University Of California Los Angeles

NIH Research Projects · FY 2026 · 2023-02

PROJECT SUMMARY The overarching goal of the proposed study is to uncover the molecular mechanism underlying FOXF1-mediated temporal and spatial coordination of multiple alveolar endothelial and epithelial cell subtypes. FOXF1 (Forkhead Box F1) is a transcription factor that plays a pivotal role in lung vascular development, homeostasis, and repair after injury. Heterozygous deletions or point mutations in FOXF1 are associated with alveolar-capillary dysplasia with misalignment of pulmonary veins (ACD/MPV), a lethal lung developmental disorder with no cure. Although the Foxf1 mutant mouse model has been created to study ACD, there are certain variations in gene signatures of EC subtypes and developmental timing of the alveolarization in mouse vs. human, limiting its application in understanding ACD human etiology. Thus, it remains unclear how FOXF1 regulates downstream gene networks to drive the formation of alveolar endothelial cell (EC) subtypes and maintain normal EC-epithelial cell (EpiC) crosstalk during alveologenesis in human. Our preliminary studies showed that FOXF1 mutations lead to distinct cell population and transcriptomic changes in two newly identified alveolar EC subtypes- aerocyte (aCap) and general capillary (gCap), based on single nuclei RNA-sequencing in control and ACD human lung tissues. More interestingly, although FOXF1 does not express in epithelial lineage, alveolar type 1 (AT1) EpiC population was significantly reduced, and damage-associated transient epithelial progenitors (DATPs) were increased in FOXF1 mutant human lung. Ligand-receptor binding analysis revealed disrupted TGFβ signaling in aCap (TGFB2)-AT1 (TGFBR2/3) interaction. Therefore, we hypothesized that FOXF1 regulates distinct pathways in aCap and gCap cells, and FOXF1-dependent TGFβ2 secretion by aCap is critical in maintaining AT1 identity and function. We propose to test this hypothesis with the following specific aims: Aim 1: Determine the role of FOXF1 in regulating differentiation and function of alveolar EC subtypes. Aim 2: Determine the impact of aCap cells on maintaining AT1 identity and function. Aim 3: Uncover FOXF1 mediated early lung development using iPSC derived organoid systems. For Aim 3, we established 3D vascularized alveolar organoid models from control and ACD induced pluripotent stem cells (iPSCs), to study FOXF1 gene regulation and dynamic EC-EpiC interactions across multiple lung developmental stages. Completion of the three aims will provide granular mechanistic insights into the spatial and temporal patterning of intercellular signaling pathways driven by FOXF1 in human lung alveologenesis, and provide new therapeutic targets to re-establish normal alveolar-capillary interface in various lung developmental disorders.

NIH Research Projects · FY 2026 · 2023-02

PROJECT SUMMARY/ABSTRACT Glioblastoma (GBM) is a uniformly fatal disease with very few clinical options. Recent work from our lab and others indicates that abnormal signal transduction, originating from oncogenic drivers and loss of tumor suppressors, results in heightened glycolytic flux in GBM. Correspondingly, inhibition of oncogenic signaling or downstream signal transduction pathways using targeted therapies can induce rapid and specific alterations in glycolysis, resulting in reduced tumor energetic and biosynthetic capacity, making the tumor vulnerable to further therapeutic exploitation. Such an imaging biomarker would be useful for providing unique insight into glucose metabolism and behavior, allowing clinicians to identify and ultimately exploit potential therapeutic vulnerabilities. While 18F-fluorodeoxyglucose (18F-FDG) PET imaging is an obvious candidate biomarker for imaging glycolysis as it is used ubiquitously in other cancers to monitor tumor metabolic behavior and treatment response, 18F-FDG PET uptake is a measure of overall glucose utilization, not specifically glycolysis. To overcome this ambiguity and provide more specificity for glycolysis, we propose combining standard of care 18F-FDG PET with fast pH and oxygen-sensitive amine chemical exchange saturation transfer spin-and-gradient-echo echoplanar imaging (CEST-SAGE-EPI), a molecular MRI technique that can estimate both acidity from lactic acid and oxygen utilization, as well as perfusion and diffusion MRI to account for the effects of blood flow/volume and cell density. We hypothesize combining 18F-FDG PET, amine CEST-SAGE-EPI, perfusion MRI, and diffusion MRI to create a “glycolytic index”, or GI, will allow us to accurately quantify glycolytic flux within heterogeneous tumors on widely available clinical imaging systems for use in studying glucose metabolism and response to a variety of targeted therapies in human GBM. The current study will investigate the central hypotheses that: (Aim 1) biopsied tumor tissue undergoing high levels of glycolysis via RNA expression, protein expression, and bioenergetics analyses can be reliably detected, correlates with direct measure of tissue pH, and strongly associated with a “glycolytic index” created by combining 18F-FDG PET, amine CEST-SAGE-EPI, perfusion MRI and diffusion MRI; and (Aim 2) changes in this “glycolytic index” can be detected by perturbing glucose metabolism using a brain penetrant EGFR inhibitor specifically designed for GBM and correlate with pharmacologic alterations and alterations in glycolytic signaling in patients with IDH wild-type, EGFR amplified GBM.

NIH Research Projects · FY 2026 · 2023-02

ABSTRACT Although anti-retroviral therapy (ART) slows disease progression, ART is a life-long therapy. Significantly, ART is not curative. It does not eliminate reservoirs of replication-competent virus. Thus, when ART is discontinued, HIV emerges from reservoirs and rapidly spreads, leading to disease progression towards AIDS. One strategy for clearing these reservoirs of latently infected cells, the principal if not sole source of continued infection, is to use a kick and kill approach, in which latent cells are “kicked” or activated from latency, allowing their subsequent “killing” or clearance by viral cytopathic effects, immune effector cells or additional therapies targeted at HIV- infected cells. To this end, we show proof-of-concept that a kick and kill strategy with uniquely effective latency reversing agents (LRA) and NK cells remarkably targets the HIV reservoir in a humanized mouse model, leading to a milestone of treatment interruption. Our next goal is to further enhance our kick and kill components to eradicate all replication-competent reservoirs of virus present during ART. We will design, synthesize, and investigate promising new compounds, the best kick components uncovered thus far, with the overall goal of producing superior LRAs and synergistic strategies that efficiently and safely purge the latent HIV in vivo. LRAs have been used to induce HIV expression from latent cells, but thus far have been limited by suboptimal efficacy, tolerability issues, and/or biodistribution concerns. Here, we address these problems using new LRA concepts and structures to improve efficacy, tolerability and control biodistribution. We investigate protein kinase C (PKC) modulators, which are the most potent and efficacious LRAs reported thus far. Within this family we have identified the best performers yet reported, inspired by bryostatin-1, prostratin and ingenol esters and new LRA scaffolds of the ingenane, tigliane, and epoxy-tigliane families. We have found that the chemical conversion of bryostatin-1 into a prodrug (slow-release) version results in a novel LRA with superior activity (60% v. 98%) and significantly improved tolerability (20-fold increase in therapeutic window). Thus, our goal is to advance this study of these new LRAs and chemically synthesized prodrugs using a highly collaborative team with expertise in novel computer-based design, synthesis, medicinal chemistry, state-of-the-art in vitro assays, and sophisticated in vivo animal modeling. To move this program toward clinical entry, optimal LRAs and prodrugs will be used in conjunction with a “kill” approach (natural killer cells) in humanized mice latently infected with HIV to assess the efficacy of the kick and kill strategy. We will accomplish our goals through the following Specific Aims: 1) Evaluate in vitro and in vivo new generation latency reversal agents based on new LRA scaffolds and their prodrugs, representing the most effective and best tolerated LRAs reported thus far, 2) Define and selectively activate PKC isoforms that enhance HIV latency reversal and improve tolerability, and 3) Develop new synergistic strategies to deplete the HIV reservoir. Collectively these studies will advance our unique and superior preclinical LRAs towards clinical testing.

