University Of California-Irvine

NIH Research Projects · FY 2025 · 2022-07

Project Summary/Abstract – Neuroimmunology Training Program at the University of California, Irvine Neuroimmunology is a rapidly growing field of research that touches a number of critical human diseases, including Alzheimer’s disease, multiple sclerosis, epilepsy, spinal cord injury, and viral encephalopathies. Traditionally, researchers have been trained in either neuroscience or immunology, whereas the Neuroimmunology Training Program (NITP) at the University of California, Irvine seeks to develop and train the next generation of researchers in both fields with a cross-disciplinary approach focused on the interplay between the immune and nervous systems during disease. This application requests support for 4 pre-doctoral trainees who will be selected from an outstanding pool of candidates within our relevant graduate programs. Moreover, UCI has a diverse graduate student population and expects at least 50% of trainees supported with NIH funding will be underrepresented minorities in the biomedical sciences. This application is the result of ongoing collaborations between high-caliber faculty on campus who recognized the need to develop a training program specific to the challenges of neuroimmunology. The NITP will formally bring together 24 faculty members from across the neuroimmunology research spectrum to participate in mentorship and program-wide activities to share expertise and further develop the neuroimmunology field. The training program will be overseen by two faculty directors and an advisory committee focused on selecting and supporting trainees who are highly likely to exhibit continued success within the diverse field of neuroimmunology research. The NITP program directors will initiate programming at UCI to enhance the quality of research and mentoring experiences of trainees and set them up for career success. All in all, UCI’s NITP proposal demonstrates the exceptional training record of our faculty mentors, unique resources to support research, and robust institutional support. From this strong foundation, the NITP will provide an outstanding opportunity for trainees to develop intellectually, advance and optimize their thesis research projects, create a valuable network of colleagues, and prepare for a highly successful research career focused on the crossroads of immunology and neuroscience.

NIH Research Projects · FY 2024 · 2022-06

Project Summary/Abstract Individuals receiving care in nursing homes disproportionally experience adverse outcomes due to multidrug-resistant organisms. This investigation will focus on an endemic and virulent pathogen common to nursing homes – methicillin-resistant Staphylococcus aureus (MRSA), and a highly emerging antibiotic resistant fungus – Candida auris, both of which have been linked to substantial morbidity and mortality in U.S. nursing homes. While MRSA has been a major prevention target in hospitals, little has been done to address this pathogen in nursing homes despite the fact that nursing homes have a 3-fold higher MRSA prevalence than hospitals and MRSA carriers in nursing homes have a 40% risk of infection per year. Risk in nursing homes due to MRSA is now compounded by C. auris, which has been termed the “fungal MRSA” due to similar transmission characteristics, including a remarkable propensity to colonize the body and persist on surfaces for prolonged periods. C. auris has been associated with intractable outbreaks in nursing homes with high attributable mortality; 5-10% of known carriers develop invasive infections and 30- 60% of those with invasive infection die as a result. Thus, determining which nursing home residents are at greatest risk for MRSA and C. auris carriage is crucial for effective response and control. The overall goal of this proposal is to generate novel data on MRSA and C. auris carriage and contamination in nursing homes to inform interventions to control these important pathogens. The first objective is to identify nursing home facility characteristics and resident risk factors associated with MRSA and C. auris carriage. Results from this objective could target high-risk residents for screening and prevention activities. The second objective is to determine if high-contact care activities (e.g., dressing, bathing) for MRSA and C. auris carriers cause contamination of high-touch objects in their immediate environment. If so, focused post-activity cleaning could be important to reduce MRSA and C. auris contamination and mitigate spread. I (Gabrielle Gussin, MS) am pursuing a Ph.D. in Public Health at the University of California, Irvine. This F31 fellowship will enable me to bridge my previous Master’s training in Systems Biology with skills in epidemiology, clinical research, and population health. I will be mentored by a multidisciplinary team with expertise in clinical infectious diseases, epidemiology, multidrug-resistant organisms, public health, nursing home operations, and biostatistics to support my proposed aims and career goals.

NIH Research Projects · FY 2025 · 2022-06

Project Summary Spinal cord injury (SCI) results in long-term functional impairments due to loss of cord tissue and limited regeneration. Human neural stem cell (hNSC) transplantation has exciting potential as a treatment for SCI, but the complex interactions between hNSC and the extrinsic microenvironment are poorly understood. The objective of this proposal is to address this gap in knowledge, enabling both optimization of therapeutic donor hNSC transplantation, as well as new insights into in vivo signaling/transcriptional networks, and the consequence of these networks for hNSC localization and fate after SCI. Critical to this is goal is elucidating mechanisms of immune-NSC signaling. Spinal Cord Injury (SCI) causes disruption of the blood-spinal-cord barrier, and a robust influx of serum proteins, including C1q. SCI also results in a multiphasic and prolonged immune response, in which infiltrating and resident immune cells also secrete C1q. We have shown that C1q influx is chemoattractive for transplanted hNSC, inducing hNSC migration towards and clustering at the injury epicenter, and driving hNSC towards an astroglial lineage. Blockade of C1q in vivo releases both migration and lineage selection, and enhances SCI repair and locomotor recovery. We have also shown that C1q directly modulates hNSC migration, proliferation, and differentiation in vitro via a receptor-mediated signaling mechanism. Using an unbiased screen, we identified novel interactions between C1q and five candidate receptors expressed by hNSC. Among these is CD44, a receptor with an established role in regulating cellular behavior. Our published data identify CD44 as a principal mediator of hNSC chemoattraction to C1q in vitro and in vivo, and show that C1q-CD44 signaling also modulates hNSC fate. Further, CD44 deletion in hNSC in an acute transplantation paradigm in vivo enhances SCI repair and locomotor recovery. The central hypotheses of the proposed aims are that C1q-CD44 signaling in NSC alters the NSC transcriptome via CD44-ICD heterochromatin modulation, and that deletion of CD44 in transplanted hNSC after SCI will enhance repair. Aim 1 investigates the effect of CD44 KO on hNSC gene expression at baseline and in response to the CD44 ligands C1q, HA, and osteopontin. Aim 2 tests the effect of CD44 deletion on the repair capacity of hNSC transplanted into the SCI microenvironment, and the dependence of this effect on C1q. Aim 3 investigates the effect of CD44 KO in hNSC on localization and fate in relation to signaling and transcriptional networks in vivo after SCI

