University Of California Los Angeles

NIH Research Projects · FY 2026 · 2024-01

Project Summary This is an application for a K23 award for Ana Monteiro, MD, PhD, a Pulmonary and Critical Care physician at the University of California Los Angeles. The goal of this proposal is for Dr. Monteiro to establish herself as a young investigator in patient-oriented research of acute respiratory distress syndrome (ARDS), with a focus on vascular injury as a contributor to pulmonary physiologic dysfunction and worse outcomes in ARDS. This K23 award will provide Dr. Monteiro with the support necessary to: 1) study the biologic endotype of ARDS involving vascular injury, pulmonary physiologic dysfunction and worsening mortality; 2) determine the feasibility and utility of measuring peripheral blood markers to determine pulmonary disease severity; 3) become an expert in analysis of large datasets of both clinical and transcriptomic nature; 4) become proficient in the use of bulk and single cell transcriptomic analysis; 5) become an expert clinical and translational researcher in ARDS; and 6) develop an independent translational research career. Dr. Monteiro’s plan to achieve these goals is supported by a multidisciplinary mentoring team of experts. Her primary mentors, Drs. Michael Matthay and Anil Sapru, have extensive experience in translational ARDS research and in the career development of early-stage investigators. Dr. Monteiro will also work with Dr. Matteo Pellegrini, a bioinformatics expert and world leader on the science of bulk and single cell transcriptomics, Dr. John Belperio, an expert in post- transplant primary graft dysfunction with extensive experience with biospecimen handling and biobanking and a recognized pulmonary educator, Dr. Steve Dubinett, a world class clinical and translational researcher of cancer immunology, and Sitaram Vangala, the Director of the Medicine Biostatistics core and an expert in causal inference. ARDS is characterized by an increased inflammatory response that induces epithelial and vascular damage and respiratory failure. This proposal will investigate the causal pathways connecting vascular injury to respiratory failure by utilizing previously collected data and plasma samples from the completed ROSE-PETAL network trial and the ongoing observational cohort study (LOBAR) that will prospectively collect biospecimens, mechanical ventilation data, and clinical outcomes. This proposal represents an innovative approach by addressing the feasibility and utility of evaluating proteomic, transcriptomic and cell-level blood markers including circulating endothelial cells in identifying novel pathological pathways and determine pulmonary disease severity. The Specific Aims are: 1) Test whether local or systemic markers of endothelial injury best predict lung dysfunction and mortality in ARDS; 2) Leverage bulk RNA sequencing of blood to characterize and quantify endothelial damage in ARDS; and 3) An exploratory aim to characterize biological derangement of CECs in ARDS using cell-level transcriptomic analysis. Addressing these gaps in knowledge may promote non-invasive analytic techniques for future ARDS studies and reveal novel pathways in ARDS pathogenesis for therapeutic targeting. The research and training outlined in this proposal will form the basis for an R01-level proposal designed to study interventions tailored to patients with a vascular injury predominant endotype of ARDS.

NIH Research Projects · FY 2025 · 2024-01

PROJECT SUMMARY Myocardial infarction (MI) and coronary artery disease (CAD) are the leading causes of death in Western societies. Individuals with CAD are typically asymptomatic, with the first manifestations often being major adverse cardiac events (MACE), such as MI, stroke, or sudden death due to the rupture of an atherosclerotic plaque. However, despite the clinical significance of these thrombotic events, our understanding of the genetic and molecular basis of MI remains incomplete. Furthermore, even though most patients with MI have CAD, not all patients with CAD develop MI. This observation suggests that some of the mechanisms that predispose to MI may be distinct from those that establish and promote atherosclerosis. This concept is supported by the results of our recent multi-national genetics collaboration with >830,000 subjects, which identified several novel loci that were associated specifically or more strongly with MI than CAD. Genomics and bioinformatic analyses implicated SLC44A3 as the causal gene at a previously unrecognized MI-specific locus on chromosome 1p21. In recent follow-up studies, we used a more direct comparative genetics strategy among CAD patients with and without MI (CAD+/MI+ vs CAD+/MI-). These efforts revealed additional genetic factors that were strongly associated with MI but not CAD itself, as well as provided confirmatory evidence for SLC44A3 being a novel MI-specific locus. To our knowledge, SLC44A3 and the other newly identified loci represent the only genetic factors that exhibit this MI-specific association pattern. However, independent replication, prioritization, and functional validation of these observations is still required in order to classify their association signals as being specific for MI and not CAD. Our overall hypothesis, which is supported by substantial preliminary data, is that SLC44A3 and other newly identified positional candidate genes represent genetic risk factors that specifically or more strongly predispose to MI than CAD per se. To validate this hypothesis, we propose a series of integrative genetics, bioinformatics, and functional analyses in humans and mouse models. In Specific Aim 1, we will comprehensively elucidate the genetic landscape of MI in patients with CAD through a combination of large-scale meta-analyses and whole-exome rare variant analyses with multi-ancestry cohorts. Candidate causal genes for MI among CAD patients will be prioritized through integration of robust bioinformatics, fine- mapping, and functional genomics analyses. In Specific Aim 2, we will use a translational in vivo mouse model of plaque rupture to experimentally validate Slc44a3 as an MI-specific susceptibility gene. Taken together, the proposed studies will use innovative and complementary approaches to elucidate the genetic basis of MI among CAD patients, provide functional validation of high probability candidate causal genes in mouse models, and help prioritize novel targets for therapeutic development.

NIH Research Projects · FY 2025 · 2024-01

Project Abstract Learning is one of the essential building blocks of cognition. Individuals with mental health conditions, such as bipolar disorders and schizophrenia, often show symptoms related to learning. A great deal of evidence exists indicating that the orbitofrontal cortex (OFC) and anterior cingulate cortex (ACC) are both heavily involved in flexible learning under uncertainty, with the basolateral amygdala (BLA) sending robust bidirectional connections to both cortical structures. I hypothesize that BLA provides OFC and ACC with dissociable signals that delineate a difference in the expected reward and what was received, vital information for adaptive learning. In Aim 1, rats will be tested on a novel, dynamic, restless bandit task for flexible learning under different probabilistic schedules where the reward contingencies switch within the session. While rats perform this task in some sessions, we will chemogenetically inhibit BLA. A subset of these rats will also express GCaMP6f in OFC and GRIN lenses directly in this region so that we can use miniscopes to record calcium traces while the freely-moving rat learns. In parallel Aim 2, rats learning on the same task will instead have BLA on- or off-line while I record calcium traces in ACC. These approaches will allow us to study how the uncertainty representations in OFC and ACC differentially depend on BLA input. My central hypothesis is that OFC and ACC use BLA-supplied information differently: OFC receives information from BLA that is needed to detect first reversals and setting future adjustments, whereas ACC uses information from BLA to approximate changes in probabilities over time.