NIH Research Projects · FY 2026 · 2023-02

Project Summary / Abstract Parkinson disease (PD) is the second most common neurodegenerative disease, leading to disability and death for individuals, and significant costs for caregivers and society. Cognitive impairment is a common cause of functional impairment in PD and a central feature of the related disorder Dementia with Lewy Bodies (DLB). To date, there are no disease-modifying therapies to prevent the development or progression of these symptoms. In both PD and DLB, intraneuronal inclusions of the protein alpha-synuclein (α-syn) in limbic and cortical regions correlates with cortical hypometabolism, hallucinations, and progression to dementia, suggesting a central role for α-syn in cognitive impairment. However, the specific effects and mechanisms by which α-syn pathology impacts the function of cortical neurons and circuits remain unknown. In addition, the cortex exhibits regional vulnerability, both to the deposition of α-syn and to the degree of functional impairment, for unknown reasons. Thus, major gaps remain in our understanding of how cortical circuits become dysfunctional in PD and DLB and how specific features of cortical circuits impact the spread and accumulation of α-syn. Here, Dr. Zeiger will lead a research group to test the hypothesis that a reciprocal relationship exists between α-syn pathology and neuronal activity, such that cortical α-syn accumulation directly disrupts neuronal activity, and conversely, that changes in neuronal activity influence the progression of α-syn pathology. In Aim 1, Dr. Zeiger’s group will use a novel model system in a mouse model of PD to directly define how α-syn impacts the function of different disease-relevant cortical circuits. Innovative longitudinal two-photon imaging methods will be used to simultaneously monitor neuronal activity and the accumulation of α-syn inclusions with single-cell resolution. This will then be correlated with behavioral studies to better understand how α-syn-mediated circuit dysfunction leads to cognitive and motor symptoms. The impact of co-existing Alzheimer’s disease amyloid-beta pathology on α-syn-mediated circuit dysfunction will also be tested. In Aim 2, Dr. Zeiger’s group will test the hypothesis that changes in activity can increase or decrease the accumulation of α-syn in the cortex. Advanced transgenic mouse lines and viral tools will be used to specifically manipulate the activity of different components of corticostriatal circuits to define how the activity of specific sub-populations of neurons contribute to the progression of PD pathology. Together, these studies will uncover basic mechanisms about how cortical circuits are affected in PD and DLB. This information is also of great importance for future translational studies aiming to use therapeutic neuromodulation to treat symptoms arising from cortical circuit dysfunction or potentially even slow disease progression in PD and DLB.

NIH Research Projects · FY 2026 · 2023-02

Abstract Heart transplantation has become the mainstay lifesaving therapeutic strategy for a growing number of patients with irreversible, end-stage heart disease. However, numerous challenges must be met to improve long term heart allograft rejection. Although immune therapeutics (ITs) used to prevent rejection have improved over time, they are still unable to eliminate acute and chronic rejection effectively. The use of more intense and potent IT regimens, adopted commonly by transplant programs, can reduce the survival of heart transplant patients by increasing their chances of developing metabolic syndrome, post-transplant malignancy, and serious infection. Therefore, a significant unmet need exists to develop novel and innovative strategies to increase the efficacy of ITs and to reduce their toxicity. Although targeted drug delivery using nanotechnology or antibody-drug conjugates (ADCs) has sparked great interest in the cancer field, its application to transplantation remains to be developed. Over the past several years, we have made major strides to introduce a wide range of targeted therapeutics to the heart transplantation research field. In transplantation, presentation of donor allo-antigens to recipient T cells in the draining lymph nodes (DLN) is fundamental to the generation of alloreactive T cells that traffic to the allografts and cause rejection. The overall hypothesis of this proposal is that targeted delivery of ITs to the DLN and allografts not only increases the efficacy of ITs, but it also decreases their toxicity through reduction of their systemic dosage. In this proposal, we devise a clinically applicable active targeted delivery method for ITs to LNs and organs to promote allograft acceptance in murine models of heart transplantation. We also plan to examine the operating mechanisms that result in prolongation of heart allograft survival by our active targeted delivery platform. These experiments will employ murine heart transplant models, nanoparticle synthesis, advanced antibody-drug conjugation, comprehensive immune phenotyping assays, and sophisticated imaging studies to understand the kinetics of T cell trafficking and payloads in the tissue. Supported by our extensive expertise, as well as established models, techniques, and data, this multidisciplinary collaborative approach sets forth for the first time a well-balanced, innovative, and clinically applicable targeted delivery platform. The studies proposed here have the potential to yield results that could be paradigm-shifting in our approach to immunosuppressive therapy in transplantation.

NIH Research Projects · FY 2026 · 2023-02

ABSTRACT Voice therapy remains the primary treatment option for phonotraumatic vocal hyperfunction, one of the most frequently occurring conditions to affect the voice. Voice therapy aims to modify hyperfunctional vocal behavior through vocal techniques or exercises, often with a focus on vibratory sensations in certain parts of the airway. It is generally believed that these techniques and exercises induce adjustments in the larynx and vocal tract that increase vocal efficiency and lower vocal fold contact pressure, an important contributing factor to vocal fold injury. However, such understanding is largely based on theoretical and numerical simulations, and there have been few experimental data supporting these hypotheses. Additionally, although voice therapy likely leads to multiple simultaneous laryngeal and vocal tract adjustments, information about the specific adjustments and their impact on vocal fold contact pressure is often vague. Currently, voice therapy outcomes are often evaluated based on patient-reported and other secondary measures. To date, no objective measures have been identified that would allow clinicians to reliably monitor and predict the progress of voice therapy with greater accuracy than is currently available. The goals of the proposed research are to (1) experimentally validate findings and hypotheses from previous numerical simulations on favorable laryngeal and vocal tract configurations that consistently reduce vocal fold contact pressures in excised human larynx experiments; and (2) investigate the effectiveness of voice therapy methods in reducing vocal fold contact pressures and in eliciting the hypothesized laryngeal and vocal tract configurations to do so, and the ability of these maneuvers to predict voice therapy outcomes.

