University Of California, San Diego

NIH Research Projects · FY 2025 · 2009-07

The NIBIB Graduate Training Program in Multi-Scale Analysis of Biological Structure and Function at the University of California San Diego was established in 2005. Its goal is to train a new cadre of scientists who can cross disciplinary boundaries to solve important biomedical problems that span scales of biological organization from molecule to organism. Pre-doctoral trainees are drawn exclusively from a formal Interdisciplinary Ph.D. specialization in Multi-Scale Biology (the “Interfaces Graduate Training Program”), which includes students from 9 highly ranked participating home Ph.D. programs (Bioengineering, Biological Sciences, Biomedical Sciences, Chemistry and Biochemistry, Mechanical and Aerospace Engineering, Neurosciences, Materials Science & Engineering, Chemical Engineering and Nanoengineering). Students apply at the end of their first year of graduate studies. This T32 program brings together 39 interdisciplinary training faculty from 14 departments. Since its inception and at the time of the last T32 renewal, 48 predoctoral trainees on this T32 had graduated, including 8 from Biological Sciences, 20 from Engineering departments, 8 from Health Sciences and 12 from the Physical Sciences. In the current renewal period (Yr-16) it has supported 6 trainees from the Health Sciences (2), Engineering (4) with 27 competitive prospective applicants pending review and placement for the continuation (Yr-17). A central feature of the training curriculum is seven hands-on graduate laboratory courses that introduce students to advanced techniques for measuring and analyzing living systems at scales of biological organization spanning from molecule to whole organism. Students use state-of-the-art facilities and technologies from mass spectrometry to live cell microscopy and magnetic resonance imaging. Computational labs cover multiscale modeling, neurodynamics and data sciences. The scientific focus on multi-scale analysis of biological structure and function reflects a fundamental challenge of modern biomedical science in developing and applying novel quantitative approaches from the physical, engineering, biological and health sciences to integrative problems in biomedicine. Regular program activities, including bi-weekly graduate seminars, annual symposia and retreats, course open houses and quarterly program meetings, promote interactions between students and faculty from different scientific disciplines. The dual-mentored training program is successful in promoting new interdisciplinary collaborations in important areas including developmental biology, neuroscience and cancer, cardiovascular disease, diagnostics and drug discovery. This T32 continues to train the most competitive student body to be effective leaders in structurally integrated multi-scale analysis of biological function. It includes formal instruction in Rigor and Reproducibility, has an expanded Alumni Mentor Network for trainees and a structured co-mentored interdisciplinary research rotation for all prospective students.

NIH Research Projects · FY 2024 · 2008-07

Project Summary/Abstract The Neurosciences Graduate Program (NGP) at UC San Diego (UCSD) is committed to training the next generation of neuroscience leaders. The NGP brings together world-class research institutions and laboratories at UCSD, The Salk Institute, The Scripps Research Institute, and the Sanford Burnham Institute, to create one of the largest and most diverse neuroscience environments in the world. The proposed training program combines this environment with a progressive, quantitatively rigorous curriculum covering multiple neuroscience disciplines, mentored research with world-leading investigators, collaborative opportunities across clinical and academic settings, and mentored professional development. Research productivity and placement of prior NGP trainees is outstanding, with most trainees continuing in scientific research and higher education. The NGP consistently ranks among the top graduate programs in US. The proposed training program supports 1st and 2nd-year NGP students and is endorsed by strong institutional support. The program reinforces close, productive interactions between students and faculty. Incoming students receive intensive hands-on laboratory training in a two-week Boot Camp that provides a unique bonding experience. Students choose thesis labs after completing the core courses and research lab rotations in the first year. Student progress is closely monitored through formal evaluations, with individually tailored career advising and mentorship. Scientific interactions among students and faculty are facilitated through student-run journal clubs, discussion courses, student talks, colloquia, outreach programs, recruitment activities, and an annual retreat. The NGP has met prior goals to increase program size by enhancing institutional support, and to strengthen recruitment and retention of underrepresented students. Representation of URM students in the NGP is now the highest among all UCSD STEM graduate programs, and the overall size of the program has increased by nearly 40%, to 102 PhD students, since 2012, while recruitment and admission have remained highly competitive (applications have doubled since 2007). Our guiding mission to develop tomorrow's leading neuroscientists is founded on rigorous skills in experimental design, statistical methodology and quantitative reasoning. Over the next five years, the NGP has set a goal to strengthen and comprehensively integrate the tenets of quantitative rigor, reproducibility, and research transparency into all aspects of the training program. This includes broadening the quantitative scope of the NGP by expanding the successful Computational Neuroscience specialization, modifying curricula, and altering mentoring practices to anticipate future challenges for data collection, access, and analysis. Our goal is a broad interdisciplinary neuroscience training environment that emphasizes strong quantitative skills coupled to rigorous experimental design and statistical methodology.

NIH Research Projects · FY 2026 · 2007-08

SUMMARY The Interdisciplinary Research Fellowship in NeuroHIV (IRFN) is a two-year research education program anchored on the premise that our future success in tackling the complexity of clinical problems in neuroHIV depends on the availability of researchers with the training to imagine problem-solving approaches that cut- across and integrate multiple relevant research disciplines. To this end, we have followed an interdisciplinary and translational model of research training aimed at bridging the gaps left by single discipline approaches. Our program functions as a neuroHIV-themed Special Institute emphasizing interdisciplinary and translational research through immersion into the vibrant research setting of the HIV Neurobehavioral Research Program (HNRP) and two main programmatic components: mentored research and focused didactics. Participants receive close mentoring by experts in the field, leveraging the expertise of preclinical and clinically oriented neuroHIV researchers. The IRFN outlines a clear progression toward independence in order to consolidate each Fellow’s future success. Participants learn to approach neuroHIV research questions from an interdisciplinary and translational perspective, with potential clinical applications as an essential end point of their work. In the proposed renewal we will equally engage clinically trained as well as basic postdoctoral and early career neuroscientists seeking to apply their talents to research on patient-oriented problems in neuroHIV. This serves our translational goals by engendering “cross-pollination” of ideas. The research experiences of IRFN fellows will be in the laboratories of high-caliber, nationally and internationally recognized neuroHIV researchers. Core competencies will cover current thinking in NeuroHIV, from molecular to behavioral phenomena, general research principles, research ethics, and grant writing skills. Essentials of good mentoring will also be taught formally using evidence-based curricula. Additional didactics will center on professional development and electives to enhance participants’ knowledge and individuation in areas of interest. Principles of equity, diversity, and inclusion will be upheld across all components of the IRFN. Proposed for this renewal is the introduction of seed funding for Fellows to conduct a focused, vetted pilot project in an area aligned with NIMH HIV research priorities and the research themes within the HNRP, with the aim of facilitating a future extramural funding application. The IRFN features: (1) outstanding faculty who have a long history of mentoring researchers to become independent investigators, (2) individualized education, including research experiences that are tailored to individual needs, (3) core and flexible didactic experiences, including lectures by leading neuroHIV researchers, and (4) active evaluation and oversight of the program by a multidisciplinary advisory committee.

