University Of California-Irvine

NIH Research Projects · FY 2024 · 2020-09

Project Summary / Abstract Dementia and age-related cognitive decline is an escalating major health concern in the United States. Approximately 20% of the US population will be 65 or older by year 2030, and roughly 8 million of these individuals are expected to suffer from Alzheimer’s disease (AD). We propose to examine detailed AD-related neural circuit mechanisms that will be critical for developing new AD treatment strategies by use of two complementary AD mouse models, which share many features of human AD. Our guiding hypothesis is that AD-related neurodegeneration causes maladaptive changes of memory circuit connections and neural ensemble activities in the hippocampus. We discovered recently in the mouse that non-canonical subicular back- projections to hippocampal CA1 underlie object-place learning, a prominent impairment in AD. This circuit has been recently identified in human brain. We will test our hypothesis that significant impairments in bidirectional information processing between hippocampal CA1 and the subiculum (SUB) develop over time during AD progression. In Aim 1, we will determine the effect of AD-like neurodegeneration on local and global circuit connections to hippocampal CA1 and SUB excitatory neurons. We will map and compare circuit input connections and output projections of excitatory CA1 and SUB neurons in adult control, and AD-like mice using retrograde monosynaptic rabies tracing and anterograde monosynaptic herpes simplex virus (HSV) tracing. Further, we will perform experiments in postmortem human hippocampus of aged-matched control and AD patients to map the SUB-CA1 pathway in human brains and understand detailed changes of this brain circuit in AD patients. In Aim 2, we will test the hypothesis that neurodegeneration in AD-like mice degrades object- location memory encoded by hippocampal CA1 and SUB excitatory neurons. To map neuronal activity to behavioral performance, we will use in vivo miniature microscopic imaging to examine and compare spatial representations of CA1 excitatory neurons and SUB excitatory neurons during open-field exploration, track- based route-running and object-location memory tasks. Thus, we can longitudinally track progressive AD-like functional defects. In Aim 3, we will determine whether spatial memory can be rescued by patterned stimulation of the non-canonical SUB-CA1 back-projection in the AD model mice. Human literature and our preliminary data show high relevance of our proposed research for Alzheimer’s disease. Together, the proposed research will advance our understanding of specific neural mechanisms underlying AD etiology and help to identify new therapeutic targets in humans.

NIH Research Projects · FY 2024 · 2020-09

Project Summary/Abstract It is hard to overstate the importance of monoclonal antibodies in the life sciences. Antibodies are critical tools in biomedical research and diagnostics (e.g. western blotting, immunoprecipitation, cytometry, biomarker discovery, and histology), are one of the most rapidly growing class of therapeutics, and are the basis for myriad new strategies in cancer therapy, such as checkpoint inhibitors that are revolutionizing treatment. Unfortunately, current methods for the generation of custom antibodies, including animal immunization and phage display, are slow, costly, inaccessible to most researchers, and often unsuccessful. We propose Autonomously EvolvinG Yeast-displayed antibodieS (AEGYS), a system for the continuous and rapid evolution of high-quality antibodies against custom antigens that requires only the simple culturing of yeast cells. We believe this can be achieved by combining cutting-edge generative machine learning algorithms for antibody library design with a new technology for in vivo continuous evolution and a yeast antigen-presenting cell that we will engineer. If successful, AEGYS should have a transformative impact across the whole of biomedicine by turning monoclonal antibody generation into a rapid, scalable, and accessible process where any lab with standard molecular biology capabilities can generate custom antibodies on demand simply by “immunizing” a test tube of yeast cells with an antigen. We anticipate that this democratization of antibody generation will also result in an explosion of crowdsourced antibody sequence data that will train our machine learning algorithms to design better antibody libraries for AEGYS, starting a virtuous cycle. We ourselves will use AEGYS to generate a panel of subtype- and conformation-specific nanobodies against biogenic amine receptors including those that respond to acetylcholine, adrenaline, dopamine, and other neurotransmitters, so that we can understand their role in neurobiology and addiction.!

NIH Research Projects · FY 2024 · 2020-09

PROJECT SUMMARY For too long, studies of the Blood-Brain Barrier (BBB) have ignored the blood component of this interface, focusing almost exclusively on the cells of the Neurovascular Unit (NVU). The goal of the FOA to which we are responding aims to change this: “The intent of this FOA is to stimulate the development of a new field of blood-based science by re-defining the neurovascular unit as a component of the blood-brain interface. This will facilitate development of human- based neurovascular-blood models to identify targets for diagnostics and regulation of the blood-brain interface…” The NVU is comprised of endothelial cells (EC), pericytes and astrocytes, and a complex basement membrane, which work together to severely limit the free movement of molecules from the blood into the brain parenchyma. In response to local signals during development BBB EC develop tight junctions and have very low rates of transcytosis. The side-effect of this is that access of potentially therapeutic drugs into the brain is also compromised. In this proposal we will build on our well-established human Vascularized Micro-Organ (VMO) platform to create a novel blood-brain interface model, the VMO-B. In this model a network of human microvessels anastomoses to microfluidic channels representing an artery and a vein and are induced to a BBB phenotype by Wnt signaling. The vessels are invested by pericytes and contacted by astrocyte foot-processes. Importantly, we will run a blood substitute – VMOBlood – through the vessels that will mimic the composition of blood, including protein and lipid content. We will then use the VMO-B to investigate the process of BBB breakdown in the pathogenesis of Huntington’s disease. We already have preliminary data suggesting that expression of mutant HTT protein in EC causes BBB deficits. We will investigate crosstalk between blood and the cells of the NVU, and how expression of mHTT in each cell type affects cell-cell communication and barrier function. In the R61 phase we will pursue three aims: Aim 1 Develop a stable MPS BBB model with perfused microvasculature; Aim 2 Incorporate flow of blood into BBB microfluidic model; and, Aim 3 Characterize key transporters at the blood-brain interface. In the R33 phase we will use this platform to examine the role of the blood-brain interface in the pathology of HD through an additional two aims: Aim 4 Test the hypothesis that expression of mHTT in EC disrupts transport across the BBB leading to changes in the neural micro-environment; and, Aim 5 Test the hypothesis that expression of mHTT disrupts multiple cell-to-cell interactions at the blood- brain interface. Completion of this project will not only shed light on the neuropathology of Huntington’s disease, but will also yield a platform ideally suited to drug development and investigating the role of the blood- brain interface in numerous neurological diseases including Alzheimer’s disease, Multiple Sclerosis, Parkinson’s disease, stroke, CADASIL, and traumatic brain injury.

