University Of California, San Francisco

NIH Research Projects · FY 2025 · 2025-08

Tuberculosis is caused by infection with Mycobacterium tuberculosis and is a major global health threat with nearly 10 million new cases and 1.7 million deaths every year. 40-60% of patients with TB are not initiated on effective treatment, in large part due to the lack of informative diagnostics. Whole blood transcriptomic signatures have been extensively investigated as biomarkers, but the most promising signatures when implemented in multiple countries, was not useful for targeting short-course TB preventive therapy, and has substantial overlap with transcripts induced by other viral respiratory infections. We will pursue the highly translational concept that plasma cell-free RNA (cfRNA) is a promising new class of blood borne biomarker for TB. cfRNA measures cell death of circulating cell types and peripheral tissues and provides a fundamentally different window into disease dynamics relative to whole blood RNA (wbRNA). Our hypothesis is supported by a case-control study (see pilot studies) of 251 adult patients from three cohorts in Uganda, Vietnam and the Philippines in which plasma cell-free RNA signatures differentiated patients with active TB disease and symptomatic TB-negative patients with high sensitivity (97.1%) and specificity (85.2%) and correlated with measures of disease burden including CXR score. This test performance exceeds the minimum accuracy criteria for a TB triage test and outperforms best-in-class wbRNA biosignatures. We will couple well-characterized cohorts of TB patients from multiple countries, with advanced molecular assays and computational approaches i) to validate plasma cfRNA signatures in a large patient cohort of 1,378 adult participants recruited at clinical sites in five countries (samples available, Aim 1), ii) to compare the diagnostic accuracy of cfRNA against other host response readouts (data available), including Xpert TB Host Response (Xpert HR), Chest X-ray (CXR) and C-reactive protein (CRP) (Aim 1), iii) to translate the most promising cfRNA signatures to a prototype PCR assay (Aim 1), iv) to test the possibility to predict severity of disease on CXR, a key feature of current TB treatment stratification algorithms (Aim 2), and iii) to assess the utility of cfRNA signatures as a test of cure, and to monitor for relapse (Aim 3). Our specific aims are: Successful implementation of this study will provide a comprehensive evaluation of plasma cell-free RNA as an analyte to identify active TB disease in patients living with and without HIV and with and without diabetes, and to monitor therapeutic interventions. These studies have great potential for human health impact: there is an acute need for more informative biomarkers of TB, and cfRNA in plasma represents a fundamentally new class of biomarker. Successful implementation of this study will inspire future studies to translate promising cfRNA signatures into point-of-care assays and to develop cfRNA signatures of TB progression and incipient TB.

NIH Research Projects · FY 2025 · 2025-08

Statement of the Problem: Pulmonary fibrosis (PF) is a chronic lung disease characterized by tissue scarring and is common in interstitial lung diseases (ILDs). ILDs contribute significantly to global mortality and healthcare expenses. Some ILDs are considered idiopathic, but research indicates that exposure to inhalants like vapors, gases, dust, and fumes at work or in the environment can promote fibrosis and inflammation, leading to PF. Most research focuses on treatments and comorbidities, neglecting the impact of preventable occupational and environmental exposures. Additionally, marginalized communities with higher exposure rates are rarely studied. Investigating inhalational exposures can help shape environmental policies and workplace safety, preventing PF in affected communities and vulnerable workers. Specific Aims: I aim to use epidemiologic tools to assess the occupational and environmental risk factors and progression of fibrotic ILD, analyzing a large dataset, the California Electronic Death Registration System (Cal- EDRS), and an ongoing prospective cohort, the University of California San Francisco UCSF ILD Cohort Study. In Aim 1, I plan to systematically develop a new PF-specific job-exposure-matrix (PF-JEM) and measure the association between occupational exposure and PF in the Cal-EDRS. In Aim 2, I will assess the interaction of environmental and occupational exposures on the occurrence of PF in the Cal-EDRS, using air pollution data from the CalEnviroScreen and geospatial techniques. To achieve Aims 1 and 2, I will utilize a case-control study design in the Cal-EDRS to measure the association between occupational and environmental exposures using multiple predictor models and stratified analysis. Finally, in Aim 3, I will evaluate the interaction of environmental and occupational exposures on clinical outcomes of IPF in the UCSF ILD Cohort Study, including survival, using multivariable Cox proportional hazards analysis with stratification. Significance of the results. The Cal-EDRS and the UCSF ILD Cohort Study offer a unique opportunity to study the interplay of occupational and environmental exposures on PF utilizing state-of-the-art exposure assessment techniques of a JEM and residential address geocoding. This study is innovative through its linkage of a novel PF-JEM to both a rich dataset of vital statistics records and an ongoing cohort study to investigate the risks and clinical patient outcomes of PF due to inhalational exposures. Career Development: With the above proposal, Dr. Gandhi will achieve her training goals of 1) Epidemiologic occupational exposure assessment, 2) Advanced environmental exposure assessment using geospatial techniques, and 3) Survival analysis and clinical outcomes assessment of exposed patients with ILD. The K23 award will facilitate her transition to independence as a physician-scientist who utilizes innovative epidemiological methods and exposure metrics to develop a research program focusing on clinical outcomes of patients with occupational and environmental lung disease.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY/ABSTRACT Background: Despite the success of T cell therapies in treating hematologic malignancies, solid tumors remain a significant challenge due to their dense fibrotic stroma, immunosuppressive microenvironments, and antigen heterogeneity. Current adaptive cell therapy approaches struggle to overcome these barriers, highlighting the need for novel strategies. Myeloid cells, including macrophages and dendritic cells, possess inherent abilities to infiltrate tumors, secrete cytokines, and cross-present antigens within the tumor microenvironment, making them ideal candidates for therapeutic engineering. However, engineering these cells is technically challenging, and tumors often co-opt myeloid cells to suppress adaptive immunity. We aim to overcome these obstacles by applying advanced genetic engineering tools to reprogram myeloid cells, enhancing their tumoricidal activities and resistance to polarization into immunosuppressive states. Toolbox: We have developed a toolbox of new techniques that will allow us to overcome key engineering challenges in human myeloid cells. Recognizing that nucleofection can lead to significant toxicity and dysfunction, we have found that using enveloped delivery vehicles (EDVs) to deliver Cas9 preserves myeloid cell viability and functionality. Additionally, through a collaboration with the Landau lab, we have shown that lentivirus incorporating the Vpx system leads to highly efficient transduction of human myeloid cells. We have further engineered these lentiviruses to express a mutant VSVG and scFvs targeting myeloid-specific surface proteins, enabling selective transduction of specific myeloid compartments. Approach: 1) CRISPR Gene Editing: These tools will enable us to perform CRISPR-based knockout and base editing screens in primary human macrophages and dendritic cells to identify and modify key genes that regulate myeloid cell polarization and effector functions. In addition, we will explore base editing of genes with known roles and mutations in autoinflammatory diseases driven by overactive myeloid cells. 2) Synthetic Receptor (Innate-CAR) Library: To complement these gene editing approaches, we will design and test a library of synthetic receptors, which we call Innate-CARs, to enhance myeloid cell immunogenicity. These Innate-CARs will combine a tumor- specific scFv with intracellular domains from a variety of diverse innate immune receptors and intracellular proximal signaling molecules to optimize myeloid cell responses to tumor antigens. After we screen and identify top-performing Innate-CARs and gene edits, we will use a variety of immunodeficient and immunocompetent preclinical models to assess these enhancements in CAR-myeloid cell antitumor immunity. 3) In Vivo Engineering: Using our novel myeloid-targeting lentiviruses, we will evaluate the efficiency and efficacy of in vivo manufactured Innate-CAR myeloid cells in tumor-bearing humanized mouse models. Impact: By exploring the synthetic space of myeloid cell biology, we aim to push the boundaries of current immunotherapy paradigms and pave the way for new, effective living medicines to treat refractory solid tumors.

