University Of California, San Diego

NIH Research Projects · FY 2025 · 2022-08

Abstract Mental health problems such as autism are highly prevalent in the population and incur great suffering and financial costs. Yet there is currently a dearth of biomarkers that accurately predict their diagnosis or prognosis. Characterizing the contributions of high-dimensional biomarkers to susceptibility of such complex disorders is critically important for advancing our understanding of their etiology and for developing new treatments. The fraction of variance explained (FVE) by a set of biomarkers is a measure of the total amount of information for an outcome contained in the predictor variables. It is a fundamental quantity in much of mental health-related research, e.g., human microbiome, proteomics, gene expression, etc. Canonical examples where the FVE is of fundamental interest include Genome-Wide Association Studies (GWAS) and neuroimaging, both crucial tools for understanding the biological basis of mental health disorders. GWAS have successfully mapped thousands of genetic factors by mass-univariate association of millions of single nucleotide polymorphisms (SNPs), but the top significant associations, even in aggregate, account for only a small proportion of susceptibility. To assess the amount of information in GWAS, the SNP-heritability, h2SNP, quantifies the FVE among all GWAS SNPs in aggregate, regardless of significance. Similarly, the FVE by brain imaging measures captures variation in the brain related to mental illness, which again appears to be highly distributed. In both the genetic and brain imaging domains, the number of predictors is extremely large, in the order of thousands to millions, far larger than the number of subjects. As a result, the specific associations with each predictor unit cannot be estimated, and effects of specific loci are extremely difficult to identify. In contrast, the FVE can be reliably estimated from data, even if only univariate summary statistics are available. Estimating FVE requires sophisticated statistical methods designed for these particular, high-dimensional data. In this proposal, we propose a general framework for FVE estimation, applicable to high-dimensional data including both GWAS and brain imaging settings. We develop foundational theory establishing the validity and consistency of FVE estimation, develop new methods for evaluating the required conditions in real data, and develop methods for partitioning FVE into more local components, allowing understanding of the distribution of contributions to susceptibility in a top-down approach. We apply these methods to the Adolescent Brain Cognitive Development (ABCD) Study, comprising longitudinal, multi-modal brain imaging, GWAS data, and autism-related assessments for 11,875 participants aged 9-10 at baseline and continuing into early adulthood.

NIH Research Projects · FY 2026 · 2022-08

Project Summary The misuse and abuse of prescription pain relievers, such as oxycodone, contributed to the unprecedented opioid epidemic in the United States. The opioid crisis has devastating consequences on public health including a surge in opioid misuse and related overdoses. Research is urgently needed to develop better treatments for opiate addiction. Despite substantial knowledge of the pharmacokinetic and behavioral effects of oxycodone in various animal models, only a small number of candidate genes and neuroanatomical systems affected by opioids have been studied. Recent technological advances in the field of single cell genomics are promising avenues for the unbiased discovery and characterization of brain cell types that respond to opioids. In response to this RFA, we leverage an innovative multi-omics methodology (Single Cell Multiome ATAC + Gene Expression) to map the transcriptome and epigenome from the same cell across thousands of cells in brain regions relevant to the effects of opioid exposure. To this aim we will use a rat model of extended access to oxycodone intravenous self-administration that recapitulates several neuroadaptations also observed in humans with opioid use disorders (OUD). This approach provides an exceptional opportunity to systematically explore the cellular diversity of the opioid system and, at the same time, the causative mechanisms that regulate cellular states based on the associations between epigenetic changes and the expression of target genes in individual cells. We will integrate this innovative multi-omics methodology with rigorous computational approaches to explore the cellular organization the opioid system in multiple brain regions and different stages of OUD progression (initial exposure, escalation of use, acute withdrawal, prolonged abstinence, and cue- induced relapse). We have provided strong preliminary that support the feasibility of our proposed plan for the following aims. In Aim 1, we will collect brain tissues at different stages of the extended access to oxycodone intravenous self-administration (ivsa) protocol and we will generate single cell genomics data from both male and female rats that are exposed to either saline or oxycodone. In Aim 2, we will integrate these transcriptomic and epigenomic datasets to identify changes in cellular states, genes and upstream regulators that are associated with different stages of oxycodone use. This approach will facilitate the identification of linkages between cis- regulatory elements and target genes. In Aim 3, we will validate key cell type-specific findings by RNA-FISH and identify the top 3 target genes for functional validation. To this aim, we will use a viral-mediated CRISPR- Cas9 system to modulate addictive behaviors in rat models of oxycodone self-administration. The results of this study will enable future studies that may identify new targets for treatment and prevention of OUD.

NIH Research Projects · FY 2026 · 2022-08

Project Summary Numerous comorbidities have been identified as relatively common among children and adolescents with prenatal alcohol exposure (PAE) or fetal alcohol spectrum disorders (FASDs) including sleep disturbances, hypertension, abnormal eating behaviors, altered growth patterns, and comorbid depression and anxiety. In addition, emerging data suggest that several adult diseases of developmental origin, such as diabetes, atherosclerosis, cardiovascular and autoimmune disorders are over-represented and have earlier age at onset in adults with FASDs. It is imperative to better understand the prevalence and co-occurrence of these disorders as early as possible in the life course of children and adolescents with PAE, ideally at the sub-clinical stage, in order to intervene in clinically meaningful ways. Building on the existing Collaborative Initiative on Fetal Alcohol Spectrum Disorders (CIFASD) longitudinal cohort study in Ukraine, we aim to fill this critical gap in knowledge in two ways. First, we will compare the prevalence and characteristics of subclinical and clinical signs/symptoms of current and developing metabolic and other chronic diseases and contributing factors in 180 children/adolescents with PAE age-matched to 120 children/adolescents with no/minimal PAE. This includes comparing prevalence of premorbid or comorbid hypertension, hyperlipidemia, impaired glucose tolerance/insulin resistance, and cardiovascular disease and also comparing growth parameters, physical activity, dietary intake, adverse childhood experiences, sleep disturbances, and measures of anxiety and depression. Second, we will compare findings on a panel of experimental measures of structure or function that can help illuminate mechanisms of PAE-related comorbidities across the lifespan in the same cohort of 300 children and adolescents. Experimental measures include capillary microvasculature, telomere length, and patterns of miRNA expression. Findings that are actionable will translate on the individual level to clinical guidance provided to the participant and caregiver. Furthermore, in keeping with one of the primary goals of CIFASD5, findings of this study will directly inform future intervention targets in children and adolescents to help remediate, ameliorate or prevent progression of pre-clinical or clinical conditions identified in the study evaluations. We will also work collaboratively with other investigators in the CIFASD Consortium to interactively address the overall goals of the Consortium in improving diagnosis and treatment of FASD.

