lowering drugs, statins, is associated with lower incidence of AP and decreased mortality. However, there is little known about cholesterol metabolism in the exocrine pancreas and its’ dysregulation in pancreatitis. The effects of statins and other cholesterol-lowering drugs on acinar cell cholesterol homeostasis and AP responses have not been studied. We here propose a novel hypothesis for the pathogenic mechanism of pancreatitis: that lysosomal/autophagy dysfunction causes dysregulation of acinar cell cholesterol homeostasis, leading to mitochondrial oxidative stress and pathologic responses of pancreatitis. Our preliminary results indicate that both preclinical models and human pancreatitis are associated with profound dysregulation of cholesterol homeostasis in acinar cells, and that lysosomal/autophagy dysfunction associated with AP plays a key mediatory role in these effects. They further show the role of cholesterol dysregulation in disease severity, in particular mitochondrial oxidative stress and inflammation. The hypothesis will be tested in three Specific Aims: 1). Investigate dysregulation of acinar cell cholesterol homeostasis in experimental and human pancreatitis and its role in pancreatitis responses. 2). Determine the role of cholesterol dysregulation in pancreatitis caused by disrupted lysosomal/autophagy pathways. 3). Examine the role of cholesterol dysregulation in mitochondrial oxidative stress leading to inflammation in pancreatitis. The proposed research is significant because it will establish cholesterol metabolism as a clinically relevant modulator of pancreatitis severity and identify potential molecular targets, amenable for pharmacologic intervention, to normalize cholesterol metabolism and thus reduce pancreatitis severity. In particular, we will elucidate the mechanisms of the effects of statins and other cholesterol-modulating drugs on pancreatitis.

NIH Research Projects · FY 2026 · 2023-04

This grant application aims to identify and characterize the role of Piezo in cells of the muscularis during baseline and stretched states. Bowel motility disorders and acute bouts of bowel obstruction are common clinical problems and can be severe, and we do not fully understand their mechanisms or have effective treatments. One crucial mechanism controlling bowel motility is mechanosensing, allowing each bowel segment to sense and respond to stretch. Various cell types within the intestinal muscularis control motility, sense stretch, and induce contractions. Among these cells are the components of the SIP syncytium comprised of smooth muscle cells (SMC), interstitial cells of Cajal (ICC), and PDGFRcells. These cells respond to stretch and receive inputs from enteric neurons (EN), glia, and enteroendocrine cells (EEC) that modulate SIP syncytium activity. However, the mechanism underlying the ability to sense and respond to stretch has not been thoroughly evaluated. Here we propose to investigate the role of Piezo in this process. Piezo is a relatively new calcium channel that functions as a mechanosensor in numerous cells, including those in the gut. Here, we will focus on its role in smooth muscle cells, interstitial cells of Cajal, and PDGFRcells of the small intestine. To perform these experiments, we have developed novel methods to maintain murine cells of the muscularis in an in vitro system. We will also use physiologically tunable hydrogels to examine the consequences of stretch in this setting. Finally, we will use various genetic approaches to explore the effects of mechanosensing in SIP cells of the gut. After this study, we anticipate that we will further elucidate the biomechanical and physiological consequences of disrupting a mechanosensitive channel that alters muscularis function and highlight myopathy's indirect effect on the adjacent epithelial layer to exacerbate the dysmotility further.