NIH Research Projects · FY 2025 · 2007-07

Renewed funding is requested to continue a T32 training program to train the next generation of prevention scientists with expertise in HIV and related co-morbidities among substance users. Our program builds upon two joint doctoral programs in Public Health and Interdisciplinary Research on Substance Use offered in partnership between the University of California San Diego (UCSD) School of Medicine and the San Diego State University (SDSU) Graduate Schools of Public Health and Social Work, and a doctoral program in Biostatistics offered in the newly founded UCSD Herbert Wertheim School of Public Health. Our objectives are: 1) To provide interdisciplinary training experiences for pre-doctoral students and postdoctoral fellows in epidemiology, health behavior, and biostatistics, and public health who wish to focus on prevention research at the intersection between substance abuse and HIV or other syndemics (e.g. viral hepatitis, TB, STIs, overdose, stigma, trauma); 2) To support advanced training in key NIH research areas, including a new focus on data sciences applied to substance use and HIV or related syndemics in both domestic and international settings; 3) To train individuals in the responsible conduct of research (RCR) with human subjects, especially in international and cross-cultural settings. In sum, during the past 4 years, our program supported 26 trainees (11 predoctoral and 15 postdoctoral fellows).  Of completed trainees 2017-2021, (8 predocs and 8 postdocs), all but 1 are still active in the field. Time to matriculation for predocs averaged 3 years. Five K-series awards were newly awarded to postdocs.  Our 26 predocs and postdocs published 84 and 116 manuscripts, respectively, 44% of which were first authored. We request continued support for 4 predoctoral and 4 postdoctoral trainees, who will be mentored from a pool of 30 Preceptors. Depending on their level of training, mentees complete courses in substance use and infectious diseases, RCR instruction, seminars on scientific rigor, presentations on 'Work In Progress', and seminars (e.g., Writing Circle). Our active research projects in nearby Mexico and numerous other lower and middle income countries offer the opportunity for unique, hands-on international training experiences and a robust infrastructure for trainees to develop into independent investigators focused on prevention of HIV and related syndemics among substance using populations.

NIH Research Projects · FY 2025 · 2007-07

The UC San Diego Department of Radiology is submitting a competitive renewal of its postdoctoral Clinician- Scientist Training Program. The objective of the program is to train clinician-scientists in imaging research, promote their career development, and cultivate their passion for academic radiology. Clinician-scientists are necessary for the development and translation of new imaging technologies into clinical practice, which may otherwise remain on the bench without direct application to human disease. To support and nurture a pathway for physician-scientist trainees, we have leveraged our institutional resources to implement a unique and 5-Year Residency Program that integrates rigorous research and intense clinical education. Into this program, we admit up to three radiology residents per year. All our trainees are MDs or DOs, and most have combined MD/PhDs. The trainees dedicate their first year to laboratory research, followed by 32 weeks of protected research time during the subsequent 4 years of clinical training. The additional research time allows trainees to continue to cultivate projects initiated during the first year, publish results, and apply for grant funding, building an academic portfolio that allows them to transition to academic faculty positions. Trainees select from a strong pool of faculty research mentors at UCSD, who are themselves highly productive researchers with track records of strong collaborative research and grant support from NIH and industry, many of whom serves as models of the physician-scientist career. For this proposal, we have assembled 12 Radiology and 12 non‐Radiology research mentors with an average grant support of over $1.1M per faculty member. Scientific areas span the translational spectrum and include molecular imaging, magnetic resonance imaging, quantitative ultrasound methods, microCT, deep learning image analysis, and imaging biomarker validation. Supplementing these robust career mentorship relationships are numerous opportunities to promote resident education and engagement. Regular monthly lectures and workshops are given by notable experts in topics relevant to the research residents, such as academic career development, success in research, and responsible conduct of research. Participation in scientific conferences, departmental Grand Rounds, and other meetings offer opportunities for residents to share their work through formal presentations. Senior research residents serve as program chief residents to learn leadership and administrative skills, facilitate trainee feedback, provide mentorship to their more junior colleagues, and help ensure the program supports the trainees’ needs. Our graduates emerge with strong foundations in research and clinical radiology, positioned to become successful clinician-scientists with the potential to shape and drive the continued advancement of our field.

NIH Research Projects · FY 2025 · 2007-05

SUMMARY/ABSTRACT The objective of the T32 funded “Integrated Fellowship on the Epidemiology and Prevention of Cardiovascular Disease" is to rigorously train physicians and behavioral scientists in epidemiologic and behavioral research methods focused on preventing cardiovascular diseases by a) providing trainees with an integrated, comprehensive, and intensive 2-year research training experience in CVD prevention and/or behavioral medicine, b) linking trainees with highly experienced and dedicated mentors who will supervise the research experience and evaluate their progress, and c) providing instruction to these trainees on multiple related components of the research process, including relevant didactic coursework, protection of human subjects in research, confidentiality requirements, elements of appropriate and unbiased analysis of data, and finding post-training employment. The program began in 2007 focused on epidemiology and prevention. During that first funding period (2007 – 2012), we learned that, while all trainees are focused on prevention, some had an epidemiologic focus while others were more interested in behavioral medicine. In order to accommodate these different interests, and for the funding period from 2012 – 2017, we changed the structure of the program by expanding the leadership to two Co-Directors; one with experience in cardiovascular epidemiology (Criqui) and the other with experience in behavioral medicine (Marcus), while retaining an Associate Director (Allison). During that funding period, the number of positions was expanded from four to five (2 predocs and 3 postdocs). During the next [current] cycle (2017 – 2022), the number of trainees increased to six (2 predocs and 4 postdocs) and the leadership was changed such that Dr. Allison became the Program Director and Dr. Marcus remained the Co-Director, while Dr. Criqui became the Senior Associate Program Director. Two years into this funding cycle, Dr. Marcus left the University of California at San Diego (UCSD) to become the Dean of Public Health at Brown University. To address this change, Dr. Criqui became the Co-Director. For the proposed funding period (2022 – 2027), and since Dr. Criqui will be retiring, Dr. Allison will remain the Program Director and we propose Dr. David Strong, who has specific expertise in behavioral medicine, to be the program Co-Director. To develop the potential future leadership of the program, we also propose to add two junior faculty: Jan Hughes-Austin as Associate Program Director and Isac Thomas as Assistant Program Director. Both have completed our T32 program, have active research programs and are dedicated to mentorship of junior trainees. To achieve the program objectives, faculty for the proposed program have been recruited from Divisions across the Schools of Medicine and Public Health. Faculty have also been recruited from the Graduate School of Public Health at San Diego State University (SDSU), which has teaching programs in both epidemiology and health behavior. Notably, UCSD and SDSU co-sponsor two joint doctoral programs closely linked to this proposal: Public Health and Clinical Psychology.