NIH Research Projects · FY 2026 · 2020-09

PROJECT SUMMARY/ABSTRACT The rod outer segment (ROS) houses all the protein components necessary for visual phototransduction. Genetic defects in these proteins have been linked to human retinal-degenerative diseases. Insights obtained from detailed structural and functional analyses, in vitro and in vivo, have advanced our understanding of the etiology of related retinopathies, but several fundamental questions remain. Accordingly, we propose two thematically and experimentally linked specific aims that fill critical gaps pertaining to the subunit assembly of rod phosphodiesterase 6 (PDE6) and its role in ROS organization. PDE6 is a key enzyme of our vision, and it is implicated in retinopathies; thus, an advanced understanding of its subunit structures, particularly in vivo, is essential to elucidate the consequences of its dysfunction. Specific Aim 1. Through enzymatic inactivation and N-terminal truncation, determine the relative contributions of the PDE6α and PDE6β subunits to the function and structural organization of the rod photoreceptors. Aim 1A. Via selective enzymatic inactivation, determine the relative contributions of the PDE6α and PDE6β subunits to the stability and activity of tetrameric PDE6αβγγ. Based on structures of the PDE6αβγγ complex and other related members of the PDE family, the H599A mutation in PDE6? and the H597A mutation in PDE6β are expected to render these PDE6 subunits catalytically inactive by disabling hydrolysis. We have developed single heterozygote knock-in mouse bearing the respective mutant PDE6 catalytic subunits. Moreover, we generated novel mouse models featuring N-terminal truncations (2-48 of PDE6α and 2-46 in PDE6β). Single heterozygote knock-in mice with deletions in the respective N-termini of the PDE6 subunits will enable us to thoroughly characterize the resultant effects on the structure of the rod photoreceptor cells. Aim 1B. Characterize the PDE6 architecture in complexes with lipids and small molecules, using native mass spectrometry. Using this highly innovative technology we will quantify PDE6 subunit arrangements in different activation states with Gt and small ligands (cGMP, GDP/GTP, PDE6 inhibitors). Specific Aim 2. Delineate the impact of PDE mutations on the structural integrity of the ROS at nanometer resolution. Cryo-electron tomography (cryo-ET) provides the least destructive and highest resolution method to investigate cellular structures at the molecular level in an environment similar to the native state. Aim 2A. Identify changes in the structure and frequency of interdiscal spacers in the ROS of mutant-PDE6 mice compared to WT. Aim 2B. Assign the physical locations and light-dependent dynamics of key proteins of the ROS, including membrane-bound rhodopsin. We intend to take advantage of recent technological advances to investigate other individual proteins in the ROS, including rhodopsin. By elucidating the molecular details of normal and aberrant ROS, we will better understand the ensuing pathology resulting from mutations in PDE6 and other key components of phototransduction. Furthermore, the findings from this project could facilitate the development of a rational approach to alleviate retinal dystrophies affecting ROS structure.

NIH Research Projects · FY 2025 · 2020-09

Project Summary Normal aging is typically associated with pervasive declines in cognitive, motor and sensory function, however, there are substantial individual differences: some older adults experience mild impairments while others experience severe cognitive declines. Understanding the neural bases of individual differences during aging is imperative in designing future interventions to address age-related cognitive impairments. Using behavioural testing, functional MRI, spectroscopy and pharmacological manipulations in human adults, I propose to investigate the scope, cause and consequences of age-related decline in two neural factors that may play a role in these individual differences: (1) neural distinctiveness (how similar/confusable neural activation patterns are in response to different stimulus categories) and (2) brain signal variability (moment-to-moment change in neural activity independent of task). Both these measures have been found to decline with age and both have been associated with individual differences in behavior. During the predoctoral (F99) phase of the training, my research will focus on healthy aging: 1) investigating the scope and cause (specifically role of GABA levels) of age-related decline in neural distinctiveness in sensory regions, 2) the cause of age-related declines in brain signal variability, and 3) the behavioral consequences of age-related declines in these two neural measures. During the postdoctoral (K00) phase, I will extend my previous research to again study neural distinctiveness and brain signal variability, but now in the context of memory and hippocampal dysfunction, and in a clinical population (patients with Mild Cognitive Impairment, MCI). I will use task-based fMRI to measure neural distinctiveness, resting-state fMRI to measure brain signal variability, and MR spectroscopy to measure levels of various neurotransmitters (including glutamine, glutamate, NAA, and GABA), all in the hippocampus, in healthy younger and older adults as well as MCI patients. I will also collect behavioral data from the same participants during the Mnemonic similarity task (MST), a highly sensitive measure of hippocampal dysfunction. I propose to investigate a) age-related changes in neural distinctiveness and resting state variability in the hippocampus, b) the neurochemical basis of these neural changes, and c) the behavioral and pathological consequences of these neural changes. For all the MCI patients, I will also have access to a rich dataset of other biomarkers (e.g., longitudinal measures of CSF and PET-based amyloid and tau) collected at UCI’s Alzheimer’s Disease Research Center (ADRC). I will therefore be able to examine neural distinctiveness and brain signal variability in the context of the Amyloid Tau Neurodegeneration (biomarker profiling) Framework. Together, this research could lead to the development of preclinical markers for AD and open new avenues for early pharmacological interventions to treat cognitive declines in healthy and pathological aging.

NIH Research Projects · FY 2024 · 2020-08

SUMMARY Humanity is confronting a pandemic caused by the new Corona Virus 2 (SARS-CoV-2) infection. Our long- term goal is to develop a potent prophylactic pan-Coronavirus vaccine to stop/reduce past, current and future Coronavirus infections and/or diseases. While SARS-CoV-2-induced antibody and CD4+ and CD8+ T cell responses are critical to reducing viral infection in the majority of asymptomatic individuals, an excessive proinflammatory cytokine storm appears to lead to acute respiratory distress syndrome in many symptomatic individuals. Major gaps: Identifying the epitope specificities, the phenotype and function of B cells, CD4+ T cells and CD8+ T cells associated with “natural protection seen in asymptomatic individuals (those who are infected, but never develop any major symptoms) should guide the development of a future coronavirus vaccine. Preliminary Results: We have made significant progress in: (A) Identifying a priori potential human B-cell, CD4+ and CD8+ T cell target epitopes from the whole SARS-CoV-2 genome; (B) Identifying “universal” epitopes conserved and common between: (1) previous SARS and MERS coronavirus outbreaks, (2) current 4388 SARS-CoV-2 strains that now circulate in the United States and 184 other countries; and (3) SARS-like coronavirus strains currently found in bats that have the potential to produce future human outbreaks; (C) Applying our scalable self-assembling protein nanoparticles (SAPNs) antigen delivery platform to produce prototype multi-epitope pan-Coronavirus vaccine candidates, that incorporate conserved protective epitopes from human and bats Coronaviruses, and demonstrated their B- and T-cell immunogenicity in HLA transgenic mice; and (D) Generating a novel “humanized” susceptible HLA-DR/HLA-A*0201/hACE2 triple transgenic mouse model in which to test these vaccine candidates. Our hypothesis is that one of our pan-Coronavirus vaccine candidates, containing conserved “asymptomatic” SARS-CoV-2 B- and T-cell epitopes that are mainly recognized by the immune system of “protected,” asymptomatic individuals would protect from SARS-CoV-2 infection and disease, upon intranasal delivery. To test this hypothesis our Specific Aims are: Aim 1: To test in vitro the antigenicity of conserved Coronavirus epitopes, we recently identified from the whole SARS-CoV-2 genome, using blood-derived antibodies, CD4+ T-cells and CD8+ T-cells from SARS-CoV-2-infected symptomatic vs. asymptomatic individuals. The immunodominant conserved “asymptomatic” epitopes will be identified and used in our multi-epitope pan-Coronavirus vaccine candidates. Aim 2: To test in vivo the safety, immunogenicity, and protective efficacy of highly conserved multi-epitope pan-Coronavirus vaccine candidates, delivered mucosally, to our novel “humanized” susceptible triple transgenic mouse model. Successful completion of this preclinical vaccine project is expected to identify a broadly protective pan- Coronavirus vaccine candidate that could quickly proceed into an FDA Phase 1 clinical trial.