NIH Research Projects · FY 2026 · 2023-04

ABSTRACT: The incidence of cardiac arrest in the United States exceeds 300,000 per year with an average survival rate of ~11%. Over 500,000 cardiac surgeries and procedures, which require detailed cardiac diagnostics and intense monitoring, are performed to treat arrhythmias and structural heart disease in the US each year, which together carry a morbidity and mortality risk of 1-30%, depending on a patient’s comorbidities. The fundamental hypothesis underlying this proposal is: Progression of arrhythmogenesis reflects heterogeneities in cardiac electrical substrate that are amplified by heterogeneities in autonomic control. As such, interventions that mitigate autonomic heterogeneities should be (and are) anti-arrhythmic. A major unmet need in the field of Neurocardiology is technologies that provide real-time predictive assessments of cardiac and autonomic status that would then allow for rapid and targeted closed-loop neuromodulation therapies to intervene in the progression of arrhythmogenesis. The primary goal of this proposal is to develop bioelectronic technologies for high-resolution, real-time concurrent measurements of cardiac autonomic and electrophysiological parameters and to use that information to modulate autonomic function in a feedback control manner. Advances in analytics for data derived from intra-myocardial multi-pole electrodes, coupled with the deployment of thin-film 2-D microarrays to the epicardium, will define electrical heterogeneities across the border zone areas of the ischemic heart. Autonomic assessment will include real-time measurement of regional cardiac neurotransmitter release profiles, leveraging electrochemical cyclic voltammetry (catecholamine) and capacitive immunoprobe (neuropeptide measurements), each novel to the cardiac setting. The ability to provide real-time readouts of vascular and cardiac neurochemicals, when combined with our advances in direct epicardial and endocardial mapping of the cardiac electrical substrate, provides our team the ability to 1) identify subjects at high risk for sudden cardiac death; 2) define specific contribution of abnormal electrophysiological substrate as amplified by heterogeneities in autonomic neurotransmitters; and 3) tailor closed-loop neuromodulation therapeutic interventions to the underlying pathology. To this end, three aims are proposed. Aim 1: To develop bioelectronic interfaces, platforms/modules, and analytical tools for real-time in vivo assessments of multiple cardiac interstitial and vascular neurotransmitter levels. Aim 2: To define dynamic interactions between focal cardiac neurotransmitter release and modulation of regional cardiac electrical function in reflex response to cardiac stress. Aim 3: To implement a Multi Input, Multi Output (MIMO) closed-loop control of cardiac transmitters. The translational potential of such a closed-loop neuromodulation system will find application in intraoperative, post-operative and critical care settings.

NIH Research Projects · FY 2026 · 2023-04

Abstract Prostate cancer is the most commonly diagnosed non-skin cancer in men, and the second most common cause of cancer death for men. It is a high-incidence, high-fatality, high-morbidity and high-cost cancer that is growing increasingly frequent in our aging population. Clinically, the majority of prostate cancers present as indolent, and are unlikely to significantly influence a man’s health over his lifetime. Nevertheless, a significant number of prostate tumors are diagnosed while localized but have substantial metastatic potential. Once these colonize distant sites, they become almost uniformly lethal. Current standard of care for clinical risk-stratification involves serum abundance of prostate specific antigen (PSA), a digital rectal exam and biopsy. While these are beneficial, ~30-40% of men are over- or under-treated. Therefore, a central problem in prostate cancer remains understanding this dramatic variability in the aggressiveness of localized prostate cancers. We hypothesize that the clinical and molecular evolution of localized prostate cancers are shaped by germline genomic features. Strong preliminary data support this idea. Prostate cancer is the most heritable solid cancer. It shows strong variability across ancestries, and specific genetic features predict both risk of incidence and disease aggression. We will test our hypothesis with three complementary aims. Aim #1 quantifies germline-somatic interactions using transcriptome-wide association studies (TWAS) and pathway-somatic interaction analysis. Aim #2 then identifies ancestry-based germline-somatic interactions. Finally Aim #3 will assess the generalizability of germline-somatic interactions for clinical risk prediction by developing a targeted DNA- sequencing panel and evaluating biomarker potential in large patient cohorts. To achieve these aims, we will leverage publicly available datasets as well as biobanking repositories at UCLA, linked to both established and novel bioinformatics methods. Together, these aims provide three complementary strategies to quantify how the specific clinical and molecular evolutionary features of localized prostate cancer are influenced by specific germline polymorphisms.