NIH Research Projects · FY 2026 · 2023-02

Project Summary/Abstract This application seeks to advance statistical methods within the Bayesian inferential paradigm for disease map- ping and spatial boundary analysis. Disease mapping is an epidemiological technique used to describe the geographic variation of disease and to generate etiological hypotheses about the possible causes for apparent differences in risk. The last decade has seen an explosion of interest in disease mapping, with recent method- ological developments in advanced spatial statistics and increasing availability of computerized Geographic In- formation Systems (GIS) technology. Spatial biostatisticians, data scientists and epidemiologists today routinely encounter datasets requiring multi- or high-dimensional disease mapping in the presence of spatial-temporal misalignment, where “dimension” refers to (a) the number of cancer types being studied, (b) the number of spa- tial units (e.g., census-tracts, counties) in the map, and (c) the number of temporal units (time points) at which the data are observed. This application offers novel classes of stochastic process-based graphical models with specific attention to spatially-temporally misaligned data and modeling of multiple cancers. The versatility and scalability of the proposed framework will allow epidemiologists and public health researchers to account for information from multiple sources including, but not limited to, environmental factors and climate-related vari- ables at arbitrary resolutions in spatial-temporal “BIG DATA” settings. The proposal will subsequently develop a rigorous framework for multivariate boundary detection on maps, where boundaries delineate regions with significantly different spatial effects.

NIH Research Projects · FY 2024 · 2023-02

Project Summary The present application proposes a developmental research plan to investigate the structure-function relationship of individual presynaptic complexes in mammalian vestibular hair cells. These complexes incorporate synaptic ribbons that can exhibit broad architectural heterogeneity, the functional significance of which is not known. The distribution of presynaptic architectures in the primary hair cell phenotypes (i.e. types I and II) within vestibular epithelia, and the unique dendritic specialization known as the calyx (encapsulating type I hair cells), render traditional methods of investigating synaptic function inappropriate for elucidating the functional characteristics of individual synaptic sites. Recent advances in the development of optical biosensors and viral transduction strategies provide the foundation for novel capabilities to detect and quantify neurotransmitter release at individual synapses. iGluSnFR is a genetically encoded, membrane bound glutamate sensor. When expressed at the postsynaptic membrane, it emits a fluorescent signal proportional to glutamate release. Recent key investigations demonstrated that when packaged with an AAV9 capsid and a synapsin promoter, inner ear afferent neurons are transduced and iGluSnFR is expressed. This strategy directs the sensor to the appropriate postsynaptic targets for measuring glutamate release from individual hair cell synapses. When coupled with strategies for post-recording elucidation of synaptic ribbons an association between glutamate release and synapse structure can be made. The project includes three Aims to: 1) optimize transduction in vestibular afferent neurons; 2) develop and optimize recording strategies to capture the time- resolved glutamate release from individual synaptic sites; and 3) evaluate the methods in a mouse model for which presynaptic function in type I hair cells is drastically attenuated. Immunohistochemical processing following optical recording will enable the direct association of immunolabeled ribbons with the recording sites, for which ribbon volume provides a proxy of its architecture. The development of these methods provides the foundation future studies of pathologic conditions whose etiologies are proposed to involve synaptopathies. This investigation will enable future investigations of synaptic function in normal and pathologic conditions, and provide a platform for the rigorous evaluation of novel treatments of inner ear dysfunction.

NIH Research Projects · FY 2026 · 2023-01

PROJECT SUMMARY/ABSTRACT This study endeavors to answer the following, potentially paradigm-changing question: in humans, does gut leak increase during the menopause transition (MT); and if so, does gut leak lead to immune activation, bone mineral density (BMD) decline and fractures? In murine models, a newly uncovered mechanism of bone loss is a menopause-related diminution of gut barrier integrity, and its downstream sequelae, which include translocation of gut microbe-derived antigens, immune activation, osteoclastogenesis, and bone loss. This study will further investigate whether this leaky gut pathway of hypogonadal bone loss in mice also occurs in humans; our pilot work suggests that it does. In a longitudinal study of 65 women from the Study of Women's Health Across the Nation (SWAN), we found that a “leaky gut phenotype,” characterized by diminished gut barrier integrity and translocation of gut microbe-derived antigens, increases during the MT. We investigated the leaky gut phenotype using a plasma marker of decreased gut barrier integrity (fatty acid binding protein 2 [FABP2]), and a plasma marker of translocation of microbial antigens (soluble CD14 [sCD14]). FABP2 and sCD14 increased from pre- to postmenopause, and greater levels were associated with higher C-reactive protein (a non-specific inflammation marker available in SWAN) and lower BMD. This application proposes a vastly more definitive examination of the leaky gut phenotype across the MT and its longitudinal relations to immune activation, BMD, and fracture in a larger SWAN sample. Confirming the leaky gut phenotype is related to bone loss during the MT could open a potent avenue of osteoporosis prevention because: 1) average BMD loss during the MT and early postmenopause (~6 years) totals 1 T-score unit; and 2) faster BMD decline during this interval relates to fractures, independent of peak BMD. We will measure FABP2, sCD14, and a panel of immune markers salient to the leaky gut pathway of bone loss using banked plasma collected from 1,054 SWAN participants before, during, and after the MT. Aim 1 will characterize the trajectory of change in each marker of the leaky gut phenotype from pre- to postmenopause. Aim 2 examines whether within-individual increases in leaky gut phenotype markers are associated with increased immune activation. Aim 3 tests whether within-individual increases in the leaky gut phenotype are associated with decreased BMD. Aim 4 assesses whether larger increases in the markers of the leaky gut phenotype during the MT are associated with greater rates of future fracture. Completing these Specific Aims will substantiate whether the leaky gut phenotype is associated with immune activation, bone loss, and fracture in women. Positive results would motivate future studies that could tests interventions aimed at maintaining gut barrier integrity and lessening the amount of translocated gut microbe-derived antigens. This research agenda could ultimately generate a new way to combat osteoporosis: by blocking a MT-related increase in the leaky gut phenotype, before substantial bone loss occurs.