NIH Research Projects · FY 2026 · 2025-07

ABSTRACT: The Trans-Omics for Precision Medicine (TOPMed) project has reached a critical size threshold. Freeze 10 of the TOPMed cohort now includes n=180,852 individuals with high coverage WGS, with over 1.074 BILLION variants characterized. Beyond genomic data, TOPMed also includes n=73,294 individuals with RNA-seq gene expression data, n=92,659 individuals with metabolomic data, n=85,684 individuals with methylation data, and n=43,057 individuals with proteomic data. These ‘omics phenotypes enable rich characterization of the multiple dimensions of biology that are relevant for human disease. Importantly, 60% of individuals identify as non-White with n>51k of individuals identifying as Black/African American, n>34k identifying as Hispanic/Latino, and span multiple HLBS phenotypes. We will utilize the TOPMed project data to address two pressing questions. First, how do race, ethnicity, and genetic ancestry contribute to complex traits across the continuum of human populations in the US? Second, how do alleles at different frequencies in different genetic ancestry groups contribute to complex traits? This project will leverage data from whole genome sequencing (WGS), RNAseq expression, metabolomics, and a bevy of heart, lung, blood, and sleep disorders to make headway understanding how to keep the continuum of human populations at the forefront of precision medicine.

NIH Research Projects · FY 2026 · 2025-07

Project Summary/Abstract Despite advances in treatment over the past decade for neonatal hypoxic ischemic encephalopathy, approximately 50% of infants continue to have long-term cognitive, motor and language impairments at 2 years of age. There remains an unmet need to identify subpopulations of infants at birth who are at highest risk for specific neurodevelopmental impairments and who will most likely benefit from new, targeted, delayed therapies. Expert MRI scoring systems, currently the standard evaluation method of MRIs obtained for clinical trials, demonstrate limited accuracy at identifying specific impairments. We hypothesize that compared to expert reader scoring of MRI, quantitative characterizations of the severity and location of brain injury on neonatal brain diffusion MRI are more significantly correlated with motor and language outcomes at 2 years of age. We plan to use diffusion MRI analysis techniques on the recently completed High-dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) trial, and the just-released, first-of-its-kind public Boston Neonatal Brain Injury Dataset (BONBID) data. The HEAL data is unique in that (a) it is the largest modern HIE cohort in the US (N=500); (b) MRIs were acquired at 4-5 days of age using a harmonized protocol across 17 sites; and (c) detailed 2-year neurobehavioral tests included Bayley Scales of Infant Development-III (BSID-III). Our specific aims are: 1) Correlate severity of brain injury with 2-year motor and language BSID-III scores in the HEAL cohort. We will define brain injury severity by computer-extracted continuous ADC metrics: injury lesion volume at ADC z-score percentiles, intra-lesion ADC heterogeneity (histogram statistics), and lesion geometry (sphericity, elongation, regularity). We will correlate these injury severity metrics in specific brain regions known to correspond with motor and language function with BSID-III motor and language scores, respectively. 2) Correlate location of brain injury with 2-year motor and language BSID-III scores in the HEAL cohort. We will define brain injury location at both the voxel and white matter tract (connectivity) levels. Using voxel-wise lesion symptom mapping (v-LSM), we will identify voxels where presence of injury is significantly correlated with BSID-III scores. Subsequently, using connectome-based LSM (c-LSM), we will identify fiber tracts where the presence of injury anywhere along the tract is significantly associated with BSID-III scores. 3) To test the accuracy and generalizability of our injury severity and location metrics, we will use advanced statistical modeling and machine learning methods to find the optimal combination of severity and location metrics that produces the highest association with 2-year outcomes. We will further test our hypotheses in a separate HIE cohort (BONBID) to evaluate the generalizability of our techniques. We anticipate this multipronged quantitative diffusion MRI study will offer a mechanistic understanding of how quantitative measures of HIE injury severity and location impact neurodevelopmental outcomes. Our findings will inform future development of individualized quantitative MRI biomarkers, and ultimately serve as an early, reliable secondary endpoint to facilitate and expedite future therapeutic innovations.