NIH Research Projects · FY 2025 · 2023-04

Abstract Human papillomavirus (HPV) causes 33,700 US cancer cases per year, 4,000 deaths and $4 billion in cancer- related medical costs. Despite an effective vaccine, in 2020 less than 60% of US adolescents 13-17 years of age completed their HPV vaccine series. Key barriers are suboptimal clinician communication to address parental vaccine hesitancy, and ineffective office systems causing missed opportunities for vaccination. Our research team tested two promising implementation strategies (ISs) in primary care practices to address these barriers: online clinician communication training (“STOP-HPV-Online”) which trains clinicians on communication techniques and addresses parent hesitancy, and a multi-component IS (“STOP-HPV-LC”) that involves both clinician communication training plus office-based changes in workflow learned on monthly learning collaborative group phone calls. Both ISs were deployed by our research team. Widespread scalability requires the ISs to be deployed by health systems since most primary care practices are now part of health systems. For Aim 1 we will adapt the two ISs for deployment by 8 health systems, and also describe baseline strategies used by these systems. We will partner with the American Medical Group Association® (AMGA),the main national organization of health systems. More than 8 health systems have already expressed interest in the study. We will use a mixed-methods approach and the RE-Aim/PRISM framework to evaluate the effectiveness and implementation processes of the health-system deployed implementation strategies. We will assess how health systems deploy core IS functions and how they and practices adapt specific activities (forms) within each IS. Aims 2-3 will use a 3-arm clustered RCT, randomizing 72 practices within the 8 health systems to STOP-HPV- Online, STOP-HPV-LC, or usual care control. Aim 2 will compare the effectiveness and cost-effectiveness of the two ISs to control and to each other over a 12-month IS period and another 12-month maintenance period. The primary outcome for Aim 2 is HPV vaccine initiation; secondary outcomes are vaccine series completion and cost-effectiveness of the IS. Aim 3 will assess provider, practice, and health system factors relevant to implementation of the two ISs. The primary outcome is adoption (uptake of core IS functions such as clinicians completing the online modules); secondary outcomes include reach (e.g., % clinicians participating), practice/provider factors (e.g., organizational readiness) associated with improvement in rates, and maintenance of core IS functions by practices over 12 additional months. We will develop and disseminate online implementation guides for health systems and practices to use, and AMGA will help spread the ISs to their other health systems. By the end of the study, we will have two scalable ISs for AMGA and any health system to improve HPV vaccination rates and reduce HPV-related cancers.

NIH Research Projects · FY 2024 · 2023-04

Project Abstract Parkinson’s Disease (PD) and atypical parkinsonian syndromes are neurodegenerative diseases in which symptoms include movement disorder, often autonomic dysfunction, and sometimes dementia. Due to high symptom overlap, patients with these diseases often are misdiagnosed leading to high levels of anxiety and depression, and to difficulty in developing therapeutic intervention. The parent grant examines candidate biomarkers for these diseases in serum and CNS-originating extracellular vesicles (EVs) isolated from the serum. However, these candidates are based on current knowledge whereas other, perhaps superior biomarkers may not yet have been discovered. Unbiased proteomics-based biomarker discovery is a promising approach but is practically challenging in CNS-originating EVs. Therefore, we will use EVs isolated from the culture media of iPSC-derived neurons from patients with the same parkinsonian diseases, and healthy controls. These studies may lead to discovery of novel biomarkers that will further aid the diagnosis, monitoring, prognosis, and treatment of parkinsonian diseases. The supplement will support a talented graduate student co-mentored by the PI and a proteomics expert. The student already has generated preliminary data demonstrating that the experiments are feasible and promising. The co-mentoring, formal classes, interaction with collaborators, and multiple professional-development opportunities will help preparing the student for a successful and productive career as a scientific researcher.

NIH Research Projects · FY 2025 · 2023-04

Project Summary/Abstract Organic synthesis plays a crucial role in the development of small molecule therapeutics. New methodologies that allow for the introduction of defined stereocenters and difficult-to-access motifs, such as quarternary stereocenters, are particularly desirable. Moreover, there is growing interest in the use of unconventional synthetic building blocks to generate such complexity, as the use of uncommon starting materials provides new strategies and retrosynthetic disconnections that may prove broadly useful. The proposed research involves the use of amides in transition metal-catalyzed reactions to generate enantioenriched products bearing quaternary stereocenters. Although amides have historically been avoided as synthetic building blocks, they have recently been employed in transition metal-catalyzed reactions that proceed via C–N bond activation. However, amide cross-coupling methods that make quaternary stereocenters are rare and no catalytic enantioselective examples have been reported. The success of the proposed studies would push the limits of known amide cross- coupling methodology, provide methods to access defined quaternary stereocenters, and offer new strategies for synthetic chemists to utilize in the construction of drugs and complex molecules.