NIH Research Projects · FY 2026 · 2022-06

PROJECT SUMMARY/ABSTRACT Nearly every aspect of T cell biology is determined in part by the relative expression of a multitude of cell-surface proteins. For example, the relative expression of co-stimulatory and co-inhibitory receptors impact pro- versus anti-inflammatory outcomes. N-glycosylation is a critical but poorly understood regulator of cell- surface protein turnover. Virtually every cell-surface and secreted protein is modified with covalently attached complex carbohydrates at asparagine (N) residues. These N-glycans are variably edited by a large number of glycosylation enzymes along the secretory pathway, producing many possible glycan structures. The N-glycan branching pathway serves as a key gateway between relatively simple high-mannose structures and more complex N-glycans that carry glyco-epitopes recognized by numerous families of carbohydrate-binding proteins, known as lectins. The branching pathway controls N-acetyllactosamine (LacNAc) incorporation into N-glycans, which are recognized by the galectin family of soluble lectins. At the cell surface, the interaction of multivalent soluble galectins with glycoproteins carrying LacNAc units, leads to the formation of a molecular lattice-like structure. This galectin-glycoprotein lattice affects cell surface organization, receptor mobility in the plane of the membrane, and endocytosis rates. In part by regulating cell surface expression of CD4, CD8, IL2Rα, CTLA-4, and the T cell receptor (TCR), N-glycan branching regulates T cell development, TCR signaling, T cell activation, T cell proliferation and pro-inflammatory versus anti-inflammatory differentiation. Based on studies of these receptors, a model has emerged of the lattice as a unidirectional regulator of cell- surface retention which opposes glycoprotein loss and promotes cell surface retention. However counter- examples to this model have recently emerged demonstrating that some receptors are regulated in the opposite manner. Thus a comprehensive and unbiased analysis of branching regulated changes is needed. Furthermore, an understanding of the mechanisms involved that promote expression of some receptors while hindering expression of others is also lacking. Without such detailed information, therapeutic targeting of the complex glycosylation pathways that regulate T cell function will be limited. We have developed an approach to examine branching mediated effects on cell-surface expression at the proteome scale. We provide proof-of- concept that this approach is reliable and informative and propose to use it to tackle this outstanding aspect of T cell biology. In Aim1, we will extend this approach to more physiologically relevant primary T cells and examine a range of N-glycan branching states to derive a complete and informative picture. We will also adapt our approach to globally determine endocytosis and recycling rates of branching regulated proteins. In Aim 2, we will test the hypothesis that cargo adapter proteins in the clathrin-mediated endocytosis pathway cooperate with N-glycan branching to differentially regulate receptor turnover and expression. Together these studies will dramatically increase our knowledge of branching mediated regulation of T cell biology.

NIH Research Projects · FY 2026 · 2022-06

Project Summary/Abstract The ability to learn, consolidate and retrieve information begins to decline with normal aging, a major risk factor for Alzheimer’s Disease (AD) and dementia. In addition to aging, sedentary behavior ranks first in the US and third in the world as a risk factor for causing cognitive decline and exacerbating AD. Greater and accelerated rates of cognitive impairment in women with AD underscore the need for identifying the mechanisms by which exercise prevents cognitive decline in normal aging and AD in both sexes. As observed by our labs and others, hippocampus-dependent learning is facilitated by exercise in situations that are usually subthreshold for encoding and memory consolidation and requires the induction of brain-derived neurotrophic factor (BDNF). Our data suggest that specific exercise patterns can engage a ‘molecular memory’ for that experience that persists through periods of sedentary behavior and enables a short exercise session, to again, induce hippocampal BDNF and facilitate memory. We have proposed that epigenetic mechanisms mediate this “molecular memory” of exercise, as the epigenome represents a signal transduction platform that is capable of encoding past experience, current metabolic states (because nearly every epigenetic modification is a metabolite) and establishing stable changes in cell function that lead to long-term changes in behavior. Preliminary data in this proposal lead us to propose the novel hypothesis that specific patterns of exercise establish a molecular feedback loop that integrates rate-limiting aspects of acetyl-CoA metabolism and histone acetylation/methylation mechanisms to modulate gene expression required for long-term memory formation and synaptic plasticity. Our goal in this proposal is to define, in aging wild type and 5xFAD female and male mice, the exercise parameters that establish a molecular memory, to investigate the effect of exercise on acetyl-CoA metabolic pathways and histone modifications and to determine whether manipulations to this molecular feedback loop overcome deficiencies in synaptic plasticity and memory formation in aging and 5xFAD female and male mice. We propose three Aims. Aim 1 - Determine how specific exercise patterns affect synaptic plasticity and memory formation in aging wild type mice and 5xFAD mice. Aim 2 - determine the effect of exercise on acetyl-CoA metabolic pathways, histone modification, and gene expression in aging wild type mice and 5xFAD mice. Aim 3 - determine the effect of ameliorating hippocampal acetyl-CoA deficiencies in aging and 5xFAD mice on gene expression, synaptic plasticity and memory formation. Overall, successful completion of the research in this proposal will improve our understanding of how the epigenome integrates information from metabolism (acetyl-CoA dynamics) and experience (exercise), how this interplay becomes impaired with aging and in the context of AD, and how pharmacological modulation of acetyl-CoA dynamics may improve age- and AD-related cognitive dysfunction.

NIH Research Projects · FY 2025 · 2022-06

PROJECT SUMMARY/ABSTRACT Vision problems are prevalent among older adults, with about 92% of Medicare enrollees ages 65 and older using vision correction, and 39% of Medicare enrollees who use vision correction reporting trouble seeing even with eyeglasses. Visual impairment is associated with increased morbidity and mortality, including an increased risk of falls and hip fractures. While most fee-for-service Medicare enrollees do not have coverage for routine eye exams and glasses, some low-income Medicare enrollees have comprehensive vision coverage if they qualify for full Medicaid benefits (“dual eligibles”) and reside in a state with a Medicaid program that covers vision services. The objective of this proposal is to use quasi-experimental methods to estimate the effect of Medicaid coverage of routine eye exams and glasses on eye care access and fall-related outcomes among dual eligibles during 2000-2019. The central hypothesis is that coverage of vision services will increase eye care visits and reduce the risk of falling by improving vision. The central hypothesis will be tested by pursuing three specific aims: 1) to examine the effects of Medicaid vision benefits on measures of access to eye care and vision including eye care visits, unmet needs for glasses, out-of-pocket spending on routine eye care, self-reported trouble seeing, functional limitations due to vision, and Medicare claims-based measures of past-year treatment for glaucoma, cataracts, and age-related macular degeneration; 2) to examine the effects of Medicaid vision benefits on fall-related outcomes including self-reported falls, fall-related injuries, and activity limitations due to fear of falling and administrative measures of treatment for falls; and 3) to evaluate the effects of Medicaid vision benefits by sex, race and ethnicity, diabetes diagnosis, and by Alzheimer’s disease, related dementias, and memory loss. The research proposed in this application is innovative because it will use several complementary data sources including linked survey and administrative claims data to examine measures of eye care access and fall-related outcomes, compile a comprehensive database of Medicaid vision benefit policies over a more than 20 year period to be shared with researchers, combine a quasi-experimental approach with a 9 year panel of individual longitudinal data, and apply newly developed methods to address variation in the timing of state policy changes. The proposed research is significant because the number of adults ages 65 and older is projected to more than double over the next 40 years. Correspondingly, the prevalence of vision problems and injurious falls is likely to increase significantly over this period. The proposed aims will produce the first estimates of the effects of Medicaid vision benefits on eye care access and fall-related outcomes among dual eligibles. The public health impact of this research will be to provide critical, timely, and policy relevant evidence on the effects of increased access to vision care among older adults and the role of public health insurance.