NIH Research Projects · FY 2026 · 2007-02

Abstract The UCSD Collaborative Clinical Trials Unit (CTU) will bring together seven dynamic U.S. and International Clinical Research Sites (CRSs) to facilitate innovative scientific synergies and leverage research collaborations among investigators across our CTU and to contribute our scientific expertise and our diverse participant populations to further the research priorities of the NIAID HIV/AIDS Adult Therapeutics Clinical Trials Network and the HIV Prevention Clinical Trials Network. Our seven CRSs include: 1) the UCSD Antiviral Research Center (AVRC) CRS; 2) the University of Southern California (USC) CRS; 3) the University of Colorado Hospital (UCH) CRS; 4) the Houston AIDS Research Team (HART) CRS; 5) the University of Miami CRS; 6) the Chennai Antiviral Research and Treatment (CART) CRS, and; 7) the Durban International (DI) CRS. Each will bring considerable strength to achieve the future research goals of two of the four NIAID networks. Our Collaborative CTU brings together a wealth of expertise, experience, and the high quality performance required to conduct complex clinical trials in the following areas: HIV cure and functional cure; viral persistence and latent reservoirs; broadly neutralizing antibody approaches to treatment and prevention of HIV; pathogenesis and treatment of HIV-related inflammation, coinfections and comorbidities; new antiretroviral drugs and novel formulations for HIV treatment and prevention; treatment and prevention of tuberculosis (TB) in persons with mono- and HIV-coinfection; and biomedical, socio-behavioral, and multipurpose technology strategies to prevent HIV transmission (including pre-exposure prophylaxis [PrEP], HIV preventive vaccines, and molecular epidemiology to target “hot spots”) in populations at high risk for HIV transmission. Our CTU provides access to and long-standing experience with community engagement in underrepresented Hispanic/Latinx, Black/African American, African, and South Asian populations at risk for or affected by HIV and its complications. Our U.S. CRSs span several of the highest burden regions for chronic and new HIV infections in the southeast (Miami), south (Houston), southwest (Denver) and border regions (Los Angeles, San Diego) identified in the U.S. “Plan to End the HIV Epidemic” campaign. Our international CRSs include two of the highest burden regions globally for both HIV and TB, particularly drug-resistant TB (Southern India and South Africa). We will address the following specific aims. Specific Aim 1: To provide outstanding, innovative scientific contributions and leadership to the HIV/AIDS Adult Therapeutics Clinical Trials Network and the HIV Prevention Clinical Trials Network. Specific Aim 2: To provide effective and efficient administrative and financial resource management. Specific Aim 3: To engage and partner with diverse communities affected by HIV to shape network scientific agendas and to recruit, enroll and retain a broad diversity of research trial participants in network studies.

NIH Research Projects · FY 2026 · 2007-01

The HIV Centers for Underrepresented Populations in Research Clinical Trials Unit (CURE CTU) will be comprised of five highly experienced and successful Clinical Research Sites (CRS) within the continental U.S. and a sixth new CRS located at Children’s National Medical Center in Washington, DC. Each of the CRSs has >20 years of experience conducting clinical research in pregnant women, infants, children, adolescents and young adults with and at-risk for HIV infection. Each of the HIV CURE CRSs is located in one of 48 counties or in Washington DC, geographic locations that have been targeted by the U.S. President’s initiative to end the HIV epidemic. The CURE CTU management is located at the University of California San Diego; Dr. Stephen A. Spector will serve as the Principal Investigator. The six CRSs are located at Baylor College of Medicine/Texas Children’s Hospital in Houston, TX, Ann & Robert H. Lurie Children’s Hospital of Chicago, IL, Northwestern University, St. Jude Children’s Research Hospital and the University of Tennessee Health Science Center in Memphis, TN, University of Miami, Holtz Children’s Hospital, Miami, FL, Children’s National Medical Center in Washington, DC, and the University of California, San Diego, CA. The CURE CTU is the only unit specifically focused on research in pregnant women, women, children, adolescents and young adults less than 25 years in the continental U.S. funded through NIAID. The Specific Aims address many of the targeted high priority areas of the four NIAID proposed Networks. Aim 1: Identify novel and durable interventions to reduce reservoirs and control HIV replication in the absence of ART (ART- free remission) (ACTG Aim 1 and IMPAACT Aim 2). Aim 2: Advance ART of pregnant and postpartum women with HIV, to optimize maternal and infant health outcomes, and accelerate the evaluation (PK, safety, antiviral efficacy), licensure and optimal use of potent and durable ARVs for pregnant women, infants, children and adolescents with HIV (IMPAACT Aim 1). Aim 3: Design and conduct studies of broadly neutralizing antibodies (bnAbs), alone and in combination, and long-acting antiretroviral agents and delivery systems for pre-exposure prophylaxis (PrEP) (ACTG Aim 2, HPTN Aim 1, IMPAACT Aim 1). Aim 4: To investigate vaccination of HIV- exposed and unexposed infants to induce broad immune responses including broadly neutralizing antibody (HVTN Aim 4). Specific Aim 5: Design and conduct studies to evaluate multipurpose prevention technologies that concurrently prevent HIV and pregnancy, sexually transmitted infections or opioid dependence (HPTN Aim 2). Aim 6: Determine optimal and feasible methods for the prevention and management of complications and co-infections of HIV infection and their treatment in infants, children, adolescents and pregnant and postpartum women (IMPAACT Aim 4). Aim 7: Prevent or improve the treatment of HIV-related non-infectious co- morbidities and evaluate strategies to cure hepatitis B virus infection in people with/without HIV (ACTG Aim 4, HVTN Aim 1).

NIH Research Projects · FY 2025 · 2006-09

PROJECT SUMMARY Centrosomes, the major microtubule organizing centers in animal cells, are duplicated precisely once per cell cycle to catalyze microtubule generation for rapid bipolar spindle assembly and ensure accurate chromosome segregation. Centrosome amplification and fragmentation are frequently observed in cancer cells and are thought to contribute to their chromosome instability and aneuploidy. Centrosomes are comprised of a centriolar core that recruits pericentriolar material matrix to dock microtubule-nucleating g-tubulin-containing complexes (γTuCs). Given the central role of centrosomes in cell division and their frequent aberration in cancer, there has been significant interest in developing centrosome-targeting agents for cancer therapy. In this proposal, we elucidate distinct centrosomal microtubule generation mechanisms that contribute to spindle formation and address how the primacy of the centrosome as the dominant site for spindle microtubule generation is maintained. The dominance of centrosomes as mitotic microtubule nucleation centers, which reinforces bipolarity of the spindle, is ensured in part by the mitotic kinase PLK1, which independently controls expansion of the pericentriolar matrix and matrix-anchored microtubule nucleation during mitotic entry. PLK1 executes both tasks by phosphorylating distinct regions of the primary structural component of the pericentriolar matrix (CDK5RAP2 in humans, Cnn in Drosophila and SPD-5 in C. elegans). In Aim 1, we will pursue parallel biochemical and in vivo approaches in the C. elegans embryo to determine how PLK-1 phosphorylation remodels the pericentriolar matrix component SPD-5 to enable gTuC docking and activation. We will also determine how centrioles recruit and organize the mitotic pericentriolar matrix and dictate its size, inspired by preliminary data indicating that the mitotic pericentriolar matrix is not simply an expansion of interphase pericentriolar matrix, but is an independent entity. In addition to phosphoregulation enforcing dominance of centrosomes as microtubule-generating sites, the primacy of the centrosome is ensured by the ubiquitin ligase TRIM37, which functions as a “guardian of the centrosome”. TRIM37 prevents rogue collections of centrosomal proteins from forming ectopic microtubule- organizing centers. In Aim 2, we address how TRIM37 recognizes and suppresses ectopic centrosomal protein assemblies, by focusing on its signature TRAF domain that is unique in the TRIM superfamily, its potential ability to oligomerize, and its ubiquitin ligase activity. Centrosomes in human cells have at least two mechanisms for microtubule generation that independently support spindle assembly: the well-studied pericentriolar matrix- anchored mechanism and a pericentriolar matrix-independent centriole-anchored mechanism. In Aim 3, we investigate the assembly and function of a specific type of ectopic microtubule-organizing center formed in TRIM37 mutant cells that is independent of the pericentriolar matrix, concentrates core centriolar proteins, and robustly supports spindle formation in the absence of centrosomes. This effort should shed light on poorly understood pericentriolar matrix-independent mechanisms for spindle microtubule generation in human cells.