NIH Research Projects · FY 2026 · 2024-01

PROJECT SUMMARY Ischemic stroke, characterized by acute loss of blood flow to the brain caused by thrombus or embolus, accounts for 80% of all stroke cases and is a leading cause of disability in adults in the U.S. The loss of blood flow creates a zone of complete infarction (the core) and a surrounding zone of surviving tissue, where much of the limited repair after stroke occurs (peri-infarct tissue). In this repair, angiogenesis and the formation of new connections (axonal sprouting) are two key components. The proposed predoctoral NRSA aims to examine innate cellular responses to a potential stroke therapeutic, a biocompatible hydrogel scaffold with nanoparticle-immobilized vascular endothelial growth factor, that promotes infiltration of endothelial cells and axons from the surrounding peri-infarct. I hypothesize that introduction of this hydrogel into a cortical stroke infarct will revascularize the infarct and promote axonal sprouting and migration of glial cells and neural progenitors into the hydrogel scaffold, and that neuronal responses, particularly axonal sprouting and synaptogenesis, will be enhanced by rehabilitation of the affected forelimb in combination with the hydrogel. I will induce cortical stroke in the mouse forelimb motor cortex and inject the novel multi-component hydrogel into the stroke cavity. In the studies proposed in Aim 1, I will use 2-photon microscopic live imaging to longitudinally record and quantify the rate of vessel growth, perfusion, and permeability within the infarct and peri-infarct. To assess vascular-guided migration, tissue will be analyzed using immunofluorescence images of cell-type-specific markers, which will enable further studies investigating post-stroke signaling, blood brain barrier, and glial biology in and without the context of a hydrogel. The second aim of the project is to virally label axons that have been shown to project into the hydrogel, allowing for identification of the parent neurons and quantification of the axonal sprouting response to the hydrogel in both the stroke core and peri-infarct. Finally, to mimic a dual therapeutic approach that would be likely in a clinical setting, a third aim will investigate the effect of motor rehabilitation on axonal sprouting and connectivity with the recovering tissue stimulated by the hydrogel. Together, these aims will elucidate fundamental biological mechanisms underlying neural repair after ischemic stroke, while also establishing a paradigm to assess longitudinal revascularization and virally labeled axonal sprouting within this novel multi-component hydrogel.

NIH Research Projects · FY 2025 · 2024-01

Project Summary / Abstract We do not fully understand how the cortex adapts its limited resources to optimally represent sensory information in time-varying environments. The proposed studies aim to mathematically characterize adaptation in populations of cortical neurons by applying novel geometric analyses and developing a normative theory that accounts for the experimental data. In Aim 1, we will test two hypothetical properties of adaptation. Direction invariance posits that the direction of the population response to a given stimulus is approximately invariant to changes in its prior probability of being observed. A power law relationship postulates that the ratio of the magnitudes of population response to a fixed stimulus across two statistical environments is a power of the ratio between its prior probabilities. An empirical confirmation of these findings will deliver the first mathematical characterization of adaptation capable of predicting population responses in a new environment from the population responses in a known one. In Aim 2, we will develop a normative theory for the power law property. We will consider the hypothesis that a power law emerges as a tradeoff between discrimination performance and the metabolic cost of cortical representation. We will tackle this question using two synergistic approaches: (a) the analysis of simple, analytically tractable models of adaptation and (b) a larger class of auto-encoder models, which provide a flexible way to study the problem numerically. The proposed studies are significant because they fill a major gap in the field by taking a rigorous look at cortical adaptation at the population level, gathering critical data not yet available to the community, and analyzing them using innovative geometric analyses and theoretical modeling. These rigorous studies rely on solid concepts from representational geometry and efficient coding. Solid, preliminary findings show the work has a good chance of transforming our conceptual view of adaptation at the level of neural populations, generating ideas readily applicable to other sensory modalities and systems.

NIH Research Projects · FY 2026 · 2024-01

ABSTRACT Astrocytes are ubiquitous CNS glial cells that make extensive contacts with neurons. Astrocytes serve diverse roles, including ion homeostasis, neurotransmitter clearance, synapse formation/removal, synaptic modulation, and contributions to neurovascular coupling. Astrocytes are widely implicated in disease and in regulating animal behaviour. Astrocytes are thus critical components of neural circuits and their behavioral outputs. How astrocytes perform such varied physiological roles is a topic of intense worldwide investigation with many fascinating open questions. An exciting discovery made by us and others over the last few years is that astrocytes are heterogeneous, displaying CNS region and neural circuit-specific properties and functions. Exploring the molecular basis and function of astrocyte diversity within specific neural circuits is emerging as an important, innovative research frontier. One outstanding open task is to understand functions of molecularly defined astrocytes in specific CNS areas and to determine how they regulate neural circuits and contribute to behaviors associated with those nuclei. We address this topic for a specific population of Crym+ (protein: μ-crystallin) striatal astrocytes in relation to motor and goal-directed behavior. Interestingly, Crym is downregulated in postmortem striatal tissue in some basal ganglia diseases, implying that understanding how these astrocytes regulate neural circuits physiologically may, in the long term, inform about disease mechanisms. However, almost nothing is known physiologically about either μ-crystallin or about Crym+ striatal astrocytes in the CNS. Based on unexpected and exciting preliminary data, we hypothesize that striatal astrocytes defined by Crym regulate essential astrocyte-neuron interactions within CM striatal microcircuits that control motor and goal-directed behavior. The preliminary data to support this hypothesis are compelling and new. Specific Aim 1 will evaluate how striatal astrocyte-specific CRISPR/Cas9-mediated Crym deletion affects MSNs and astrocytes. Specific Aim 2 will study MSN activity in vivo during behavior following striatal astrocyte Crym deletion. Specific Aim 3 will explore molecular mechanisms of striatal astrocyte Crym (μ-crystallin) in relation to striatal-dependent behaviors. Completion of these aims will advance markedly our understanding of striatal astrocyte-neuron interaction mechanisms and of μ-crystallin. We believe our studies will also be paradigmatic for understanding astrocyte diversity within neural circuits and the functions that such specializations serve in relation to the striatum and the basal ganglia circuitry.

NIH Research Projects · FY 2025 · 2023-12

PROJECT SUMMARY/ABSTRACT Diabetes mellitus (DM) is the leading cause of chronic kidney disease (CKD), accounting for ~47% and ~39% of US incident and prevalent end‐stage kidney disease (ESKD) patients, respectively. Our published research has shown that hypoglycemia is a highly prevalent complication associated with higher death risk in diabetic kidney disease (DKD) patients. Diabetic hemodialysis (HD) patients are at heightened risk for hypoglycemia via multiple pathways, including 1) decreased renal gluconeogenesis, 2) impaired metabolism/ clearance of DM medications, 3) co-existing comorbidities, 4) limited in-center HD food access, and 5) intra- dialytic glucose shifts. Given the ill effects of hypoglycemia on the cardiovascular (CV) health (arrhythmia, myocardial ischemia) and psychological well-being (hypoglycemia fear, stress/anxiety) observed in non-CKD studies, and the poor survival of diabetic HD patients (<35% over 5 years) largely due to CV causes, there is an urgent unmet need to identify strategies that mitigate low glycemic complications in this population. One of the major barriers to optimal glycemic control in DKD has been the lack of access to a practical, reliable method for frequent glycemic assessment. In diabetic HD patients, conventional metrics (self- monitored blood glucose [SMBG], HbA1c) are dominantly used despite limitations in accuracy, convenience, and intermittent frequency. In contrast, continuous glucose monitoring (CGM) is a convenient, automated glycemic assessment method that has shown improved glycemic control and reduced hypoglycemia in non- CKD trials. While our pilot data of CGM in HD patients shows strong agreement with gold-standard blood glucose levels and superior identification of hypoglycemia, it remains uncertain as to whether CGM can improve glycemic control, reduce hypoglycemia, optimize patient-reported outcomes in this population. To address this knowledge gap, we propose this Multiple-PI R01 study in which we aim to conduct a parallel, two-arm randomized controlled trial (RCT) comparing real-time CGM using Dexcom G6 devices vs. usual care (SMBG 4-times/day) among 122 in-center HD patients with DM over a 12-week period. Our primary objective will be to determine the effects of CGM vs. usual care on glycemic control, defined by percent (%) of time in target glucose range (70-180 mg/dl). Our main and exploratory secondary objectives will be to determine the effects of CGM on CGM-indices of hypoglycemia, blood-based glycemic markers (HbA1c, glycated albumin, fructosamine), and patient-reported outcomes (health-related quality of life, diabetes distress, hypoglycemia fear). We will also evaluate feasibility endpoints by measuring CGM compliance during the intervention period and success/ease of implementing CGM training sessions among patients. This single- center pilot RCT is the critical first step in determining the feasibility, efficacy, and safety of CGM in diabetic HD patients, and it will provide the requisite preliminary data to inform the framework of future large-scale, multi- center corollary RCT’s with an expanded number of endpoints, participants, and sites.