NIH Research Projects · FY 2025 · 2025-07

PROJECT SUMMARY: COPA syndrome is a rare inborn error of immunity considered a monogenic interferonopathy. It is caused by autosomal dominant missense mutations in the coatomer subunit alpha (COPA) gene. The most common clinical manifestations are interstitial lung disease (ILD), arthritis, and kidney disease. Despite best-available treatment, COPA syndrome remains a highly morbid disease and patients can develop debilitating arthritis, renal failure and end stage pulmonary fibrosis. Some patients require lung or kidney transplantation. Thus, there is a critical need to identify and develop new treatments for COPA syndrome. We have the largest clinical and research cohort of COPA syndrome patients in the world. We built this cohort through our NIH-funded translational research in COPA syndrome and involvement with the COPA Syndrome Foundation. This work began when our centers collaborated in the discovery of the disease in 2015. The goal of this proposal is to validate the peripheral blood interferon (IFN) score and phosphorylated STING (pSTING) level as disease biomarkers of COPA syndrome in anticipation of clinical trials. We and others have shown that COPA syndrome is caused by abnormal accumulation, activation and phosphorylation of STING on the Golgi, which leads to chronic interferon signaling. However, it remains unknown whether pSTING levels or IFN scores dynamically change during the course of disease or in response to treatment. In this proposal, we hypothesize that peripheral blood mononuclear cell (PBMC) pSTING levels and IFN scores are biomarkers that correlate with disease severity and activity of COPA syndrome. We will collect serial samples from patients with COPA syndrome to test this hypothesis by 1) establishing the range of IFN scores in COPA syndrome and correlate these with disease phenotype, severity and activity using validated clinical outcome assessment measures and 2) determining how pSTING levels measured by multi-color flow cytometry correlates with disease activity, treatment and severity in COPA syndrome and establish the range of normal pSTING levels in healthy controls. Through our work we will perform the first and largest comprehensive natural history study of COPA syndrome and provide the first description of IFN scores in this disease. We will also establish normal values for pSTING in healthy control PBMCs using flow cytometry and report levels observed in COPA syndrome. By correlating serial data for IFN score and pSTING with scores from clinical outcome assessment measures, we will establish whether IFN scores and pSTING can serve as predictive, monitoring or response biomarkers in COPA syndrome. These results will be critical to informing future clinical trial design and implementation for COPA syndrome as we work to identify targeted therapeutics for these rare patients.

NIH Research Projects · FY 2026 · 2025-07

Abstract Infections from M. tuberculosis (Mtb) are a persistent global health threat. To develop therapies that augment protective host immune responses against Mtb and shorten TB treatment, this proposal seeks to test our central hypothesis that Mtb infection triggers autophagy factor phosphorylation that regulates host cell death mechanisms. Understanding these regulatory mechanisms will enable the development of new host cell death targets for Mtb treatment. In an unbiased phosphoproteomic analysis, we discovered Tax1bp1 (Tax1-binding protein 1) and Optineurin were significantly more phosphorylated in Mtb- versus mock-infected bone marrow- derived macrophages (BMDMs). Cytosolic autophagy receptors target pathogens for elimination by selective autophagy, which inhibits necrosis. As phosphorylation leads to signal amplification and enables protein function, we sought to test the role of Tax1bp1 and Optineurin during Mtb infection. As expected, we found Optineurin restricts Mtb growth. However, surprisingly we found that Tax1bp1 enhances Mtb growth in most cell types and during animal infection. Additionally, we found that the two autophagy receptors have opposite impacts on host cell death. Tax1bp1 enhances early host cell necrosis and delays apoptosis whereas Optineurin limits necrosis. To further determine how Tax1bp1 promotes necrosis during Mtb infection, here we will investigate whether Tax1bp1 activates inflammasomes to cause pyroptosis, a programmed form of necrosis. We will also test whether inhibition of the kinase that phosphorylates Tax1bp1 blocks Mtb growth and necrosis. To elucidate whether Tax1bp1’s function in innate immune cells promotes Mtb growth in vivo, we will take advantage of a new floxed Tax1bp1 mouse. To further test the function of Optineurin’s previously unrecognized phosphosites in controlling host cell death, we will express Optineurin phosphomutant alleles in macrophages for host cell death assays during Mtb infection. To identify additional phosphorylated host cell death factors in other macrophage types relevant to Mtb infection, we performed phosphoproteomic profiling of Mtb-infected primary human and murine alveolar macrophages (AMs). We identified five host cell death factors phosphorylated in both BMDMs and AMs that are not already known to respond to Mtb infection involved in the mTOR (mammalian target of rapamycin) pathway, which regulates autophagy and apoptosis. To test the possible roles of these five host factors in cell death during Mtb infection, we will engineer knockout macrophages for cell death assays. A better understanding of the mechanisms by which Tax1bp1, Optineurin, and previously unrecognized host cell death factors impact Mtb pathogenesis may lead to the development of host-directed therapies for TB infection that shorten the treatment duration.

NIH Research Projects · FY 2026 · 2025-07

Abstract Alzheimer’s disease and related dementias (AD/ADRD) affect more than 6 million adults over 65, with family members providing most of the care for persons living with dementia (PLWD). During AD progression, behavioral and psychological symptoms of dementia (BPSD), like agitation, anxiety, and depression, are common. This can lead to stress and depression among care partners. Thus, interventions must be developed to aid both members of the PLWD-care partner dyad. Music-based interventions are effective, non- pharmacological treatments that reduce BPSD in PLWD and care partner stress. However, most existing music-based interventions target only the PLWD or the care partner, but not both dyad members simultaneously. Improvisation music therapy is a type of music therapy that uses creative and meaningful musical exchanges to move patients toward emotionally desirable states. Improvisation music therapy promotes rapid and novel idea generation, emotional awareness, and execution of unplanned motor sequences. For these reasons, improvisation music therapy may be able to reduce stress through emotion regulation in PLWD-care partner dyads. The candidate’s long-term goal is to become an independent investigator who examines mechanisms by which music-based interventions improve health and well-being among PLWD and their care partners. For this career development award, the candidate’s short-term goal is to investigate the impact of an improvisation MT intervention prototype on behavior change (BPSD reduction in the PLWD, increased well-being and decreased burden in the caregiver) through stress reduction. The proposed research project aims to 1) standardize an improvisation music therapy intervention prototype for the PLWD-care partner dyad, 2) evaluate the feasibility and acceptability of this intervention, and 3) complete a pilot study to examine whether stress reduction and emotional regulation are potential mechanisms for positive behavior change. This K01 project combines a rigorous research program, mentorship, and didactic goals. The career training goals will help the candidate acquire: 1) content expertise in ADRD, 2) knowledge about behavioral intervention standardization using the NIH Stage Model, NIH Science of Behavioral Change, and mixed methods design, 3) content expertise in dementia caregiving, 4) experience on rigorous clinical trial design, analysis, and management, and 5) academic leadership and research skills necessary for becoming an independent academic researcher. At the project's conclusion, the proposal will have standardized a novel intervention prototype for PLWD-caregiver dyads based on improvisation music therapy. The pilot study will expand knowledge of how and why music therapy facilitates well-being for both PLWD and care partners. These results will inform a future R01 to conduct a powered, randomized clinical trial of music-based interventions to improve emotion and well-being outcomes in PLWD-care partner dyads that may ultimately lead to long-term, downstream effects such as improved quality of life.