NIH Research Projects · FY 2025 · 2022-08

PROJECT SUMMARY/ABSTRACT The Outreach Program To Inspire Minority and Underrepresented Students (OPTIMUS) within Moores Cancer Center at the University of California San Diego (UCSD) seeks to create an engaging educational experience for underrepresented minority high school students within the local San Diego region. The overarching goal of this program aligns fully with the NCI's mission to increase diversity in the biomedical and cancer research workforce. The first objective (OPTIMUS Scholars Program) aims to provide an engrossing summer cancer research fellowship program for underrepresented minority high school students (OPTIMUS Scholars). This program will pair OPTIMUS Scholars with supportive research faculty for a mentored research experience. The students will concurrently participate in a complementary educational curriculum that covers core topics in cancer research, coupled to an array of personal and professional development activities. This objective aims to generate a lasting interest in science, healthcare, and cancer research among our underrepresented students. The second objective (OPTIMUS Associates Program) seeks to integrate UCSD biomedical trainees and education graduate students (OPTIMUS Associates) in the educational and operational aspects of OPTIMUS. We will create a new interprofessional course to teach our OPTIMUS Associates the skills required to create and implement an outreach program such as OPTIMUS. We will then provide an experiential education opportunity by incorporating our OPTIMUS Associates as apprentices into the operational aspects of the OPTIMUS Scholars program. This objective strives to create a generation of biomedical trainees and education graduate students who will become future leaders in creating and implementing community-based research education programs such as OPTIMUS. The final objective (OPTIMUS Educational Outreach Program) will have OPTIMUS Scholars teach local elementary school students in their community about basic concepts of cancer and cancer prevention. Our OPTIMUS Scholars will partner with our OPTIMUS Associates to create an interactive age-appropriate curriculum to deliver to these younger elementary school students. This objective partners with a local non- profit STEM-focused organization called the Elementary Institute of Science. This objective stands to solidify fundamental concepts of cancer among our OPTIMUS Scholars (learn by teaching), and will help teach younger local elementary students about the fundamentals of cancer. Altogether, these three objectives with OPTIMUS leverage the diverse and supportive environment within UCSD to help provide engaging opportunities for underrepresented students within our local community. Support for our program will help us take important strides to creating a future cancer research workforce that reflects the diversity of our community.

NIH Research Projects · FY 2026 · 2022-08

Project Summary/Abstract Excessive alcohol drinking modulates the innate and adaptive immune systems. It is associated with gut dysbiosis and bacterial overgrowth. Consequently, it induces intestinal permeability and microbial translocation to the liver which triggers inflammation aggravating alcohol-associated liver disease. The immune system interacts, tolerates, and shapes the intestinal microbiota while monitoring for pathogens. The balance between gut tolerance and immunity is critical in the regulation of intestinal homeostasis. A balanced intestinal homeostasis is essential to prevent intestinal permeability and microbial translocation to the liver. Goblet cells regulate the intestinal immune response by secreting mucin and presenting luminal antigens to lamina propria dendritic cells (LP-DCs) through goblet-cell associated antigen passages (GAPs). LP-DCs adjacent to GAPs have preferential tolerogenic properties. Chronic alcohol overuse decreases the pool of myeloid DCs and modifies its properties. However, the effect of chronic ethanol overuse on the LP-immune response is not well characterized. The hypothesis is that chronic ethanol exposure alters goblet cell biology resulting in the dysfunction of LP-DCs with tolerogenic properties adjacent to GAPs. Hence, a lack of antigen presentation to tolerogenic LP-DCs would induce an imbalance of the intestinal homeostasis. Therefore, goblet cells might have a central role in the onset of alcohol-related liver diseases. To explore the proposed hypothesis, aim 1 will investigate the impact of chronic alcohol abuse on goblet cell biology. It will assess goblet cell numbers, GAP formation, mucin secretion, and the consequent alterations in the LP-immune system in mice and humans. Aim 2 will define the impact of GAPs and mucin from goblet cells on ethanol-induced liver disease in ethanol-fed mice with both, loss and gain of function approaches. Finally, aim 3 will explore a pharmacological approach to manipulate goblet cells to prevent ethanol-induced liver disease in mice subjected to chronic ethanol feeding. This pharmacological intervention will induce LP-DCs with tolerogenic properties by stimulating GAP formation to regulate the mucosal immune system. The proposed study will characterize the role of goblet cells in preclinical models of ethanol-induced liver disease and patients with alcohol use disorder using cutting edge microbiomics and state-of-the-art technology. The proposed intervention will find innovative strategies to prevent alcohol-associated liver disease in patients.

NIH Research Projects · FY 2025 · 2022-08

PROJECT SUMMARY (Overall) The proposed “Center for Team Effectiveness to Accelerate EBP Implementation in Children’s Mental Health Services (TEAMS)” will leverage organizational team effectiveness research (TER) to develop and test novel team-based implementation strategies, methods, and tools to improve the reach, quality, and effectiveness of care delivered in public systems serving children with mental health needs - specialty mental health, schools, pediatric healthcare, and child welfare. Gaps between evidence-based practices (EBPs) and routine care persist and limit the quality and effectiveness of services for children. High performing implementation teams are essential to effective services and team-level mechanisms can hinder or facilitate EBP implementation. There is substantial research on team development interventions developed for the military, business, and other complex contexts, but they not been leveraged to improve children’s mental health. The TEAMS Center will create the essential administrative and scientific infrastructure to conduct team-based implementation research to improve children’s mental health outcomes. It will bring together experts in children’s mental health implementation research, EBPs for children and adolescents, implementation strategies, models, and methods, TER, and computer science. We propose to: (1) establish a highly efficient and well-functioning Center for community-partnered children’s mental health implementation research; (2) integrate TER and natural language processing to advance implementation science models, designs, and measures; and (3) leverage the Center’s expertise and infrastructure to design, build, and test team-based strategies to improve the implementation and effectiveness of EBPs across service systems. The Administrative Core will apply TER strategies to Center operations to optimize communication and decision-making; foster interdisciplinary collaboration and partnership with community stakeholders; and promote the development of internal and external trainees. The Methods Core will advance implementation science models to incorporate TER and natural language processing, adapt and develop measures to examine team-based implementation strategies and mechanisms, and clinical/service outcomes. Center research will adapt and test team development interventions selected from those with evidence in other contexts. The Signature R01 will test a combination of team development interventions [e.g., communication training via handoff protocols, team performance monitoring] to improve implementation and effectiveness of the Collaborative Life Skills Program for children with ADHD in schools. The developmental projects will test after-action reviews to improve shared decision making regarding mental health services in child and family teams in Child Welfare Services (R34#1); implementation team charters to improve distance training for two autism EBPs in specialty mental health and schools (R34#2); and team communication training to facilitate depression screening in a pediatric health care system (R34#3). Additionally, the Center will solicit and fund two pilot projects per year led by internal and external teams of investigators and community partners.