NIH Research Projects · FY 2026 · 2023-12

ABSTRACT The non-alcoholic fatty liver disease (NAFLD) spectrum is now the most common cause of liver diseases, and responsible for the biggest proportion of liver transplants. The liver is a central hub that coordinately regulates the metabolism of many nutrients, including lipids. The liver is not designed for long-term storage lipids, instead acting as a distributor of lipids with high short-term storage capacity. Long-term lipid accumulation in the liver, in the form of triglycerides causes steatosis which can progress to non-alcoholic steatohepatitis (NASH), both of which are part of the NAFLD spectrum. Identification of the molecular mechanisms of pathways that control lipid metabolism, both systemic and liver specific are essential for the discovery of disease-preventing therapeutic targets. Bile acids are both signaling molecules and detergents that facilitate lipid absorption in the gut. While much has been studied in recent years about bile acid signaling, the role of bile acids as detergents that facilitate the absorption of different fatty acids has been less well studied. We recently showed activation of the bile acid receptor FXR reduces liver lipid accumulation in part due to lowering of bile acid-mediated lipid absorption. To determine how bile acids alter the absorption of different fatty acids, we have developed and validated a novel AAV-CRISPR strategy to disrupt specific bile acid metabolism genes exclusively in the liver. Using these tools, we show that specific modulations in the total amount and/or composition of bile acids has profound effects on liver steatosis. To measure lipid absorption quantitatively and accurately, we have established a non-invasive mass spectrometry-based approach to measure the absorption of different dietary fatty acids in the intestine in vivo. We have also developed complimentary imaging modalities to visualize lipids in the intestine. Using these assays, we have shown that modulating bile acids dramatically reduces lipid absorption but retain preferential absorption of polyunsaturated fatty acids. These changes contrast with inhibition of lipases in the gut (using Orlistat) which reduced the absorption of all fatty acids. Here, we have designed two specific aims utilizing a combination of in vivo and in vitro systems to test the hypothesis targeting bile acids results in specific and beneficial changes in lipid absorption that are protective against NAFLD or are pathogenic and drive liver fibrosis. Completion of these studies will further the understanding of the role of bile acids as detergents, implicate bile acid metabolism as an important contributor in the pathogenesis of NAFLD/NASH, and potentially establish new therapeutic strategies to target NAFLD.

NIH Research Projects · FY 2026 · 2023-12

Project Summary/Abstract Altered neural-immune (NI) gene expression has been observed in postmortem brain tissue from individuals with schizophrenia and other neurodevelopmental disorders. One mechanism by which NI function may affect the brain is through effects on neurite outgrowth and synaptic pruning during development; however, the effects of NI gene expression on in vivo brain development and behavior are not known. A major barrier to understanding how interindividual differences in NI expression relate to heterogeneous developmental trajectories is the inability to measure gene expression in the living human brain. Through a coordinated set of multimodal analyses, the current proposal aims to define the polygenic architecture of NI gene expression to generate a genome-wide resource for individual-level prediction and characterization of its impact on brain and behavioral trajectories in the pediatric population. Integrating functional genomic data from the PsychENCODE Consortium with several other large-scale resources, we will perform a multi-ancestry genome wide association study (GWAS) to identify the genetically regulated component of NI expression (GREx) in >4,000 human brain samples (Aim 1). Next, using genetics data in >11,000 multiethnic youth from the Adolescent Brain Cognitive Development (ABCD) Study, we will compute individual-level predictions of NI GREx and test the relationship with longitudinal trajectories of structural brain development (Aim 2). Finally, to examine how interindividual variability in NI GREx may relate to clinically-relevant symptomatology, we will test the relationship between NI GREx and age-related change in dimensional measures of mental health relevant to psychosis and other related neurodevelopmental disorders (Aim 3). By examining links between NI GREx and brain development in a large population- representative cohort of children, this project has the potential to inform our understanding of mental health as a continuous construct, and to aid in the prospective identification of individuals at heightened risk for psychosis and other psychiatric disorders. These aims are in-line with the NIMH strategic plan to define the brain mechanisms underlying complex behaviors, and to examine mental illness trajectories across the lifespan. The proposed research will take place at the University of California, Los Angeles (UCLA) under the mentorship of Drs. Daniel Geschwind, Carrie Bearden, Bodgan Pasaniuc, and Wesley Thompson, experts in functional genomics, psychosis spectrum disorders, computational genetics, and longitudinal statistical analyses, respectively. The proposed K01 will provide the PI with mentored research training in transcriptomics, including the analysis and interpretation of post-mortem human brain RNA-sequencing data, multi-ancestry GWAS, the neurobiology of psychosis, and statistical methods to model longitudinal data. This research and training will lay the foundation for the PI’s career development as a leading expert in the neurogenetic etiology of psychosis and pleiotropic psychiatric disorders. Results will support a future R01 extending this work into clinically ascertained populations and will elucidate the genetic mechanisms underlying neurodevelopmental heterogeneity in youth.

NIH Research Projects · FY 2026 · 2023-12

ABSTRACT Repetitive Transcranial Magnetic Stimulation (rTMS) is effective for treatment of Major Depressive Disorder (MDD). Clinical improvement with rTMS is believed to reflect engagement of a target mood-regulating circuit. This innovative proposal aims to enhance target circuit engagement through stimulation at an individual’s optimal resonant frequency (RF). Circuit connectivity is maintained by oscillations at one or more RFs specific to that circuit for that individual. Personalizing stimulation frequency is an opportunity to optimize rTMS effectiveness, but there has been no method to identify optimal RF for rTMS treatment in a patient-specific way. We developed a novel TMS-electroencephalography (TMS-EEG) “interrogation” method that identifies RFs by examining the degree of resonance induced by stimulation frequencies from 5–18 Hz for a target circuit originating in left dorsolateral prefrontal cortex (DLPFC). Frequencies are then ranked based on resonance properties (degree to which they increase connectivity in the target circuit) and the highest-ranked frequency is identified. Our pilot data suggest that MDD treatment at maximum RF (rTMSRF-MAX) rapidly modifies connectivity and leads to early symptom improvement, providing preliminary support for a RF-based personalized approach to rTMS. This project will provide a mechanistic understanding and validation of the RF approach through three aims and hypotheses: 1. Establish reliability of a method for RF determination in a DLPFC-based target circuit. H1: An individual’s RF median values and rankings will be stable across repeated measurements; 2. Demonstrate superior neurophysiologic engagement of the target circuit with rTMSRF-MAX stimulation. H2: rTMSRF-MAX will be associated with greater increases in connectivity in a left DLPFC-based target circuit than rTMS at the lowest ranked resonant frequency (rTMSRF-MIN); 3. Contrast the neuroanatomic distribution and degree of target circuit engagement by rTMSRF-MAX and rTMSRF-MIN stimulation. H3: Whole-brain EEG source localization will display a distinct distribution and degree of regional brain activation following rTMSRF-MAX and rTMSRF-MIN, with rTMSRF-MAX better engaging circuits previously reported to be related to antidepressant response. 80 MDD subjects will undergo TMS-EEG interrogation at a neuroanatomically-defined left DLPFC region. We will measure the resonance profile across the 5-18 Hz frequency range on three occasions for each individual to evaluate the temporal stability of RF measurement. Subjects then will undergo separate stimulation sessions with rTMSRF-MAX and rTMSRF-MIN. We will compare the two frequency conditions with regard to the degree of stimulation-induced changes in EEG connectivity in the target circuit. Finally, we will utilize EEG source localization to determine the neuroanatomic distribution of the connectivity effects of rTMSRF-MAX vs. rTMSRF-MIN, and compare the distribution to determine if rTMSRF-MAX better alters connectivity within previously reported treatment-responsive circuits. Findings provide a foundation for a novel personalized rTMS approach and inform design of a future clinical trial to test whether the rTMSRF method enhances treatment outcomes.