NIH Research Projects · FY 2026 · 2023-01

PROJECT SUMMARY The overarching goal of the research presented in this application is to understand what make some genomic loci more susceptible than others to environmental chemical perturbation. Using inorganic arsenic (iAs) as a model environmental toxicant of high human relevance, we will seek to mechanistically investigate how epigenetic crosstalks dictate locus-specific sensitivity to arsenic. iAs is a model epigenetic toxicant owing to its well described impact on global DNA hypomethylation coinciding with a reduction in the levels of the universal methyl donor SAM, used towards DNA and histone methylation. However, this model of epigenetic mechanism of iAs has been acknowledged as largely unsatisfactory since (1) even in the context of global DNA hypomethylation, some loci show hypermethylation while others show no change, and (2) the effect on histone methylation are non-uniform with many methylated histone marks showing increases while others show a decrease. Here, we propose to build on compelling preliminary data obtained through highly quantitative Mass Spec and metabolomic studies that show that in mouse ESCs, at levels where sodium arsenite does not cause a significant increase in ROS levels, a pronounced decrease in SAM, DNA methylation, and in several histone marks, such as H3K36me2/3, are observed. However, H3K27me3 levels are increased while H3K9me3 levels are unchanged. Furthermore, RNA-seq studies revealed even in the context of profound transcriptional changes, repetitive elements that are repressed by deposition of H3K9me3 remain transcriptionally silenced following sodium arsenite exposure. Thus, we hypothesize that epigenetic crosstalks can differentially compete for the reduced SAM pool caused by iAs exposure, thereby driving locus sensitivity. To test this hypothesis, we will use mouse ESCs where crosstalks are well characterized. In aim 1, we will characterize the genome-wide changes in DNA methylation and in 3 distinct histone PTMs. We will also test whether these epigenetic alterations caused by iAs require the metabolic activity of the arsenic methyltransferase AS3MT. In aim 2, we will use a combination of knock-down, over-expression, and profiling approaches to mechanistically interrogate in the context of arsenic exposure the role of the well-characterized crosstalks between DNA methylation and histone PTMs at distinct genomic loci. Finally, in aim 3, we will examine the reprogrammability of arsenic-induced epigenetic alterations as ESCs are differentiated into early stage germ cells and go through profound waves of epigenetic remodeling. At the completion of these aims, we will have established the comprehensive profile of changes in DNA methylation and 4 histone PTMs following arsenic exposure. We will also have determined how epigenetic crosstalks mediate locus-specific sensitivity to arsenic and their ability to be reprogrammed in PGCs. This work will firmly establish the central role of epigenetic crosstalks in the response to environmental insults.

NIH Research Projects · FY 2026 · 2023-01

Dozens of malaria species, of the genus Plasmodium, infect human and nonhuman primates worldwide. At least eight of these parasite species have moved from primate reservoirs into human populations, including historical host expansion of P. vivax and P. falciparum, the two primary malaria-causing agents in humans worldwide. As we make progress towards elimination of these common malaria parasites, emerging host switches or expansions that introduce new or rare malaria parasites into human population are an increasing barrier to global elimination. Indeed, in parts of Southeast Asia, a zoonotic malaria parasite is now the main cause of clinical malaria. The lack of genomic resources for zoonotic malaria strains, particularly from wild primates, has been a major barrier to understanding the emergence of malaria parasites and their risk for spread in human populations. Using the emerging zoonotic parasite from Brazil, P. simium, as a case study, we combine whole-genome sequencing of multiple parasite and their host populations to characterize the genetic basis of host specificity and evolution in malaria parasites. P. simium is an ideal system because it is a close relative of the well-studied P. vivax, and importantly, has recently shifted host ranges twice, first from historical human P. vivax into primates, and more recently back into humans. To interpret this new genomic data, we will combine experimental techniques with development of a whole-genome simulation framework that incorporated aspects of parasite lifecycle to better interpret neutral genetic diversity. This opens up recent developments in simulation-based inference techniques that we will use to infer the population history of South American malaria parasites, the timing of zoonoses, and identify loci under selection in multiple hosts. The function of candidate loci identified from computational approaches will then be tested with a specially- developed transgenic line expressing P. simium genes and computational modeling of protein structures from host and parasites. In sum, we combine insights from parasite genomics with complementary analyses of whole genomes from their wild primate hosts—from computational methods development to functional experiments—giving insight into the selective pressures that parasites face inside hosts and host-specific susceptibility.

NIH Research Projects · FY 2025 · 2023-01

Project Summary/Abstract Developmental language impairments are common in the general population, affecting approximately 1 in 10 children. Despite this prevalence, little is known about the etiology of language difficulties observed in conditions such as Autism Spectrum Disorder (ASD). Earlier therapeutic interventions for language impairments have consistently been associated with better language and social outcomes, making it important to develop a better understanding of the neural apparatus supporting successful language acquisition during the first year of life. This project will improve our understanding of language development by longitudinally examining how neural language processing and language network connectivity before an infant’s first birthday relate to later trajectories of receptive and expressive language skills. This proposal will leverage data from two ongoing NIH-funded longitudinal studies to examine the neural processing of native vs. non-native language (Aim 1), functional connectivity within language networks (Aim 2), and the structure of white matter tracts supporting cross-talk between language hubs (Aim 3). Language delays have been associated with aberrant language-related neural activity and network connectivity in both typically and atypically developing populations. Yet although newborns can already distinguish their native language from other languages, no study has longitudinally examined the neural signatures of native language learning in early infancy. Importantly, infant imaging studies have seldom employed adequate sample sizes and repeated observations necessary for rigorous assessment of neurodevelopmental changes in brain connectivity within language networks. Here, fMRI data collected with a stimulus-evoked language paradigm as part of the UCLA ACE (NICHD P50 HD055784) will be used to chart neural responses associated with native language learning during the first year of life in infants at high and low risk for ASD. Longitudinal resting-state fMRI and Diffusion Tensor Imaging (DTI) data from the Baby Connectome Project (1U01MH110274) will be used to thoroughly characterize the early development of functional and structural connectivity, respectively, across brain regions implicated in language processing. Finally, across all aims, differences in brain activity and connectivity during infancy will be related to later language trajectories to identify early predictors of atypical language development. The candidate, Lauren Wagner, will carry out these studies as a Neuroscience graduate student at UCLA under the tutelage of Drs. Mirella Dapretto and Lucina Uddin who, together, have vast expertise in neurodevelopment, pediatric imaging, language development, advanced neuroimaging methods, and ASD. UCLA’s infrastructure, collaborative environment, and research training resources offer the candidate an ideal training environment in which to carry out these aims. This F31 NRSA Fellowship will provide the applicant with comprehensive training in MRI, statistical modeling, teaching, and dissemination of results that, altogether, will lay the foundation for a successful academic research career focusing on neurodevelopmental disorders affecting language acquisition.