NIH Research Projects · FY 2025 · 2006-09

PROJECT SUMMARY The objective of this application is to highlight the San Diego Pelvic Floor Consortium (SDPFC) site qualifications to continue in the next cycle of the Pelvic Floor Disorders Network (PFDN). The success of the SDPFC in the PFDN has largely been due to our proven two-site model, which combines the strength of a tertiary academic medical center (University of California San Diego – UCSD) and a large volume community based health maintenance organization (Kaiser Permanente San Diego – Kaiser). Our site has contributed meaningfully over the past three cycles by designing and selecting cutting edge clinical trials ideally suited to this multi-centered, multi-disciplinary research network. We intend to continue to foster novel research ideas and work collaboratively with the other clinical sites and the data-coordinating center to refine studies ideally suited to clinical trials requiring large-scales and diverse populations. We boast a history of successful concept development, experience in survey development and refinement, successful implementation and recruitment for large-scale clinical trials, extensive experience in implementation of randomized trials of behavioral and surgical interventions, and maintaining high retention rates and quality data. Our proposed SMART design randomized trial of Transurethral Bulking Agent vs. Single Incision Sling (BASIS) represents an innovative and timely study of novel treatment approaches for women with stress urinary incontinence. The 15 members of the SDPFC are a diverse group of urogynecologists and urologists with the depth and breadth of scientific and clinical expertise necessary for the PFDN to continue advancing the field. Additionally, our site has an established research institution, funded by the NIH sponsored Clinical & Translational Science Award, with the full spectrum of resources and personnel available to conduct basic science, translational, epidemiologic, behavioral, and clinical research across a diverse racial/ethnic community. The SDPFC is poised to continue to recruit subjects into existing and upcoming trials at the highest levels. The intellectual contributions, leadership experience, diversity and experience in collaborative research projects makes the SDPFC ideal for this network.

NIH Research Projects · FY 2025 · 2006-07

PROJECT SUMMARY/ABSTRACT This renewal application seeks funding to continue the highly successful Cancer Therapeutics Training (CT2) Program at the Moores Comprehensive Cancer Center at the University of California, San Diego. About 40% of Americans will develop cancer in their lifetime. More than 600,000 fall to cancer each year. The mission of the CT2 program is to train PhD and MD-physician-scientists who will become the next generation of leaders in the field of cancer drug and therapeutics in each of the major steps required for successful translation of laboratory- based discoveries into safe and effective therapeutic agents. The CT2 training is designed to position trainees to play key leadership roles in the field of oncology therapeutics. The 31 faculty of the CT2 Program are all Members of the Cancer Center and are appointed in 11 departments in the School of Medicine, the Skaggs School of Pharmacy and Pharmaceutical Sciences or the general campus. Each faculty preceptor is an accomplished investigator and educator with a history of training superb postdoctoral fellows. Each has substantial peer-reviewed cancer or cancer-related research funding. All of the participating faculty are conducting translational research and have been selected because of their interest in new cancer therapeutics. This program is extensively integrated with other activities of the UC San Diego Moores Cancer Center and the extensive biotech/pharma industry in San Diego. The goal is to recruit and retain 8 MD and PhD scientists in this two-year program that will position them for careers in the development of new cancer drugs or the diagnostics needed to guide the use of these drugs in the era of personalized medicine. The training program components include: the completion of formal didactic teaching sessions that cover tools essential to the drug development process; the conduct of one or more steps in therapeutic development research project under the direction of a faculty preceptor; and required participation in individual development plans, including yearly attendance at the annual meeting of the American Association for Cancer Research or an equivalent national meeting. Trainees are also expected to participate in Cancer Center and Departmental seminars, research rounds, and journal clubs to expand the breadth of their understanding of cancer research and prepare formal project plans and practice or real grant applications for review by the Executive Committee. Methods are in place to ensure that all trainees are properly instructed in the principles of responsible conduct of research and scientific integrity. Trainees are recruited nationwide and special efforts are made recruit and retain exceptional candidates from groups historically underrepresented in biomedical sciences.

NIH Research Projects · FY 2025 · 2006-06

SUMMARY CD8 T cells play a key role in the elimination of intracellular infections and malignant cells and can provide long- lived protective immunity. In the response to infection, CD8 T cell metabolism is coupled to transcriptional, translational, and epigenetic changes that are driven by extracellular metabolites and immunological signals. These programs facilitate the adaptation of CD8 T cells to diverse and dynamic metabolic environments encountered in circulation and tissues. Defining the metabolic adaptations of CD8 T cells to specific tissue environments informs our understanding of how these cells protect against pathogens and tumors and maintain function at tissue barrier sites. Following the resolution of infection, a portion of effector CD8 T cells differentiate into long-lived memory CD8 T cells that either recirculate or establish long-lived tissue-resident memory T cells (TRM). Lodged in tissues throughout the body, CD8 TRM make up a significant portion of the T cell arsenal against reinfection and tumorigenesis. TRM adaptation is of special relevance at tissue-barrier sites, such as the small intestine (SI), where exposure to the microbiome, opportunistic pathogens, and diverse as well as fluctuant amounts of nutrients possible. However, the functional metabolic adaptations of T cells to tissue residency, including any variations between tissue types, are only beginning to be understood. We have found that TRM undergo tissue- specific metabolic adaptations and highlight the cholesterol biosynthetic pathway, and Srebp2, a key transcriptional regulator of cholesterogenesis to be of special relevance for SI-TRM formation. Based on these preliminary data, we hypothesize that the sustained induction of the cholesterol biosynthetic pathway is a key adaptation by SI TRM and that understanding the basis for this dependence will shed light on memory T cell homeostasis. We propose to: Aim 1) Investigate the role of Srebp2 in differentiation and homeostasis of effector and memory T cell populations and to uncover the relevant intermediates and products of this pathway for TRM, and Aim 2) Place Srebp2 in the transcriptional network that drives SI TRM and establish the impact of known SI TRM-inducing tissue cues on Srebp2 expression. Results from these studies will be crucial to the understanding of how CD8 T cell fate and function are mechanistically connected to their metabolism and will help design therapeutic approaches that harness the beneficial actions of CD8 T cells.