NIH Research Projects · FY 2026 · 2023-12

PROJECT SUMMARY/ABSTRACT Prostate cancer is the most common and second deadliest non-skin cancer in American men, accounting for 26% of new cancer diagnoses and 9% of cancer deaths in men. Active surveillance, radical prostatectomy and radiotherapy are commonly used treatments for clinically localized prostate cancer. However, current risk stratification methods cannot be used effectively to avoid subjecting patients with clinically indolent cancers to unnecessary interventions, causing significant morbidity and cost. The primary components currently involved in screening are the digital rectal exam (DRE) and serum biomarkers, such as PSA, PCA3, PHI, and 4Kscore. Unfortunately, despite advances in these tests, overdiagnosis remains a major problem due to limited specificity. As a result, 90% of patients diagnosed with prostate cancer receive treatment, even though up to 60% of those patients could be candidates for active surveillance. Such treatment often results in long-term reductions in functional outcomes. The research objective of this R01 is to develop novel markers and models to both more accurately detect aggressive cancer and to forecast its arrival. Using a large cohort of patients, we first plan to identify novel pathomic and germline features that indicate the presence of aggressive cancer or its precursors. We then plan to implement an integrative graph convolutional network (GCN) combined with a convolutional neural network (CNN) to generate new multi-modal representations of underlying cancer state within the entire prostate. The framework will combine multiparametric magnetic resonance imaging (mpMRI), digital histology images, germline features, biomarkers, and other predictors. We will also implement a baseline nomogram risk model for comparison, as well as several new nomogram models that incorporate our newly identified features.

NIH Research Projects · FY 2025 · 2023-12

The brain has two strategies for behavioral control. Goal-directed actions that rely on prospective consideration of their outcomes and consequences, and habits, reflexive responses performed without forethought of their consequences. Overreliance on habit contributes to maladaptive perseverative behavior, which characterizes numerous psychiatric conditions, including autism. Environmental factors, like chronic stress, and genetic alteration, can tip the balance between actions and habits. However, our knowledge of the brain mechanisms by which these factors influence habits is lacking, limiting our understanding of maladaptive behaviors in psychiatric conditions, and how to treat them effectively. Therefore, the broad goal of my research is to reveal specific neuronal mechanisms that allow genes and the environment to modulate behavioral control. Accumulating evidence suggests the dorsomedial striatum (DMS) is central for controlling goal-directed actions. Inhibition of the DMS, particularly Drd1+ direct pathway neurons, disrupts goal-directed control, resulting in a bias toward habits. The basolateral amygdala (BLA) is a known hub for stress-responsivity in the brain and projects onto DMS Drd1+ neurons. My postdoctoral work has revealed that BLA-DMS activity supports goal- directed learning and is suppressed after chronic stress exposure. Further, I found that activation of BLA-DMS projections in stressed animals is sufficient to restore goal-directed control. This led me to the intriguing hypothesis that chronic stress dysregulates DMS Drd1+ control of goal-directed learning via BLA-DMS input. Through the proposed research, I will reveal how chronic stress changes the DMS Drd1+ neuronal activity associated with goal-directed learning, at the population and single-cell levels, and how BLA input facilitates this. I will accomplish this using cellular resolution in vivo calcium imaging with miniscopes, combined with projection- specific chemogenetic manipulation, in mice (Aim 1; K99). In my independent phase, I will apply these techniques to a mouse model of 16p11.2 microdeletion, a genetic alteration associated with autism and that is known to dysregulate striatal function. Specifically, I will examine the vulnerability to premature habits of 16p11.2 mice, normally and after stress, and assess amygdala-striatal control, using cell-type specific in vivo calcium imaging with miniscopes, slice electrophysiology, and projection-specific optogenetic manipulations (Aim 2; R00). My findings will provide a mechanistic understanding of habitual control normally, after stress, and in a model of autism-associated genetic alteration. This will facilitate future work into the molecular and cellular mechanisms of this phenomenon and ultimately serve my goal of improving treatment approaches for psychiatric conditions. I will conduct my K99 training in the Wassum Lab at UCLA, with the guidance of a remarkable mentoring team that has pioneered the open source miniscope technology. This environment will provide me with the necessary intellectual and technical training I need to launch my independent research program studying the mechanisms that allow environmental and genetic factors to modulate behavioral control strategies.

NIH Research Projects · FY 2025 · 2023-12

Project Summary/Abstract Trypanosoma brucei is a flagellated protozoan parasite responsible for sleeping sickness, a vector-borne disease that causes great human suffering and economic burden and is endemic to sub-Saharan Africa. In addition to its own medical importance, T. brucei represents a group of related human parasites. Because of easy genetic manipulation, T. brucei is also a valuable model organism for studying flagellum/cilium biology. To survive, be transmitted, and cause disease, T. brucei must sense and respond to environmental signals. This is especially important for a vector-transmitted parasite, because it must respond to multiple host environments. Sensing is achieved by signal transduction pathways that detect external changes and convert these into cellular responses. Little is known about these pathways and mechanisms in T. brucei, or other related pathogens – this is a critical knowledge gap and potential source of discovery of new treatments. Cumulative evidence shows the T. brucei flagellum is a critical platform for cAMP signaling that controls cell movement, cell-cell communication, chemotaxis, movement through tissues, transmission through the insect vector and pathogenesis in the mammalian host. It has also been demonstrated that the flagellum tip is an important domain for organizing cAMP signaling, and models hypothesize mechanisms for tight control over cAMP distribution, retaining cAMP near sites of generation and downstream effectors. Surprisingly, however, spatial arrangement of cAMP production and propagation has been directly examined. Moreover, almost nothing is known about effectors in the flagellum that transmit cAMP effects. Thus, fundamental questions regarding trypanosome cAMP signaling mechanisms remain unanswered. We are well-positioned to answer these questions by employing our state-of-the-art quantitative tools for phosphoproteomics of flagellar subdomains, functional signaling assays, and new tools for live imaging of cAMP fluctuations inside cells. Our specific aims are to (1) identify and functionally characterize cAMP-effectors and (2) test hypotheses for mechanisms of cAMP signal distribution and propagation through the flagellum. To identify proteins regulated by cAMP (1a), we established a platform to obtain the cAMP-dependent phosphoproteome and we will use this to find target proteins altered by cAMP. For functional analysis (1b), we will examine motility and signaling in mutants lacking the proteins or phosphorylation sites identified in part (1a). This aim will provide novel insights into the function of individual cAMP effectors as well as the broader role of phosphorylation as a mechanism of transducing cAMP signaling in trypanosomes. To determine distribution of cAMP, we will visualize cAMP fluctuations using a genetically encoded FRET sensor in live cells (2a). We will use this FRET-based system to study propagation of the cAMP signal in response to external stimuli and test tenets of the current flagellum microdomain cAMP signaling model (2b).