NIH Research Projects · FY 2024 · 2023-01

NIH Research Projects · FY 2026 · 2022-12

PROJECT SUMMARY In the present proposal we will investigate new tissue processing protocols designed to preserve DNA, as well as the morphology. We will preserve, process, and make available human ear tissue to inner ear basic researchers they will be able to compare with their animal models. We have experience using high-resolution advanced imaging techniques to the postmortem temporal bones, and also the membranous structures of the inner ear. We propose to develop and apply these imaging techniques systematically and to correlate the imaging findings with the temporal bone histopathology aiming to visualize structures with non-destructive techniques. In Specific Aim 1) we will serve as part of a collaborative network providing technical services for procuring, preparing, sectioning, and distributing high-quality human inner ear tissues aiming to increase interest in the use of human inner ear tissues for basic scientists. We will continue to procure post- mortem temporal bones aiming to minimize post-mortem times and will facilitate and reach out to additional prospective researchers through the collaborative network and through meetings and provide human inner ear tissues of high-quality. We will create hematoxylin and eosin digital shareable library with our archive of temporal bones, and this library will be shared through the National Temporal Bone Registry to scientists. We will disseminate protocols for temporal bone collection, processing, and inner ear tissue processing and provide hands-on instruction on these protocols on demand and via zoom conferences. In Specific Aim 2, we will develop new tissue collection and processing techniques for temporal bones by using animal temporal bones to develop techniques which preserve DNA, mRNA and proteins and preserve morphology. We aim to develop new tissue processing protocols which will allow for the use of immunofluorescence, DNA extraction and sequencing, and the application of RNAScope, a powerful in situ hybridization tool. A new protocol will be developed to further optimize sequencing the DNA from the extracted DNA using temporal bones specimens to correlate the gene sequencing with the histopathology. In Aim 3. We will improve temporal bone inner ear visualization using novel non-destructive imaging techniques which we will correlate with histopathology. In Aim 4, we will develop a deep learning-based stain transformation framework to visualize specific anatomical structures such as the spiral ganglion neurons to obtain accurate histopathological analysis.

NIH Research Projects · FY 2026 · 2022-12

ABSTRACT Cardiovascular Disease (CVD) is the leading cause of death in the United States. Atherosclerosis is a hallmark of CVD and underlies many adverse events. Increased dietary lipid intake is a major contributor to the increased CVD disease burden. Elevated plasma lipids, particularly in the form of LDL cholesterol, accelerate atherosclerosis, the major cause of CVD. Emerging evidence suggests that other lipids, such as triglycerides (TAG), play a role in the development of CVD, independent of LDL cholesterol. To date, lipid lowering therapies have mostly focused on lowering LDL cholesterol, yet adverse events continue to rise. In this application we put forth the framework and hypothesis that modulating bile acids, the body’s natural detergents, can be protective against the onset of atherosclerosis. Dietary lipids such as TAG and cholesterol ester (CE) are insoluble and require detergents (bile acids) for absorption. Bile acids are synthesized from cholesterol in the liver. There are many different bile acids which differ in their chemical structure which results in different properties as detergents and also as signaling molecules. Therefore, the liver is a central hub that coordinately regulates the bile acids, and by extension, the metabolism of many nutrients, including lipids. We have developed a central hypothesis that lipid absorption is regulated by the type and amount of bile acid that is secreted into the intestine following a meal. We hypothesize that bile acids are the key conduits that drive a gut-liver communication axis to regulate lipid absorption. We have selectively targeted enzymes in the bile acid synthetic pathway to elicit specific changes to bile acid levels, allowing us to study how changes in bile acid levels and composition alter lipid absorption in vivo. 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 dietary lipid species has been less well studied. To determine how bile acids alter the absorption of different lipids, we have developed and validated a novel AAV- CRISPR strategy to disrupt specific bile acid metabolism genes exclusively in the liver of adult mice. We have also established a non-invasive and quantitative mass spectrometry approach to measure the absorption of different dietary fatty acids in the intestine. Using these tools, we show that specific modulations in the total amount and/or composition of bile acids have profound effects on fatty acid absorption and atherosclerosis progression. Furthermore, we show that specific changes in bile acids can further accelerate and exacerbate atherosclerosis. We have designed two specific aims to test the hypothesis that defined changes in bile acids, mediated by specific disruption of enzymes of the bile acid synthesis pathway are protective against atherosclerosis. Completion of these studies will further our understanding of the role of bile acids as detergents and implicate bile acid metabolism as an important contributor in the pathogenesis atherosclerosis and CVD.

NIH Research Projects · FY 2025 · 2022-12

PROJECT SUMMARY/ABSTRACT The overall goal of this research proposal is to characterize the mechanosensory behaviors of skin-penetrating parasitic nematodes that enable the location and invasion of a host organism. Skin-penetrating parasitic nematodes, including the threadworm Strongyloides stercoralis, infect nearly one billion people worldwide and are major sources of neglected tropical disease. S. stercoralis is normally found in the soil as infective third- stage larvae (iL3s); soil-dwelling iL3s engage in a variety of behaviors that are thought to increase the likelihood of host contact. The hypothesis that the sensation of mechanical stimuli by S. stercoralis iL3s and the ensuing behavioral response are together integral to host seeking and skin penetration has long been postulated but has not been tested. Furthermore, the underlying mechanotransduction pathways and mechanosensory neuronal circuits are not known. The experiments in this proposal will address this gap in knowledge. The first set of experiments will characterize the behavioral response of S. stercoralis iL3s to vibrations resembling those generated by humans walking on soil. Specifically, the extent to which vibration attracts iL3s and promotes behaviors that facilitate host attachment, including nictation, will be examined in detail. In parallel, an in-depth analysis of the behavioral paradigm of skin penetration will be conducted using human skin. The proposed experiments will also determine whether the stiffness or texture that is particular to human skin promotes skin penetration. Behaviors induced by exposure to vibration and host skin will also be studied in other species of parasitic nematodes – the skin-penetrating human-parasitic hookworm Ancylostoma ceylanicum and the passively ingested murine parasite Heligmosomoides polygyrus – and the free-living nematode Caenorhabditis elegans to identify species-specific behavioral adaptations of skin-penetrating nematodes. Additionally, this work will identify the mechanosensory genes and circuits that underlie host seeking and skin penetration by using a combination of approaches: transcriptional reporters for genes that encode predicted mechanoreceptors to identify putative mechanosensory neurons; targeted mutagenesis of the same genes with CRISPR/Cas9 followed by tracking of behavior; chemogenetic silencing of potential mechanosensory neurons using the histamine-gated chloride channel HisCl1 followed by behavioral studies; and imaging of calcium transients in the same neurons upon stimulation. Together, the work in this proposal will identify the mechanosensory behaviors that are specific to skin-penetrating parasitic nematodes that enable host contact and host invasion. Existing therapeutics for strongyloidiasis do not prevent re-infection; this work may alleviate the problem by uncovering novel molecular targets for the development of preventive anthelmintic drugs and topical creams.