NIH Research Projects · FY 2025 · 2022-06

Summary/Abstract: Alzheimer's disease and related dementias (ADRD) is a public health crisis compounded by the insufficient number of skilled clinicians and investigators with high quality training and expertise to provide care and conduct translational research. It is vital to foster a new generation of physician researchers that possess a diverse array of knowledge and skills, including understanding basic (genetics, molecular and cellular biology, neuroscience), patient level (clinical care, neuropsychology, fluid biomarkers, neuroimaging, epidemiology), and cross cutting (biostatistics, ethics) research design and methods. Thus our proposed SMAART T35 program will grow the pipeline of medical students with research experiences inspiring new physician scientists to focus their careers in the ADRD space. The low availability of skilled ADRD translational physician scientists represents a threat to the national ADRD research agenda. Therefore, in this T35 application we propose to engage MD students in hands on research, mentoring, publishing, career development and leadership. Through our leadership expertise in multidisciplinary translational ADRD research we aim to enhance the diversity and availability of physician scientists through these three specific aims: 1) Champion mentored career development by providing an integrated program that consists of outstanding leadership and oversight at all levels. 2) Create a flexible and innovative curriculum that emphasizes both core and advanced competencies in clinical, translational, and basic science 3) Maximizing access to Summer Mentoring and Research Training (SMAART) Program. Through formal check ins and ADRD themed journal clubs, trainees will receive guidance and support from the Program directors. The program will longitudinally track students through the four years of medical school encouraging continued engagement in research activities.

NIH Research Projects · FY 2025 · 2022-06

Contact PD/PI: LEE, ABRAHAM Acoustic microvortices instrumentation for dosage controlled, high efficiency cell engineering Abstract - In years 2018 and 2020, Nobel Prizes were awarded to pioneers in cancer immunotherapy and the gene editing CRISPR-Cas9 method. This has ushered in a new era of cell engineering that demands technological innovations to produce genetic-modified and reprogrammed immune cells (e.g., T cells). CAR T cell immunotherapy is one type of cell therapy that has already achieved success in the clinic for treating cancer. The holy grail is to produce universal CAR T cells, genetically modified and engineered allogeneic T cells derived from healthy donors that avoid immunologic rejection. This requires gene engineering techniques such as CRISPR-Cas9 that can deliver multiplex gene insertions and knock-outs with controlled dosage to enhance viability and efficacy of the engineered cells. Although viral vectors are the method of choice for cell engineering, there are major concerns over their safety as well as the complex, costly preparation process. Nonviral transfection methods are alternatives to viral vectors that avoid the deleterious byproducts such as immune-mediated toxicity and oncogenic transgene concerns. Here we introduce the Acoustic-Electric Shear Orbiting Poration (AESOP) platform that addresses several of the known challenges for nonviral transfection techniques, including cell viability and dosage-controlled intracellular delivery while achieving relatively high throughput. AESOP is based on a microfluidic platform termed “lateral cavity acoustic transducers (LCATs)” that can form an array of microvortices activated by acoustic energy. The main innovation of the AESOP platform is the trapping of suspended populations of cells in tunable 3-D microvortices and incorporating a two-step membrane disruption strategy to precisely permeabilize cell membranes. By trapping cells to tumble in whirlpool-like microvortices, this platform optimizes the delivery of intended cargo sizes with uniform poration of the cell membranes via mechanical shear followed by the modulated enlargement of these nanopores via electric field. Using AESOP, we will focus on technology development for producing the universal CAR T cells. By controlling dosage, a decreased amount of CRISPR reagents in cells could reduce off-target effects. Furthermore, the uniform delivery enables the delivery of large cargo sizes necessary for immunotherapy-related gene transfection and gene editing. This 4-year project has four specific aims: 1- Generate acoustic microstreaming vortices for uniform cell membrane nanopores and uniform local mixing; 2- Demonstrate uniform electric field enlargement of nanopores for cargo delivery; 3- Design prototype AESOP instrumentation and 4- Quantitative benchmark of AESOP for intracellular delivery of large size cargos with dosage control for the development of universal CAR T cells.

NIH Research Projects · FY 2026 · 2022-06

PROJECT SUMMARY Tissue stem cells are rare, undifferentiated cells that are capable of self-renewal and are essential for fueling the homeostasis and regeneration of the tissue in which they reside. They are often quiescent, and when activated, they proliferate and differentiate to produce mature cell types with specialized functions. Stem cell activities are jointly controlled by the intrinsic gene expression program and the signals from the surrounding tissue microenvironment. Dissecting the intrinsic and extrinsic mechanisms that govern stem cell quiescence and activation is important not only for gaining fundamental knowledge of tissue and stem cell biology, but also for understanding how to manipulate cell fates in tissue engineering and regenerative medicine. Myriad regenerative epithelial tissues, such as mammary gland, skin, and prostate, house stem cells in their basal cell compartment. We use two mammalian tissues, mammary gland and skin, each with its unique advantages and clinical relevance, as complimentary model systems to study both general and tissue- specific mechanisms underlying the regulation of basal cell fate and stem cell activities. Our research has elucidated the function of key transcription and chromatin factors in mammary and skin basal/stem cell gene regulation, and how these factors interface with major signaling pathways to control the activation, proliferation, differentiation, and epithelial-mesenchymal plasticity of basal stem cells. The recent advent of single-cell sequencing technology has enabled us to systematically probe the cellular and molecular heterogeneities of mammary and skin basal cells, allowing a deeper and more comprehensive understanding of their compositions and characteristics as well as providing novel insights into the sequence of events in stem cell activation and differentiation. In the next five years, we will continue to employ a multi-disciplinary approach combining single-cell genomics and spatial gene expression mapping with tissue-specific gene knockout and lineage tracing, in vivo and ex vivo stem cell assays, as well as molecular studies to address two major knowledge gaps regarding mammary basal stem cells: how their quiescence is maintained and active expansion is achieved. Specifically, we will test the innovative hypothesis that a low level of Wnt/b-catenin signaling and molecular cross-talks between basal cells and specific macrophage subsets are critical for maintaining basal stem cell quiescence. We will also characterize the novel function and regulation of a newly discovered subset of basal cells as transit amplifying progenitor cells that serve as workhorses to drive basal cell expansion during mammary epithelial morphogenesis, homeostasis, and regeneration. When and where applicable, we will perform parallel analysis on skin in order to identify potentially general principles and strategies underlying basal cell-macrophage cross-talks. Our findings will expose novel intrinsic and extrinsic regulators of basal stem cell quiescence and active expansion. This knowledge is fundamental to preventing stem cell depletion and regenerative diseases as well as to understanding cancer cell dormancy.