NIH Research Projects · FY 2026 · 2023-12

ABSTRACT Cardiovascular diseases, including ventricular arrhythmias and heart failure, are an important cause of morbidity and mortality in the U.S. Ventricular arrhythmias (VT/VF), after myocardial infarction (MI) and in the setting of cardiomyopathy, remain an important cause of sudden cardiac death (SCD). While important sex differences in the incidence of SCD and VT/VF exist in the setting of ischemic and non-ischemic cardio- myopathy, the mechanisms behind these sex differences remain unknown. It is established that the autonomic nervous system plays an important role in the genesis of VT/VF and progression of heart failure. Chronic sympathetic activation and reduced parasympathetic function increase the risk of VT/VF and SCD. Pathological autonomic neural remodeling in response to MI alters myocardial responses to catecholamines, modifies myocardial innervation patterns that exacerbate electrical heterogeneities, and leads to alterations in sympathetic and parasympathetic efferent and afferent signaling, setting up the substrate for VT/VF and its dynamic modulation by the autonomic nervous system. Yet, it is unknown if there are sex differences in cardiac autonomic remodeling that underly the clinical differences observed in the presentation and outcomes of VT/VF after MI and in ischemic cardiomyopathy in men vs. women, and whether the sex hormone, estrogen, is a mediator of these differences. In order develop tailored and targeted therapies, it is critical to understand mechanisms that underly sex differences in sympathetic and parasympathetic dysfunction in the setting of cardiac disease. In this proposal, we aim to test the novel hypotheses that (1) sex differences exist in cardiac autonomic remodeling after MI and that these differences underly the occurrence of ventricular arrhythmias in males vs. females, and (2) estrogen plays a critical role in responses of the autonomic nervous system to myocardial injury, and hence pathogenesis of ventricular arrhythmias. In specific aim 1, we will test whether myocardial signaling in response to sympathetic and parasympathetic neurotransmitters and neuropeptides differ between male and female infarcted mice using optical mapping and novel FRET imaging techniques of intracellular cyclic AMP signaling. In aim 2, we will test whether sex differences exist in (i) cardiac innervation patterns (using tissue clearing), (ii) afferent and efferent responses to optogenetic stimulation of specific autonomic neural pathways, and (iii) autonomic ganglia neuronal changes and oxidative stress after MI. Aim 3 will evaluate the role of estrogen in improving MI induced myocardial and autonomic remodeling. Understanding sex differences in these fundamental autonomic and myocardial pathways has the potential to accelerate development of personalized, novel, sex-based disease-modifying therapies and tailor available therapies more appropriately by sex, reducing complications and side-effects.

NIH Research Projects · FY 2026 · 2023-12

PROJECT SUMMARY Skin-penetrating nematodes, including the human-parasitic threadworm Strongyloides stercoralis, infect over one billion people worldwide and are a major source of morbidity in low-resource settings. Infections can cause gastrointestinal distress, stunted growth and cognitive impairment in children, and even death in the case of S. stercoralis infection. S. stercoralis infective larvae are developmentally arrested third-stage larvae that navigate through the soil searching for hosts to infect. When they find a host, they infect by skin penetration, resume growth and development inside the host in a process called activation, and navigate through the host body to the small intestine. These parasites encounter widely varying levels of ambient oxygen (O2) and carbon dioxide (CO2) throughout their life cycle, ranging from the near-atmospheric levels of O2 and CO2 they encounter as infective larvae host seeking at the soil surface to the low O2/high CO2 levels they encounter as parasitic adults residing in the human intestine. However, remarkably little is known about gas sensing in S. stercoralis or any other mammalian-parasitic nematode. We propose to investigate the behavioral, neural, and molecular mechanisms of gas sensing in S. stercoralis. We will conduct an in-depth, quantitative analysis of the behavioral responses of S. stercoralis to acute changes in ambient O2 and CO2 levels as well as O2, CO2, and combined O2/CO2 gradients using automated worm motility tracking. We will compare the responses of infective larvae, activated infective larvae, free-living adults, and parasitic adults to changes in ambient O2 and CO2 to determine how O2/CO2-evoked behaviors vary across life stages. We will then map and functionally characterize the neural microcircuits that mediate behavioral responses to changes in ambient O2 and CO2. We will test the hypothesis that the S. stercoralis homologs of sensory neurons and interneurons that mediate gas sensing in C. elegans also mediate gas sensing in S. stercoralis but contain functional adaptations that enable parasite-specific behavioral responses. Finally, we will identify and characterize the O2 and CO2 receptors that are required for gas sensing in S. stercoralis. Together, our results will provide insight into how skin-penetrating nematodes use gas sensing to find and infect human hosts. In the long-term, our results may identify new molecular targets that could inform the design of novel anthelmintic drugs.

NIH Research Projects · FY 2025 · 2023-12

PROJECT SUMMARY/ABSTRACT The purpose of the Predoctoral Individual National Research Service Award (F31) is to provide the candidate with mentoring and research experiences that will promote candidate’s development as an independent researcher, with particular emphasis in spatial-temporal trend and longitudinal analysis as well as multi-level modeling in maternal and child health among populations diagnosed with syphilis. Objectives of the training are to develop knowledge and skills to: 1) gain research experience using state-of-the-art methods using a large longitudinal surveillance dataset and publish the research findings as the first author; 2) advance epidemiological training focused on knowledge of the epidemiology of substance abuse and sexually transmitted infections and gain statistical skills for mediation and longitudinal analyses; and 3) obtain Skills for a successful academic career and professional development, including ethics, the dissemination of research findings, and the development of collaborative scientific relationships. Training activities will include didactic coursework and specific workshops, directed readings and one-on-one tutorials with mentors, and instruction in the responsible conduct of research. The candidate will receive mentorship from a Training Committee comprised of nationally renowned experts in the fields of substance use, maternal and child health, sexually transmitted diseases (STDs), and longitudinal data analysis at the University of California, Los Angeles. The specific aims of the proposed research are to: 1) measure spatial-temporal trends in methamphetamine (meth) use incidence rates among women of reproductive age (15-44 years old), pregnant women, and congenital syphilis (CS) case mothers who are diagnosed with syphilis in Los Angeles County between 2011 and 2020; 2) determine whether temporal trends in prenatal care visits, syphilis treatment during pregnancy, and delivery of infants with CS among pregnant women diagnosed with syphilis differ by meth use; and 3) apply syndemic theory to examine meth use, high-risk sexual behaviors, homelessness, and social vulnerabilities that co-occur and test how the co-occurrence of these factors are associated with no prenatal care and CS incidents among pregnant women diagnosed with syphilis. The research aims will be accomplished by conducting spatial- temporal trend analysis and advanced statistics such as structural equation modeling and cross-legged panel modeling. Quantitative data will come from STD surveillance system and sample size will be determined by the number of women at reproductive age diagnosed with syphilis (N=6,014) and infants born with syphilis (N=426) in Los Angeles County between 2011 and 2020. Findings from the proposed research will position the candidate to propose a F32 or K01 proposal to pilot test a theoretically-driven, mixed methods intervention that addresses the multiplicity of risks among meth using women in the context of STDs and access to reproductive health.