NIH Research Projects · FY 2025 · 2022-08

PROJECT SUMMARY After the chromosomes are segregated by the microtubule-based mitotic spindle, cytokinesis completes cell division, partitioning the contents of the mother cell to the two daughter cells. Cytokinesis is accomplished by constriction of an acto-myosin contractile ring that forms on the cortex in an equatorial band encircling the cell equator. Cytokinesis failure generates tetraploid cells that are a common intermediate in the genesis of cancers. Upregulation and mutation of cytokinesis regulators has also been implicated in different cancers, and inhibitors targeting cytokinesis are of interest as potential chemotherapeutic agents, motivating efforts to understand the mechanisms that pattern cortical contractility during cytokinesis. To ensure that each daughter cell receives an equivalent genomic complement, the position of the contractile ring is specified by the anaphase spindle. The spindle sends two superimposed signals to the cortex: (1) a positive signal promoting contractile ring assembly that is generated by set of bundled microtubules, called the central spindle, that forms between the separating chromosomes, and (2) a negative signal generated by the microtubule asters that suppresses the contractility of the non-equatorial cortex. The proposed work focuses on the molecular basis for these two signals that collectively direct contractile ring assembly. A central component of the positive signal promoting contractile ring assembly is centralspindlin, a tetrameric complex formed by a dimer of kinesin-6 and a dimer of CYK4. Centralspindlin is phosphorylated by the mitotic kinase PLK1, which concentrates on the central spindle; it subsequently diffuses to the adjacent plasma membrane where, through mechanisms that remain largely unclear, its CYK4 subunit engages with and activates the ECT2 guanine nucleotide exchange factor (GEF). Active ECT2 in turn generates an equatorial zone enriched for the master regulator of contractile ring assembly, RhoA-GTP. In Aim 1, we address the major open question with respect to positive cytokinesis signaling: the mechanism of ECT2 activation by centralspindlin. To understand how the microtubule asters suppress contractility on the non-equatorial cortex, which occurs at the same time as positive signaling from the central spindle, we developed an assay monitoring clearing of contractile ring proteins from the cell poles in the C. elegans embryo. Using this assay, we identified Aurora A kinase as an essential mediator of aster-based contractility suppression. In Aim 2, we build on this work to identify the Aurora A targets that mediate contractility suppression and extend analysis of this mechanism to human cells. Aim 3 addresses an important gap in understanding how the cell cycle state that supports contractile ring assembly is generated, and assesses whether the duration of cytokinesis, like that of mitosis, is monitored by a p53-based mitotic stopwatch mechanism that eliminates potentially problematic cells from the population.

NIH Research Projects · FY 2025 · 2022-08

Project Summary/Abstract Background: Transcriptional mechanisms that regulate epidermal homeostasis have been well established but recently we have discovered that mRNA export mechanisms play prominent roles in maintaining epidermal self-renewal. We have shown that RBM15 associates with the NXF1 exporter only in stem and progenitor cells while ZC3H18 associates with NXF1 in differentiated cells. This association allows RBM15 or ZC3H18 to control the mRNA export of key transcripts involved in epidermal growth and differentiation. Objective/hypothesis: This proposal seeks to understand the regulation of epidermal stem and progenitor cell self-renewal and differentiation through post-transcriptional mechanisms. We have identified RNA binding proteins that are necessary for the export of self-renewal mRNAs to promote epidermal self-renewal. Similarly we have identified RNA binding proteins that are necessary to export differentiation inducing mRNAs to promote epidermal differentiation. Furthermore mutations in these proteins can lead to clonal expansion of the skin due to altered regulation of epidermal growth and differentiation. Specific Aims: (1) To determine the role of RBM15 and ZC3H18 on epidermal growth and differentiation. (2) To determine the molecular mechanisms of RBM15 and ZC3H18 wildtype and mutant proteins impact on epidermal homeostasis. Study Design: To study epidermal homeostasis in a more clinically relevant setting, we generate 3-dimensionally intact human skin, containing human epidermal cells (that have been permanently knocked down for RBM15 or ZC3H18) in the context of human dermal stroma and basement membrane, regenerated on immune compromised mice. By using this model, we can perform loss of function experiments on RBM15 or ZC3H18 in regenerated human skin to characterize their role in epidermal growth and differentiation. We will also use RNA immunoprecipitations followed by next generation sequencing to determine the RNAs associated with these proteins.

NIH Research Projects · FY 2024 · 2022-08

Project Summary/Abstract Spontaneous speech undergoes subtle but significant changes years, or even decades, before the onset of dementia. Signs of change in speech, or speech markers, include the use of syntactically simpler structures, reduced idea density, and more filler words, nonspecific nouns, and higher frequency words (Berisha et al., 2015; Snowdon, 1996). Such changes are potentially useful clinically for early diagnosis of dementia and are more broadly interesting for understanding normal and impaired language production. The proposed studies will investigate speech markers of Alzheimer’s Disease (AD) prior to diagnosis (i.e., in prodromal AD) in Spanish-English bilinguals. Speech markers have not been investigated in bilinguals even though use of two languages might magnify the cognitive mechanisms underlying speech production and sensitivity to prodromal AD. Bilinguals may exhibit unique speech markers not found in monolinguals, and some of the same markers as monolinguals but with differential sensitivity across their two languages. When bilinguals speak, they must choose which language to speak and must avoid interference from the language they are not using, tasks that may be especially difficult when speaking in the relatively less proficient, or non-dominant, language (L2). By contrast, speech in the dominant language, or L1, is relatively more automatic, at least in some aspects, and is also the language in which bilinguals may have their highest level of semantic knowledge and linguistic skill. These key differences between L1 and L2 lead to different expectations about which aspects of speech in each language should be most sensitive to cognitive decline (Aim 1) and most strongly correlated with other domains of cognitive functioning (Aim 2). To test these hypotheses, in Aim 1, we will examine archival data of spontaneous speech in bilinguals who were cognitively healthy at the time of testing but years later developed a diagnosis of Probable AD to identify linguistic markers of prodromal AD in L1 and L2. In Aim 2, we will prospectively examine relationships between L1 and L2 spontaneous speech markers and general cognitive functioning (measured by a battery of neuropsychological tests) and will test the hypothesis that time- pressured picture-naming, a recently identified speech marker of dementia risk (Stiver et al., 2021) may be a better speech marker of prodromal AD than naming with unlimited time because of greater demand it places on executive control. By examining the intersection of speech production and cognitive decline in bilinguals the proposed studies will inform models of bilingualism and will shed unique light on the role of executive control in supporting speech production more generally. The intersection between these fields of study may also lead to improved methods for early identification of AD in a diverse demographic. Lastly, this research project will enhance the applicant’s graduate school training and greatly increase her chances to have a productive career as a bilingual speech-language pathologist with specialized training in research on aging and AD, and with a focus on bilingualism which is often correlated with minority status in the USA.