NIH Research Projects · FY 2026 · 2022-05

PROJECT SUMMARY/ABSTRACT Myeloproliferative neoplasm (MPN) is a hematologic malignancy characterized by the clonal outgrowth of hematopoietic cells with a somatically acquired mutation most commonly in JAK2 (JAK2V617F), which leads to excessive production of myeloid lineage cells. Patients with early stage MPN can spontaneously progress to myelofibrosis, a more aggressive stage of the disease with an average survival rate of two years. Moreover, MPN patients have a significant risk of developing acute myeloid leukemia (AML). The traditional approach to therapy in MPN is simply to reduce the risk of blood clots with aspirin, manage symptoms, and observe for progression of the disease. Therapeutic intervention is focused on patients with late stage disease, mostly due to the lack of currently available therapies that halt progression. There is thus a need for interventions that impact disease progression in MPN. Preliminary work by the laboratory of Dr. Fleischman, in collaboration with mathematical modelers Komarova and Wodarz, has shown that inflammation can accelerate the growth rate of JAK2V617F mutant cells relative to JAK2WT cells, and that this can potentially have a variety of consequences for the evolution of mutant cells at homeostasis. This suggests the possibility of a new treatment modality for early stage MPN, in which the evolutionary fate of the JAK2V617F mutants is altered and disease progression is delayed or halted. The overall goal of this proposal is to investigate how this can be achieved. In Aim 1, experiments are proposed that document the dynamics of JAK2WT and JAK2V617F mutant cells in isolation with and without inflammation for the purposes of model construction and parameterization. We will also interrogate the intracellular mechanisms responsible for the differential response of JAK2V617F mutants to inflammation. In Aim 2 we will perform experiments in which JAK2WT and JAK2V617F mutant cells are combined in mouse models with and without inflammation. This will quantify how the number of mutants influence the kinetic parameters of wild- type cells, which is important because we know that mutants themselves can increase inflammation and hence alter the dynamics. In Aim 3 we will measure how a panel of existing drugs impact the kinetic parameters of cells and use our model to predict combinations and dosing schedules that will lead to diminution of the mutant cells. Many treatment scenarios (in sequence and in combination) will be explored, and the most promising therapeutic approaches predicted by the model will be tested experimentally. This can identify better and currently unknown ways in which to utilize existing drugs. On a more exploratory level, the validated mathematical model can suggest which parameter(s) to target in which ways to make treatment more efficient than can be currently done. This information would facilitate development of future treatments and guide drug discovery and could be translated into a future clinical trial.

NIH Research Projects · FY 2026 · 2022-05

Project summary: The vast majority of mammalian genes produce alternatively processed mRNAs through alternative splicing and alternative polyadenylation (APA). Different mRNA isoforms produced from the same gene can encode distinct proteins and/or they may be differentially regulated. Recent studies have revealed essential roles of mRNA alternative processing in many biological processes and mis-regulation of alternative splicing and APA has been causally linked to a wide range of diseases, including cancer and neurodegenerative diseases. However, the mechanism and functions of alternative mRNA processing remain poorly understood.Antibody secretion by B cells is a major component of our immune response and mis-regulated antibody response underlies many auto-immune diseases. B cell activation and differentiation require a sophisticated gene regulation cascade. Previous works, including ours, have provided insights into the transcriptional regulation mechanisms governing this process. However, it is clear that post- transcriptional gene regulation, such as alternative splicing and APA, also play an important role. In 1980, several landmark studies reported the first example of alternative RNA processing: the Immunoglobulin M (IgM) heavy chain gene (IghM) produces two APA isoforms, which encode a membrane-bound and a secreted IgM respectively. Additionally the IghM APA is developmentally regulated. Subsequent studies, however, have failed to provide a consistent mechanistic model for this APA switch. Furthermore, it remains unknown how widespread the APA regulation network is and what the functional impact of APA regulation is during B cell activation and differentiation. In our preliminary studies, we provided evidence that transcription factors, core mRNA 3’ processing factors, and RNA-binding proteins regulate IghM APA. In addition, we discovered that B cell activation leads to a significantly change in the APA patterns of ~900 genes, including those encoding key cell fate regulators and signaling proteins. Based on these preliminary results, we hypothesize that the APA of IghM and a large gene network are regulated at multiple levels and that APA regulation plays an important role in B cell functions. To test these hypotheses, we have designed the following specific aims: 1) Identify regulators of B cell activation-induced IghM APA switch using a biochemical and genetic approach; 2) Systematically characterize the mechanisms of B cell activation-induced IghM APA switch; 3) Determine the role of APA regulation in B cell activation and differentiation. Successful completion of the proposed studies will provide fundamental insights into APA regulation and function. More importantly, our results will reveal the role of post-transcriptional gene regulation in B cell development and B cell- mediated immune response, which will pave the way for better strategies for developing vaccines and treatment for autoimmune diseases.