NIH Research Projects · FY 2026 · 2006-01

Title: Mechanisms of Compartmentalized cAMP Signaling Project summary: As a ubiquitous second messenger, cyclic AMP (cAMP) regulates a variety of processes that are critical to cell physiology, such as cell growth, proliferation, metabolism, survival and mobility. In pancreatic β cells, cAMP and its main effector cAMP-dependent protein kinase (PKA) are dynamically regulated in response to glucose or hormones such as glucagon-like peptide-1 (GLP-1), and in turn regulate β cell functions such as insulin release and proliferation. Despite extensive studies over the last >40 years, the mechanism by which the cAMP/PKA signaling pathway regulates different cellular functions with exquisite specificity is still not well understood. A better understanding of this ubiquitous signaling pathway is crucial to developing therapeutic strategies for clinical conditions such as obesity and type 2 diabetes mellitus, especially considering the therapeutic uses of GLP-1 drugs. Two long-standing mysteries have puzzled the field for more than 40 years. First, phosphodiesterases (PDE), the enzymes involved in degrading cAMP, have been suggested to play critical roles in the formation of cAMP nanodomains to account for specific signaling, yet the low catalytic efficiency of PDEs and fast diffusion of cAMP cannot explain this model of cAMP compartmentation. Secondly, A-Kinase anchoring proteins (AKAPs) are known to bind the regulatory subunits of PKA and assemble signaling complexes containing PKA holoenzymes, specific substrates, and other regulators, thereby directing and modulating specific biological effects of cAMP signaling; yet in a classical model, cAMP binding to the regulatory subunits leads to the dissociation of the catalytic subunit of PKA (PKA C), destroying the PKA signaling micro-compartments. Our recent discoveries of biomolecular condensates formed by the PKA regulatory subunit RIα led to a new conceptual framework that addresses both mysteries. We discovered that RIα undergoes liquid-liquid phase separation (LLPS) and that these condensates serve as a dynamic buffering system to sequester cAMP, allowing PDEs to effectively create cAMP microdomains. We also found that PKA C is retained in these condensates via a noncanonical PKA holoenzyme, which is critical for maintaining low basal PKA activity in the cytosol. Altogether we published 28 peer-reviewed journal articles (with 2 additional manuscripts). In the current proposal, building on these discoveries, we will test our hypothesis that formation of the noncanonical holoenzyme complex within both RIα condensates and AKAP-assembled signalosomes underlies high signaling specificity and functional versatility of cAMP/PKA signaling in β cells. Specifically, we will develop novel molecular tools to interrogate the spatiotemporal regulation of cAMP/PKA signaling in living cells, examine the signaling impact of the cytosolic RIα condensates and plasma membrane AKAP nanoclusters and investigate compartmentalized glucagon-like peptide-1 receptor (GLP-1R)-mediated signaling in β cells.

NIH Research Projects · FY 2025 · 2005-08

Project Summary/Abstract This is a renewal application from the University of California San Diego (UC San Diego), in conjunction with two neighboring institutions (the Sanford-Burnham-Prebys Institute and the Salk Institute), for a 5-year renewal of the Medical Student Training in Aging Research (MSTAR) program, in response to the RFA-AG-25-009. Over the past 20 years, we have trained 300 students nationwide. Since the last renewal, a majority (65%) of our MSTAR students have come from racial/ethnic minoritized groups, 28.6% from underrepresented minoritized groups, 67.3% women, and 22.4% from disadvantaged backgrounds. Most of our MSTAR students have presented at national conferences and are co-authors of peer-reviewed manuscripts. After graduation, all our trainees have continued training in major programs, with several pursuing academic careers in aging research and geriatrics. The proposed program is designed to expand the pipeline of new physician investigators in the field of aging. It will provide full-time support for 8-12 consecutive weeks of research and clinical training during summer, provided by faculty to 18 medical students annually from across the country. We will make special efforts to recruit medical students from underrepresented racial or ethnic minoritized groups, trainees with disabilities, and those from disadvantaged backgrounds. All trainees will spend the summer in San Diego, working under the supervision of some of the finest molecular, translational, health services, and clinical scientists with outstanding track records of NIA and other federal funding and of research training of medical students. A primary focus of our program will be on aging well in the context of age- associated disorders and disabilities. The strengths of our faculty range from basic and molecular biology to clinical, epidemiology, and therapeutic research on aging and age-related disorders such as Alzheimer’s disease and other dementias, cancer, cardiovascular diseases, age-related macular degeneration, arthritis, substance use disorders, health equity, and depression. The most important aspects of this program will be hands-on research experience and developing a long-term mentoring relationship. In addition, a combination of didactics and clinical exposure to geriatrics will reinforce the skills learned in the direct research experience. The trainees will give an oral presentation at a workshop at UC San Diego held in early August and work with their mentors to submit an abstract at a national conference and develop a publishable manuscript within a year. An Executive Committee will oversee the recruitment and training of the students. There will be a rigorous and extensive program evaluation by trainees, participating faculty, an External Advisory Board, and other stakeholders, as well as long-term follow-up. A website will facilitate continued communication among the trainees and their mentors.

NIH Research Projects · FY 2025 · 2005-05

PROJECT SUMMARY For the development of an organism from a single cell, the genome must be duplicated and precisely distributed during every cell division. Given the astronomical number of cell division events involved in building and maintaining organisms (by one estimate, the adult human body is made up of 40 trillion cells, with at least a couple of trillion dividing every day), it becomes critical that the distribution of the replicated genome to daughter cells, a process known as chromosome segregation, occurs with extremely high accuracy. Errors in chromosome segregation underlie birth defects/infertility and are sufficient to trigger the genomic havoc that is a hallmark of cancer. Thus, understanding the mechanisms by which cells ensure accurate chromosome segregation during cell division has both fundamental and therapeutic significance. Our work is focused on kinetochores, protein machines that assemble on mitotic chromosomes to orchestrate their segregation. Kinetochores coordinate multiple microtubule-interfacing activities that collectively orient and segregate chromosomes, while also integrating mechanical events with signaling mechanisms that control the decision to either remain in or exit from mitosis. Our early work identified a conserved set of proteins, referred to as the KMN network (for Knl1 complex, Mis12 complex, Ndc80 complex) that lies at the heart of these coordinated kinetochore functions. In Aim 1, we focus on the ability of kinetochores to both accelerate and delay exit from mitosis, which we propose optimizes mitotic duration to allow sufficient time for all chromosomes to connect to the spindle, while also minimizing time spent in a vulnerable phase when major cellular functions such as transcription, translation and secretion are downregulated. The work we propose tackles major open questions related to this duality of mitotic timing control by kinetochores. The primary mechanical activity of the kinetochore is to couple to dynamic spindle microtubules. Several distinct microtubule-interfacing activities concentrate at kinetochores as well as on mitotic chromatin, which makes analysis of chromosome-microtubule interactions challenging in a cellular context. In Aim 2, we describe a "blank slate–add back" approach, in which we eliminate all microtubule-interfacing activities on mitotic chromosomes and then add them back in isolation. This approach complements traditional loss-of-function analysis and will be used to study the microtubule-interfacing activities at kinetochores that orient and center chromosomes on the spindle and that shut of the signal that prevents mitotic exit until microtubule attachments are made. Finally, to achieve accurate segregation, kinetochore-microtubule interactions must be tightly regulated. In Aim 3, we focus on the poorly understood regulatory mechanism by which a spindle pole-generated gradient of the mitotic kinase Aurora A controls kinetochore-microtubule attachments. As Aurora A is amplified in specific cancer contexts, this effort has the potential to reveal cancer-specific dysregulation of chromosome segregation and suggest potential new therapeutic avenues.