NIH Research Projects · FY 2026 · 2022-11

SCIENTIFIC ABSTRACT Five New World mammarenaviruses (NWMs) cause life-threatening viral hemorrhagic fever. NWM transmission to humans most commonly occurs through inhalation of aerosolized viral particles or direct contact with virus-containing rodent excreta or secreta. Pathogenic NWMs are considered priority pathogens by federal and international public health agencies because they pose a significant public health risk and threat to national security. Thus, there is an urgent need to develop new strategies to treat NWM infection. A distinguishing feature of the pathogenic NWMs is the ability to enter cells through human transferrin receptor 1 (TfR1), also known as CD71. Binding of NWMs to TfR1 occurs through the interaction of their envelope glycoprotein GP1 subunit to the apical domain of TfR1, outside of the transferrin (Tf) binding site, which presents a target for the development of broadly active therapeutics that disrupt viral GP1 attachment to TfR1 without interfering with cellular uptake of iron. We have developed a mouse/human chimeric antibody (Ab), ch128.1/IgG1, targeting the apical domain of human TfR1 that effectively competes with pathogenic NWM cellular entry in vitro and provides protection in a model of lethal JUNV disease that we developed using transgenic mice expressing human TfR1 (huTfR1 Tg mice). Consistent with the competitive nature of the Ab mechanism of action, protection was superior using a ch128.1/IgG1 mutant with impaired FcgR and C1q binding, resulting in lack of Ab Fc receptor effector functions (Fc silent; Fc/s). Consistent with human data, we also found that increased interferon-a (IFN-a) blood levels are important in the pathogenesis of severe NWM infection. We have also recently developed a humanized version of ch128.1/IgG1 (hu128.1), which not only increases the human content of the Ab variable regions for human use but also retains the chimeric Ab properties and exhibits superior thermal stability, making it a better therapeutic candidate. We hypothesize that TfR1 can be used as an effective target to neutralize NWM infection, not only using the anti-TfR1 Ab ch128.1/IgG1 Fc/s but also using a new hu128.1 Fc/s as monomeric IgG1 and also as polymeric IgM-like IgG1 Ab. We also hypothesize that the use of an antagonistic Ab specific for IFN-a/b receptor IFNAR-1 (MAR1-5A3 Ab) would be effective in preventing severe NWM disease, used as a monotherapy or combined with anti-TfR1 Abs. To test our hypotheses, we have four Specific Aims. Aim 1: Define the ability of ch128.1 Fc/s and MAR1- 5A3 as monotherapy or combination therapy to inhibit/eliminate NWM infection in huTfR1 Tg mice; Aim 2: Develop a hu128.1 Fc/s and an IgM-like hu128.1 IgG1 Fc/s as novel therapeutic Abs against NWM infection; Aim 3: Define the antiviral activity of hu128.1 Fc/s and IgM-like hu128.1 IgG1 Fc/s in cell culture and huTfR1 Tg mice NWM infection models; and Aim 4: Define the properties of a selected anti-TfR1 Ab in non-human primates (NHPs). This project will develop the scientific basis for the use of novel anti-TfR1 and anti- IFNAR-1 Abs to treat NWM infection and result in a better understanding of the associated disease.

NIH Research Projects · FY 2025 · 2022-09

Project Summary For almost 50 years, scientists have investigated the relationship between eye movement control and the activity of neurons in the frontal eye field (FEF), superior colliculus (SC) and lateral intraparietal area (LIP). The general findings of these studies have been that neurons in all three areas are important for eye movement behavior, but they have identified very few differences between the areas, implying that they all do similar things. Recently, a small number of labs have started using more naturalistic free-viewing behavioral tasks and have found a number of substantive differences in neural responses across these areas, suggesting that they each play a unique role. Based on these data, we formed a hypothesis about the roles of each area and how they may function as a network to generate behavior. Briefly, we have proposed that LIP acts as simple priority map that is constantly accessible, FEF activity controls the timing of saccades and SC activity represents the final decision about where to look. In addition, a subset of neurons in FEF keeps track of where the animal has looked. Building on this previous work, the current proposal has two main aims. The first is to fill in two gaps of our knowledge that are essential in finalizing our hypothesis. As part of this aim, we propose to record from SC neurons in a free viewing visual foraging task to confirm that SC activity is not affected by stimulus identity in ongoing search. We also propose to record from FEF neurons in an even more natural version of our task to make sure that suppression we have previously seen during maintained fixation is a mechanism for controlling the timing of eye movements as opposed to a mechanism related to reward expectation. The results of these studies will refine our hypothesis and set us up for the second main aim of the proposal, which is to test whether our hypothesized roles are functionally valid. This second aim is broken into 3 components. In each, we will causally test aspects of our hypothesis. In the first experiment, we will microstimulate LIP at different times to test whether the suppression we have identified in FEF controls the flow of information from LIP to guide saccades. In the second experiment, we will inactivate LIP while recording from FEF and SC. The results of this experiment will test the hypothesis that LIP activity drives saccadic behavior via FEF and SC and, if it does not, these recordings should identify which area does play a role in guiding behavior. In the third experiment, we will inactivate FEF while recording from SC. This will allow us to test three additional aspects of our hypothesis: whether FEF activity guides behavior and whether this is also represented in SCI; whether the tracking signal in FEF in functionally relevant; and whether the activity in FEF is involved in controlling the temporal flow of saccades. These results will solve a decades-long question of why we have multiple brain areas by providing a clear indication of what the roles of LIP, FEF and SC are in everyday visual behavior. Given that patients across a broad spectrum of neurological diseases have abnormal eye movement behavior, these results may aid in the development of pharmacological or behavioral methods to combat these problems.

NIH Research Projects · FY 2025 · 2022-09

Breast cancer is the most common solid cancer and the second leading cause of cancer death among U.S. women. Multiple studies have shown that screening mammography decreases breast cancer-related mortality, but the implementation of screening has inefficiencies and limitations that contribute to potential harms. False- positive results and wait times for further evaluation are well-documented mammographic harms. Approximately 10% of all screening exams are recalled for diagnostic workup, of which 95% are found to be false positives, potentially resulting in benign biopsies and overdiagnosis. The percentage of women recalled for further diagnostic workup varies between 8-14%, depending on the radiologist. Moreover, the anxiety experienced by a woman with a recent abnormal mammogram is significant. Many women sleep poorly and struggle to focus as they await a more definitive diagnostic workup. Given these limitations of screening, our overarching goal is to minimize practice variabilities associated with recalls, reduce patient anxiety, and increase patient satisfaction. We propose to assess the feasibility and effect of introducing artificial intelligence (AI) solution at the point of care to (1) reduce the overall callback rate, (2) increase patient satisfaction by providing immediate screening results, and for women who require further diagnostic workup, (3) eliminate the delay between screening and diagnostic workup. The AI solution enables immediate “online” interpretation of screening exams in a high- volume breast screening program. For women with abnormal mammograms, real-time interpretation of the screening exam permits women to be scheduled for a diagnostic exam on the same day. This goal is accomplished in three aims. Aim 1 will validate and integrate an AI algorithm to triage screening mammograms within our institution’s breast screening population. We will ensure that the algorithm performs at an expected level (i.e., non-inferior to existing radiologist performance) and integrate and refine the algorithm to communicate results clearly and efficiently to target users. Aim 2 will design and assess an AI-enabled workflow for same-day diagnostic exams. We will analyze the current state of care, identify impediments to implementing this program, and develop changes to the care pathway to allow an AI intervention. In Aim 3, we will implement and evaluate the impacts of an AI-enabled same-day diagnostic imaging paradigm in three stages: (1) a pilot stage, involving a subset of women undergoing screening using 2D screening mammography at a single site; (2) an implementation stage, involving a larger group of women undergoing 2D and 3D screening mammography at a single imaging center; and (3) an expansion stage, involving women being screened at a second imaging center. UCLA Health is a unique environment to evaluate this paradigm given the large number of screening exams performed annually (>40,000 exams) and the distributed nature of its breast screening program across twelve geographically separated imaging centers. The expected outcome of this project is a generalizable approach for evaluating and integrating AI algorithms to effect improvements in care delivery.