NIH Research Projects · FY 2025 · 2023-11

PROJECT ABSTRACT Congenital Heart Disease (CHD) is the number one birth defect worldwide, with 2.4 million people (1.4 million adults) in the United States. Those figures are expected to double in the next decade with more than 90% of CHD patients reaching adulthood. Despite medical and surgical advancements, 50% of adults with CHD have neurocognitive deficits, depression and heart-focused anxiety that can affect their daily life. However, there are no studies that examine sex differences in psychosocial and neurocognitive outcomes in adults with moderate to complex CHD. Only a few studies have examined either neurocognitive function or psychosocial outcomes in adults with CHD. Those studies have shown deficits in neurocognitive domains such as attention, executive function, processing speed, working memory and intelligence. These deficits place the patient at higher risk for lower educational attainment, unemployment, disability, poor self-care, increased mortality and morbidity, lower quality of life and potential loss to medical follow-up. Unfortunately, small sample sizes in these few studies limited further analysis based on sex / gender differences. To address this critical gap, we will recruit 180 CHD participants between 18 to 40 years of age with a diagnosis of moderate-to-complex CHD from the Ahmanson/UCLA Adult CHD Center. An additional sample of 40 healthy controls will be recruited from the Los Angeles community for comparison. This cross-sectional, comparative study will include measurements to assess neurocognition, anxiety/depression, social determinants of health, mental and physical functioning, social support, and quality of life. Clinical data include ventricular ejection fraction (EF), number of cardiac surgeries, CHD severity and menopause status in females. Specific Aim 1) Examine sex /gender differences in psychosocial, physical functioning, social determinants of health (SDoH), and neurocognitive scores in adults with moderate to complex CHD compared to age-, sex-, and ethnicity-matched controls. We hypothesize that males will have worse neurocognitive scores compared to females with CHD and matched controls, while females with CHD will have worse psychosocial scores compared to males with CHD and match controls. Specific Aim 2) Determine the relationship between neurocognitive scores and sex, clinical factors, SDoH, psychosocial, and physical functioning in adults with moderate-to-complex CHD. We hypothesize that greater number of surgeries, lower EF, worse physical function, higher levels of anxiety and depressive symptoms, less social support, negative SDoH, and male sex will be associated with worse neurocognitive scores in adults with moderate to complex CHD. This study will contribute to new knowledge on the association of sex / gender differences related to neurocognition and psychosocial outcomes in aging adults with CHD. The clinical implications are substantial as results will support the development of targeted interventions to improve neurocognitive and psychosocial outcomes in this high-risk, growing population.

NIH Research Projects · FY 2026 · 2023-11

PROJECT SUMMARY Skin-penetrating nematodes, including the human-parasitic threadworm Strongyloides stercoralis, infect nearly one billion people worldwide and are a major source of morbidity in low-resource settings. Infections can cause chronic gastrointestinal distress, stunted growth and cognitive impairment in children, and even death in the case of S. stercoralis infection. Skin-penetrating nematodes have a soil-dwelling infective third-larval stage that actively searches for a host to infect using host-emitted sensory cues, and then invades the host by penetrating directly through the host’s skin. Host invasion via skin penetration is an essential step of the parasitic life cycle, yet remarkably little is known about this process. We propose to investigate the behavioral, neural, and molecular mechanisms that mediate skin penetration in S. stercoralis and the closely related rat parasite Strongyloides ratti. We will leverage new methods we recently adapted for mechanistic studies of these species, including methods for CRISPR/Cas9-mediated targeted mutagenesis, reversible chemogenetic neuronal silencing, and in vivo calcium imaging. In Aim 1, we will elucidate the behavioral program that leads to skin penetration using in vitro and ex vivo skin-penetration assays. We will compare the behaviors of S. stercoralis and S. ratti infective larvae on host vs. non-host skin to identify behavioral sequences specific to host skin. We will also compare the responses of infective larvae vs. non-infective life stages to identify behaviors that are specific to infective larvae. Finally, we will compare the behaviors of S. stercoralis and S. ratti infective larvae to those of distantly related skin-penetrating infective larvae, passively ingested infective larvae, and free-living larvae to gain insight into the evolution of skin-penetration behavior. In Aim 2, we will investigate the role of dopamine signaling in regulating skin-penetration behavior. We will test the hypothesis that the Strongyloides dopaminergic neurons are mechanosensory neurons that detect the texture of the skin surface and initiate skin-penetration behavior upon contact with host skin. We will also functionally characterize the response properties of the dopaminergic neurons upon contact with host skin. In Aim 3, we will identify and functionally characterize the mechanosensory neurons and mechanotransduction pathways that recognize specific mechanical features of host skin and enable the infective larvae to burrow through the skin. We will also compare mechanosensory function in Strongyloides spp. and the free-living nematode C. elegans to pinpoint the specific mechanosensory adaptations of the parasites that support skin penetration. Together, our results will provide key insights into the molecular and neural mechanisms by which skin-penetrating nematodes invade hosts, which may inform the development of novel topical anthelmintics.

NIH Research Projects · FY 2025 · 2023-09

Project Summary / Abstract Virtually all U.S. adults will develop multimorbidity (coexistence of multiple chronic conditions) by late adulthood. The sequelae are substantial: vulnerability to acute illness, disease exacerbation, hospitalization, disability, poor health-related quality of life, and mortality. Despite this, there are no viable, patient-centered measures for multimorbidity in the electronic health record (EHR) that include a comprehensive inventory of conditions based on their impacts on physical functioning in community-dwelling adults and are thus broadly applicable for the general population. The absence of such tools impedes systematic efforts to develop effective interventions for patients with multimorbidity. To bridge these gaps, this proposal aims to develop and validate a robust, clinically relevant, readily-available EHR-based multimorbidity-weighted index (eMWI) that accurately ascertains disease presence using EHR data and is applicable for diverse populations across the lifespan. The central hypothesis is that a comprehensive multimorbidity index that weights conditions based on their impacts on physical functioning can more precisely quantify multimorbidity and provide a better model fit to predict key health outcomes than prior measures. This hypothesis is strongly supported by our preliminary results using large national surveys and survey-linked claims data, in which we rigorously developed and validated a comprehensive set of 91 chronic conditions weighted by their average impacts on physical functioning over the disease life course, thus incorporating illness burden and physical functioning into a clinically meaningful measure applicable for the general population. As a transformative step for multimorbidity measurement in patient care, population health, and research using EHR data, the team aims to 1) improve multimorbidity measurement by more accurately ascertaining disease cases, and merging these with validated physical functioning disease weights to create a new patient-centered eMWI applicable to diverse populations; 2) assess the validity of eMWI via its association with key clinical outcomes: multimorbidity progression, hospitalization, and mortality; and 3) test the applicability of eMWI to national population health and policy by applying it to evaluate the risk of severe and fatal COVID-19 among vaccinated vs. unvaccinated adults based on their multimorbidity. This study uses large, diverse EHR data from 6 California health systems (>6 million adults) with unique data linkages to census data, and the largest, most nationally-representative National COVID Cohort Collaborative (N3C) dataset (>5 million COVID cases). The results will yield a new, validated, patient-centered multimorbidity index for EHR data – the eMWI – to help guide clinical decisions, population- health management, policy, and research for diverse populations. The team anticipates that eMWI can directly impact future practice and outcomes in which multimorbidity and functional status impact everyday treatment decisions and outcomes. eMWI will be readily available in standardized code for other EHR data. Overall, these results will improve the quality of care and health outcomes for diverse, aging adults with multimorbidity.