NIH Research Projects · FY 2025 · 2004-08

Project Summary We will continue to refine our computational modeling approach to the design, construction and char- acterization of genetic circuits. We will develop new microfluidic tools to grow and observe how single cells and bacterial colonies respond to heterogeneous environmental conditions (in Aims 1 and 2) and we will test engineered adaptive strains in tumor spheroids (in Aim 3). The quantitative analysis of cellular behavior across multiple experimental platforms will inform mathematical models that will be used to identify key design characteristics, which will then be rigorously tested using previously established tech- niques. Two Postdocs, a Staff Research Scientist, and two Graduate Student Researchers will work with Drs. Hasty and Tsimring on multiple aspects of the project in an integrated manner. Our track record demonstrates our ability to train personnel in a multi-disciplinary approach that has led to new tools for synthetic biology, along with an increased understanding of gene and signaling networks generally. Our past characterization of bacterial circuits in animal tumor models highlighted the need for a pre- dictive understanding of how engineered bacteria function in heterogeneous environments. Accordingly, our Specific Aims focus on computationally-driven engineering of (i) adaptive synthetic clonal populations, (ii) spatially organizing colonies that respond to heterogeneous environments, and (iii) thermally-activated gene circuitry that enables low density population capping during initial strain differentiation. Specifi- cally, our first aim will generate phenotypic heterogeneity and thereby rapid adaptation to environmental condition within a clonal population. We will co-transform two distinct plasmids with shared replication machinery to couple their copy numbers and generate copy number heterogeneity. Our prelminary mod- eling predicts that single strains carrying coupled plasmids are not only capable of phenotypic adaptation to environmental stimuli, but also can retain their divergent state in the absence of continued stimuli. We propose that this suggested memory property of our populations can be engineered to be either reversible using plasmid stabilization or permanent using inducible copy number repression. Our second aim will center on the development of a new multi-dimensional microfluidic system to investigate engineered popu- lation patterning within tumor-relevant small molecule gradients. Preliminary modeling presented in the proposal characterizes the conditions when single strains with coupled plasmids can differentially colonize across tumor-relevant heterogeneous environments. Lastly, we will engineer an ultrasound-activated liv- ing therapeutic within nonuniform tumor environments. Following spatial differentiation of two adaptive strains, we will use ultrasound to “flip” a toggle switch from low density growth to high population-cycling growth. We will test this system in colo-rectal tumor spheroids, using methods developed in the previous cycle of this grant.

NIH Research Projects · FY 2025 · 2004-07

R01 CA104509-15 “Molecular Mechanism of Leukemogenesis involving AML1-ETO” PROJECT SUMMARY Cancer is the most devastating human disease in the world, affecting almost everyone directly or indirectly. Acute myeloid leukemia (AML) is a highly heterogeneous and aggressive hematological cancer. One of the most common genetic abnormalities in AML is the t(8;21) chromosomal translocation, resulting in the fusion transcription factor AML1-ETO. Due to currently unclear reasons, t(8;21) AML patients are younger and respond to initial induction chemotherapy better than most other AML patients. However, only 50-60% of t(8;21) AML patients respond to initial chemotherapy and ~40% of initial responders relapse. Further treatment options after relapse are limited and prognosis is generally poor. Therefore, we still need to understand the unique molecular basis of t(8;21) AML to expand therapeutic options for treating and saving these patients. Our long-term goal is to identify critical molecular pathogenic events that promote development and maintenance of AML as potential therapeutic targets. The overall objectives of this competitive renewal application are to elucidate the critical chromatin remodeling events that promote t(8;21) AML and to characterize vulnerabilities of t(8;21) AML that will facilitate elimination of leukemia cells. Our central hypothesis is that molecular alterations directly caused by expression of AML1-ETO provide unique pathological conditions of t(8;21) AML, which can be targeted by novel therapies. To attain the overall objectives, the following two specific aims will be pursued: 1) Analyze the combinatory effect of t(8;21) and KIT mutations on leukemogenesis through integrative transcriptome and epigenome studies in mouse models and 2) Characterize glutathione and oxidative phosphorylation in sensitizing t(8;21) AML to cell death. Together, these proposed studies are based on our accumulated knowledge, our most recent findings, and the potential therapeutic impact of the work. Collectively, this proposal will address important unanswered questions in t(8;21) AML and provide valuable insights into the molecular pathology of human leukemia.

NIH Research Projects · FY 2025 · 2004-07

Electroencephalography (EEG), the first function brain activity imaging modality, has several natural advantages over metabolic brain imaging modalities. EEG is noninvasive, low-cost, and lightweight enough to be used for recording in lifelike situations. A major shift in scientific perspective on the nature and use of human electrophysiological data is now ongoing, a shift to using EEG data as a source-resolved, relatively high-resolution 3D cortical source imaging modality. The EEGLAB signal processing environment is a readily extensible open-source software project of the Swartz Center for Computational Neuroscience (SCCN) of the University of California, San Diego (UCSD). EEGLAB began as a set of EEG data analysis running on MATLAB (The Mathworks, Inc.), released by Makeig on the World Wide Web in 1997. EEGLAB was first released from SCCN in 2001. Now 21 years later, its reference paper {Delorme, 2004 #1} has over 18,450 citations (increasing by 6.8 per day), its opt-in EEGLAB discussion email list links over 6,000 researchers, its EEGLAB news reaches over 15,000, and an independent 2011 survey of 687 research respondents reported EEGLAB to be the software environment most widely used for electrophysiological data analysis in cognitive neuroscience. EEGLAB citations and other metrics show that EEGLAB adoption is still growing steadily. Here, we will greatly augment the power of the EEGLAB environment by providing support for processing both intracranial (iEEG, sEEG) and mobile brain/body imaging (MoBI) data (EEG and behavior), and will further integrate tools for performing high-resolution source imaging from EEG (or iEEG) data. Its suitability for multi-modal brain/behavioral recording is one of the strengths of EEG recording compared to other imaging modalities. Multimodal data review and processing tools will be incorporated into EEGLAB, to further support the development of tools for processing mobile brain imaging data. We will develop a framework for source connectivity analysis using (1) a hierarchical Bayesian framework for clustering effective source processes identified by independent component analysis on multiple measures across subjects and studies and (2) region of interest (ROI) dynamics estimation by beamforming. We will further revise the EEGLAB architecture to use a file and metadata organization compatible with the Brain Imaging Data Structure (BIDS) specifications. These tools will integrate the Hierarchical Event Descriptor (HED) event annotation system to enable innovative meta-analyses across data from multiple studies. These continuing developments will further the use of non-invasive and (as per clinical need) invasive human electrophysiology for 3-D functional cortical brain imaging, thereby accelerating progress in noninvasive basic and clinical human brain research using highly time- and space-resolved measures of brain electrophysiological dynamics.