NIH Research Projects · FY 2025 · 2022-08

Project Summary Small molecules are critical for proper regulation of stem cell behavior in multicellular organisms. Consequently, defects in the biosynthesis, perception, or metabolism of these compounds can cause developmental abnormalities and disease. Despite the critical importance of small molecules, the vast majority of our understanding of their functions is derived from indirect measurements. Typically, studies of small molecule biology are limited to genetic or biochemical approaches that ascribe functional roles to compounds based on the properties of the genes or proteins that interact with these molecules. Alternatively, small molecules are studied using chemical analysis approaches that homogenize bulk tissue and destroy the native context of the signals. High-resolution spatial information is critical in development, where stem cells comprise only a small fraction of the tissue. To enable deeper investigations of chemical regulation of stem cell behavior, my lab will apply technologies capable of directly measuring the localization and activity of small molecules in their native developmental contexts. This work will be done using plant roots, which are a powerful developmental system. Roots store all of their stem cells at the root tip, which generates a developmental gradient that can be examined in a single slice of tissue. My lab will leverage this gradient to investigate the role of small molecules in stem cell decisions. We will map the developmental chemistry of plant roots using mass spectrometry imaging and visualize small molecule interactions with proteins using a synthetic fluorogenic reporter. Metabolite-driven developmental mechanisms will be explored in depth by investigating citrate and retinaldehyde (retinal), two highly conserved metabolites with novel roles in root stem cell divisions and identity. This research will generate: 1) high-spatial resolution atlases detailing the chemical profiles of stem cell decisions, from regeneration to differentiation 2) novel insight into pathways that promote proliferation in stress-resilient stem cell subpopulations and 3) elucidation of dynamic metabolite-driven signaling pathways that regulate stem cell patterning. Our results suggest that there are many small molecules with important developmental roles that await discovery. Conducting research at the intersection of chemistry and developmental biology will provide mechanistic insight into stem cell decisions that would not be possible using a single-disciplinary approach. Accordingly, this work will enrich our understanding of the conserved and divergent principles that govern stem cell patterning, maintenance, divisions, and fate acquisition.

NIH Research Projects · FY 2025 · 2022-08

7. Abstract Alzheimer’s Disease (AD) is typically considered to be a Gray Matter (GM) disease and is characterized by pathological changes including extracellular Amyloid β (Aβ) plaques and NeuroFibrillary Tangles (NFTs). However, recent studies have shown oligodendroglial degeneration and myelin impairment in White Matter (WM) in preclinical AD before Aβ plaques and NFTs appear. Intracortical myelin loss is also among the earliest events in AD. Myelin can increase brain “connectivity” by ~3000-fold. Myelin impairment can disrupt axonal transport, integrity, and plasticity, leading to a massive reduction in signal transduction. Given its indispensable role in the development and maintenance of elaborate cognitive functions, loss of myelin could play a key role in the pathogenesis of AD. A non-invasive MR imaging technique that can accurately evaluate myelin could therefore be of critical importance for precise diagnosis of AD and monitoring the effectiveness of treatment. MRI has been widely used in the diagnosis of AD. Structural MRI is an integral component of the clinical assessment of AD patients in which atrophy is the key finding. More advanced techniques such as Diffusion Tensor Imaging (DTI), quantitative Magnetization Transfer (MT), multi-component T2, multicomponent-Driven Equilibrium Single Pulse Observation of T1 and T2 (mcDESPOT), have been proposed for quantitative imaging of GM and WM in AD. However, all these techniques are based on conventional data acquisitions with Echo Times (TEs) on the order of several to tens of milliseconds. These TEs can detect signal from long T2 water components (intra/extracellular water, CSF, and/or myelin water), but are too long to detect signal from myelin with extremely short T2s (< 1 ms). It is highly desirable to develop MRI techniques to directly image myelin, quantify myelin content, and map its T1 and T2. Ultrashort Echo Time (UTE) sequences with TEs <0.1 ms allow direct detection of signal from ultrashort T2 species. The main challenge is selectivity, because long T2 water components demonstrate far higher signal than myelin. Adiabatic Inversion Recovery (IR) pulses provide uniform inversion and nulling of the longitudinal magnetizations of water components, making it possible to selectively image myelin. The initial goal of this study is to further develop, validate, and compare 3D Double Echo Sliding Inversion REcovery UTE (DESIRE-UTE) and Short TR Adiabatic Inversion Recovery UTE (STAIR-UTE) sequences for direct imaging of myelin in phantoms, specimens, and AD mice. The final goal is to evaluate the two 3D UTE sequences in a cross-sectional study of healthy volunteers and patients with Mild Cognitive Impairment (MCI) and AD. Our central hypothesis is that the 3D DESIRE-UTE and STAIR-UTE sequences will robustly detect changes in myelin in GM and WM of the brain, and that greater loss of myelin will be associated with poorer cognitive performance. The 3D DESIRE-UTE and STAIR-UTE biomarkers may improve the diagnostic capability of MRI for identifying dementia at an early stage within a window where disease-modifying therapy is effective, and allow monitoring the effectiveness of therapy.

NIH Research Projects · FY 2026 · 2022-08

Cell intrinsic innate immunity is a barrier that all viral pathogens must overcome or otherwise subvert in order to successfully complete their infectious lifecycle. Collectively, these pathways detect non-self or danger associated molecules, and, in response, produce signaling proteins called interferons that induce both local and systemic anti-pathogen responses. These responses ultimately drive the clearance of most acute infections, although they also lead to much of the observed pathology. Most, if not all, viral pathogens encode antagonists of these pathways; frequently at the level of interferon production. One such pathogen, human influenza A virus, is so successful that only around 0.5% of infected cells successfully detect viral infection at early timepoints. Nevertheless, that small fraction of responders is crucial to the course of disease—individuals with defects in interferon pathways are often at extremely high risk of complications or death following infection by respiratory viruses, including influenza. Paradoxically, while most viral populations maintain stringent suppression of host detection, they replicate with relatively low fidelity. For influenza, only about 10% of viral particles can successfully complete the viral lifecycle. The rest of the particles are capable of entering cells and exposing potential innate immune ligands, but nevertheless fail at some step to produce infectious progeny. Regardless, the vast majority of virions, even those which cannot complete the viral lifecycle, still go undetected. What mechanisms, then, allow viral populations to remain undetected by host cells despite failing so frequently at replication? As a starting point to this ambitious line of inquiry, we are focusing on several discrete mechanisms in influenza A virus for which we already possess either preliminary data or the capacity to readily procure such data: 1) How the structure of the segmented genome of influenza A virus influences the range of potential immunostimulatory failure 2) How the multifunctionality of influenza’s predominant innate immune antagonist, NS1, influences rates of viral detection, and 3) How polymerase error rate may be subject to innate immune pressure. To address these questions my group will use a combination of variant analysis, deep mutational scanning, and more classical molecular virology. By profiling the challenges viral populations must overcome to evade innate immunity, and the mechanisms by which they do so, it is our hope to better inform models of viral evolution and potentially even identify novel therapeutic routes exploiting those challenges. viral Critically, our approaches have already identified key components of the viral lifecycle that are subject to surveillance, and have identified viral variants with desirable properties as potential vaccine candidates or oncolytic therapeutics.