NIH Research Projects · FY 2025 · 2023-09

Project Summary Decades of studying animal development and in vitro human cell culture have produced many observed tight correlations between the duration of a cell’s cycle and its identity or the fates of its progeny. These links represent a unique opportunity to understand the regulatory relationships between genetic programs of cell fate and the regulation of the cell cycle, both central questions in the study of development, tissue homeostasis, regeneration, and proliferative disorders such as cancer. The nematode Caenorhabditis elegans has been a powerful model in which to study the regulation of cell fate and cell cycle control owing to its genetic tractability, transparent body and embryo, and stereotyped cell lineage. Like most nematodes, C. elegans exhibits eutely or a fixed number of somatic cells in each individual of the same sex. Cell fate in the wild-type animal can thus be determined solely on the basis of its lineage history, for which we have developed extensive tools and approaches for automated reconstruction via 3D timelapse microscopy. Using C. elegans and genetic perturbations that result in transformations of cell fate with its lineage, in combination with automated lineage tracing and spatial transcriptomics approaches, we will investigate the mechanisms by which cell fate influences the duration of a stem cell’s cell cycle as well as the mechanisms by which the duration of a cell cycle can influence cell fate. The work described in this proposal represents a novel approach to considering these links, enabled by our development of lineage tracing technologies and quantitative approaches to discovering structure in cell lineages. Building on this expertise, as well as our imaging resources and collaborations with other tools developers, theorists, and developmental biologists, we will continue to advance the state-of-the-art in lineage- resolved studies of metazoan development. In particular, using our advances in deep learning techniques to enable label-free automated lineage tracing in non-model species in which transgenesis remains impossible or difficult, we will leverage an evolutionary approach to understanding the design principles of gene networks that drive cell fate decisions and control cell cycle progression in the early embryo. Over the next five years we will complete detailed characterizations of co-dependencies between cell cycle timing and cell fate in the C. elegans embryo, create a molecular atlas of cell fate and cell cycle regulation in wild type and mutant C. elegans where cell fate patterning is perturbed, and complete the reconstruction and quantitative analysis of the embryonic lineages of S. stercoralis, P. pacificus, and C. angaria. In the long term, we plan to extend our molecular analyses to these species as well, beginning with C. angaria as an attractive model for studying the evolution of cell fate control networks and their interactions with regulators of the cell cycle. These insights will be of broad value to our understanding of developmental processes, and the resources we will establish will facilitate the work of others on diverse problems in emerging model systems.

NIH Research Projects · FY 2024 · 2023-09

Project Summary: Firearms are a major source of preventable morbidity and mortality in the United States, contributing to over 45,000 deaths in 2020 and leading to substantial costs to society. Recent analyses estimate that one-third of firearm decedents had consumed alcohol, while other studies have demonstrated an association between alcohol use and firearm-related suicide. The intersection between firearms and alcohol use is a topic that has received relatively little attention to date, but policy interventions that address that intersection have wide public support and may offer new directions for tackling the large and growing burden of firearm-related harms. One challenge is how to address these problems without unduly burdening the large number of gun owners who are unlikely to harm themselves or others. Consistent with priorities established in the Institute of Medicine/National Research Council Report Priorities for Research to Reduce the Threat of Firearm-Related Deaths, this study will identify public policies that target the intersection of alcohol and firearms and provide a rigorous evaluation of their potential impacts on firearm-related homicide, suicide and unintentional deaths over the 2010 to 2022 period. To accomplish these objectives, the study will identify and analyze the scope and content of legal texts related to state laws that explicitly target alcohol impairment/use and firearm sales, ownership and use. The potential impact of these laws will then be assessed using state-level data from the National Vital Statistics System (NVSS) while controlling for the rest of the firearm and alcohol policy context within states. The role of potential effect modifiers such as age, sex, and race/ethnicity will then be assessed for each outcome, including intimate partner homicide, using individual- level data from the National Violent Death Reporting System (NVDRS). The multidisciplinary team of attorneys, engineers, public administration and public health scholars will employ legal research, content analysis, rigorous machine learning and causal inference methods, as well as multi-level and inverse-probability regression analyses to objectively and rigorously examine the scope of these laws, assess their impact (if any) on firearm-related deaths, and identify any factors that may moderate their effects over a long time period. In addition to publishing findings from the analyses, the study team will produce an interactive web-based tool for public use that allows users to understand the alcohol, firearm and alcohol-related firearm policies in their states, as well as visualize firearm-related deaths in their states over the time period. This proposal is responsive to RFA-CE-23-006 Funding Option A.

NIH Research Projects · FY 2024 · 2023-09

ABSTRACT Cardiovascular disease (CVD, including heart disease and stroke) is the leading cause of death worldwide and in the United States (U.S.), accounting for 2.8 million deaths in 2018 alone and with a prevalence nearing 50%.1,2 Related to this are long working hours, which remain quite high in the U.S. when compared to other countries.3,4 Recently, a series of systematic reviews and meta-analyses have identified a robust and dose-dependent relationship between long working hours and CVD.5–9 These reviews reported that working more than 55 hours a week was associated with a higher risk of CVD mortality in the European workforce. However, this association has not yet been systematically investigated in U.S. working populations, constituting a critical research gap that demands address. Our objective is to conduct secondary data analysis, in response to PAR-18-798, to better understand the relationship between long working hours and CVD mortality risk in the U.S., using data obtained from the National Health Interview Survey (NHIS) series of studies. The NHIS is an annually updated, large, nationally representative, and rich dataset featuring detailed information on demographics, working conditions, and health and disease status. The NHIS dataset represents a premiere opportunity to investigate the contribution of long working hours to excess CVD mortality. We propose to use the NHIS sample data from 1997- 2014 and the NHIS mortality data up to 2015 to examine associations between long working hours and CVD mortality, with a cumulative total of 18 years of follow-up. Our specific aims are to (1) investigate associations of long working hours with total CVD mortality; (2) investigate associations of long working hours with heart disease mortality as well as stroke mortality; and (3) test effect modification of demographic status (age, sex, race, region, and socioeconomic status (SES)) in the associations of long working hours with total CVD mortality, heart disease mortality, and stroke mortality, respectively. We hypothesize a dose-response relationship between long working hours and CVD mortality amongst the U.S. working population, and that this association will be modified by social and demographic characteristics. Our expected outputs and outcomes in the intermediate term anticipate the successful achievement of the specific aims, constituting the provision of high-quality, robust scientific evidence assessing the association of long working hours to CVD mortality in the U.S. This project has national and global relevance, and addresses goals set by the National Occupational Research Agenda (NORA) Health Work Design and Well-being sector and the NORA Cancer, Reproductive, Cardiovascular, and Other Chronic Disease Prevention cross-sectors. The ultimate long-term societal impact and contribution of this project would be to leverage such data to shape and inform interventional policy directives related to the limitation of working hours for the sake of CVD prevention. This represents a most critical opportunity in applying a Research to Practice (r2p) approach in reducing the occupational mortality burden of CVD.