NIH Research Projects · FY 2024 · 2004-02

Project Summary/Abstract: The splicing of mRNA is a complex biological process that enormously enhances the diversity of proteins within a limited set of protein-coding genes in the cell. While integral for normal function, errors in splicing can occur and lead to various diseases including muscular dystrophy, Alzheimer's disease, parkinsonism, cardiovascular disease, ataxias and cancers. Splicing relies on essential factors known as SR proteins that bind precursor mRNA and then selectively incorporate other protein/RNA elements ultimately leading to a macromolecular machine known as the spliceosome that performs the necessary excision of certain non-coding elements. The SRPKs are a family of protein kinases that phosphorylate and direct SR proteins to the nucleus where they participate in these essential splicing functions. Although much is known about SRPK function in the cytoplasm, less is known about their role in the nucleus. Furthermore, although SRPKs are best known for their role in splicing, we showed recently that SRPK1 phosphorylates protamines, thereby regulating protamine-to-histone exchange on the paternal genome upon fertilization. We will investigate how SRPK1 forms a complex with a second protein kinase in the nucleus to activate the phosphorylation and release of SR proteins and the U1 snRNP component U1-70K for splicing function. We will also explore how SRPK1 uses a novel recognition mechanism compared to SR proteins to phosphorylate protamines and induce DNA phase transitions and genomic decondensation necessary for oocyte development. These studies will involve a broad range of biophysical and biological techniques including mass spectrometry, molecular and cell biology, enzyme kinetics, and confocal microscopy. Overall, the experiments outlined in this proposal will address the key functions of the protein kinase SRPK1 in controlling protein diversity as well as at the earliest stages of life.

NIH Research Projects · FY 2025 · 2003-08

ABSTRACT A diverse U.S. biomedical research workforce is essential for developing innovation in basic, clinical, translational research and healthcare and is necessary for improving the nation’s health. Despite decades of efforts to increase underrepresented racial / ethnic groups and women in science their proportional representation remains markedly low, especially in academia. The renewal application for the San Diego IRACDA Scholars Program aims to enhance the successful transition of diverse biomedical scientists into independent academic careers. San Diego “SD IRACDA” is a mentored postdoctoral career development training program that provides training in rigorous and reproducible research, teaching training based on scientific principles and professional skill development. SD IRACDA combines a mentored research-intensive experience at the University of California, San Diego (UCSD) and mentored teaching training experience at San Diego City College and San Diego State University (SDSU), two large undergraduate institutions that serve diverse student populations. The overarching goal of SD IRACDA is to enhance the transition of diverse biomedical scientists into independent academic careers, thereby increasing the diversity of academic faculty. The specific objectives are to: 1) recruit and train a diverse pool of postdoctoral scholars that conduct rigorous and reproducible research within the scope of the NIGMS-mission, 2) use evidence-based strategies to enhance career skill development and effective mentorship of postdoctoral scholars, and 3) to provide teaching training in scientific teaching principles and evidence-based practices. Other objectives are to enhance the science curriculum at our partner-teaching intensive institutions, and to provide research opportunities for partner institution faculty and students and role models and mentorship of students, thereby increasing the number of diverse students participating in research and entering graduate programs in biomedical sciences. Since its inception in 2003, SD IRACDA has trained 103 scholars, 62% are from underrepresented backgrounds and 59% are women. Program evaluation has demonstrated that 63% of all SD IRACDA scholars and 56% of underrepresented scholars have obtained independent faculty positions (94% tenure-track) including a high percentage at R1 institutions, 32% of all scholars and 34% of underrepresented scholars, respectively. Of SD IRACDA faculty alumni, 55% have received independent grant awards with the highest percentage (31%) from the NIH. SD IRACDA scholars publish, obtain academic faculty positions and receive post-fellowship funding at a greater rate compared to NIH F32-supported postdoctoral fellows at UCSD. SD IRACDA has further benefitted the partner institutions, San Diego City College and San Diego State University, by providing new and improved science curriculum, authentic research experiences and critical mentoring for underrepresented students to enhance academic advancement and train the next generation of scientists.

NIH Research Projects · FY 2025 · 2002-12

The overall mission of the UCSD/UCLA DRC centers on supporting research in the prevention and treatment of diabetes and its complications to ultimately improve the lives of patients. For the past 22 years, our DRC has been unique in linking together the diabetes/metabolism research activities of two major universities within the UC system and their affiliated institutions in Southern California. This effort has fostered new collaborations and interactions between outstanding scientists within and across these institutions. Our research base is comprised of the following focus areas: Integrative Physiology, Cell Signaling and Transcriptional Regulation, Genetics and Genomics, Translational Sciences and Complications. Each of these areas has outstanding leaders who facilitate interactions and sharing of resources. The DRC has played an important role in promoting the careers of young scientists as they move to the status of independent investigators by awarding pilot and feasibility grants. As an acknowledgement of our success in this effort, UCSD and UCLA have agreed to provide $100,000/year in additional unrestricted funds to augment our P&F program. The DRC will continue to advance scientific and intellectual interactions by organizing and facilitating meetings, lectures, and mentoring efforts that are part of our Enrichment Program, and we continue to pay special attention to including diverse viewpoints and experiences. We will further accelerate diabetes research at the DRC Institutions by providing state-of-the-art services through five cutting edge cores: A) The Transgenic and CRISPR Mouse Core, B) Metabolic and Molecular Physiology Core, C) Epigenetics and Genomics Core, D) Human Genetics Core, and E) Biological Imaging Core. All our research cores have been updated with new services and the latest technologies in response to the needs of our faculty and the many advances in this field as they relate to diabetes and metabolism research. Our efforts to support the cores and facilitate collaboration have been successful, as can be judged by the numerous collaborative publications in high impact journals and the substantial peer review grant support our faculty have accrued. The current competitive renewal application includes many new scientific and technological advancements, including the incorporation of new services that are now available to our members in a streamlined fashion. Our future plans include the continued seamless integration of research at all participating institutions to enhance technology and research capability within the DRC, with the addition of a new cadre of affiliated investigators at neighboring institutions. We will continue to promote the careers of promising young investigators through our successful P&F Program, and to accelerate translational research activity and collaborations through interactions with the CTSA programs at both institutions and beyond.