NIH Research Projects · FY 2025 · 2022-08

SUMMARY The placenta, uterus, and fallopian tubes act in concert to achieve successful pregnancy outcomes. They undergo marked changes in structure and function during pregnancy, coordinating with one another and other maternal organs via direct and distant cell-cell interactions. Here, we propose to generate and integrate data from in vivo imaging and ex vivo histopathologic and multi-omic bulk, single-nucleus, and spatial profiling data, in order to generate reference multiscale 3D maps of healthy human pregnant female reproductive organs across pregnancy. These will serve as key frames of reference for future studies aiming to discover how perturbation of tissue structure and function leads to organ dysfunction and disease. Our team is well-equipped to achieve this goal, with expertise in clinical Obstetrics & Gynecology and Placental/Perinatal Pathology, imaging, spatial molecular profiling, single-cell omics, extracellular matrix (ECM) biology, data management, and computational biology. We will leverage our well-established translational research infrastructure to recruit diverse cohorts of healthy pregnant women. We will then perform in vivo imaging using MRI and ultrasound to delineate tissue structure, perfusion, inflammation, calcifications, and other features. After delivery/surgery, tissues will be rapidly sampled, processed, and stored in multiple ways (fresh, flash frozen, preserved in solutions for optimal nucleic acid analysis, and FFPE) to enable generation of high-quality data using a variety of molecular approaches, with additional samples retained for future studies. Detailed review of clinical data and formal histopathologic evaluation of adjacent tissue sections will be performed to confirm that normal tissue has been obtained from subjects with normal outcomes. Initial ex vivo analysis includes extracellular matrix proteomics, and bulk and single-nucleus RNAseq and ATACseq. The results of these studies will be analyzed to identify targets for the subsequent imaging mass cytometry (IMC) and spatial transcriptomic studies. These data types will be integrated to enable mapping of the relationships among different cell types and between cells and the surrounding extracellular matrix on the microscopic level. We note that generation of multiple data types from adjacent samples, and the use of the Multi-Ome assay (which performs RNAseq and ATACseq data indexed to the same nuclei) and spatial transcriptomic methods with immunohistochemistry-based pre-imaging, will enable us to bridge between diverse datasets. The unique populations of endothelial cells in the placenta and the endothelial mimicry of the extravillous trophoblast will provide unique opportunities to integrate with other endothelial-centric HuBMAP projects (e.g. lymphatic system, endothelial atlas, and kidney atlas). Close interactions with other HuBMAP Centers will be established to enable harmonization of data and metadata standards, sharing of resources (e.g. antibodies with HuBMAP Centers that are developing/using CODEX and MIBI-TOF), rapid adoption of new technologies, collaborative data analysis, and rapid sharing of data with the HIVE and the broader scientific community.

NIH Research Projects · FY 2025 · 2022-07

Cardiomyopathy (CMY) is a worldwide problem associated with high morbidity and mortality. CMY patients may present with symptoms attributed to heart failure (HF), arrhythmias, cardiac conduction system abnormalities, and sudden cardiac death. Recently it has been increasingly recognized that genetic screening for etiologies of CMY is important, and that defects in cardiomyocyte (CM) proteins in cellular junctions can cause CMY. Mechanical and electrical coupling of CM occurs at the intercellular connection between CM, termed the intercalated disk (ID). The ID provides essential properties to allow the heart to function as a syncytium. Structural elements of the cardiac conduction system (CCS) such as the atrioventricular (AV) and sinoatrial (SA) nodes have cellular arrangements and intercellular connections that vary from working CMs in the atrium and ventricle. Understanding more about proteins essential for normal function of working CMs and CCS cells is critical to advance our knowledge of the basis of cardiac disease, and remains understudied. This proposal is focused on Vinculin (VCL) and Zonula Occludens (ZO) proteins, which bind directly to one another, are located in the ID and the lateral membrane of working CMs and have known links to human disease. Our global hypothesis here is that VCL, ZO-1 and ZO-2 have unique roles in preserving cardiac function, conduction, and rhythm, given their location in CMs and in the CCS. We propose two aims. AIM 1 will evaluate how loss of ZO and VCL proteins from CMs alters contractile function and the molecular phenotype of the working CM and adult heart. We hypothesize that with postnatal loss of CM ZO and VCL proteins, cell-cell communication and integrity of the working myocardium will be disturbed, resulting in contractile dysfunction. CM ZO loss is expected to be distinct from that caused by loss of CM VCL, despite these proteins directly binding one another. Unique mouse models in hand will be used to evaluate the effects of loss of ZO and VCL from mature CMs basally and after the heart is faced with stress. We will assess whole heart, tissue and single cells using physiological, biochemical, and microscopic evaluations, as well as a novel approach to single cell transcriptomics and single cell proteomics, to pursue the mechanistic basis for how ZO and VCL protein loss causes CMY. Differences by sex and in atria vs. ventricle will be considered. AIM 2 will determine the function of ZO-1 and VCL in cardiac conduction and rhythm. Deletion of VCL from CM caused ventricular arrhythmias and sudden death, while loss of CM ZO-1 produced CCS dysfunction. We hypothesize that these two proteins have unique roles in controlling cardiac rhythm and conduction, despite their direct binding, due to interactions with connexins and membrane ion channels. Using patch clamping, high-resolution confocal microscopy to detect Ca2+ transients, optical voltage/Ca2+ mapping, and single cell transcriptional and proteomic studies, we will test how loss of ZO-1 leads to altered SAN and AVN function and excitation-contraction coupling, and how loss of VCL leads to ventricular arrhythmias and sudden death.

NIH Research Projects · FY 2026 · 2022-07

Project Summary Research Resource Identifiers, RRIDs, are persistent identifiers for key research resources such as antibodies, cell lines, organisms and digital assets. They are in use in over 1300 biomedical journals and are supplied by authors to uniquely identify which resources are used within a study. The RRID project was launched as a grass- roots effort in 2014 to improve the identifiability of research resources in the biomedical literature. RRIDs depend on the collaboration of journals with comprehensive registries and stock centers, which provide an authoritative identifier for each resource type. The introduction of RRIDs has had a significant impact on our ability to identify and track the use of research resources in the biomedical literature. Papers that use RRIDs have improved identifiability of resources from <50% to >90%. RRIDs make it easier to track usage, assign credit, and aggregate information about how resources perform in the literature. Towards that end, we have assembled a curated knowledge base that provides information on RRID use in the literature. Because RRIDs are served from a central database which is used broadly by scientists as they write their papers, the portal can also serve as a central hub for disseminating critical information about how such reagents perform. For example, the RRID portal provides warnings on contaminated cell lines provided by Cellosaurus. However, such information on other types of resources is much more dispersed. Therefore, we built a related knowledge base, Resource Watch, that enhances the information about RRIDs. The RRID project has been bootstrapped on top of existing NIH-funded projects, but given its growth and importance to biomedicine, we seek to unify the current RRID project into a self-supporting entity.