NIH Research Projects · FY 2024 · 2020-07

Project Summary/Abstract More than 1.7 million cases of Chlamydia trachomatis infections are reported to the CDC each year, making it the most commonly reported infectious disease in the country. C. trachomatis causes an intracellular infection, and we have discovered that this bacterium causes two effects on an infected host cell that have not been previously described: 1) loss of the primary cilium, which is a solitary surface projection on most differentiated cells in the body; 2) re-entry of a quiescent host cell into the cell cycle. These novel host-pathogen interactions may have been missed because the conventional Chlamydia cell culture infection model uses cycling cells that lack primary cilia. In Aim 1, we will determine if Chlamydia infection causes loss of the primary cilium by inducing cilia disassembly through the AurA regulatory pathway of the host cell. In Aim 2, we will investigate how Chlamydia causes cell cycle re-entry and will determine if the infection involves and dysregulates known cellular regulators of cell cycle re-entry and progression. In Aim 3, we will study if and how Chlamydia-induced primary cilia loss and cell cycle re-entry promote the chlamydial infection. We will also investigate if these two host-pathogen interaction are functionally linked or independent from each other. Successful completion of these studies will define two novel host-pathogen interactions: no microbe is known to cause primary cilia loss, and only viruses, but not bacteria, have been shown to cause quiescent host cells to re-enter the cell cycle. Interventions to prevent Chlamydia-induced primary cilia loss and cell cycle re-entry may lead to a novel therapeutic strategy against Chlamydia infections.

NIH Research Projects · FY 2024 · 2020-07

Project Summary Cancer is the leading cause of death for Asian Americans, the fastest growing U.S. immigrant group projected to outnumber Latinx Americans by 2065. Provision of high-quality supportive care for Asian American cancer patients with metastatic disease is critically needed; however, there is a dearth of literature on this topic. Within the Asian American population, Confucian-heritage East Asian and Southeast Asian ethnic groups share cultural values and norms relevant to tailoring cancer care, and a goal of the K99 phase is to generate mixed- methods data on supportive care needs specifically for Chinese-, Vietnamese-, and Korean-descent (CVK) patients with metastatic cancer. Findings from the K99 phase will be shared with research participants and applied collaboratively to develop culturally relevant supportive care resources in the R00 phase. The overall training objective of this Early K99/R00 is to provide Dr. Kim with additional years of mentorship to become a highly qualified independent investigator at the intersection of culture and supportive oncology. Training goals include developing competencies in: 1) patient/family-centered and stakeholder-engaged cancer care research, 2) patient-reported outcomes, needs, and preferences in metastatic cancer, 3) advanced mixed- methods research particularly for working with non-English speaking participants, and 4) psychosocial intervention development in cancer. Through the proposed training, Dr. Kim’s background in qualitative and quantitative research, culturally-grounded research in Asian American populations, and cancer-related coping processes will be integrated to solidify expertise in mixed methods and cultural implications for psychosocial/behavioral cancer control as she transitions into an independent tenure-track faculty position. During the K99 phase, Dr. Kim will be under the primary mentorship of Dr. Annette Stanton at UCLA, alongside a strong co-mentorship team of experts (Drs. Marjorie Kagawa-Singer, Qian Lu, Anna Lau) committed to advancing Dr. Kim’s career. The proposed research will also document participants’ reflections about the experience of collaborative research for developing future guidelines on inclusive research practices that promote advocacy. Dr. Kim’s long-term plan is to develop, test, and disseminate supportive care resources and interventions that are culturally relevant and scalable, toward the ultimate goals of facilitating quality care and improving outcomes in understudied populations with metastatic cancer.

NIH Research Projects · FY 2025 · 2020-07

Summary/Abstract The landscape of biomedical research is changing at a dizzying pace. Revolutions in single cell ‘omics, high resolution imaging, computational power, and AI-assisted prediction are rapidly propelling us into a world in which the hypotheses and conclusions in a large fraction of biological and biomedical science closely depend on the computer-aided interpretation of massive datasets. The workforce development challenges associated with the transition to “big data”-infused science are great, requiring a much more interdisciplinary and more quantitative approach to training. This application requests support for the renewal of a pre-doctoral training program that produces Ph.D.s with sufficient skills in fundamental biology, mathematical and computational modeling, and data science to attack these challenges head on. The program is built upon a free- standing, interdisciplinary Ph.D. program that has been developed and refined over the past 17 years and offers training at the interface between the biological sciences and mathematics, computer science, physics and engineering. Ten pre-doctoral trainee slots are requested, for appointments intended to last two years each. Highlights of the proposed program include an extensive didactic curriculum; a focus on critical thinking skills; an emphasis on collaboration and collaborative learning; close mentoring, opportunities to develop multiple career skills; and active student involvement. The 36 program faculty members come from 28 different departments in seven schools at the University of California, Irvine, and conduct research on diverse topics within biology and medicine. The program enjoys strong campus support, and an administrative and intellectual home within the UCI Center for Complex Biological Systems, a campus-wide research unit with a long-standing commitment to promoting interdisciplinary education at all academic levels. The proposed program will prepare trainees for careers in biomedical research, teaching, and communication in both academic and non-academic settings.