NIH Research Projects · FY 2025 · 2022-09

PROJECT SUMMARY (ABSTRACT) Street medicine teams play a key role in the local overdose response, yet existing data sources lag and are no more granular than the county- or zip code level. Geolocated data exist from various sources that could be used to identify hotspots and inform street-based overdose prevention and addiction treatment, but the data sources are not harmonized or available to the public. One geographic area where these concerns are particularly acute is Los Angeles County (LAC), California, with a population of over 10 million, and which had the largest number of fatal overdoses of any U.S. county in 2020. A rising share of fatal overdoses in LAC occur among unhoused people and involve both stimulants and opioids. The objective of the project is to develop tools and processes to improve timely data acquisition from, rapid processing and integration of diverse data sources, geospatial anal- ysis of overdose hotspots (fatal and non-fatal), and nowcasting of overdose, opioid use disorder (OUD), and injection drug use in LAC. Building on our research team's work in mobile overdose prevention and treatment of OUD in LAC, we will collaborate with five local government agencies with interest and experience in improving local overdose response. Our partners span public health, medicine, emergency medical services (EMS), med- ical examiner and coroner, syringe services programs, and street-based harm reduction. Together, we propose to develop a publicly available Rapid Overdose Surveillance Los Angeles online dashboard that can provide local, granular data and more timely estimates of countywide metrics. To establish the dashboard, we pursue two specific aims. In Aim 1, we will establish data flows to collate geolocated fatal overdose data from the coroner and non-fatal overdose from EMS, adapting natural language processing (NLP) methods to classify free-text data that characterize the specific drugs involved. We then employ geostatistical methods to identify hotspots at the census tract level, providing localization to inform placement of mobile and street-based services. Finally, we will develop nowcasting models to “predict the present” of fatal and non-fatal overdose at the county-level based on incomplete surveillance data. In Aim 2, we will develop further NLP strategies to identify upstream outcomes of overdose (i.e., OUD and injection drug use) in electronic health record data. We will then incorporate metrics from substance use disorder treatment, syringe services, and street medicine to improve our estimates of OUD, injection drug use, and overdose at the county-level. We will visualize these data and nowcasting results through Rapid Overdose Surveillance Los Angeles online dashboard. Findings from these efforts will serve as a model for other jurisdictions to leverage and combine data from diverse stakeholders to improve local situational awareness of overdose. Ultimately, the goal is to produce tools and processes that can speed up the time from data to action to better provide overdose prevention and addiction treatment services.

NIH Research Projects · FY 2025 · 2022-09

Project Summary: With rapid changes in cannabis regulation (i.e., legalization) and expanded availability across the United States (US), rates of cannabis use and Cannabis Use Disorder (CUD) have increased among populations vulnerable to the negative effects of delta-9-tetrahydrocannabinol (THC), the primary psychoactive constituent of cannabis. These populations include emerging adults (18-25 years of age), older adults (≥ 55 years of age), and females. Prevalence of cannabis use is highest among emerging adults; this is of particular concern given the known risks of THC exposure during this period of late-adolescent neurodevelopment and brain maturation. While rates of use among females used to be half that of males, the gap between sexes is closing with 5.6% of female emerging adults reporting near daily use. Sensitivity to THC’s effects in females is also hypothesized to lead to negative outcomes including the accelerated progression to CUD. The most remarkable increase in cannabis use is among older adults. Prevalence of past month use among adults ages 55-64 years more than doubled between 2013 to 2019, with over 25% of older adults reporting use 1-4 times per week. Because of physiological and neurobiological changes that occur during aging, older adults may be particularly vulnerable to the negative effects of THC. Despite the increase in cannabis use among these groups, no studies to date have prospectively probed the adverse effects of acute THC exposure across adulthood. Another trend impacting the vulnerability of older adults and females to adverse effects of cannabis is the high rate of medical cannabis use in these populations with pain cited as the predominant symptom for use. This trend further establishes the urgent need to assess THC analgesia alongside adverse effects that increase risk including abuse liability, intoxication, and impairment. To understand cannabis’s acute effects that indicate increased risk of exposure among these vulnerable populations, the proposed study will compare the dose-dependent effects of smoked and oral THC, two popular routes of administration, on endpoints directly related to adverse consequences of use including abuse liability, intoxication, and impairment as a function of age and sex. Specifically, healthy male and female emerging adults (18-25 years; N=30, 15M, 15F), middle-aged adults (35-45 years; N=30, 15M, 15F) and late middle-aged adults (55-65 years; N=30, 15M, 15F) who occasionally use cannabis will be recruited for this double-blind, double-dummy, placebo-controlled study. Using a within-subjects design, all participants will be administered placebo (0mg THC), 2, 5mg unit-doses of THC (10mg), and 4, 5mg unit-doses of THC (20mg) via smoked cannabis and by oral administration. Adverse effects, analgesia, and THC pharmacokinetics will be assessed several times after smoked and oral THC administration. Findings from this study will be instrumental in establishing age and sex as biological variables in the prevention, intervention, and treatment of negative sequelae associated with cannabis use.