NIH Research Projects · FY 2025 · 2022-07

Project summary: Protein kinases are key regulators of cellular function and important therapeutic targets. Fluorescent protein-based biosensors have revolutionized the way we study these signaling enzymes and enabled direct interrogation of protein kinases in their native biological contexts. The goal of this proposal is to take this technology to the next frontier by creating a series of ultrasensitive, high-performance biosensors and developing multiplexed imaging approaches to be used in elucidating coordinated spatiotemporal signaling in cancer-immune interactions. We have assembled a strong interdisciplinary team with complementary expertise, including Dr. Jin Zhang, an expert in biosensor technologies and signal transduction, and Dr. Yingxiao Peter Wang, a renowned bioengineer whose lab focuses on engineering fluorescent biosensors, optogenetic tools, and chimeric antigen receptor (CAR) T technologies. In our preliminary studies, we developed single-FP kinase activity reporters that enable sensitive and multiplexed imaging of signaling activities in living cells. One of the newly evolved kinase biosensor achieved very high sensitivity and allowed high-resolution imaging in live mice. We have also developed an innovative technology platform that integrates directed evolution with high-throughput screening and next-generation sequencing to develop high- performance fluorescent biosensors directly in mammalian cells. In this project, we propose to integrate these technology platforms to engineer novel single-fluorophore biosensors for multiplexed imaging of PKA, CaMKII, Lck, and ZAP70 activities in living cells and perform parallel live-cell imaging to probe their dynamic activities during the CAR T and target tumor cell engagement. Cell-based immunotherapy has revolutionized cancer treatment, but still faces significant challenges. Understanding the mechanisms of cancer-immune interactions is critical for the development of enhanced therapeutic strategies. Protein kinases Lck, ZAP70, PKA, and CaMKII play essential roles in T cell activation, immunological synapse formation and cancer-immune evasion. We expect that parallel examination of these key node regulators simultaneously in cancer-immune interacting environments should reveal novel insights into the systems behaviors and identify essential links for therapeutic manipulation. While PKA, CaMKII, Lck, and Zap70 have been chosen as first-pass targets to develop and implement our systematic biosensor optimization approach, in principle, our platform can be readily extended to generate other kinase biosensors and develop biosensors capable of monitoring other posttranslational modification events in live cells. We believe that the success of this project will revolutionize biosensor engineering and kinase imaging to have a transformative impact on the treatment of cancer and other diseases.

NIH Research Projects · FY 2026 · 2022-07

Abstract The ability to find, understand, and use health-related information is essential for effectively managing one’s health. Difficulties in doing so have been linked to increased healthcare costs and are frequently observed among U.S. adults with prior justice involvement—an estimated population of 20 million. This group often reports low levels of engagement with healthcare services and irregular medical service use, contributing to untreated conditions over time. For this study, we define effective healthcare engagement as: 1) current health insurance coverage, 2) a consistent healthcare provider, and 3) use of services when needed. Few structured programs have been tested to help individuals in this group better connect with healthcare systems. We propose a longitudinal, randomized controlled trial (RCT) to assess the impact of the UCSD RELINK coach- guided health coaching program versus a self-directed learning approach. A total of 300 participants aged 18– 50 in San Diego, CA, will be enrolled and randomized equally into the two study arms. The primary outcome will measure self-reported use of healthcare services at the 6-month mark; secondary outcomes include follow- up at 12 months to assess consistency of service use. In addition, we will conduct follow-up interviews at 6 and 12 months to explore participants’ experiences with the program, how it influenced their healthcare decisions, and the degree to which they felt more prepared to engage with services. The study will provide operational insights into practical health education strategies and system navigation approaches for adults with prior justice involvement.

NIH Research Projects · FY 2025 · 2022-07

The goal of this application is to provide education that prepares Otolaryngology residents for research careers in biomedical and clinical sciences via the R25 mechanism. This will be addressed by mentored training in critical skills needed to perform high quality research, as well as in managing the conflict between research and clinical responsibilities. Structured guidance toward a career path that includes research will also be included. Our resident research education program proposes to accomplish this via the following set of Specific Aims. Specific Aim 1. To provide outstanding, mentored research training to Otolaryngology residents, providing the core skills leading to a career involving research. Research training under the supervision of high-quality, experienced mentors is a requirement for success in research, both for basic scientists and clinicians. We propose to provide such training in three focus areas: immunology, virology and molecular biology, which are strengths of our training faculty. Each of these areas play a major role in disease, and impact the mission areas of the NIDCD. In addition to mentored research instruction and experience, our training program will include targeted coursework as well as mentored training in grant-writing; managing the conflict between clinical and research responsibilities; and collaborating with research groups outside of Otolaryngology. Each trainee will also receive additional mentored research training embedded in the final three clinical training years, to reduce the gap between research training and career. Specific Aim 2. To provide structured guidance leading both to a career including research such as academics, and to additional research training resulting in independence as a clinician-scientist. Our clinician-scientists provide one-on-one counseling on the advantages of specialty training followed by an academic career that incudes research. We will also provide seminars and biennial conferences on the benefits of academic medicine. Specific Aim 3. To provide instruction in methods to enhance the rigor and reproducibility of research. Our institutions and mentors will provide didactic and practical education to address this critical area. Specific Aim 4. To recruit and provide research training to residents from all groups equally. We will take concrete steps to review applications to our residency and R25 training program with the same unbiased requirements/expectations.

NIH Research Projects · FY 2025 · 2022-07

Cancer remains a significant source of morbidity and mortality worldwide. Advances in next generation sequencing technologies have allowed extensive profiling of the genetic variants present in tumors and revealed daunting levels of inter-tumoral heterogeneity. Tumor genomic datasets have been extensively mined to reveal germline risk variants and to characterize heterogeneous patterns of somatic alteration that drive tumor progression. However, little attention has been given to interactions between genetic background and somatic changes, which could represent a major driver of heterogeneity. New evidence suggests that germline-somatic interactions are prevalent and our preliminary data support that some such interactions directly influence individual disease risk and potential to respond to therapies. This proposal will develop computational strategies to identify germline-somatic interactions and to characterize them in the context of molecular and clinical phenotypes, enabling new understanding of their role in inter-tumoral heterogeneity. Germline-somatic interactions have been challenging to study due to the limited amount of available data. To address this challenge, we have compiled tumor genomic data from public sources to boost our sample size to almost 45,000 tumor whole-exome and whole-genome sequences. Our analysis will focus on three major forces that shape the tumor genome: (i) the mutational processes that generate somatic mutations, (ii) the molecular organization of oncogenic pathways which determines the genes that can effectively drive cancer, and (iii) the immune system which acts as a selective force throughout tumor development. We will focus hypothesis testing with strict criteria for selecting germline variants and somatically altered genes likely to interact based on established tumor biology. To identify and characterize germline-somatic interactions we will: 1) Elucidate germline variants affecting the somatic mutational landscapes of human cancers 2) Reveal germline variants that modify somatic activation of hallmark oncogenic pathways 3) Establish the role of pathway-specific variant burden in cancer predisposition, overall survival, and response to immunotherapy Our team of co-investigators includes strong complementary expertise in analysis of mutational processes, genetic variation effects on molecular pathways and immunity, cancer biology, statistical methods and bioinformatic software dissemination. Careful attention will be given to statistical considerations including power, controlling false discovery rates, and validation in independent datasets. This proposal will produce A) novel bioinformatics tools designed specifically to detect and annotate germline-somatic interactions, B) new understanding of the contribution of germline variation to tumor progression, and C) a set of validated germline- somatic interactions affecting cancer risk, tumor evolution and immunotherapy response.