NIH Research Projects · FY 2026 · 2023-04

PROJECT SUMMARY/ABSTRACT Dr. Hiroki Nariai is a pediatric epileptologist/clinical neurophysiologist whose long-term goal is to be a leading physician-scientist in pediatric epilepsy, using key biomarkers to effectively treat children with epilepsy and reduce their mortality and morbidity. In this project, Dr. Nariai proposes to study medication-resistant focal epilepsy in children by integrating computational electroencephalogram (EEG) analysis, deep learning, and advanced statistics to investigate and validate high-frequency oscillations (HFOs)—a promising spatial biomarker of the epileptic brain. More than one-third of children with epilepsy are resistant to medications and are therefore potential candidates for epilepsy surgery. To achieve postoperative seizure freedom, one must remove or disrupt the epileptogenic zone (EZ), defined as the brain area that is indispensable for generating seizures, while preserving the eloquent cortex (EC), defined as the brain area that controls essential functions. Thus, identifying biomarkers that accurately localize and discriminate EZ from EC will be groundbreaking. HFOs are recorded via intracranial EEG as short bursts of high-frequency neuronal activity and are often observed in EZ. However, the major challenge is that physiological HFOs generated by healthy brain tissue complicate the clinical interpretation of HFOs. Therefore, there is a critical need to distinguish between pathological and physiological HFOs. Dr. Nariai hypothesizes that deep learning-based algorithms can distinguish pathological and physiological HFOs based on subtle morphological features linked to specific biological mechanisms. Through this K23 career development award, Dr. Nariai proposes to accomplish the following training goals: (1) acquire skills in an advanced computational EEG analysis to enable customized quantification of HFOs in a large dataset, (2) gain knowledge of the theory of deep learning and skills in its application in EEG signal processing to enable morphological assessment of HFOs, and (3) develop proficiency in advanced statistics in clinical research to validate prediction models and gain knowledge in clinical trials. Under the joint mentorship of leading researchers led by Dr. Jerome Engel, Jr., at UCLA, Dr. Nariai will build deep learning-based models in a large retrospective cohort to define HFOs expressed in EZ (eHFOs) to represent pathological HFOs. In addition, HFOs expressed in EC (ecHFOs) will be defined to represent physiological HFOs. The trained classifier will be analyzed to obtain the computational definition of eHFOs and ecHFOs. Along with demonstrating that real-time HFO analysis is feasible in a prospective cohort, eHFOs and ecHFOs will be analyzed to prove that HFOs can localize and discriminate EZ from EC. Dr. Nariai has shown preliminary results supporting the feasibility of his proposed approach. Completing the proposed goals will provide significant progress toward utilizing HFOs as a clinically useful spatial biomarker of the epileptic brain to guide epilepsy surgery, which Dr. Nariai plans to pursue as an R01 project.

NIH Research Projects · FY 2026 · 2023-04

Summary Many cases of Parkinson’s disease, and even more so atypical parkinsonian disorders, are misdiagnosed. Misdiagnosis not only causes high stress and anxiety to patients, their families, and their caregivers, but also is a major impediment to development of effective therapy for these diseases. Recently, we have demonstrated that the α-synuclein concentration in extracellular vesicles (EVs) immunoprecipitated from serum or plasma using oligodendroglial and neuronal markers, and in particular the ratio between the α-synuclein concentrations in the two types of EVs, is a sensitive biomarker for distinguishing between Parkinson’s disease and multiple system atrophy. This liquid biopsy approach requires only a minimally invasive blood draw and could lead to a major advancement in developing diagnostic tests for these diseases. Here, we propose to build upon these recent findings by constructing a biomarker panel, including several additional candidate markers, and apply the panel to two additional atypical parkinsonian syndromes—progressive supranuclear palsy and corticobasal syndrome. Serum samples for the study will be obtained from several national biorepositories as well as collected locally, prospectively, in expert clinics. The study design emphasizes biomarker analysis within the first two years of diagnosis, and in prodromal synucleinopathy, to test the utility of the biomarker panel when it is most needed. An additional goal of the project is to develop methodology for validating the cellular origin of the EVs, an urgent unmet need in the field. Success of the project will lead both to an advancement of research on biomarkers for CNS diseases using a minimally invasive liquid biopsy that can be translated into clinical use in the near future.