NIH Research Projects · FY 2026 · 2025-07

PROJECT SUMMARY Nearly half of all deaths in the industrialized world are caused by fibrosis of critical organs and tissues. Despite this fact, few available treatments prevent the progression of fibrosis and its lethal consequences. Critical gaps in our understanding of fibrosis remain, particularly what factors cause this process to switch from a self-limited homeostatic response to injury to become a progressive “chronic wound-healing” pathology, and conversely what endogenous factors help to keep fibrosis in check. Novel fibrosis-prone mouse models afford the potential to elucidate these factors and thereby reveal new anti-fibrotic therapeutic targets for a wide range of diseases. S1P is a bioactive lipid formed in the final step of sphingolipid metabolism that has been implicated in the pathophysiology of fibrosis. S1P lyase (SPL), encoded by SGPL1, is a vitamin B6-dependent enzyme that catalyzes the irreversible degradation of S1P and guards the only exit point of sphingolipid metabolism. Recently, we discovered SPL insufficiency syndrome (SPLIS), a rare genetic disorder that most commonly manifests as glomerulosclerosis. To interrogate the broader role of SPL in fibrosis, we used gene editing to generate a novel SPLIS mouse model harboring the most prevalent SPLIS-associated SGPL1 mutation, SPL R222Q, which is vitamin B6-responsive. When maintained on a diet low in vitamin B6, SPLR222Q mice exhibit SPL insufficiency, accumulate S1P and other sphingolipids in tissues and blood and, over time, develop glomerulosclerosis, whereas these phenotypes are prevented by providing a diet high in vitamin B6. In addition to kidney fibrosis, we showed that SPLR222Q mice spontaneously develop lung fibrosis and are more sensitive to bleomycin-induced pulmonary fibrosis than are wild type (WT) mice. Conversely, upregulation of SPL using an adeno-associated virus mediated SGPL1 gene therapy (AAV-SPL) prevented glomerulosclerosis in Sgpl1 knockout mice and attenuated bleomycin-induced pulmonary fibrosis in WT mice. Altogether, our findings strongly suggest that SPLIS is a harbinger of a broader anti-fibrotic role played by SPL in human physiology. We hypothesize that SPL is an endogenous anti-fibrotic factor that counteracts the pro-fibrotic actions of S1P and that the SPLR222Q mouse is a robust in vivo model in which to elucidate the role of the S1P/SPL axis in fibrosis and to test novel anti-fibrotic strategies. To confirm our hypothesis, we propose two Specific Aims: 1) Characterize the spectrum of organs affected by fibrosis and sphingolipid changes in the SPLR222Q mouse; 2) Establish the efficacy and mechanism of action of AAV-SPL anti-fibrotic therapy in the SPLR222Q mouse. Our published and preliminary findings implicate the S1P/SPL axis in fibrosis of kidneys liver, lungs and gut. Our experienced team will generate results that will establish SPL as a critical endogenous anti-fibrotic factor. We will identify pro-fibrotic sphingolipids. Lastly, we will validate AAV-SPL as a novel anti-fibrotic strategy with broad applications in many organ systems. In line with ORIP’s goals, our project will generate animal models, cryopreserved embryos, cell lines, lipidomics datasets, and viruses for sharing with the scientific community.

NIH Research Projects · FY 2025 · 2025-07

PROJECT SUMMARY/ABSTRACT Dr. Meghan D. Morris, PhD, MPH, is an Associate Professor of Epidemiology at the University of California, San Francisco, with expertise in infectious disease and social epidemiology. Her research program focuses on patient-oriented research with a primary emphasis on addressing health inequities among people who inject drugs (PWID). Her competencies include advanced skills in qualitative, quantitative, dyadic research, and community-engaged research methods. She has a long track record of mentoring scholars across various academic levels. The K24 award provides Dr. Morris with protected time and essential resources to establish a mentorship program and cultivate a new cohort of health equity researchers who will apply dyadic research methods through community-engaged research to enhance the health and well-being of PWID. Dr. Morris's K24 research strategy builds on Dr. Morris’ existing NIH-funded study (R01DA053325) of the Partner Navigation Intervention, a dyadic intervention designed to enhance HCV treatment initiation among PWID by leveraging support within injecting partnerships. Project 1 will examine how racialized discrimination affects treatment initiation and partner support dynamics, generating findings to inform future adaptations using anti-racism principles. Project 2 will pilot an adapted Partner Navigation Intervention session upon HCV treatment completion to promote continued healthcare engagement for comorbid conditions, addressing a critical gap in post-treatment care for PWID. The interdisciplinary mentoring team includes expertise in patient outcomes research, culturally responsive intervention adaptation, dyadic and quantitative research methods, and anti-racism frameworks. The K24 award will enable Dr. Morris to formalize and expand upon the team-mentoring program she has developed and piloted over the past 5 years informed by frameworks from the National Center for Faculty Development and Diversity (NCFDD) and the Signaling Affirmation for Equity (SAFE) model, utilizing a team- mentoring approach bringing together academic and community members with lived experience of substance use as near-peers. As dyadic research among substance-using populations is an emerging area of study, a national approach to mentorship to promote innovation in patient-centered research is critical.