NIH Research Projects · FY 2024 · 2020-07

SUMMARY/ABSTRACT Computational modeling approaches are rarely applied to the right ventricle even though, like left ventricular failure (LVF), right ventricular failure (RVF) is multifactorial, multiscale and causes significant morbidity and mortality. In comparison to LVF, RVF is understudied with the important consequence that no RV-specific therapies exist. Computational multi-scale modeling offers a unique opportunity to integrate dysfunction manifest at multiple scales: at the organelle level, there are impairments of mitochondria, Ca2+- handling, and myofilament function; at the tissue level, there is myocyte necrosis, apoptosis, fibrosis and capillary rarefaction; at the organ level, hypertrophy and dilation; and at the organism level, exercise intolerance. Moreover, computational modeling is ideally suited to answering the question: what are the relative contributions from abnormalities at multiple scales to the overall phenotype of RVF? We propose to answer this question with a data-driven, multiscale, computational modeling approach. Beginning with an existing mitochondrial kinetic computational model fit to healthy and RVF mitochondrial function, we will predict the emergence of dysfunction at the tissue-level. Then, fitting a myocardial tissue computational model to healthy and RVF passive and active mechanics, we will predict emergence of dysfunction at the organ-level. Finally, by adapting an existing biventricular mechanics computational model to healthy and RVF pressure-volume dynamics, we will predict the emergence of dysfunction at the organism-level, i.e., exercise intolerance. Model assumptions and predictions will be driven-by and tested against experimental data collected using state-of-the-art techniques at the organelle-, tissue-, organ-, and organism-scales at multiple time points in an established rat model of RVF. Finally, we will use our data-driven computational modeling approach to confirm the human disease relevance of mechanisms of RVF found in rodent using our state-of-the- art experimental techniques on human failing and nonfailing myocardium. Our specific aims are: Aim 1: Determine the drivers of systolic dysfunction in RVF. We hypothesize that the major driver of systolic dysfunction in RVF is impaired mitochondrial generation of ATP leading to impaired contraction of cardiac myofilaments. We will test this hypothesis with scale-specific models and multi-scale experimental data collected from rats with RVF. Aim 2: Determine the drivers of diastolic dysfunction in RVF. We hypothesize that diastolic dysfunction in RVF is driven by fibrosis and impaired myofilament relaxation. We will test this hypothesis with scale-specific models and multi-scale experimental data collected from rats with RVF. Aim 3: Determine the drivers of systolic and diastolic function in human RVF. Key predictions of organelle- and tissue-scale structural and functional drivers of RVF will be tested with multiscale modeling validated with state-of-the-art measurements at these scales in non-failing and failing human heart tissues.

NIH Research Projects · FY 2026 · 2020-06

PROJECT SUMMARY/ABSTRACT – OVERALL The theme of University of California Irvine Alzheimer’s Disease Research Center (UCI ADRC) is accelerating discovery in Alzheimer’s disease (AD) and AD Related Disorders (ADRD) research across special populations. The UCI ADRC plays a distinctive role in the ADRC network, with a rich history of studying unique groups that have been underrepresented in AD/ADRD research. We have been a leader in research on individuals 90 years and older and our center was one of the first to study participants with Down syndrome (DS), groups at increased risk for dementia but often excluded from research. We have focused strongly on the underrepresented but rapidly growing populations of older Asian American and Hispanic individuals and have helped establish the first national registry of Asian American individuals to support inclusion in AD/ADRD research. We ensure data from these populations are available to the entire ADRC network through our Clinical Core, which emphasizes the earliest signs of disease, including mild behavioral impairment; and our unique special population DS Core and Oldest-Old Core. These invaluable resources synergize with our six other ADRC cores and our Research Education Component in a center that is highly collaborative. Our Neuropathology Core has shared tissue from >1500 donated brains with >120 investigators worldwide. Our induced Pluripotent Stem Cell Core was the first of its kind in the ADRC network and has shared iPSCs with >70 laboratories worldwide and supported more than $125M in NIH-funded projects. Our Data Management and Statistical Core supports ADRC investigators through applied research and develops improved statistical methods. Our Biomarker Core implements state-of-the-art tools while researching ways to make biomarker information more accessible. Our Outreach Recruitment and Engagement Core has strong ties to the diverse local community and is a leader in the science of recruitment. The Administrative Core of UCI ADRC has consistently provided strategic leadership to ensure that our center constantly innovates, collaborates, and educates.

NIH Research Projects · FY 2024 · 2020-06

PROJECT SUMMARY: OVERALL We are proposing the creation of a research program entitled, “Increasing the therapeutic index of brain tumor treatment through innovative FLASH radiotherapy (FLASH-RT), focused on translating a novel irradiation modality rapidly into the clinic. The overall hypothesis to be tested is whether radiation delivered at ultra high dose rates (compared to the much lower dose rates used in current clinical practice) can significantly ameliorate normal tissue complications while maintaining acceptable if not improved tumor control. To test this hypothesis, the program will deploy a comprehensive series of preclinical studies across 4 projects that will evaluate effects of FLASH-RT on tumor control and neurocognition. Work at 3 performance sites (CHUV, Stanford, Indiana) will implement conventional and FLASH irradiation paradigms to evaluate how each radiation modality impacts GBM tumor control, neurocognition and associated pathologies in orthotopic tumor bearing and tumor free animals (Projects 1 and 2). A clinical trial conducted at the CHUV in Switzerland will recruit GBM dog patients to evaluate the therapeutic benefits of dose escalation using the FLASH modality. Lastly, each performance site will be involved in elucidating the mechanistic basis of the FLASH effect by altering oxygen tension during irradiation and by implementing redox sensitive transgenic mouse models. Importantly, this work will be facilitated and integrated by two critical research cores (dosimetry/physics and neurobehavioral). In the Dosimetry and Physics Core 2, radiation dosimetry will be cross-validated and technological innovation will be implemented across all irradiation platforms at the CHUV, Stanford and Indiana University. In the Neurobehavioral Core 3, animals irradiated at each performance site will be shipped to UCI where animals will be subjected to a standard and comprehensive battery of carefully controlled behavioral tests designed to evaluate how each irradiation paradigm functionally impacts cognition. The Administrative Core will serve as the organizational hub for all scientific and programmatic activities. The overall goal of this Core will be to centralize these activities while promoting efficiency in operations and transparency for the program investigators.

NIH Research Projects · FY 2025 · 2020-06

Project Summary/Abstract The MARC program at the University of California, Irvine (UCI) is a critical component of the School of Biological Sciences Outreach, Research Training and Minority Science Programs (MSP) to promote broad participation in the biomedical research workforce by increasing the number and academic excellence of trainees from diverse backgrounds pursuing Ph.D. degrees and careers in biomedical research. The MARC program has had a transformative institutional impact by preparing an unprecedented number of undergraduates from underrepresented groups that have obtained research doctorate degrees in biomedical sciences. MARC activities are designed to introduce trainees to biomedical research, improve their academic preparedness and interest in biomedical research with an increasing self-direction. MARC trainees are introduced to the excitement of generating new biomedical knowledge in a nurturing environment that stimulates their critical thinking skills, self-confidence, self-identity as scientists, with safety, rigorous research design and by conducting biomedical research responsibly, ethically, and with integrity. Independent research conducted under the direction of faculty mentors at UCI and at partner extramural sites serve as a core element to induce MARC scholars to pursue graduate school and research-focused careers. Over 80 faculty with funded research programs and experience training undergraduates (including individuals from groups underrepresented in the biomedical research workforce) serve as preceptors of MARC scholars. The MARC research training elements are integrated with the undergraduate curriculum and include, 1) individual career and academic advising, 2) a research faculty seminar series, 3) a journal club to introduce scholars to critical reading of current biomedical literature, 4) training in genomics, computational biology, statistics and methods to enhance reproducibility, 5) training in responsible conduct of research, 6) independent research directed by faculty mentors, 7) preparation to present oral presentations and posters at local and national conferences, 8) training in scientific communications, 9) workshops on application to graduate school, and 10) individual advice during the graduate school application process.