NIH Research Projects · FY 2026 · 2023-03

Project Summary/Abstract This project aims to improve our ability to support the resilience of family caregivers of adults with autism and developmental disorders as the caregivers move into later life. Based on a 30 year longitudinal study that prospectively followed families from when their children were referred for possible autism or developmental delays, we will use a social convoy model to investigate trajectories of social connectedness and isolation over the next five years as they affect caregivers’ mental health and well-being. This model describes changes in social connectedness over time that may increase vulnerability or reduce the effects of caregiver burden. We examine additional interacting factors specifically related to family caregiver well-being and mental health in families with adult children with developmental disabilities. We will use questionnaires, app-based diaries, face to face interviews and exploratory measures of biological and cognitive aging over the course of 5 years during which our sample is in their 60’s, linked to rich behavioral data from the past 20-30 years. Our objective is to identify life milestones, such as retirement and the adult child’s moving out, as well as caregiver coping strategies that allow us to support well-being and mental health in family caregivers as they age.

NIH Research Projects · FY 2026 · 2023-03

ABSTRACT Glioblastoma multiforme (GBM) is the most common type of primary brain tumor, with a five-year survival rate of only 5.5%. Chimeric antigen receptor (CAR)-T cell therapy has shown safety but limited efficacy in the treatment of patients with GBM to date. GBM is characterized by dramatic antigen heterogeneity, thus immunotherapy targeting any single antigen is unlikely to achieve complete and durable response. In addition, GBM cells and surrounding tumor stroma overproduce transforming growth factor beta (TGF-β), which not only promotes tumor growth and metastasis, but also actively modulate the immune response by suppressing T-cell function and recruiting suppressive myeloid cells. Our analysis of patient GBM biopsies further confirmed that tumor-infiltrating myeloid cells (TIMs) express both TGF-β and TGF-β receptors, indicating the presence of an immunosuppressive feedback loop in the GBM tumor microenvironment (TME). Here, we aim to develop a multi- pronged immunotherapy featuring bispecific CAR-T cells that can not only attack GBM directly, but also modify the TME to overcome immunosuppression and induce multiclonal immune responses against GBM. Our group has developed a bispecific CAR that can directly target GBM cells through recognition of IL- 13Rα2, a clinically validated GBM-associated surface antigen, while simultaneously converting TGF-β into a stimulant for the engineered T cells. We have demonstrated that bispecific IL-13Rα2/TGF-β CAR-T cells are superior to single-input IL-13Rα2 CAR-T cells in both human GBM xenograft and immunocompetent mouse models. Here, we aim to demonstrate the safety and efficacy of IL-13Rα2/TGF-β CAR-T cells for clinical translation. In addition to demonstrating clearance of IL-13Rα2+ GBM, we will explore the potential for IL- 13Rα2/TGF-β CAR-T cells to induce endogenous immune response against IL-13Rα2– tumor cells using mouse models of heterogenous GBM. We will perform in-depth analyses by flow cytometry, multiplexed immuno- fluorescence, cytometry by time of flight (CyTOF), and single-cell RNA sequencing to understand the impact of bispecific CAR-T cells on the immune composition and function in the GBM TME. We will also perform T-cell receptor beta (TCRβ) sequencing on tumor-infiltrating lymphocytes to quantify the potential for epitope spreading. We will perform rigorous safety evaluations in immunocompetent mouse models, applying worst-case scenario pressure tests to explore the toxicity profile of IL-13Rα2/TGF-β CAR-T cells. Finally, we will verify efficacy of IL-13Rα2/TGF-β CAR-T cell therapy in heterogeneous human gliomas ex vivo & in vivo, using both fresh patient GBM biopsies containing TIMs and GliomaPDOX models—i.e., mice bearing patient-derived GBM tumors that have never been passaged ex vivo and retain the genetic heterogeneity seen in human patients. Successful completion of this project will generate a comprehensive set of preclinical data in support of a phase- 1 clinical trial to treat GBM patients with this novel, multi-pronged immunotherapy option.