NIH Research Projects · FY 2026 · 2022-07

ABSTRACT The Ending the HIV Epidemic (EHE) Initiative boldly aims to reduce HIV incidence in high burden areas by 90% by 2030, yet challenges remain in measuring incidence to identify priority populations and knowing how to best allocate local resources. To date, HIV molecular surveillance-based interventions have not been linked to a reduction in HIV incidence. That is (with rare exception), public health efforts directed to individuals associated with rapidly growing HIV transmission clusters have not been shown to reduce the number of new HIV infections or the proportion of people virally suppressed in the regions or groups where these services were delivered. There are no existing resource allocation models that are informed by local molecular and HIV program data to determine how to best allocate resources relevant to EHE targets. The “Los Angeles County ASsessment of Phylodynamics to Improve Resource Equity (LAC ASPIRE)” team will use i) advanced phylodynamic approaches and prospective measures of incidence to identify populations with the highest transmission rates in Los Angeles County (LAC) and ii) economic modeling to optimize allocation of public health program resources to achieve EHE and other stakeholder targets. The ASPIRE team is a partnership between investigators at several academic universities and the LAC Division of HIV and STD Programs (DHSP). Analyses will use coded and de-identified HIV surveillance data and program data provided by the LAC DHSP. The proposed study will identify LAC populations with the highest transmission rates and denote as priority populations. We will use economic modeling to develop strategies that optimize the allocation of prevention resources to i) reduce HIV incidence, ii) improve HIV-related health outcomes, and iii) improve equity across populations. We will engage stakeholders—defined as 1) LAC DHSP personnel, 2) those directly or indirectly involved in administering HIV Programs in LAC, and 3) persons with HIV (PWH) and other key affected populations—to provide guidance on population and resource prioritization strategies that are both regionally acceptable and most likely to achieve EHE targets. The overall study objective is to develop a process to guide decision-making related to allocation of HIV program resources by public health departments informed by regional program and transmission data. Project specific aims include: Aim 1 (IDENTIFY). Identify populations that are the highest priority for HIV prevention efforts (these data will inform the epidemic model used in Aim 2); Aim 2 (ALLOCATE). Develop a user-friendly dynamic transmission model that will project the impact of alternative strategies for the optimal allocation of resources to LAC HIV prevention programs (these data will project health outcomes and cost-effectiveness); and Aim 3 (ENGAGE). Engage key stakeholders to develop a process to guide project outcomes and build capacity at the LAC Health Department for data analysis that incorporates Aim 1 and 2 methods.

NIH Research Projects · FY 2024 · 2022-07

PROJECT SUMMARY / ABSTRACT Cardiovascular disease (CVD) is a leading cause of deaths in the United States, however the underlying inflammatory pathways that contribute to CVD are poorly understood. Endothelial dysfunction is a hallmark of CVD and induced by various inflammatory mediators, many of which signal through G-protein coupled receptor (GPCRs). Thrombin, an inflammatory mediator, is generated in response to vascular injury and disrupts endothelial barrier integrity and promotes vascular leakage, a hallmark of inflammation. Thrombin activates endothelial protease-activated receptor-1 (PAR1) to disrupt endothelial barrier through the RhoA/myosin light chain (MLC) pathway. However, thrombin/PAR1-stimulated p38 mitogen-activated protein kinase (MAPK) signaling also promotes barrier permeability through a pathway that does not integrate with the RhoA/MLC signaling, suggesting that p38 acts through an uncharacterized pathway to promote inflammatory responses in endothelial cells. Our previous work showed that thrombin-activated PAR1 ubiquitination drives the recruitment of TAB2-TAB1 protein complexes on endosomes to trigger non-canonical p38 activation and endothelial barrier disruption. The mechanisms that regulate PAR1 ubiquitination/de-ubiquitination are not known. This proposal aims to understand the molecular processes that regulate PAR1-ubiquitin-driven p38 signaling and most importantly its impact on endothelial barrier integrity. The central hypothesis is that de-ubiquitination of PAR1 leads to termination of p38-mediated pro-inflammatory signaling and will be tested with two specific aims: 1) To delineate the function of PAR1-specific deubiquitinases (DUBs) enzymes in the regulation of ubiquitin-driven p38 MAPK inflammatory signaling and 2) To study the functional impact of ubiquitination / de-ubiquitination of PAR1 on endothelial barrier permeability. Using advanced biochemical, microscopic and genome-wide RNAi screening methods, the proposed research plan will allow for the first time to investigate molecular determinants that regulate the dynamics of PAR1-ubiquitination and the impact on endothelial proinflammatory responses in vitro using human endothelial cells and in vivo using mice. The contribution of this work is expected to be significant as this study will reveal new information regarding the function of PAR1 ubiquitination in driving non-canonical endosomal p38 MAPK signaling in endothelial barrier disruption, a hallmark of inflammation and will further reveal a new signaling pathway that controls endothelial barrier function, which will provide an opportunity for the development new strategies for the treatment of inflammatory responses associated with CVD.

NIH Research Projects · FY 2025 · 2022-07

The UC San Diego Genetics Training Program (GTP) is designed to provide advanced training in Genetics and Genomics to predoctoral students beginning in their second graduate year. While several degree-granting umbrella programs at UCSD include genetics or genomics research, GTP uniquely integrates trainees across programs and builds both lateral and vertical cohorts of PhD students interested in the history, practice and future applications of Genetics and Genomics in life and health sciences. Mentor laboratories encompass a broad range of basic science and clinical/translation research and span a range of organisms–including microbial, plant, experimental animal, and human subjects–but share a focus on genetic, genomic, and epigenomic mechanisms and approaches. Students who have committed to thesis research in one of these laboratories enter the GTP for advanced training activities after the first year and may be selected for support by this training grant. The GTP curriculum cuts across traditional graduate programs in participating schools, divisions and departments. GTP students take graduate core courses in Genetics and Quantitative Methods and participate in a weekly journal club during graduate years 2-4. The journal club includes rotating topics in contemporary genetics or classic, landmark papers relevant to the intellectual development of the field. GTP students select quarterly topics in consultation with participating faculty. Journal club papers and discussion are used to assess methods and logic, experimental design, data analysis, and responsible conduct of research in additional to the quarterly research topics around which they are selected. A program- wide annual retreat, organized by year 5 students and an Associate Director, includes invited outside keynote speakers and research presentations by program faculty and students. GTP has 30-40 students in training at any one time, for whom we are requesting 16 training grant slots to support 8 students per class year for two years each. Intended and realized trainee outcomes are fulfilling scientific careers in academic, government, and private industry.