NIH Research Projects · FY 2025 · 2022-09

Project Summary/Abstract End-stage kidney disease (ESKD) is a grave public health problem, affecting ≥ 800,000 Americans in 2017. The most common treatment for ESKD in the US is hemodialysis (Medicare spending rate $91,795 per-person/year). Each hemodialysis-dependent patient requires vascular access, the most common type of which is arteriovenous fistula (AVF). The first 2 devices designed to create AVFs using endovascular techniques (endoAVF), vs. traditional surgical techniques (surgAVF), were FDA-approved in 2018. Due to their novel nature, existing data on outcomes of recently-approved endoAVF devices largely arose from industry-sponsored trials aimed at demonstrating device safety and efficacy. No prospective data are available comparing results of endoAVF vs. surgAVF, but a trial to yield such data is needed to inform patient and clinician decision-making. The overall goal of the proposed research is thus to compare procedural outcomes of surgAVF vs. endoAVF, and thus acquire the data needed to inform design and execution of a full-scale randomized trial that will compare the outcomes of surgAVF vs. endoAVF. Each of the 2 available devices for endoAVF creation have specific anatomic requirements for its use. Early small-scale studies showed that ~50-60% of patients screened were eligible for endoAVF creation based solely on such anatomic criteria. No data to date indicate the incidence of patients who are anatomic candidates for one or both endoAVF devices and surgAVF, nor their willingness to participate in a randomized trial of endoAVF or surgAVF. The results of this small-R01 project will inform the design and execution of a full-scale, multi- institutional randomized trial to compare clinical outcomes of surgical vs. endovascular arteriovenous fistula. Aim 1: Determine the proportion of patients who are being evaluated for fistula creation who meet the anatomic criteria for endoAVF creation with one of the two approved devices and an upper arm surgAVF. At the 2 participating sites, we will assess anatomic suitability for both endoAVF devices and for surgAVF in all patients evaluated for fistula creation, by ultrasound screening. Aim 2: Determine clinical and patient-reported outcomes of endoAVF vs surgAVF creation to inform design of a full- scale randomized trial. Patients who are anatomic candidates for both, and who consent, will be randomized to endoAVF or surgAVF, and those who do not consent will be offered enrollment in a prospective outcomes registry. Aim 3: Determine patients' willingness to participate in a randomized trial of surgAVF vs. endoAVF or in a prospective registry of surgAVF vs. endoAVF, and the barriers to each and strategies to overcome the barriers. We will partner with the American Association of Kidney Patients to conduct a survey, with in-depth interviews of a subgroup, to assess patient preferences about study participation. In addition, we will survey and interview patients at our respective institutions about barriers and facilitators to participating in the study.

NIH Research Projects · FY 2025 · 2022-09

Project Summary The K01 application for Dr. Rajarshi Mazumder, a board-certified epileptologist at University of California, Los Angeles, will allow him to establish as an independent investigator in global health and epilepsy research. The K01 will provide Dr. Mazumder support and protect time to achieve the following career development goals: 1) gain expertise in molecular epidemiology-- training in design and conduct of research using genetic data and model the effects of genes and their interactions with environmental factors; 2) Advanced statistical training for population health; 3) Lead research in a resource-constrained setting and training in the responsible conduct of research in global health; 4) Grant writing. To accomplish his career goals, Dr. Mazumder has assembled a team of mentors with complimentary expertise in Uganda and the US. More than 80% of people with epilepsy live in low-to middle-income countries, where despite the high incidences, many commonly occurring epilepsies remain understudied and poorly characterized. Nodding syndrome and related epilepsies are such a constellation of epileptic brain disorder that occurs in several sub-Saharan African countries. Although the etiology of this disease is unknown, several studies have found a consistent association with the parasite, Onchocerca volvulus (OV). As the OV parasite is not neuroinvasive, autoimmunity to Hu-Leiomodin-1, a muscle-associated protein, due to molecular mimicry with OV antigens is thought to play a role in the pathogenesis. Studies have also found that variations in immune responses due to HLA polymorphism might also contribute to the etiology. However, the role of host genetics and its relationship to exposure to OV in the manifestation of epilepsy is yet to be systematically investigated. The central hypothesis of this proposal is that families with NS share common electroclinical features forming a distinct familial epilepsy syndrome and this electroclinical phenotype is conferred by O. volvulus-associated hu-Leiomodin-1 autoimmunity in genetically susceptible individuals. We will pursue the following aims: 1) Characterize the epilepsy sub-phenotypes that aggregate within the NS-affected families; 2) Investigate the role of genetic polymorphism in the human host underlying the pathogenesis of NS-and related epilepsies; 3) Evaluate the relationship between exposure to OV-associated Hu-leiomodin-1 antibody and host susceptibility that jointly confers risk for NS-and related epilepsies. This study has a high global health significance, as it aims to mechanistically understand how a parasitic disease modifies the risk of epilepsy in susceptible individuals. There is an urgent need of this evaluation to further mitigate the risk of a neglected tropical disease. The proposal will prepare Dr. Mazumder as an independent researcher and provide the foundation for future R01 funded studies to prevent acquired epilepsies by early identification of susceptible individuals.

NIH Research Projects · FY 2025 · 2022-09

ABSTRACT While mesenchymal stromal cells (MSCs) hold enormous promise for treating many challenging diseases, a major barrier toward clinically meaningful MSC therapies is the inability to produce potent MSCs consistently. Specifically, in vitro cultured MSCs often rapidly enter senescence in which they lose their potency. In contrast to natural in vivo senescence, such in vitro aging has been shown to be largely driven by misregulated metabolic signaling in culture. To address this grand challenge, many signaling pathways (e.g., FGF, ATM, SRT, mTOR, EGF, DDR2) have been identified for regulating senescence-related processes. Building upon these discoveries, this R35 MIRA proposal aims to develop an innovative engineering approach to delaying the MSC senescence process by collectively adjusting these signaling pathways. Specifically, we hypothesize that a sufficiently trained AI model can predict the signaling factor combination that effectively slows down or even reverts the senescence-related transcriptional drift. To achieve such a goal, my research aims to address three knowledge/technology gaps in MSC engineering (Fig. 1B): 1) how to accurately phenotype live MSCs (e.g., characteristics, proliferation, and potency); 2) how to predict signaling factors that dictate the desired transcriptional response; and 3) how to ensure the robustness of such predictions. In challenge 1, this proposal will expand our previously developed AI platform by developing approaches to acquiring large-scale AI training data that cover a wide range of MSC phenotypes and interpreting black-box deep learning models. The goal is to decipher the morphology-gene expression relationship in MSCs. In challenge 2, we will utilize deep learning to identify the signaling factor combination and predictively adjust gene expression in MSCs. In the third challenge, we will develop algorithms that improve the robustness of AI models and turn our proof-of-concept AI platforms into reliable tools for practical clinical utilizations. The immediate outcome of our proposed research will lead to a high-throughput phenotyping and engineering platform of MSCs. The proposed experimental platform will also enable us to establish better understandings in MSC mechanobiology and senescence signaling interactions.

NIH Research Projects · FY 2025 · 2022-09

Over the past few decades, research involving the neural control of breathing has centered on how the breathing rhythm is generated and how sensory systems detect internal and external changes to modulate the breathing pattern. While we have learned that the regulatory breathing rhythm originates in the medulla, we know little about the neural circuits by which breathing affects emotional state. The positive effects of controlled breathing on emotional state have been observed across many contexts and in the clinic. Using objective behavioral, physiological, and neuroanatomical parameters, we propose: i) to fully determine the neural pathways in mice from the preBötzinger Complex, the key site generating inspiratory rhythm in the medulla, to supramedullary regions, in particular to the locus coeruleus and its ascending projections, that effect and/or affect emotional state, and; ii) to establish the role of these projections from the preBötzinger Complex in mediating the effects of breathing on anxiety, fear and panic in mice. The proposed research has the potential to lead to more effective methods for treating debilitating negative emotional states