NIH Research Projects · FY 2026 · 2023-02

PROJECT SUMMARY/ABSTRACT We have proposed a comprehensive yet targeted two-year K12 training program for pediatrician physician- scientists, focusing on training bench-based researchers to become successful physician-scientists and eventual pediatric academic leaders. We believe that our training program has an outstanding track record, especially over the last decade, and we are especially excited about our junior faculty group of thriving and well-trained Scholars. We have formed new partnerships with our institutional Clinical and Translational Institute (CTSI) program, the UCLA David Geffen School of Medicine Specialty Training and Advanced Research (STAR) Program, and our departmental Children’s Discovery and Innovation Institute (CDI), to provide our Scholars more robust mentoring, grant preparation training, and overall career development. We will continue to ramp up these successful portions of our program, and have implemented a state-of-the-art comprehensive evaluation program. Our innovative program combines nurturing and rigorous mentoring, an individual development plan, core research experience, and cohort-based career development. We surround Scholars with 1) a scientific community of well-trained faculty mentors, 2) research, scientific, and career-development programs, 3) a comprehensive and innovative mentoring program, and 4) core support from our department and institution. we will train physician scientists to pursue major breakthroughs in improving child health. The overarching goal of the UCLA CHRCDA program is to increase the number and impact of pediatric physician-scientists engaged in bench research on topics relevant to child health. Our specific objectives are to: · Increase the pipeline of diverse and promising trainees to become pediatric physician-scientists · Engage the pediatric and UCLA research communities regarding the CHRCDA and its training opportunities · Promote a flexible and adaptable training environment to meet the needs of a diverse group of scholars with different degrees of research training · Facilitate outstanding mentoring · Streamline Scholar transition to independence · Synergize with other institutional training and mentoring programs, including those run by CTSI and DGSOM STAR Program · Provide Scholars access to the latest research technologies and state-of-the-art facilities and services · Foster collaborative research, promote leadership, and encourage entrepreneurship and development of intellectual property in our young scholar community · Continue to promote Scholars who are women, and double the number who are URiM, those with disabilities, and those who have experienced hardship · Emphasize the ethical conduct of research

NIH Research Projects · FY 2026 · 2023-02

Project Summary Osteogenesis imperfecta (OI) is a genetically heterogenous disorder characterized by increased bone fragility leading to fractures and primarily results from defects in the structure and/or the amount of secreted type I collagen. While bone fragility is the primary cause of morbidity in OI, pulmonary compromise is the leading cause of mortality. We and others showed that in OI there is an abnormal bone extracellular matrix (ECM) structure and type I collagen expressing cells manifest ER stress. Pulmonary mesenchymal derived cells also abundantly express type I collagen. We hypothesize that OI negatively impacts the lung through two mechanisms; secretion of an abnormal ECM and chronic ER stress. Using two OI mouse models representing major forms of OI (missense/loss of function mutations in type I collagen), this proposal will address the hypotheses that mutant type I collagen secretion and ER stress produces abnormal pulmonary morphology, affects lung cell differentiation, impairs lung damage recovery, and that altered ECM and ER stress negatively impact signaling pathways. We address these hypotheses via three aims: 1. Determine the effect of type I collagen mutations on lung postnatal homeostasis and cell differentiation/communication. Hypothesis: Mutations in type I collagen genes lead to alterations in OI lung morphology and cell differentiation. Strategy: Using Aga2 and Col1a1+/- mouse models, the lung will be studied at multiple stages of development via histological/immunohistochemical (IHC) for differentiation and ECM composition. Using in vitro epithelial cell/fibroblast co-culture organoid experiments we will define the contribution of abnormal ECM secretion to lung cell differentiation, proliferation, and apoptosis. 2. Determine the effect of ER stress due to type I collagen mutations on lung cell differentiation, tissue homeostasis, and reaction to damage. Hypothesis: ER stress in pulmonary type I collagen expressing cells affect lung cell differentiation and function. Strategy: Using the models from Aim 1, we will determine ER stress levels in pulmonary cells and whether modulating ER stress in vivo with the chaperone 4-PBA can influence cell differentiation and homeostasis. Using organoid experiments, we will define the contribution of chronic ER stress to lung cell differentiation, proliferation, and apoptosis. To study OI lung damage susceptibility, we will perform in vivo treatment of WT, Aga2, and Col1a1+/- mice with bleomycin to observe the effects of cellular damage on OI lung tissue in conjunction with the 4-PBA treatment; 3. Identify changes in lung cell population distribution and gene expression in the context of an abnormal ECM and ER stress. Hypothesis: Lungs with altered ECM and ER stress affect signaling pathways important in cell differentiation and function. Strategy: Using the Aga2 and Col1a1+/- mouse models, single-cell RNA-seq cells/tissues derived from lung will be performed to identify changes in cell development and gene expression correlated with signaling cascades localized to specific lung cell populations. Completion of these aims will reveal causative mechanisms while introducing novel treatment methods of OI pulmonary dysfunction, the major cause of mortality in OI.