NIH Research Projects · FY 2026 · 2025-07

ABSTRACT Sodium glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP1RA) are two classes of medications poised to revolutionize chronic kidney disease (CKD) care after repeatedly demonstrating their ability to prevent cardiovascular disease (CVD) and CKD progression in clinical trials. With pleiotropic benefits across type 2 diabetes mellitus (T2DM), CKD, and CVD, these medications are the central therapeutic elements of an ongoing shift in CVD prevention from disjointed risk factor control toward comprehensive, multi-organ care for Cardio-Kidney-Metabolic (CKM) syndrome. This new CKM approach holds great promise for mitigating the CVD risk that threatens over 14 million adults with T2DM and CKD within the U.S.; however, prior work from our group and others indicates that the adoption of SGLT2i and GLP1RA in CKD care is being tragically limited by poor treatment persistence. Achieving the full benefit of these medications will require novel approaches to motivate and reinforce their persistence; however, such undertakings in individuals with T2DM and CKD can be challenging — many are unaware of their diagnosis, providers underestimate their CVD risk, and the unique benefit of these medications may not be fully appreciated among the myriad of other clinical problems that arise in this medically complex, high-risk population. To tackle this enormous challenge, the proposed project will rigorously develop an effective Risk Communication Aid to translate individualized CVD risk estimation and the benefits of SGLT2i and GLP1RA treatment into joint patient-provider efforts to prevent CVD through persistent treatment. We will accomplish these goals by first investigating how the complexity of care in persons with T2DM and CKD is associated with persistent SGLT2i and GLP1RA use across a national integrated health care system using detailed clinical data from the Veterans Health Administration (VHA) (Aim 1). Then, interviews of patients and providers across the landscape of CKM care will contextualize insights from Aim 1 by pinpointing key barriers to persistent treatment using an implementation science framework (Aim 2). Finally, the knowledge gained from Aim 2 and an iterative, stakeholder-driven development process will be used to create a novel CVD Risk Communication Aid to facilitate patient-provider discussions promoting persistent SGLT2i and GLP1RA use. This tool will be piloted in the primary care setting among persons with T2DM and CKD (Aim 3). This proposal will leverage the unique advantages of VHA to develop innovations in healthcare delivery that are minimally influenced by costs to patients. Dr. Ikeme has assembled an unparalleled team of mentors with expertise in CVD risk prediction, innovative kidney care delivery, implementation science, risk communication, and biostatistics. With their guidance, this work will place Dr. Ikeme at the forefront of effective CVD prevention in CKD and lay the foundation for an independent R01-level project evaluating a Risk Communication Aid to improve the persistence of CVD preventive treatment in CKD.

NIH Research Projects · FY 2026 · 2025-07

Hearing loss has significant impact on the life of Native Americans (NAs) to participate in daily life practices that require good hearing. Noise-induced hearing loss (NIHL) is an irreversible chronic injury caused by repeated or high-intensity noise exposure. It is a major public health problem that affects 40 million (24%) adults aged 20-69 years in the United States. NAs are particularly at-risk because of conditions that disproportionately expose them to noises such as socio-environmental factors. NIHL is the only type of hearing loss that is nearly 100% preventable with appropriate education and early detection. However, no intervention has been developed to address the understudied issue of NIHL among NA adults. This randomized controlled study will test the effectiveness of a peer-group discussion model, Talking Circles (TCs), and hearing protection training program delivered in partnership with a regional population with high occupational and recreational noise exposure. The model integrates established hearing conservation education methods with screening services and behavioral assessments. A needs assessment conducted with community health partners indicated limited awareness of early hearing loss detection and a high volume of hearing aid requests. The intervention will include facilitator training for local implementation and a delayed-intervention control to assess knowledge gains and protective behavior changes. The study has three specific aims: Aim 1. To test the effectiveness of the innovative NA based TCI to increase NIHL-related knowledge and hearing protection behaviors; Aim 2. To train TCI Facilitators to deliver the hearing protection intervention independently, supporting future implementation within the partnering community; and Aim 3. To determine the prevalence of hearing loss in NA adults. A total of 400 NA adults will be enrolled through community partners and assigned to either the intervention or a delayed-control group. The primary hypothesis is that participants receiving the education program will show greater improvements in knowledge and hearing protection use at 6- and 12-month follow-up compared to the control group. The program will also evaluate long-term implementation feasibility using local training teams. The goal of this research is to inform scalable strategies for hearing loss prevention in regions with high noise exposure and improve access to preventive tools in noise-exposed communities.

NIH Research Projects · FY 2026 · 2025-07

SUMMARY/ABSTRACT Despite higher burden of methamphetamine (MA) use in people with HIV (PWH), very little is known about the impact of MA on HIV persistence, viral-host responses, immune cell activation, and end-organ damage, particularly in the central nervous system (CNS) and cardiovascular system (CVS). MA use has primarily been studied in the setting of untreated HIV, and no study to date has linked MA use directly with increased HIV transcription, tissue inflammation, immune dysregulation, and clinical outcomes during adequate ART suppression. An increasing body of literature suggests that eradication of residual virus may be necessary to improve clinical outcomes, and the impact of MA use in treated HIV on host tissue responses across the whole body that lead to tissue inflammation and damage is unknown. Our proposed RM1 will test the central hypothesis that MA induces HIV-1 transcription, even during suppressive ART, which then serves to trigger abnormal host immune activation, inflammation, and increased morbidity from the additive effects of both virus and drug use. The combined negative impact of MA and HIV-1 on the CNS and CVS, as these are areas of major clinical concern among people who use MA, and tissue damage may persist even after cessation of active drug use. An in-depth understanding of the longitudinal pathophysiology and host responses to MA use is a critical unmet need that will inform the discovery of novel therapeutic targets to reduce immune dysfunction, HIV-1 persistence and inflammation, and improve clinical outcomes and chances of HIV cure in this population. We have assembled a highly collaborative team to apply innovative, multidisciplinary tools to address the fundamental gaps in the understanding of the pathophysiological underpinnings of HIV persistence and organ damage in the setting of MA use. This unified and highly synergistic approach leverages three unique cohorts that we have developed over the past decade to test our overall hypothesis, performing the first-in-human studies directly quantifying MA concentrations in blood, CSF, and tissues of PWH on ART in relation to HIV persistence and host inflammation in the CNS and CVS: (1) a longitudinal observational tissue, blood and cerebral spinal fluid (CSF) sampling study of PWH on ART with chronic MA use; (2) an interventional study administering short-term oral MA to PWH on ART without a history of MA use disorder; and (3) the world’s first POST SCD study of autopsy specimens across the whole body from PWH on ART and toxicologically proven MA use. We will employ innovative methods, including performing whole-body PET imaging of the HIV-1 reservoir and myeloid/microglial activation, multi-omic assays to characterize the host immune response, pharmacodynamic analyses of MA, and high-resolution measures of the HIV reservoir from longitudinal blood, cerebral spinal fluid, gut and lymphoid samples. A pathophysiological understanding of these processes is essential for the discovery and targeting of novel pathways to reduce clinical morbidity and will pave the way for targeted clinical interventions or screening in PWH with MA use.