NIH Research Projects · FY 2026 · 2020-05

Huntington’s disease (HD), one of the first neurodegenerative diseases for which a genetic cause was determined, is an inherited neurodegenerative disorder that has no disease-modifying treatment. HD is caused by a CAG repeat expansion in the HTT gene encoding a polyglutamine (polyQ) tract within the amino terminal portion of Huntingtin (HTT). While the field has gained an understanding of the many cellular processes that are disrupted in HD, we do not yet understand the interplay between key proximal HD-associated events, such as the relationship between aberrant mutant HTT (mHTT) accumulation, RNA biology and epigenetic events in specific cell types in the brain. Similarly, we do not know how changes in these processes impact clinical manifestation of disease, where best to intervene therapeutically and what outcome measures may be the most informative in HD models. The overarching focus of the research proposed here is to fill vital gaps in our knowledge about how these factors impact onset and progression of HD and how that understanding might lead to new disease-altering therapies. The proposed research will leverage unique resources and methods developed in my lab and those of my collaborators and will utilize state-of-the-art technologies such as single-cell RNA-seq, mass spectrometry and cryo-electron tomography to dissect molecular mechanisms. Ultimately, treatments for this disease, including combination therapies, will likely require a much better fundamental understanding of how mHTT leads to HD pathology and death. Our recent data suggests unexpected relationships between protein posttranslational modification (PTM) pathways, aberrant mutant HTT accumulation and DNA damage responses in neurons, the latter now implicated as a critical modifier of HD age-of-onset. Using a systems biology approach we are learning how chronic expression and accumulation of mHTT impacts gene expression and now seek to develop a more comprehensive understanding of RNA biology and causal networks in specific cell types. Here I propose investigations aimed at addressing major gaps in our understanding of how the fundamental molecular and cellular events underlie how the mutant HD gene causes degeneration of specific cell populations in the brain to induce motor and cognitive decline and ultimately premature death of patients. My program benefits from the integrated use of patient iPSCs and HD mouse models and the extensive and productive collaborations we have established over many years. With the overall goal of understanding proximal and initiating events in the disease and developing therapies for HD, I propose two primary avenues of research relating to the integration of 1) protein homeostasis and 2) epigenetics and RNA biology in HD.

NIH Research Projects · FY 2026 · 2020-05

Abstract: An important unmet clinical need for patients with the demyelinating disease multiple sclerosis (MS) is an effective method for promoting remyelination that can ameliorate clinical symptoms associated with demyelination and restore motor function while limiting immune cell infiltration into the CNS. The long-term objectives of this research proposal are to i) define how chemokine signaling controls neuroinflammation and disease progression, ii) assess the effects of chemokine signaling in regulating oligodendrocyte progenitor cell (OPC) maturation and remyelination, iii) further characterize how engrafted human and mouse neural progenitor cells enhance axonal integrity, promote remyelination and influence neuroinflammation/demyelination, iv) define mechanisms by which microglia restrict the severity of demyelination and influence remyelination. To accomplish these goals, we will use a well-accepted pre-clinical animal models of MS. For over 20 years, my laboratory has used intracranial infection of susceptible C57BL/6 mice with the neuroadapted JHM strain of mouse hepatitis virus (JHMV) as a model of viral-induced demyelination to study molecular and cellular events controlling neurioinflammation, demyelination, and remyelination. Proposed experimental procedures that will aid in accomplishing our research goals will include genetic approaches through generation of mice in which targeted genes are either selectively induced/ablated to assess effect on disease progression and repair, CRISPR technology to ablate specific target genes in NPC cultures, single cell and nuclear RNA sequencing on immune cells and resident CNS cells and use of 2-photon (2P) microscopy to visualize axonal damage/repair and remyelination. Collectively, we believe our experimental goals outlined in this proposal will provide new insight into the pathogenesis of MS as well as identify new targets for therapeutic intervention to impede disease progression and promote remyelination.

NIH Research Projects · FY 2024 · 2020-04

PROJECT SUMMARY There is an urgent need to develop non-sputum biomarker-based triage and diagnostic tests for childhood tuberculosis (TB). This is particularly important for young children with HIV infection, who have high TB-related mortality but often cannot produce sputum and have lower sputum bacillary burden. Biomarker discovery for childhood TB requires ultra-sensitive platforms to measure low-abundant Mycobacterium tuberculosis (Mtb) proteins in clinical samples and greater investigation of host proteins, post-translational modifications of proteins, and metabolites that are more likely than upstream RNA expression to reflect the host-pathogen interactions that lead to TB disease. The overall objective of the proposed project is to identify Mtb- and/or host-derived biosignatures in children that can achieve World Health Organization (WHO) target product profile (TPP) accuracy thresholds for a non-sputum biomarker-based triage or diagnostic test for childhood TB. We hypothesize that biosignatures that combine Mtb proteins and host biomarkers with evidence of functional relevance to TB pathogenesis or immunity will have the best diagnostic performance. To assess this hypothesis, we will conduct biomarker discovery and initial clinical validation studies using samples from three well- characterized pediatric TB cohorts in Uganda, The Gambia and South Africa. In Aim 1, we will use an ultra- sensitive electrochemoluminescence (ECL)-based immunoassay to assess the presence of Mtb proteins ESAT- 6, CFP-10, MPT64, MPT32, and Ag85B in a discovery set of banked blood and urine samples from 100 children under 5 years old with confirmed TB and 200 with unlikely TB per NIH consensus definitions (50% HIV prevalence in both groups). In Aim 2, we will use the same discovery set to perform targeted and untargeted mass spectrometry with functional assessment through pathway analysis, in vitro models and in vivo mouse models to identify host proteins, post-translational modifications and metabolites that distinguish children with confirmed versus unlikely TB. In Aim 3, we will use the candidate Mtb and host biomarkers identified in Aims 1 and 2 to derive biosignatures with up to 10 analytes consisting of Mtb proteins only, host biomarkers only, and both Mtb- and host-derived biomarkers. Biosignatures that meet WHO TPP criteria in the discovery set will 1) be evaluated in an independent test set of banked samples from 300 children under 5 years old (100 with confirmed TB, 200 with unlikely TB; 50% HIV prevalence in each group) to verify diagnostic accuracy and establish cut- offs and 2) be evaluated in a prospective cohort of 350 children under 5 years old using the pre-select cut-offs and both microbiological and clinical reference standards. Completion of these aims will result in identification of promising biosignatures that can be further validated in large-scale field studies and translated into point-of-care triage and/or diagnostic tests for childhood TB.