NIH Research Projects · FY 2025 · 2002-09

PROJECT SUMMARY Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly termed nonalcoholic fatty liver disease (NAFLD), affects approximately 25% of adults and 10% of children in the United States. Multi-factorial in its pathogenesis, the clinical/histologic spectrum of MASLD encompasses steatosis, metabolic dysfunction- associated steatohepatitis (MASH), variable degrees of fibrosis, and cirrhosis. The presence of MASH or advanced fibrosis due to MASLD are associated with increased risks of hepatic decompensation, hepatocellular carcinoma (HCC), and death. There are currently no FDA-approved therapies for treatment of MASH. The sheer scale of the affected population creates an urgent need for effective treatments as well as non-invasive modalities and biomarkers that alone or in combination accurately 1) predict who is at high risk for disease progression in the MASLD population, 2) detect and stage MASLD, MASH, and liver fibrosis, 3) predict treatment response, as determined by ≥ 1-stage improvement in fibrosis or MASH resolution. Since its inception in 2002, the NASH CRN has worked collaboratively to characterize the natural history of MASLD, define its pathogenesis, and develop superior diagnostics and effective treatments. During the past funding cycle (2018-23), the CRN completed recruitment for the longitudinal adult and pediatric Database 2 registry (N=3,068) and the STOP-NAFLD trial (N=83). In addition, it initiated two studies: 1) Database 3, a longitudinal study of the etiology, natural history, diagnosis, treatment and prevention of MASLD and MASH with a goal of recruiting a diverse cohort, and 2) the Vitamin E Dosing Study (VEDS), a clinical trial with the primary aim of determining the minimum effective dose of Vitamin E for MASH. The NASH CRN’s highly characterized cohorts, including more than 700,000 biospecimens in the NIDDK repository, together with the investigator’s expertise in leveraging public-private partnerships, has allowed us to perform innovative clinical trials and pursuits in diagnostic development and validation that can only be addressed by engaging in a coordinated, longitudinal, comprehensive research consortium. The overriding primary objective of the NASH CRN continues to be clinical research on MASLD in children and adults. A secondary objective of high priority is to conduct translational research in MASH and MASLD and to develop superior diagnostics and treatments, with a focus on diagnostics that are non-invasive and treatments that are safe, affordable, effective and readily available. The specific aims proposed to achieve these objectives from the UCSD Clinical Center during the continuation of the NASH CRN are to 1) complete the Database 3 Study, 2) complete the VEDS Study, and 3) validate and advance development of novel non-invasive biomarkers for MASH, at-risk MASH, and advanced fibrosis or cirrhosis.

NIH Research Projects · FY 2026 · 2002-09

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NIH Research Projects · FY 2025 · 2001-04

OVERALL PROJECT SUMMARY/ABSTRACT For over two decades, the NIMH P30 HIV Neurobehavioral Research Center (HNRC) has been a leader in the neuroHIV field, supporting research that has greatly advanced our understanding of the central nervous system (CNS) consequences of HIV disease, as well as their predictors, prevention, diagnosis, and treatment. In this renewal application, we propose to continue supporting innovative, basic/mechanistic, clinical, and translational studies of HIV, its treatment, and comorbidities. This will include studies of persistence (e.g., proviral epigenetics) and eradication of HIV in the CNS (“cure” agenda) and the role of gut microbiome alterations in HIV-associated CNS disorders. Depressive disorders have long been recognized to be highly prevalent among persons with HIV (PWH) and, especially when combined with cognitive impairment, may result in adverse consequences in many areas of public health concern, including poorer healthcare engagement, antiretroviral therapy effectiveness, social engagement, and life quality. Using both dimensional and diagnostic assessment approaches to depression and cognition, we aim to support research identifying and characterizing complex neurobehavioral phenotypes in PWH, determining their underlying biological mechanisms (e.g., inflammation, gut dysbiosis), and examining their effects on critical outcomes in PWH. These aims will be achieved by drawing on data and biospecimens from a registry of over 1200 well characterized PWH and HIV-uninfected participants, who have received comprehensive HNRC examinations during the last 5 years. During the proposed renewal period, we also will enrich the HNRC data and biospecimen resource by conducting 200 comprehensive assessments per year of registry participants who are identified on briefer semi-annual assessments as undergoing changes in neuromedical status, mood, cognition, or everyday functioning. The HNRC Participant Registry also will be refreshed with new participant enrollments. Together, these evaluations aim to determine the biological mechanisms underpinning neurobehavioral changes in PWH, as well as their clinical risk factors and consequences, with a view toward informing future interventions. This renewal builds on the track record of the HNRC as a national and international leader and a resource that facilitates research on pathogenesis, phenomenology, treatment, and prevention of neurobehavioral disturbances in PWH. To accomplish these goals, we propose four redesigned Scientific Cores (NeuroBehavioral and Psychiatry, NeuroMedical, Microbiome, and NeuroVirology and Biology) that will strongly support the HNRC aims and provide intellectual leadership and technical support. An Administrative Core will support and coordinate their activities, and a Developmental Core will support innovative pilot studies and coordinate training opportunities to help advance the careers of the next generation of neuroHIV scientists.

NIH Research Projects · FY 2025 · 1999-08

SUMMARY This UC San Diego Women’s Reproductive Health Research (WRHR) Career Development Program addresses the urgent need to train physician-scientists in OB/GYN and Women's Health, so that they can develop into independent leaders who will advance Women's Health. WRHR Scholars with strong prior clinical and research experience who are committed to academic careers as physician-scientists focused on Women’s Health are selected through nationwide searches. Led by the Recruitment Officer, the Program leadership and the Diversity Committee select the most qualified candidates for consideration by the Internal and External Advisory Committees. Scholars are matched with primary Mentors, who are established scientists with relevant expertise and strong mentorship experience. The Program has a team of 22 internationally recognized Mentors, with 12 in the Department of OB/GYN & Reproductive Sciences. These Mentors, along with 41 additional Collaborators, have diverse and complementary expertise in basic, translational, and clinical research, and conduct research in a variety of relevant areas, including impacts of social and cultural factors on Women’s Health, pre- and perinatal physiology, family planning, female pelvic medicine, reproductive endocrinology, embryology, and gynecologic oncology. At any given time, there are projected to be 2 WRHR Scholars, who are appointed as Assistant Professors. The Program is organized into 2 phases: in the first 1-2 years, Scholars gain research competency; in the subsequent 3-4 years, efforts work toward research independence and academic expertise. In Phase 1, didactic and practical instruction in epidemiology, biostatistics, data management, and informatics supplements intensive research training, with minimal clinical work. In Phase 2, Scholars join the UCSD National Center for Leadership in Academic Medicine program, which teaches academic development, leadership, and organizational effectiveness and prepares the Scholar to excel as an accomplished Associate Professor. Individualized instruction in grant writing, ethics, and medical enterprise, and quarterly workshops on career advancement topics, are conducted by the highly experienced Leadership Team and Program Faculty. Program faculty closely monitor the Scholars’ progress. Program leadership meet with Scholars monthly and Individual Mentorship Committees (appointed specifically for each Scholar) meet twice per year, ensuring that the research environment and clinical demands are optimized and balanced. The Internal and External Advisory Committees review the Scholars annually to assess their advancement and determine reappointment to the Program. The success of the UC San Diego WRHR Program is demonstrated by the academic achievements of its past graduates, which includes 4 who are now members of the mentorship team. The Program looks forward to continuing to recruit exceptional Scholars, and providing them with the rigorous training in cutting-edge interdisciplinary research and career development support that will enable them to succeed as independent investigators who will make critical discoveries related to Women’s Health and translate them to the clinic.