NIH Research Projects · FY 2026 · 2025-07

ABSTRACT School-based health centers (SBHCs) provide primary care, mental health care, and other health services in or near schools that serve youth populations who otherwise may have limited access to care. Although research has documented SBHCs’ impacts on healthcare access and outcomes, only limited research has assessed which specific SBHC models and practices are most effective. Rigorous research is needed to inform the selection and implementation of SBHC models and practices, particularly given the expansion and rapidly changing landscape of SBHC operations and the heightened recognition of and need to address disparities in access. We will address these knowledge gaps by capitalizing on a longstanding partnership between our University of California, San Francisco and School-Based Health Alliance teams collecting national data on SBHCs. We will first collect comprehensive data on staffing models and healthcare delivery practices from a representative sample of SBHCs nationally. This will help us create a standard classification of SBHC models and practices to strengthen SBHC research. We will then conduct a qualitative study to identify barriers and facilitators, such as care coordination; screening, treatment, and referral practices; and school health system integration, that can hinder and facilitate the provision of equitable care in SBHCs. Lastly, we will examine national data on schools with and without SBHCs to understand whether access to SBHCs, and which service models in particular, are associated with reduced disparities in academic outcomes, such as graduation rates, chronic absenteeism, and disciplinary actions. This 4-year mixed methods study will describe current trends in SBHC models and practices and identify the models and practices associated with reduced disparities. Our specific aims are to: 1) describe current trends in SBHC staffing models and practices nationally and create a classification system to strengthen future research, design, and implementation; 2) determine the care delivery, coordination, and school health system integration practices associated with more equitably serving youth who disproportionately experience disparities; and 3) examine the association between SBHC models and academic outcomes by race/ethnicity nationally. Findings from our research will inform SBHC policy, funding, and program decisions, and hold promise to elucidate the role SBHCs can play in reducing health inequities.

NIH Research Projects · FY 2026 · 2025-07

SUMMARY Controlling chronic hypertension reduces a patient’s risk of developing life-threatening conditions over time. Traditionally, measures like home blood pressure monitoring and ongoing clinical support to provide counseling or medication adjustments are used to keep hypertension under control. However, the time, resources, and expertise required for such measures are often out of reach for patients of low socioeconomic status for whom financial and/or logistical challenges present challenges to frequent in-person care. One solution is to develop a chronic care model that includes team-based care that is primarily accessed remotely for patients with hypertension. I am currently conducting a large PCORI-funded clinical trial called Comparing Hypertension Remote Monitoring Evaluation Redesign (CHARMED, HM-2022C2-28339) to test the impact of one such model on patient engagement and outcomes. The current proposal complements this work by conducting systematic economic analyses of the costs associated with implementing that care model within the 25 safety net health systems involved in the trial. The majority of patients cared for at safety net health systems are of low socioeconomic status; thus, a focus on the costs incurred and challenges faced by these systems is more likely to inform improvements in caring for the patient populations most in need of such advances. In Aim 1, the project team, led by Dr. Elaine Khoong, one of my direct mentees, as well as Dr. Dhruv Kazi, will collect data on costs associated with equipment and utilization changes, including time-driven activity-based costing to account for personnel time spent learning and implementing the interventions. Dr. Khoong will compare bottom-line costs across all arms of the CHARMED trial (PCORI HM-2022C2-28339). In Aim 2, Drs. Lina Tieu and Lisa Ochoa- Frongia, also my mentees, will lead a study of the relationship between behavioral health care—to treat conditions like depression or anxiety, which are associated with higher risks of hypertension and related morbidity—and the clinical outcomes of hypertension patients in the ongoing clinical trial. Again, results will be compared across arms of the CHARMED trial (PCORI HM-2022C2-28339). Together, this work promises to advance patient-oriented research toward interventions that effectively control chronic hypertension within the context of safety net health systems. In leading this work, I continue my commitment to mentoring the next generation of scientists focused on patient-oriented research, including numerous opportunities for trainees to build and implement skills in implementation science, informatics, health communication, embedded/learning health systems research in safety-net health systems, pragmatic clinical trials, and gain experience in robust, longitudinal patient, family, and community engagement approaches.

NIH Research Projects · FY 2025 · 2025-07

Most children living with advanced cancer experience highly distressing symptoms, and many do not have access to subspecialist pediatric palliative care (PPC) services or clinicians trained in primary palliative care. Despite the call from national organizations for the integration of palliative care for patients with cancer, a lack of high-quality PPC education persists as a barrier to PPC implementation. From 2012-2017 the investigators of the current proposal developed and disseminated the most comprehensive PPC curriculum worldwide to date: Education in Palliative and End-of-Life Care (EPEC)-Pediatrics (NIH/NCI grant #R25 CA151000-01). The 24-module curriculum is designed to teach clinicians how to teach and advance PPC concepts. The primary target audience was pediatric oncology prescribing clinicians. The curriculum is delivered through combined online learning and face-to-face conferences. When the COVID-19 pandemic emerged, an online training platform was created, enabling remote worldwide participation. Forty conferences have been held to date, training 1,992 clinicians from 122 countries. Most participants have reported improvement in PPC knowledge, attitudes, and skills, and advancements in patient care for children with cancer and serious illnesses. Further dissemination has been achieved through five publications and dozens of academic presentations. The primary goal of this project is to improve EPEC-Pediatrics accessibility and inclusivity by targeting participants from US pediatric oncology programs outside of large tertiary centers, including non-prescribing interprofessional clinicians (e.g. social workers). The project will also address disparities in PPC education by adding faculty from underrepresented communities, such as infants. Further, the curriculum will be updated to ensure content is current and inclusive, reflecting the needs of all children with cancer and families, including those with special needs. Specific aims are to: 1) Disseminate the EPEC-Pediatrics curriculum through five annual EPEC-Pediatrics Train-the-Trainer conferences in previously geographically underrepresented areas of the US (e.g., Southern region). 2) Update and expand the existing EPEC-Pediatrics curriculum and dissemination project by: a) Seeking guidance from an interprofessional group of clinical experts (e.g., bereaved parents) to improve curriculum content and ensure it includes equitable and inclusive content; b) Strengthening the psychosocial-spiritual curriculum content through emphasis of care for special populations (e.g., infants with cancer); and c) Designing a learning pathway for non-prescribing clinicians. Successful adaptation and dissemination of a more holistic EPEC-Pediatrics curriculum will promote transfer of PPC best practices to underserved communities, ultimately changing clinician behavior and improving care for children with cancer and their families.