NIH Research Projects · FY 2025 · 2020-03

PROJECT SUMMARY/ABSTRACT Colorectal cancer (CRC) is the third leading cause of cancer-related deaths in the United States. Despite the advantages of polyp screening for early detection, early-onset CRC incidence is on an alarming rise in young adults under the age of 50. Though the underlying cause of early-onset CRC remains fully undefined, suspected risk factors include behavior and lifestyle elements that govern systemic physiology and are under the control of the circadian clock. Strikingly, epidemiology evidence links deregulation of circadian rhythms through night shift work with multiple cancer types, including CRC. The circadian clock is the endogenous biological pacemaker which controls physiological, immune, endocrine, and metabolic processes that operate to maintain organismal homeostasis within a strict 24-hour period. Several lines of evidence suggest that deregulation of circadian rhythms results in cancer initiation and progression, yet the precise molecular mechanisms and detailed signaling pathways have yet to be elucidated. Moreover, in relation to CRC, the crosstalk between the circadian clock and proliferative, metabolic, and immune pathways in the intestine are not fully elucidated, and more specifically, how this crosstalk is involved in CRC progression remains unresolved. To address this knowledge gap, we have generated a genetically engineered mouse model (GEMM) to elucidate the effects of circadian clock disruption on the intestinal epithelium that drive CRC pathogenesis. Our central hypothesis is that disruption of the circadian clock aberrantly drives crucial signaling pathways that remodel the immune landscape, promote immunosuppression, and accelerate CRC. Aim 1 of this proposal will delineate the crosstalk between the circadian clock and crucial signaling pathways that regulation inflammation in the intestine. Aim 2 will define the underlying molecular mechanism of how the clock impinges on temporal control of tumor immunity. Aim 3 of this proposal will define how the circadian clock controls cellular metabolic pathways that could contribute to immunosuppression. Taken together, our studies have important clinical implications in understanding how disruption of the biological pacemaker, on the molecular level, alters tumor initiation and disease progression to accelerate CRC pathogenesis. These findings will provide novel insight and a molecular rationale for approaches underlying therapeutic targeting of the circadian clock for the treatment of CRC.

NIH Research Projects · FY 2026 · 2020-01

PROJECT SUMMARY/ABSTRACT Genital herpes simplex virus type 2 (HSV-2) infection affects over 60 million people in the U.S. and more than 530 million worldwide. After primary infection of the vaginal mucocutaneous tissue (VMC), the virus spreads and establishes latency in the dorsal root ganglia (DRG). Currently, there are no FDA-approved vaccines for genital herpes. Antiviral drug therapies reduce genital herpes outbreaks and ease painful symptoms, but neither cures the disease nor eliminates the virus, thereby allowing the causative agent of the disease to be maintained. Our long-term goal is to develop a therapeutic vaccine to induce long-lasting protection against recurrent genital herpes. Published and preliminary results: We have made several significant findings during the last funding period: We have demonstrated that (A) Three HSV-2 antigens, glycoprotein D (gD) and the RR1 and RR2 ribonucleotide reductase subunit proteins, are mainly targeted by CD4+ and cos+ T cells from "naturally'' protected asymptomatic men and women (i.e.,those who, despite being infected, never develop recurrent genital herpes); {B) RR1, RR2, and VP22 antigens are targeted by tissue-resident CD4+ and cos+ TRM cells that reside in the DRG and VMC of protected guinea pigs; (C) A therapeutic vaccine consisting of nucleoside-modified gD, RR1, RR2 and/or VP22 mRNAs encapsulated in lipid nanoparticles (LNP) {i.e., an mRNNLNP therapeutic vaccine) protected HSV-2 infected guinea pigs against recurrent genital herpes; (D) Frequent functional tissue-resident CXCR3+co4+ and CXCR3+cos+ TRM cells are boosted in the DRG and VMC of protected guinea pigs; {E) Treatment of HSV-2 infected guinea pigs with CXCL11 chemokine (a CXCR3 ligand) "pulled" more co4+ and coa+ TRM cells specifically into infected DRG and VMC and improved protection; and (F) Long-lasting CD4+ and cos+ TRM cells expressing CXCR8 and CCR10, the receptors of VMC-specific mucosal chemokines CXCL17 and CCL28, are maintained in the healed VMC of protected guinea pigs. Based on these published and preliminary results, we hypothesize that a vaccine that boosts and maintains antiviral CD4+ and coa+ TRM cells within DRG and VMC tissues would produce safe, robust, and sustained protection against recurrent genital herpes. To test this hypothesis, we propose two Specific Aims: Aim 1. To evaluate the safety and protective efficacy, in HSV-2 latently infected guinea pigs, of a "Prime/Pull/Keep" (PPK) therapeutic vaccine that consists of (1) Priming T cells with gD, RR1, RR2 and VP22 antigens; (2) "Pulling" primed T cells into latently infected DRG and VMC tissues by the T-cell attracting chemokine CXCL11, and (3) Maintaining T cells within the VMC by employing the mucosal chemokines, CXCL17 or CCL28. Aim 2. To determine whether increasing the number, function, and longevity of antiviral tissue-resident CD4+ and coa+ TRM cells within the DRG (central neuronal immunity) and VMC (peripheral epithelial immunity) correlates with protection against recurrent genital herpes. This research project aligns with the current NIH Strategic Plan to develop "New Therapeutic Strategies for Genital Herpes." If successful, it will pave the way for testing a PPK genital herpes vaccine in humans.

NIH Research Projects · FY 2025 · 2019-09

PROJECT SUMMARY Non-alcoholic fatty liver disease (NAFLD) contributes strongly to the development of insulin resistance, and the two mutually regulate each other in type 2 diabetes. In the liver of NAFLD and insulin resistance, hundreds to thousands of genes are either upregulated or downregulated. Epigenetic modifications such as histone methylation and acetylation modulate homochromatin or heterochromatin states to enhance or suppress gene expression in a context-dependent manner. However, significant knowledge gaps exist in mapping the epigenetic landscape and identifying the major epigenetic factors regulating the development of NAFLD and insulin resistance. In the current proposal, we take advantage of the newly developed CUT&TAG technology and create an epigenetic landscape of histone modifications, including H3K4me1 (poised marker), H3K4me2, and H3K27ac (active marker), and H3K9me2 (suppressive marker) in the liver of mouse and human NAFLD. A comprehensive analysis of the histone modification landscape identifies RE1 Silencing Transcription Factor (REST) as an epigenetic modulator that coordinates the activity of these histone markers. REST recruits histone deacetylases (HDAC1&2), which deacetylate H3K27ac, and lysine-specific demethylase 1 (LSD1), which demethylates H3K4me1 and H3K9me2, to regulate gene expression. Our preliminary data show that nuclear REST protein levels are increased in the liver of mouse and human NAFLD. Insulin and glucose treatment of cultured hepatocytes mimicking insulin resistance drives REST nuclear translocation. Knocking down REST using REST antisense oligonucleotides (ASO) in the liver of adult obese mice (REST-LKD) alleviates fatty liver and improves glucose and insulin tolerance. Hyperinsulinemic-euglycemic clamp studies show that REST knockdown in the liver increases glucose uptake in adipose tissue and muscle, indicating crosstalk between the liver and adipose tissue/muscle. These data show that hepatic REST is activated in insulin resistance, and the activated REST promotes the development of NAFLD and insulin resistance, forming a vicious cycle. Our central hypothesis is that REST is the key epigenetic factor orchestrating histone methylation and acetylation to regulate lipid and glucose metabolism in NAFLD and insulin resistance. We propose three aims to investigate what causes REST activation in NAFLD and insulin resistance, why the activated REST promotes NAFLD and insulin resistance, and how the activated REST induces systemic insulin resistance. Aim 1: To determine the mechanisms for the increased REST activity in the liver of NAFLD. Aim 2: To elucidate the mechanisms by which hepatic REST regulates lipid and glucose metabolism. Aim 3: To investigate the mechanisms for improved systemic insulin sensitivity in REST-LKD mice. Successful execution of the proposal will fill the knowledge gap by mapping the epigenetic landscape and identifying REST as a key epigenetic factor that reprograms metabolic gene profiles in NAFLD and insulin resistance.