NIH Research Projects · FY 2026 · 2022-05

A strong and well-prepared STEM workforce is essential for continued progress in biomedical research and for addressing major health challenges facing society. However, many high schools have limited access to advanced laboratory experiences, research environments, and sustained mentorship in scientific fields. As a result, many students complete their secondary education with little exposure to how modern science is conducted or how they might pursue careers in biomedical research. Research shows that authentic science experiences during high school can significantly strengthen student engagement with STEM disciplines and help students envision pathways into scientific careers. Programs that connect students with university research environments provide opportunities to develop critical scientific skills, build confidence in quantitative reasoning, and gain exposure to modern research technologies that are rarely available in traditional classroom settings. To address this need, we propose the Brain Explorer Academy (BEA), an immersive neuroscience education program that introduces high school students to modern brain science through hands-on learning experiences at the University of California, Irvine. The program will operate as a two-semester after-school academy meeting twice weekly on the UCI campus and will serve students from multiple public high schools across Orange County. Through laboratory demonstrations, interactive experiments, and collaborative learning activities, students will explore how the brain supports learning, memory, and behavior while developing practical scientific skills. The program will emphasize experiential learning, mentorship from university scientists, and exposure to modern neuroscience technologies. Students will receive training in critical thinking, quantitative reasoning, scientific communication, and collaborative problem solving. Program outcomes will be evaluated using pre- and post-program assessments that measure changes in student competencies, knowledge of neuroscience concepts, and attitudes toward STEM education and biomedical careers. In parallel with program implementation, we will develop a set of digital educational resources—including instructional modules, videos, and classroom materials—to support the creation of a scalable “program-in-a-box” that can be implemented by other universities and science education programs. By expanding access to authentic neuroscience learning experiences and evaluating a scalable model for science education, the Brain Explorer Academy aims to strengthen student engagement in STEM and help prepare the next generation of students for participation in the biomedical and health research workforce.

NIH Research Projects · FY 2026 · 2022-05

Project Summary Alzheimer’s disease (AD) is the most common cause of progressive dementia in older adults, but there is no cure for this debilitating condition. We hypothesize that aging and AD-related pathologies cause maladaptive changes within hippocampal formation circuits that serve as connectome hubs for large numbers of critical brain regions, ultimately leading to age- and AD-related cognitive deficits. In response to RFA-AG-22-008, we have assembled a strong multi-investigator team across multiple institutions with complementary expertise in neural circuit mapping, next-generation AD mouse model development, single-cell transcriptomics and epigenomics analysis, and mouse brain common coordinate framework / atlas development. We will leverage the exceptional resources offered by the UCI Center for Neural Circuit Mapping, the MODEL-AD Consortium and the Allen Institute for Brain Science. We propose to perform large-scale, cell-type-specific mapping of hippocampal formation circuits to generate cellular resolution connectome data that combines molecular and anatomical annotations. To capture a more accurate composite of human AD features, we will use three complementary AD mouse models including two next-generation AD mouse models. These include 1) the 5xFAD mouse model with familial mutations, 2) the hAß-KI mouse that expresses human wild-type Aβ sequence from the endogenous mouse App locus to model late-onset AD features, and 3) Trem2 R47H knock-in mice that model the increased risk of the R47H coding variant for late onset AD. We will comprehensively map and characterize hippocampal formation brain circuits, including CA1, the subiculum (SUB) and the entorhinal cortex (EC) that show earliest neurodegeneration across AD mouse models and in human patients. These sub-circuits serve as hubs for neural processing from many other cortical and sub-cortical brain regions. We will use genetically modified transsynaptic neurotropic viruses developed by our team to map brain-wide anterograde and retrograde neural networks. The brain connectomes generated from viral tracing experiments will be enhanced with spatially resolved, single-cell transcriptomics-based molecular annotation using MERFISH (multiplexed error-robust fluorescence in situ hybridization). We will identify molecular candidates that confer vulnerability versus disease resistance as we superimpose spatial transcriptomic data on AD-modulated circuit connectomes. The entire data set will be annotated using the Allen Mouse Brain Common Coordinate Framework to facilitate resource and data sharing. Our work will improve our understanding of brain circuits susceptible to aging and AD towards developing better early diagnostic tools and new treatment strategies for AD.

NIH Research Projects · FY 2025 · 2022-05

Abstract We propose a new interdisciplinary skin biology training program at the University of California, Irvine. The Program builds on a strong group of skin biology mentors affiliated with a NIAMS-funded Skin Biology and Disease Research Core Center (UCI Skin). The goal is to develop skin biologists that will be highly skilled in integrating bioengineering, including imaging, and computation into their research to make discoveries in skin biology. The four trainees will be a mixture of graduate students (three slots), including MD-PhD students, and postdoctoral fellows (one slot), including dermatology residents pursuing postgraduate research training. The mentors include several investigators whose work focuses on skin biology and collaborating investigators from other scientific disciplines. Each trainee–irrespective of whether the primary mentor is a skin biologist or from an allied field–will pursue an interdisciplinary project at the intersection of skin biology and one of two cross-disciplines: systems biology or bioengineering/imaging. In their research activities, the trainees will be guided through dual mentoring by a skin biologist and a mentor from a complementary field. In addition to laboratory-based research training, the program includes lectures in skin biology and skin diseases, a weekly Skin Club for data presentations, seminar series, retreats and a yearly symposium. The program also offers a menu of career development activities that can be individually tailored to each trainee based on their interests and career goals.

NIH Research Projects · FY 2026 · 2022-05

PROJECT SUMMARY 22q11.2 Deletion Syndrome (22q11.2DS), the most common of the microdeletion syndromes, is caused by hemizygous loss of 0.7-3 Mb of DNA on chromosome 22 and results in a constellation of clinical phenotypes. The core phenotype originates from disrupted development of the pharyngeal apparatus. Particularly affected are the second heart field-dependent heart structures, great vessels, parathyroids, thymus, and lower craniofacial and face muscles. Although approximately 50 genes may be deleted, it is the haploinsufficiency of the transcription factor TBX1 that recapitulates most of the critical phenotype associated with 22q11.2DS. Genetic and developmental mouse studies have established that TBX1 is critical for typical development of the pharyngeal endoderm, a transient anatomical structure necessary for development of the thymus, parathyroids, and 4th pharyngeal arch arteries. Despite this central role, very little is known regarding the molecular mechanisms by which TBX1 functions in the pharyngeal endoderm. While a handful of studies have attempted to study the role of TBX1 in human cells, the cell types they have been conducted in are not representative of the appropriate developmental stage where and when TBX1 plays its critical role. To date, an effort to integrate all the critical genes into a pharyngeal endoderm or 4th pharyngeal arch arteries network has not been attempted, particularly in human cells. This R01 leverages recent development of an in vitro model which faithfully mimics the formation and progression of human pharyngeal endoderm, thereby providing an unprecedented opportunity to tease out the functions of TBX1 in its physiological context. Specifically, this model will be used to identify the transcriptional targets and partners of TBX1 (Aim1), investigate the role of TBX1 as epigenetic regulator of the human pharyngeal endoderm (Aim2), and mechanistically investigate newly discovered putative regulatory regions of the TBX1 locus (Aim3). The overarching hypothesis is that TBX1 is at the center of a Gene Regulatory Network critical for both the formation and maturation of the pharyngeal endoderm and the morpho-patterning of the surrounding mesoderm and neural crest cells. The proposed work is expected to identify the molecular mechanism at the basis of TBX1 haploinsufficiency and identify pathways which could be rescued through pharmacological intervention. Dissection of the epigenetic and molecular machinery responsible for pharyngeal endoderm formation will be instrumental in informing the generation of cell therapies for 22q11.2DS.