NIH Research Projects · FY 2025 · 2023-09

Project Summary or Abstract The successful application of magnification devices for reading and daily tasks is predicated on their correct use by individuals with low vision (LV). Barriers related to transportation, geography, and/or health-related concerns often limit LV patients’ ability to attend several in-office training sessions as part of low vision rehabilitation (LVR) to optimize visual function with magnification devices. A promising solution is real-time videoconferencing to provide telerehabilitation, involving remotely delivered LVR services by a LVR provider in-office to a patient at home. Telerehabilitation for LV appears to be feasible and acceptable by both patients and LVR providers, with preliminary evidence that its efficacy for enhancing reading ability may be similar to in-office LVR. However, it has not yet been fully demonstrated whether telerehabilitation is at least as effective as in-office usual care for LV follow-ups. This would be critical information for LV providers for reassurance that either modality is acceptable. Another key issue in LVR is the need for an effective system to continually assess how patients are functioning at home. Ideally this would involve a non-invasive, efficient method to assess when magnifier device abandonment occurs, so that a timely telerehabilitation session can be initiated. Bluetooth low energy (BLE) beacon sensors attached to the handles of magnifiers can collect longitudinal data regarding environmental changes, which might serve as a helpful indicator of magnifier use patterns by LV patients at home. Specifically, we propose to conduct a randomized non-inferiority trial of the potential for telerehabilitation to enhance visual ability by providing remotely-delivered LVR training to use magnification devices and/or visual assistive mobile apps in comparison to in-office usual care LVR. This will provide an evidence basis for whether the effects of two interventions are not clinically and statistically different from each other. This is important to determine if a novel service delivery mode (i.e., telerehabilitation), that might be safer, more resource efficient, convenient, may improve adherence and/or access to care, is at least as effective as a more established approach (i.e., in-office) with proven effectiveness. We aim to show how telehealth services can be made readily accessible to those with LV, as well as the value of annual follow-ups via telerehabilitation. We will determine whether BLE beacon sensor data are valid indicators of hand-held optical magnifier usage by LV patients at home. We anticipate that beacon sensors attached to hand-held optical magnifiers will measure increased temperature and/or humidity when motion is detected. Beacon sensor data will determine if it is feasible to remotely assess when magnifiers are used or abandoned, and if their frequency of use changes following telerehabilitation or in-office LVR. We envision that telerehabilitation can improve patient outcomes as an alternative, effective method for the provision of follow-up LV services. This is a high priority given the increasing prevalence of LV, paucity of LV providers, and barriers to care. Beacon sensors are a novel solution for monitoring LV patients beyond the clinical office visit, which could enhance patient management with timely LV services and evaluation of LV device use.

NIH Research Projects · FY 2024 · 2023-09

Abstract Social interaction is an evolutionarily conserved toolkit, critical to the survival and development of a wide variety of species. Impaired social interaction is one of the key symptoms across many neuropsychiatric disorders, including autism spectrum disorder (ASD) and schizophrenia. Therefore, elucidating the underlying neural circuits and computations of social behaviors is essential to understand the causes and mechanisms of many neurological disorders with a strong translational implication. Social interaction is dynamical in nature as it often involves a constant feedback loop of actions and reactions of all participating individuals. However, current approaches in social neuroscience often overlook this property and mostly focus on the underlying neural processes within a single individual. To fully understand how the social brain functions in health and disease, it is critical to examine the integrated system of all social participants and the neural properties that emerge from it. One of such emergent features is inter-brain synchrony. In recent years, substantial effort has been dedicated to investigating how neural dynamics across individuals are coordinated during social interaction. Using non- invasive recording techniques, many human studies have demonstrated that inter-brain synchrony emerges across social participants in various social contexts. In fact, it has also been shown that inter-brain synchrony is altered in individuals with social deficits caused by psychiatric illnesses. Despite such remarkable findings, technical constraints limit the extent of investigation and leave open various questions: how inter-brain synchrony emerges from cellular-level circuit components, and how these dynamics are related to computational processes that support healthy or impaired social interaction? Integrating a novel machine-learning approach with state-of- the-art in vivo calcium imaging in freely interacting mice, the proposed experiments will address how inter-brain synchrony (inter-brain neural correlation) arises in different genetically-defined neuronal populations in the medial prefrontal cortex (Aim 1). This work will also characterize the potential alteration of inter-brain synchrony and its behavioral implications in Shank3 mutant mice – an established ASD mouse model (Aim 2). The insights derived from this research will expand our understanding of how the information shared across multiple interacting brains can shape on-going social interaction, shedding new light onto how inter-brain synchrony can serve as a putative biomarker for impaired social interaction in ASD and laying the groundwork for new approaches to treat psychiatric illnesses.

NIH Research Projects · FY 2026 · 2023-09

PROJECT SUMMARY/ABSTRACT Gestational diabetes mellitus (GDM), one of the most common and growing complications in pregnancy, presents striking racial and ethnic disparities. Asian American women are twice as likely to have GDM as non- Hispanic White women and there is also substantial heterogeneity in GDM rates across Asian subpopulations. The molecular mechanisms and upstream determinants for the high and heterogeneous risk of GDM across Asian subpopulations remain largely understudied since they are under-represented in health research. As one of the fastest-growing racial and ethnic groups in the US, it is crucial to better understand the molecular differences and similarities across Asian subpopulations to help elucidate the pathophysiology underlying their high and heterogeneous risk of GDM. Metabolomics is a powerful tool for comprehensively evaluating global metabolic signatures and understanding biological pathways. However, metabolomics studies among pregnant individuals are still limited and most have no or few Asian Americans. This study aimed to fill the current data and knowledge gaps for GDM disparity research by using a highly cost-efficient design that leverages the existing and unique resources: the California (CA) Alpha-fetoprotein Screening Program (CA-AFSP) and the Pregnancy Environment and Lifestyle Study (PETALS). In the discovery sample from the CA-AFSP program which covers >74% of the pregnant individuals in Southern CA, we propose to perform integrated untargeted and targeted metabolomic profiling using stored serum samples collected in early-mid pregnancy (15-19 gestational weeks) from 1500 individuals of four Asian subpopulations (i.e., 375 each of Chinese, Filipinos, Indian, and Vietnamese). We will identify metabolomic signatures in early-mid pregnancy associated with GDM in the CA-AFSP program and determine which metabolites and pathways overlap across all Asian Americans or distinguish across Asian subpopulations (Aim 1). We will construct an external validation set from the above four Asian subpopulations who participated in the PETALS cohort at Kaiser Permanente Northern CA. The PETALS is a well-characterized cohort with anthropometrics, multi-domain survey data, comprehensive health data from state-of-the-art electronic health records, and serum metabolomics assessed at 16-19 gestational weeks. We will validate GDM- related metabolomic signatures in the PETALS cohort for all Asian Americans and each Asian subpopulation (Aim 2) and examine associations of upstream lifestyles and social determinants of health (SDOHs) with GDM risk and metabolic signatures and whether metabolomic signatures partially mediate the association between upstream lifestyles and SDOHs with GDM risk (Aim 3). As the largest-scale study to date, our integrative approach encompassing metabolomics, lifestyles, and SDOHs provides an unparalleled opportunity to elucidate mechanisms of the drastic racial and ethnic disparities in GDM and to inform precision preventions for the high- risk, heterogeneous Asian subpopulations. Thus, this study has the potential to improve minority health and health equality in our nation.