NIH Research Projects · FY 2025 · 2019-09

NIH Merit Award (R37) extension request-R37CA240806, Xiang, (Shawn) Liangzhong The Overall Objective of this application is to enable in vivo dosimetry during radiation therapy in cancer patient to the end-user– the medical physicist. Our Hypothesis is that X-ray-induced Acoustic Computed tomography (XACT) can be used for 4D in vivo dosimetry in patients. In XACT, pulsed x-rays are absorbed and converted to heat. The resulting thermoelastic expansion generates a 3D acoustic wave, which can be detected by acoustic detectors to form images. The amplitude of the acoustic waves is proportional to X-ray absorption, and therefore encodes dose information. Our overall strategy is to design/construct a 3D XACT dosimetric scanner, and to test/refine the imaging prototype under clinical conditions based on an Academic-Industrial partnership among University of California, Irvine (UCI), University of Oklahoma Health Sciences Center (OUHSC), and PhotoSound Technologies Inc. Our original specific aims in year 1-5 are: (Specific aim 1) Evaluate the basis of the XACT imaging in radiotherapy dosimetry; (Specific aim 2) Develop a 3D XACT imaging system for clinical implementation; and (Specific aim 3) Validate the performance of XACT under clinical conditions. For year 6&7, we propose to develop dual-modal XACT/US imaging system that combines both XACT and pulse-echo ultrasound imaging. It can be used for 1) real-time monitoring the misalignment between the targeted tumor and the delivered radiation beam during radiotherapy, and 2) quantitative dose measurement in vivo, which will push the current paradigm to high-precision radiotherapy. This discovery is the first time in history that radiation dose in tissue could be directly visualized with high spatial and temporal resolution. If successful, the ability to localize the radiation beam and map the radiation dose will enable a paradigm shift towards high-precision radiotherapy.

NIH Research Projects · FY 2026 · 2019-09

ABSTRACT Since the 1980s, the US public’s exposure to ionizing radiation has increased, largely due to increasing radiation from diagnostic medical procedures such as computed tomography (CT) exams. The doses from such procedures are typically low but may be repeated over time and increase in frequency in later life. Quantitative estimates of radiation-associated cancer risk are primarily derived from the study of Japanese atomic bomb survivors. Questions have been raised about the appropriateness of using a study of atomic bomb survivors as the basis for contemporary estimates of radiation risk from protracted, low dose exposures. The parent study for this proposal assembled an international cohort of 308,000 radiation dosimeter-monitored workers from some of the world’s most informative cohorts in the United Kingdom, France, and USA, in a project called INWORKS. Here, we propose a major update that extends follow-up of each national cohort by at least 10 years, anticipated to yield more than a fifty percent increase in the number of cancer cases in the pooled analysis and support an innovative set of analyses to directly address questions relevant to radiation protection for low dose exposure to ionizing radiation in adulthood: 1) radiation-associated risks for solid cancer and leukemia; 2) cancer site-specific radiation risks; 3) cumulative absolute excess cancer risk estimates and their coherence with the risk models currently used to inform radiation protection and decision- making; 4) modification of site-specific excess relative rates (per unit dose) with time since exposure and age-at-exposure; and, 5) combined analyses of information from INWORKS and the Japanese atomic bomb survivor data to yield superior estimates of low dose radiation- cancer mortality associations. We leverage state-of-the-art G-estimation methods for cumulative risk estimation, Bayesian methods for data smoothing, and applied decision theory to guide policy-relevant summarizations of these empirical data. The study will provide a direct assessment of radiation risk following protracted, low dose radiation exposures in adulthood; and the findings will complement evidence regarding radiation risks derived from the study of Japanese atomic bomb survivors. The proposed study builds logically upon results of the highly successful parent study and is likely to exert a sustained influence on the field and make a major contribution to national and international radiation protection recommendations. Research outputs will be disseminated via peer-reviewed journals, presentations, a project website, and engagement with radiation protection organizations.

NIH Research Projects · FY 2026 · 2019-09

PROJECT SUMMARY This project, focused on biomedical big data analysis in cancer research, represents a response to the ongoing need for initiatives that enhance the capabilities of researchers in the field. As the volume and complexity of cancer-related data continue to grow, equipping researchers with data analysis skills and conceptual understanding is paramount. The 12-day workshop component of the renewal proposal aims to provide participants with the essential knowledge and practical skills necessary for proficiently handling and interpreting large-scale datasets, especially different types of omics data in cancer research. By fostering competence and confidence in data analysis, the workshop will contribute to a more informed and skilled research community, thereby enhancing the utility and value of the NCI-funded data. Through its rigorous curriculum and hands-on training, our proposal aligns with current data analysis challenges while providing flexibility and adaptability over the performance period. The proposal is a follow-up to two previous rounds of funding and underscores our ongoing commitment to advancing cancer research through robust data analysis techniques. The continued demand for big data training is supported by the results from the survey of our workshops and the substantial number of applications to the workshop each year. This proposal includes an updated course that leverages the successes and insights gained from the current big data courses for cancer researchers and the previous courses on big data training for biomedical researchers supported by NIH/BD2K, ensuring the topics are adapted to the constantly evolving nature of big data in cancer research. Our multidisciplinary team includes expertise in basic cancer research, clinical oncology, bioinformatics, biostatistics, and computer science by harnessing the collective expertise from the Chao Family Comprehensive Cancer Center of the University of California, Irvine (UCI), University of Colorado Cancer Center, and the Anvil supercomputer (number 143 on the Top500 list of the world's most powerful supercomputers). University of California, Irvine is in a unique position to lead a big data education program through partnerships with the current American Association for Cancer Research (AACR) epidemiology workshop team, the Frederick National Laboratory for Cancer Research (FNLCR), the Cancer Informatics for Cancer Centers (Ci4CC), and the Big Ten Cancer Research Consortium (Big Ten CRC). By targeting cancer researchers who appreciate the value of big data but lack the analytical skills necessary, this renewal proposal will incorporate new topics in current cancer research and establish a cohesive big data community for sustainable communications of workshop participants. The overarching goal of the proposed renewal project is to empower the participants with skills and confidence to efficiently manage, visualize, analyze, integrate big data, and derive meaningful insights from the analyses, which can help them meet the critical need of the growing availability of precision oncology-based treatments.