NIH Research Projects · FY 2026 · 2022-05

PROJECT SUMMARY The UC Irvine Vision Science Training Program (VSTP) is specifically designed to train PhD and MD/PhD candidates who will advance research on the causes, diagnosis, progression and treatment of human visual impairments. The goals of this multidisciplinary, inter-departmental training program are to (i) provide high quality research training in basic sciences disciplines that are relevant to vision research and (ii) provide opportunities for interdisciplinary collaborative and translational research so that our trainees can skillfully function in an interactive research environment and draw clinical correlates from their basic findings. A strength of our program will be that all trainees will receive mentoring that is both discipline-specific, i.e. departmental and thematic, i.e. within and across four broad visual sciences areas that encompass the VSTP; (a) Anterior segment and ocular surface, (b) Metabolism & visual processing, (c) Retina and retinal diseases, and (d) Lens. Through our program’s progressive design, trainees will first participate in didactic training to establish a strong foundation in cell and molecular biology, followed by additional didactic training in the biochemistry and molecular biology of all major components of the eye and visual processing. They will then acquire advanced understanding in an area of specialization via advanced courses and thesis research, which are organized according to the four research themes described above. The VSTP leverages UC Irvine’s robust vision science community, bringing together an outstanding group of clinicians and scientists with strong track records of vision research and mentoring. By leveraging these strengths, the VSTP is uniquely poised to produce vision scientists that can creatively apply contemporary research approaches toward understanding problems in vision and ophthalmology.

NIH Research Projects · FY 2026 · 2022-05

PROJECT SUMMARY Alzheimer’s disease and related disorders (ADRD) research represents a major national investment. ADRD clinical research faces delays and risks to internal and external validity resulting from challenges to efficient accrual, especially inadequate inclusion of populations at increased risk for disease due to social determinants of health. Recruitment registries are tools to accelerate accrual in ADRD research. Registries are repositories of potentially eligible individuals who have consented to be contacted about studies, reducing the need for serial recruitment by enabling bolus enrollment of ready cohorts. Few data address essential questions about registry design, conduct, and effectiveness in aiding ADRD research recruitment. How best to recruit and retain participants to registries and whether registries can address the urgent need to diversify clinical research samples are unknown. Furthermore, how registry samples compare to other research populations has not been investigated. This proposal investigates traditional and modern approaches to registry recruitment and asks critical questions about inclusion of participants from underserved neighborhoods and registrant retention. Given that registries are, by definition, convenience samples, we also aim to quantify the bias associated with these recruitment tools and develop methodology for addressing this bias. This project will produce essential information about resource utilization in recruitment registries and provide critical guidance for the field about how best to use these important tools.

NIH Research Projects · FY 2025 · 2022-05

Millions of people worldwide suffer vision loss from progressed stages of age-related macular degeneration and retinitis pigmentosa. Through the disease, much of the retinal pigment epithelium (RPE) and many photoreceptors are irreversibly lost and new cutting edge treatments using trophic factors or gene therapy are ineffective because the tissues are no longer present to be rescued. Our goal is to remediate vision loss through transplantation of retinal progenitor tissue sheets into the degenerated retina. In rodent models of retinal degeneration (RD), several studies have demonstrated that retinal progenitor sheets successfully integrate into the host retina, through synaptic connectivity between the transplant retina and host, and evoke responses to flashes of light in the superior colliculus (SC, a midbrain visual nucleus and direct target of retinal ganglion cells). However, in order to determine the complexity and quality of visual information provided by the transplant visual responsivity must be determined at a greater level of detail and in structures such as higher visual cortex where more complex visual processing occurs. Our main hypothesis is that transplants of fetal- and hESC-derived retinal progenitor sheets will drive complex and specialized visual responses in visual cortex (Aims 1 and 2), as well as visually guided behavior, and, that feedforward and feedback cortical circuitry at the level of specific neuronal cell types will be more similar to normal rats than RD rats without transplants (Aim 3). These studies will be performed using two rat models that are effectively blind by 3 months of age - through a collaboration combining visual neurophysiology expertise and cutting edge neural circuit tracing using genetically modified rabies viruses from the PI with the unrivaled surgical skills for retinal sheet transplantation and expert breeding knowledge of transgenic RD rats by the CO-PI. This project directly addresses the NEI Audacious Goals Initiative to regenerate the eye and visual system.

NIH Research Projects · FY 2026 · 2022-04

Irvine Summer Institute in Biostatistics and Undergraduate Data Science Project Summary The goal of this project is to establish a Summer Institute in Biostatistics and Undergraduate Data Sci- ence at the University of California, Irvine. The investigators will develop short courses in modern method- ology and practice of biostatistics and data science. These courses will highlight applications in cutting edge biomedical research, will train students in fundamentals of biostatistics, data science, and com- puting, and will culminate in a team project co-supervised by statisticians and biomedical scientists. In addition, the institute will include sessions helping students improve their transferrable skills: e.g., oral and written presentation skills. Particular attention will be paid to mentoring and career guidance. The institute will culminate with a mini-symposium with keynote lectures and a student poster session. One of the main goals of the proposed institute will be attracting mathematically inclined undergraduate students, especially from groups that are underrepresented in STEM fields, to the field of Biostatistics and Biomedical Data Science. UC Irvine is ideally suited for hosting the proposed institute. The institute leadership team consists of UC Irvine Statistics faculty. The Department of Statistics at UC Irvine is heavily invested in biomedical research directly relevant to the mission of the National Heart, Lung, and Blood Institute and National Insti- tute of Allergy and Infectious Diseases, which guarantees that there will be no shortage of highly qualified summer institute instructors. Design and analysis of clinical trials, causal inference, modeling of infectious disease dynamics, analysis of big data in genomics, transcriptomics, and image analysis provide a small sample of potential applications that will be used as examples in the institute short courses. Another ad- vantage of Statistics faculty being at the helm of the summer institute is vast experience of the leadership team and the rest of the department faculty in teaching and mentoring undergraduate students. The School of Information and Computer Science, which houses Computer Science, Informatics, and Statistics Depart- ments, is a national leader in Data Science education and research — the school is home to one of the first in the nation Data Science undergraduate degree programs and Data Science Institute that serves as a hub of data-driven research at UC Irvine. UC Irvine successful recruitment of underrepresented populations has been recognized by Hispanic-serving institution and Asian American and Native American Pacific Is- lander Serving Institution designations. The summer institute recruitment of participants will tap into UC Irvine existing programs and infrastructure for reaching out to underrepresented student groups. The con- fluence of Biostatistics and Biomedical Data Science expertise, investment in Data Science research and pedagogical innovations, and strong commitment to diversity and inclusion ensures that Irvine Summer Institute in Biostatistics and Undergraduate Data Science will be a successful endeavor. 1