NIH Research Projects · FY 2025 · 2022-07

ABSTRACT Alzheimer’s disease (AD) presents a formidable therapeutic challenge, as current interventions have failed to slow disease progression. The majority of AD genetic risk variants identified by GWAS reside in non- coding regions of the genome, suggesting that alterations in gene expression contribute to susceptibility for sporadic AD. Multiple reports now suggest that Herpes Simplex Virus 1 (HSV1) and other microbes can accumulate in the brain to increase the incidence of AD/dementia. While there is evidence linking reactivation of latent HSV1 infection to AD, the pathological potential of the latent state per se has not been addressed. Furthermore, there is now concern that COVID-19, which is caused by the pandemic SARS-CoV-2 and can include neurological and neurocognitive sequelae, might impact the onset or course of AD. Here we propose to advance recent findings by employing powerful new genomic technologies to characterize the cell type-specific transcriptional impact and cell autonomous vs non-cell autonomous effects of specific viral gene products, including HSV1 latency lncRNA transcripts and the SARS-CoV-2 Spike protein, that contribute to neurotoxic programs characteristic of sporadic AD. Using a modified single-nucleus sequencing approach, which allows for DNA accessibility and global transcription to be assessed simultaneously in the same nucleus, we will continue our interrogation of human control and AD brain samples to reveal cell type-specific aging vs pathological trajectory trees for each CNS cell type in sporadic AD, ultimately allowing for the identification of the key transcription factors acting at implicated regulatory enhancers. This will enable us to elucidate how viral gene products alter enhancer landscapes and transcriptional networks related to sporadic AD in various neuronal and non-neuronal cell types and subtypes. In addition, we will investigate the hypothesis that the sense (S) and antisense (AS) LATs impact transcription by associating with specific regulatory elements in the host genome in collaboration with the co-regulator KAP1 to impact expression of multiple AD susceptibility loci. We further hypothesize that the S-LAT influences the AD process by causing neuronal dysfunction and inflammatory glial activation, at least in part, through down-regulation of gene clusters encoding KRAB zinc-finger proteins (KZFPs) that normally repress human endogenous retrovirus (HERV) repeats, whereas the AS-LAT tempers these deleterious effects by promoting an anti-inflammatory gene expression profile and can further mitigate the innate immune response as well as cell death programs through direct inhibition of the AD-associated, sentinel kinase PKR in a non-genomic fashion. Collectively, the proposed studies will yield crucial cell type-specific insights into pathological trajectories in sporadic AD that may be subject to modulation by diverse infectious as well as non- microbial insults to the brain.

NIH Research Projects · FY 2025 · 2022-07

Abstract The overall goal of the proposed research is to identify novel aspects of human innate lymphoid cell (ILC) biology in airway diseases using patient-oriented research (POR) and through mentoring junior clinical investigators. The candidate has a strong record of mentoring individuals at many levels including clinical investigators in multiple specialties. The mentoring plan includes recruitment and training of fellow and faculty investigators from three disciplines (allergy, otolaryngology, and pulmonary) within the UCSD Center for Asthma and Sinus Disease center of excellence to foster the careers of junior investigators and perform outstanding POR. There are currently large gaps in our understanding of the roles of ILCs in human sinus disease and asthma which cause significant morbidity worldwide. ILCs are divided by the types of cytokines they secrete and ILC2s that secrete Th2 cytokines have been shown to promote airway inflammation in animal models. Importantly, recent work has shown that ILC2s are increased in samples from patients with asthma and chronic rhinosinusitis (CRS). Our group was the first to show that ILC2s are increased in a subgroup of nasal polyps in CRS that contain eosinophils and are also recruited to the nose after aspirin challenge in patients with aspirin-exacerbated respiratory disease (AERD). AERD patients have severe sinus disease with nasal polyps, moderate to severe asthma, and respiratory reactions to aspirin and similar compounds. In the current proposal, we will test the hypothesis that through the use of cutting-edge technology (single cell RNA-seq) we will be able to identify specific subgroups or “endotypes” of patients with CRS and asthma by tissue and blood ILC subset composition. We also posit that biologic blockade of type 2 inflammation in AERD, asthma and CRS patients will reduce ILC2 recruitment to the airway. Critically, this award will provide protected time for POR in sinus disease and asthma and allow for outstanding mentorship of the next generations of POR investigators.

NIH Research Projects · FY 2024 · 2022-07

ABSTRACT A diverse U.S. biomedical research workforce is essential for developing innovation in basic, clinical, translational research and healthcare and is necessary for improving the nation’s health. The proposed University of California (UC) San Diego Building a Respectful, Inclusive Culture (BRIC) Program will develop training modules that will catalyze changes in scientific, clinical, and research training environments optimal for productive learning and research - free from harassment, intimidation, and discrimination - where everyone feels safe and treated in a respectful and supportive manner. The outcomes of a pilot study of the proposed training modules, conducted for a small group of faculty, are highly encouraging. The overarching goal of the UC San Diego BRIC Program is to create a culture of respect, psychological safety and inclusion and support in the academic environment allowing trainees and learners to work and learn in an environment conducive to the pursuit of excellence, free of harassment and discrimination. The specific objectives are: 1) to recruit Health Sciences faculty participants with an emphasis on faculty mentors and researchers that participate in UC San Diego NIH-supported T32 training programs, including four large NIGMS-supported T32 programs and other training programs that focus on individuals underrepresented in the biomedical workforce, such as including the Initiative for Maximizing Student Development (IMSD) and Institutional Research and Career Development Award (IRACDA), 2) to train Health Sciences faculty participants using an evidence-based curriculum tested in our pilot BRIC program to enhance a culture of respect, psychological safety and inclusion and support, 3) to evaluate the effectiveness of the BRIC program on training environments using a randomized case/control study design, and 4) to assess the impact of the BRIC program on the Health Sciences climate. We will integrate instruments measuring psychological safety and inclusion into our published Health Sciences Faculty Climate Survey and resurvey our faculty at the end of the proposed study. The UC San Diego BRIC Program is directed by two PIs with a history of mentoring and training. They have been successful in designing and implementing career development and mentoring programs specifically for women and individuals from underrepresented racial/ethnic backgrounds. The PIs are both women and one is from an underrepresented background and have led numerous successful faculty career development programs and well-respected track record of leading extramurally-funded training programs. The BRIC Program will be administered centrally through the UC San Diego Health Sciences Office of Faculty Affairs. The BRIC training modules will be made available to the scientific and educational community, as well as to the general public.