NIH Research Projects · FY 2026 · 2019-09

PROJECT SUMMARY Atomistic molecular simulations provide a suite of testable observables that yield essential mechanistic insights into a variety of diseases, ranging from cancer to neurodegenerative disorders. These insights are vital for the development of therapeutic strategies. Yet, accurately modeling complex processes such as order-disorder transitions, ionic interactions, and events at the biomembrane interface remains a formidable challenge with current methods. This is largely due to the intricate modeling required for electrostatic and polarization effects across varying structural states and solvent environments – an endeavor that current approaches struggle to perform efficiently. Our hypothesis to address the accuracy requirement is that biomolecules situated in diverse chemical contexts are best modeled within a polarizable framework to ensure satisfactory transferability. Departing from traditional methods, our polarizable Gaussian Multipole (pGM) model represents charges and multipoles with Hermite-Gaussian functions, rather than the conventional delta functions. This advanced representation enhances the model's accuracy, self-consistency, and transferability. Nonetheless, a known drawback of polarization treatments is their tendency to compromise simulation efficiency. To address this, we are pioneering a multi-scaled framework that integrates all-atom polarizable, coarse-grained polarizable, and continuum polarizable models. These models are designed for consistent interaction within multi-scaled simulation methods, facilitating more efficient interfacing. Our plan can be summarized in the following four areas: (1) the development of pGM force fields; (2) the development of continuum pGM solvent models; (3) the development of coarse-grained pGM models; and (4) the validation and application of our computational models to biomedical challenges. We will apply our models to significant biomedical issues, with a particular focus on biomolecular recognition and its association with conformational changes and allostery. To ensure our models address the most pressing challenges, such as order-disorder transitions linked to biomolecular recognition, we will validate them against these complex phenomena. Our commitment extends to the annual release of new models and tools, aiming to provide a broad and enduring contribution to the biomedical research community.

NIH Research Projects · FY 2025 · 2019-08

PROJECT SUMMARY This proposal is the resubmission of the first competing renewal application for five years of funding to support Training in Microbiology and Infectious Diseases at UC Irvine. The primary objective of this Training Program is to provide doctoral students with integrated training in three focus areas: 1) microbial structure and metabolism, 2) microbe-host interactions, and 3) microbial communities. The rationale behind this training structure is that there will be tremendous value in individuals with fluency in these related areas that are vital to combating and/or exploiting microbes to positively impact human health and the environment. The Training Program will leverage areas of excellence at UCI in microbial ecology, microbe-host interactions, and structural biology to bring together faculty trainers with expertise in microbial pathogenesis, molecular genetics, metabolism, structure, immunity and infectious diseases, and microbial diversity. The program will be comprised of 20 well-funded training faculty (9 women, 11 men, of which 3 are URM faculty) from the Schools of Biological Sciences, Medicine, and Physical Sciences at UCI. The faculty mentors conduct research on microbiology and infectious diseases at the molecular, cellular, organismal, population, and microbiome community levels. UCI has a strong history in microbiology, infectious disease, and microbiome research. The Training Program will ensure that the trainees will be equipped with the necessary tools and expertise to pursue a productive and independent career in microbiology. In the renewal, there is a new emphasis in data science and bioinformatics to reflect the evolving needs in the microbiology field. In addition to faculty mentorship, the trainees will benefit from seminars, journal clubs, research in progress talks, an annual career panel, outreach events, and an annual symposium. Trainees will also receive funds to travel to and present their research at a national meeting in their field. Finally, UCI is home to the NIH-funded GPS-STEM program, which will ensure that trainees have exposure to career development seminars, workshops, and mentorship throughout their training. The renewal application requests support for four predoctoral trainees, who will be drawn from students who enroll at UCI through one of several gateway or departmental programs. In our last funding period, the mean GPA of appointed trainees was 3.90, reflecting a strong overall academic performance by the potential trainees. All appointed trainees who have graduated have remained in a science-related field. Notably, 66.7% of our trainees were URM students during the last funding period. UCI has been recognized as a Hispanic-serving institution (HSI) and an Asian American, Native American, and Pacific Islander serving institution (AANAPISI), and the Training Program is expected to reflect this rich cultural and ethnic diversity on the UCI campus.

NIH Research Projects · FY 2025 · 2019-07

Project Summary The Howard Schneiderman Interdisciplinary Training Program in Learning and Memory is based at the University of California - Irvine Center for the Neurobiology of Learning and Memory (CNLM), a top-ranked and highly visible organized research unit established in 1983 by the UC Regents with James L. McGaugh as its Founding Director. The Center’s interdisciplinary faculty are working to achieve a complete and integrated understanding of how the brain stores and remembers information across all levels from molecules to mind. Of the Center’s more than 90 active research faculty, 21 are the core training faculty for this program, representing strengths in molecular, cellular, circuit, systems, cognitive and computational neuroscience of learning and memory. The program’s goal continues to be to train the next generation of innovative leaders in neuroscience by empowering them with the skills, knowledge, and team science core values necessary to comprehensively understand the neural basis of learning and memory. The program is aimed at predoctoral trainees with five slots offered every year and an average duration of appointment of less than 2 years. It features 9 key components that provide unique education training in the range of skills required for a successful research career in learning and memory: (1) a problem-focused seminar course that promotes transdisciplinary and divergent thinking in learning and memory; (2) a course on neural dynamics and computation; (3) a workshop on transdisciplinary team science; (4) workshops on research-intensive academic careers (Life Skills for the Academic); (5) a series of workshops on quantitative approaches to scientific inquiry; (6) participating in journal clubs; (7) participating in professional development, networking, and conference travel activities; (8) participating in T32 program retreats; and (9) participating in mentoring meetings. The activities fulfill many of the advanced requirements for coursework and do not increase time to degree completion. The program also provides ample opportunities for leadership and service, as well as value added beyond the T32 trainees to extend to other students in the same laboratories. We focus on empowering mentors with training and skills through Mentor Training and continue to use our joint preceptorship program to train junior mentors. The overall training program leverages the existing resources and activities in UCI’s graduate training, adds new training components that are unique to trainees of this program, and provides a host of optional activities for professional development. Desired outcomes include successful completion of PhD, published manuscripts, quantified improvement in transdisciplinary thinking and behavior, individual fellowships (e.g. NRSA), successful placement in postdoctoral training, and subsequent career in research-intensive or research-related areas. With several value-added components, this training program will continue to successfully prepare our trainees to be future leaders in the neurobiology of learning and memory.