NIH Research Projects · FY 2026 · 2022-03

PROJECT SUMMARY/ABSTRACT Learning and remembering the locations of resources while avoiding dangerous locations is a major challenge for complex organisms. Although the neural representations of known environments have been well studied, comparatively little is known about how that spatial knowledge is acquired in the first place. Here, we address the important problem of how people learn and remember new environments. In particular, we aim to investigate a fundamental type of spatial knowledge, the path connections between locations (‘graph knowledge’). A topological graph consists of place nodes linked by path edges which could generate routes, but without exact metric distances and angles, like a subway map. When it comes to learning spatial knowledge, it seems intuitive that active navigation should facilitate, however, we do not yet understand the mechanisms behind this advantage. Our overarching hypothesis is that interactions of a prefrontal- hippocampal-striatal (PHS) circuit support graph learning, particularly during active decision making about exploration. Combined with decision making and reinforcement learning mechanisms, the PHS pathway is hypothesized to facilitate memory during learning. Based on this model, interactions and functional communication within the PHS circuit are critical to new learning. The goals of this fundamental basic research proposal are to 1) determine the trajectory of navigational learning, including both behavioral and brain network dynamics, 2) identify the underlying brain mechanisms behind active decision making during graph learning, and 3) answer fundamental questions about the relationship between decision making and memory. In Specific Aim 1, we will determine exploration behaviors that facilitate graph learning. We will compare a variety of graph structures, environmental openness, and scale to determine the robustness of graph learning. In Specific Aim 2, we will use novel fMRI methods to examine changes in the formation of cohesive groups of brain areas (‘communities’), harnessing the dynamics of learning. We will use this technique to identify brain networks supporting active compared to passive learning. In Specific Aim 3, we will compare the brain networks found in graph learning with those in non-spatial and non-Euclidean graphs. These studies will test for brain networks common across different types of graphs, as well as those unique to spatial graphs. The outcomes will provide insights into fundamental processes of navigation, learning, and memory, and will help answer questions about learning beyond the realm of navigation. The PHS circuit is relevant to mental disorders involving reinforcement and reward learning, including OCD, depression, and Parkinson’s Disease. These studies will establish a vital link between spatial navigation and the PHS circuit, and will form the basis for computational approaches to navigation, learning, memory, and breakdowns of the PHS circuit. The far- reaching impact of this research includes assessing the function and dysfunction of this circuit in clinical populations to better understand disease mechanisms.

NIH Research Projects · FY 2025 · 2022-03

Enhanced Imaging of the Fetal Brain Microstructure The fetal period of brain development is critical as it involves complex processes of cell proliferation, neuronal migration, and myelination that are particularly vulnerable to disturbances from adverse events in utero and conditions that develop during gestation. Specifically, hypoxia caused by abnormal circulation, is hypothesized to disrupt neuronal migration thereby causing altered brain connectivity and adverse neurological outcomes. Abnormal brain connectivity has been depicted in newborns and adolescents with critical congenital heart disease (CHD) using diffusion-weighted imaging (DWI). Gross brain abnormalities have also been identified and quantified prenatally in CHD using in utero T2-weighted magnetic resonance imaging (MRI), but the precise location and timing of disrupted neuronal migration that leads to these abnormalities, has remained unclear due to technological limitations of in utero DWI. In this project we aim at developing new DWI technologies that remove these barriers to improve our understanding of the maturation of fetal brain microstructure as well as the origins and patterns of its alterations in utero. In particular, we aim to develop new techniques to address the limitations of current fetal DWI technology by effectively mitigating and compensating for motion and geometric distortion artifacts during acquisitions. This project therefore seeks to create a paradigm shift in the way fetal DWI is acquired and analyzed. The three specific aims of the project are to 1) create a prospectively motion-corrected slice navigation system for fetal brain DWI, 2) enhance fetal DWI acquisitions with artifact reduction and compensation by developing new imaging and image reconstruction techniques for dynamic field mapping, and 3) evaluate fetal brain maturation in congenital heart disease. We will assess the utility and impact of the technologies developed in this project by analyzing and comparing a large pre-existing cohort of fetal DWI scans with the scans prospectively acquired from both typically-developing (TD) and CHD fetuses with these new techniques. Moreover, we expect to gain important knowledge about early disruptions to neuronal migration pathways and formation of brain connections due to compromised circulation and hypoxia in fetuses with CHD. By making fetal DWI more reliable and robust, this study will mitigate a critical barrier to making progress in the fields of developmental neurology and neuroscience. Improved understanding of the impact of adverse events in utero on fetal brain growth and the trajectories of altered brain development can help guide neuroprotective and therapeutic interventions, and enable early, more effective treatments for neurological diseases and mental disorders. Fetal DWI plays a crucial role in establishing such an understanding as it is uniquely able to depict the microstructure of the fetal brain in utero.

NIH Research Projects · FY 2026 · 2022-03

PROJECT SUMMARY/ABSTRACT Multiple sclerosis (MS) and other autoimmune diseases constitute a major healthcare burden at a cost of >$125 billion per year. Autoimmune disorders arise from a failure of immunoregulatory networks. Regulatory T (Treg) cells expressing transcription factor forkhead box protein 3 (Foxp3) are indispensable components of these networks. Moreover, recent studies from several groups suggest that Treg cells also facilitate tissue repair, in addition to exerting immunosuppression. During autoimmune diseases, Treg cells are activated in lymphoid organs and home to non-lymphoid target tissues where they persist in specialized niches to limit inflammation and facilitate tissue repair. Our overall goal is to determine how these Treg cell niches operate in the central nervous system (CNS) to ameliorate autoimmune neuroinflammation at cellular and molecular levels. Direct visualization of cell behavior often leads to surprises, new hypotheses, and follow-up experiments contributing to a better understanding of the mammalian immune system, and how autoimmunity and infectious diseases can be effectively treated. Building on our expertise in two-photon (2-P) imaging at the cellular level, and Ca2+ signaling at the molecular level, we will use the experimental autoimmune encephalomyelitis (EAE) mouse model of MS to: 1) elucidate the local cues that drive survival, functional organization in niches, and motility behaviors of Treg cells in the spinal cord; 2) investigate how Treg cells selectively target processes that incite neuroinflammation. Our experimental approach includes evaluation of the Piezo1 channels as promising therapeutic targets to selectively expand Treg cells, an ideal strategy to curb ongoing autoinflammatory responses while preserving the immune system’s ability to fight new infections. Although this proposal is targeted specifically to MS, in a broader context our project will provide fundamental insights into how Treg cells fine-tune tissue inflammation so that better Treg-modifying therapies can be developed for autoimmune disorders, organ transplantation, cancer, and infectious diseases.