NIH Research Projects · FY 2025 · 2025-07

PROJECT SUMMARY/ABSTRACT The primary goal and laser focus of our conference, CTTACC, is to accelerate and advance the translation of cell therapies, regenerative approaches, and novel blood products in critically ill patients, all of which are the most rapidly developing areas in transfusion medicine and cell therapies. Trauma and critically ill patients suffer from severe morbidity with few therapeutic options. This is the sixth CTTACC conference organized by Dr. Pati and the CTTACC organizing committee. We anticipate 120 to 150 participants from a variety of backgrounds including academia, industry, the FDA, and federal funding agencies. This meeting is presented by the University of California San Francisco, Department of Laboratory Medicine and the UCSF Center for Research in Transfusion Medicine and Cell Therapies (CTMCT). The 2025 conference is unique in that it is also hosted by the Armed Forces Institute of Regenerative Medicine (AIRM) and Colorado State University. The general plan for the agenda is as follows: the first day is structured to focus on topic areas such as cellular therapies and transfusion medicine in acute and chronic trauma and critical care. Topics will include ARDS, spinal cord injury, neurotrauma and cardiac disease. The first day will also include sessions related to the novel discovery of regenerative factors in blood and specific topics in trauma and transfusion medicine. These talks will set the stage for the second day by presenting innovative technologies that are present and available for development. The second day will include a whole half day military health session which will be focused on four principal areas pertaining to strategies for battlefield care of injured soldiers. The four focus areas include 1) novel blood products on the battlefield, 2) rapid diagnostics for injured patients, 3) acute care of organ failure in remote areas, and 4) acute care of neurotrauma on the battlefield and remote settings. The military health session is designed to generate topic areas for future funding and research development. A consensus paper is planned to be written based on the findings from this session. The second day will also include discussion of novel blood products derived from stem cells and novel blood products currently in development. On the second day an afternoon session will focus on advancing the field of cell and gene therapy editing beyond oncological applications. An FDA regulatory session will discuss challenges in the approval of these novel products. On the last day, which is a half day, a federal agency funding panel will be participate in Q&A by participants interested in future funding opportunities. A panel of key journal editors for these topic areas (Transfusion, Stem Cells, Cytotherapy, Journal of Trauma and Journal of Translational Med) has been assembled. As in years past, we anticipate this conference will support the advancement of the field of transfusion medicine and cell therapies in trauma and critical care.

NIH Research Projects · FY 2025 · 2025-07

Project summary: Metastatic castration-resistant prostate cancer (mCRPC) is an advanced, particularly aggressive, and treatment- resistant form of prostate cancer. Existing therapies, such as chemotherapy and radiation, frequently result in significant side effects and the development of resistance, undermining their long-term effectiveness. The tumor- targeting approach employs an antibody-drug conjugate (ADC) to deliver cytotoxic drugs directly to cancer cells via antibodies, minimizing damage to healthy tissue. Similarly, alpha particle therapy provides precise radiation targeting, reducing off-site delivery. However, these antibody-based treatments are also associated with adverse effects at therapeutic doses, often requiring dose reductions to subtherapeutic levels. In response to these challenges, our project proposes a novel tumor-targeted combination therapy designed to enhance efficacy and reduce toxicity. Utilizing the distinct modes of action of cytotoxic drugs (like monomethyl auristatin E, MMAE) and the radioactive isotope Actinium-225, which exhibit non-overlapping toxicities, we plan to co-deliver these agents directly to cancer cells. This approach aims to create a novel synergy that effectively combats cancer without the typical adverse effects. Aim 1 of this project focuses on developing a single CD46-targeting antibody dual-labeled with MMAE and Actinium-225, for synergistic therapeutic efficacy with reduced toxicity. This innovative combination will be rigorously tested against metastatic and drug-resistant tumors. Aim 2 involves constructing tumor models resistant to current treatments such as Enzalutamide and PSMA-targeted radioligand therapy to evaluate the efficacy of our dual-labeled agent. We anticipate this tumor-targeted strategy will successfully treat resistant tumor types at critical metastatic sites, including bone and lymph nodes. Aim 3 will expand our strategy to target two antigens overexpressed on tumor cells, using separate antibodies to deliver the cytotoxic drugs and Actinium-225. This method is anticipated to further enhance the precision and effectiveness of our therapy. Through this project, we employ a transformative approach in treating advanced mCRPC by combining the targeted drug delivery of ADCs with the precise radiation targeting of alpha particle therapy. By co-delivering cytotoxic drugs and Actinium-225, we aim to enhance treatment outcomes and overcome the limitations posed by conventional therapies, including their associated toxicities.

NIH Research Projects · FY 2026 · 2025-07

Project Summary Learning about environmental stimuli that predict meaningful outcomes such as rewards is crucial for the survival of an organism. Cue-reward learning has historically been described by the “learning curve”, which appears gradual in group-averaged behavioral data from many animals. However, it was shown nearly two decades ago that learning curves from individual animals are not as gradual, but instead display an abrupt appearance of behavioral learning. Such abrupt learning has been described as reflecting a sudden insight into task structure. Despite this demonstration, little work has focused on understanding the distributed brain networks that support such sudden behavioral learning of cue-reward associations. Here, we focus on the network and single cell changes that precede both conditioned behavioral responding and dopamine release in nucleus accumbens and during cue-reward learning. While many studies focus on the role of cue evoked dopamine release in behavioral responding, our approach is fundamentally different as it identifies signals upstream of dopaminergic learning and/or behavioral responding. Based on theoretical models of reinforcement learning, we hypothesize that such signals will be conveyed by brain regions that maintain a timeline of experience, thereby providing the template from which cue-reward associations can be extracted by DA neurons to guide learning. Based on published and preliminary data, we will test the hypothesis that a network spanning lateral entorhinal cortex (LEC), hippocampal CA1, and orbitofrontal cortex (OFC) guide DA signaling during acquisition of cue-reward associations. To test this hypothesis, we will use a combination of large-scale two-photon calcium imaging, high-density electrophysiology with Neuropixels probes, dopamine sensor fiber photometry, behavior measurements and circuit dissection approaches around abrupt cue-reward learning in individual mice. We will analyze the data using a host of approaches to quantify latency of neural learning in each region and identify the causal flow of information between the different regions. We will also analyze the nature of learned representations in neurons that precede DA signaling, which will allow a distinction between theories of associative learning. Collectively, this proposal aims to close a fundamental gap in our understanding of the neural mechanisms guiding insight learning.