NIH Research Projects · FY 2026 · 2022-02

PROJECT SUMMARY Infection causes inflammation, which contributes to pathogen clearance and survival of the host organism. However, failure to regulate the inflammatory response can often lead to multiple organ damage and lethality for the host. In the current COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), patients with elevated cytokine levels are often associated with severe symptoms and mortality. This indicates hyper-activation of specific inflammatory molecules might be as much a contributing factor to mortality and morbidity as the virus itself. Thus, there is a dire need to better understand the gene activation dynamics upon infection and develop therapies to manage the inflammatory response. In 2016 we have shown that epigenetic inhibition of factors controlling chromatin remodeling of inflammatory genes, like Topoisomerase 1, can reduce inflammatory gene expression and rescue lethality during bacterial and viral infection, suggesting that these effects may be applicable in the setting of COVID-19 as well. Topoisomerase 1 inhibitors are FDA approved and in the list of WHO essential medicines, thus their widespread usage and cheap cost can be leverage if they are active against COVID-19 as they are in many other infections. In this proposal, we will characterize the role of Top1 and epigenetic factors controlling chromatin topology during SARS-CoV-2 infection and will test the feasibility of use of Top1 inhibitors as drugs for the treatment of COVID-19 in animal models. We will perform mechanistic and preclinical test using epigenetic inhibitors in comparison with immune blockers used in clinical trials and the current standard of care (glucocorticoids).

NIH Research Projects · FY 2026 · 2022-02

PROJECT SUMMARY/ABSTRACT Philadelphia chromosome-like B cell acute lymphoblastic leukemia (Ph-like ALL) is an ALL subtype that disproportionately affects the Hispanic community and is characterized as having a poor response to therapy, a high risk of relapse, and a peak onset in adolescents and young adults. While lacking a BCR-ABL fusion, nearly 65% of Ph-like ALL cases carry a rearrangement in the cytokine receptor-like factor 2 (CRLF2) gene, the most common being a chromosomal translocation with the immunoglobulin heavy chain locus (CRLF2-IgH) resulting in overexpression of CRLF2 and low survival. One comparative study found that Ph-like ALL occurred in 68% of Hispanics versus 23% of Whites and of those, 78% of Hispanics had disease associated with CRLF2 rearrangements compared to 22% of Whites, indicating a clear cancer disparity. The long-term goal is to develop predictive diagnostics based upon a patient’s genetic background to address cancer disparities. The overall objectives for this proposal are to leverage genetic and molecular expertise on the etiology of B cell malignancies to determine the mechanism underlying CRLF2-IgH formation and determine how changing levels of B cell-specific factors and epigenetic imprinting predispose Hispanics to this translocation and thus Ph-like ALL. The central hypothesis is that DNA double-strand breaks (DSBs) leading to CRLF2-IgH translocations result from a mechanism involving activation-induced cytidine deaminase (AID) and DNA methylation and that differential regulation of these processes in Hispanics is driving the cancer disparity. The rationale for this project stems from results showing that CRLF2 DSBs resulting in CRLF2-IgH translocations are highly enriched in a 311 bp cluster region. DSBs within this cluster occur at motifs recognized by AID and these motifs contain CpG sequences that are also sites of DNA methylation. Evidence shows that meCT deamination is more detrimental that CU deamination and more likely to result in DSBs. Determining if aberrant AID expression and changing DNA methylation patterns account for increased CRLF2-IgH formation in Hispanics is critical in addressing the Ph-like ALL disparity and will be tested through three specific aims: 1) Define the molecular mechanism of CRLF2-IgH formation; 2) Determine genetic and epigenetic factors underlying Ph-like ALL disparities in Hispanics; and 3) Develop a molecular assay to detect CRLF2-IgH translocations and compare treatment response in Hispanics and non-Hispanics. The innovative aspects of this work are identification of a 311 bp DSB cluster associated with CRLF2 instability, application of new molecular and genomic techniques in human cells to address the etiology of Ph-like ALL, and the use of patient material from the UCI comprehensive cancer center that serves a large Hispanic population. This work is significant as it will address a major cancer health disparity in the Hispanic community and develops a novel diagnostic for early detection of new or relapsed disease while at the same time unravelling a molecular mechanism that is not only relevant to Ph-like ALL, but also to several additional B cell malignancies.

NIH Research Projects · FY 2025 · 2022-02

PROJECT SUMMARY Petroleum extraction is increasingly common in urbanized areas, and yet, epidemiological research on the health consequences for nearby urban residents is sparse. Los Angeles (LA) County, California has the largest urban oilfield in the country and is home to thousands of active oil wells in very close proximity to homes and schools. Few protections are in place to prevent the release of pollutants into nearby residential areas and understanding the impacts to air quality and health among neighbors is urgently needed to inform public health protections. The overall goal of this study is to extend a robust community-academic partnership to assess the health effects of exposures to oil drilling wells and inform public health actions in South LA, a predominantly low-income multiethnic community of color that faces environmental health disparities. To achieve this, the University of Southern California and Occidental College have formed a collaboration with Redeemer Community Partnership, a longstanding neighborhood-based organization in South LA that addresses the health and well-being of local families. Preliminary collaborative research demonstrates episodic oil-related neighborhood air pollution events and adverse impacts on respiratory health among residents living closer to drill sites. The proposed project, the Los AngeleS Voices on Oil, Community, the Environment and Salud study (LAS VOCES), will examine links between urban oil drilling, air quality and respiratory health, and enhance the capacity of the South LA community to take action based on the identified the environmental or health impacts. The proposed collaborative, community-driven project will 1) engaged exposed communities; 2) quantify the impact of oil drilling on air quality using an innovative low-cost sensor network: 3) establish a diverse cohort to assess longitudinal respiratory health of residents living near oil wells in different stages of production; and 4) develop an action- oriented community public health plan leveraging interviews with diverse stakeholders. Our work will fill a critical gap on impacts of urban oil drilling activities on neighborhood respiratory health and air quality through a prospective study, as well as identify how diverse stakeholders might work together to protect public health for vulnerable populations living nearby urban oil drilling. This project will advance community and scientific knowledge through participatory research.