NIH Research Projects · FY 2026 · 2025-07

PROJECT SUMMARY Rheumatoid Arthritis (RA) is a chronic, destructive autoimmune disease that primarily targets joints. It affects millions globally and is associated with both disability and reduced lifespan. Antigen-dependent activation of CD4 T cells contributes to disease onset. However, the specific antigens that activate CD4 T cells and the mechanisms by which they evade tolerance remain undefined. Therefore, our long-term goal is to identify the earliest events that activate self-reactive T cells and define the mechanisms they employ to subvert tolerance. This knowledge may reveal vulnerabilities in disease-causing T cells that could lead to new diagnostic and therapeutic interventions. To identify the early mechanistic events that break T cell tolerance, we use the SKG mouse model in which a hypomorphic Zap70 kinase allele impairs TCR signaling; this deficit allows autoreactive thymocytes to escape negative selection, leading to mature autoreactive T cells that cause autoimmune arthritis resembling RA. Our group identified a subset of highly arthritogenic CD4 T cells in these mice. This subset of CD4 T cells is enriched for T cells that recognize superantigens (Sags) from an endogenous retrovirus (ERV) known as the mouse mammary tumor virus (MMTV). ERVs are implicated in human autoimmune disease, but determining their causal role has been exceptionally difficult. Our preliminary data indicate that these Sag-reactive T cells, which are normally deleted in the thymus of wild-type mice, escape deletion in SKG mice, accumulate in arthritic joints, and contribute to disease pathogenesis. These findings suggest that ERVs may play a crucial role in initiating and sustaining autoimmune responses. Furthermore, we find a similar process may be occurring in human RA synovial tissue. The central hypothesis of this proposal is that ERV Sags break immune tolerance and drive RA by persistently engaging and activating self-reactive T cells. To test this, we will use genetic engineering to create and study Sag-reactive CD4 T cells in both SKG and wild-type mice, assessing their role in arthritis initiation and analyzing their activation states and clonality through single-cell sequencing. Parallel human studies will explore the TCR repertoire and transcriptomes in RA synovial T cells. Additionally, we will eliminate MMTV Sags in SKG mice to examine their effects on T cell development, activation, tolerance mechanisms, and arthritis progression, providing insights into the influence of ERVs on central and peripheral tolerance. This research will elucidate how ERVs and their Sags influence T cell activation and tolerance, potentially leading to new therapeutic strategies for RA and related autoimmune diseases.

NIH Research Projects · FY 2025 · 2025-07

Project Summary With widespread resistance of malaria parasites to older agents, artemisinin-based combination therapies are the mainstay for antimalarial treatment, but efficacy is threatened by resistance to artemisinins and partner drugs. New antimalarial drugs are needed. Spearheaded by the Medicines for Malaria Venture (MMV), a robust pipeline of new lead antimalarial compounds is under development. However, resistance to new agents can be anticipated. In a number of cases drug targets and resistance mechanisms have been identified, but studies have focused on small numbers of P. falciparum laboratory strains. It is critical also to consider sensitivity to lead antimalarials of fresh P. falciparum field isolates, especially isolates from Africa. With these data, genotypic and additional phenotypic analysis can allow identification of mechanisms underlying varied susceptibility, as we have described for multiple compounds to date, informing optimal development of next- generation combination antimalarials. This application seeks continued funding for a project characterizing susceptibilities of malaria parasites isolated in Uganda and Burkina Faso to lead antimalarials under development. We offer state-of-the-art assessment of ex vivo P. falciparum susceptibilities linked to high throughput genotypic characterization to improve our understanding of mechanisms of drug action and resistance. As supported by data generated to date, we hypothesize that African P. falciparum isolates will demonstrate varied sensitivity to lead antimalarial compounds, and that characterization of genotypes and phenotypes of field isolates will identify shared resistance mechanisms and guide selection of optimal combination therapies. These results will be of great value as we develop next-generation combination antimalarials and continue efforts toward discovery of additional novel compounds. Our specific aims will be: (1) to characterize ex vivo susceptibilities to lead antimalarial compounds of P. falciparum field isolates, (2) to characterize genotypes to identify mediators of decreased susceptibility in field isolates to lead antimalarial compounds, and (3) to characterize phenotypes of drug sensitivity outliers to elucidate mechanisms of resistance of lead antimalarial compounds. Our studies will define resistance mechanisms for the most important new compounds under development as antimalarials and inform choices of optimal antimalarial drug combinations and the direction of continued drug discovery efforts.

NIH Research Projects · FY 2025 · 2025-07

Project Abstract (Edited version) In response to RFA-TW-21-004, the University of California Global Health Institute (UCGHI), including UC San Francisco (UCSF), UC San Diego (UCSD), UC Los Angeles (UCLA) and UC Davis (UCD), along with a network of 21 collaborating institutions internationally, proposes to continue our successful GloCal Health Fellowship (GloCal). Our international sites are well-established, work in regions with significant health challenges, and stand to benefit from our program’s capacity building, mentorship training and alumni support. GloCal is the only UC-wide health training program, and our track record shows that we: 1) Recruit pre- and postdoctoral trainees from various disciplines and backgrounds who aspire to build interdisciplinary academic research careers in health; 2) Provide outstanding, interdisciplinary education and training in health in collaboration with faculty mentors from participating UC campuses and collaborating international institutions; and 3) Provide each trainee with a rich and enduring mentored research experience that fosters scientific and career development in health. The program also advances long-term objectives to 1) Develop models of interdisciplinary, innovative health research and training designed to ensure healthy lives and promote well- being for all; 2) Enhance health networks between the UC and our international partners and recruit faculty leading innovative health research; and 3) Strengthen a long-lasting model of collaboration between the UC and our international partners that develops research capacity that advances locally-led and locally-relevant research. GloCal will recruit candidates from a pipeline of 65 T32 and 13 D43 programs. GloCal trainees are at different career stages, but all receive: 1) A 9 or 12-month, hands-on research experience onsite with one of our international partners—international fellows will spend their first 2 to 3 months of the program at UC and earn a certificate in ‘conducting health research’; 2) A strong, interdisciplinary mentored research experience; 3) Instruction in health through onsite and online courses; and 4) Career development to ensure that they attain their short-term goals and succeed in transitioning to the next career stage. GloCal leadership and standing committees ensure that these program components form a seamless, integrated experience supported by evaluation and continuous improvement. Strengths and innovations of the program include: 1) A unified consortium under UCGHI that includes four UCs at the leading edge of health 2) Recruitment of U.S. trainees from across UC and the UCLA-Charles Drew University partnership; 3) Mentors offering training across various disciplines (e.g., medicine, nursing, dentistry, public health, veterinary science, and social sciences) and in research methods; and 4) Leveraging common resources across the four participating UC campuses (UCGHI, CTSAs and CFARs).

NIH Research Projects · FY 2026 · 2025-07

PROJECT SUMMARY Homologous chromosome pairing during meiosis is a central process underlying Mendelian inheritance, in which homologous chromosomes move through the nuclear interior to locate and pair with their homologs, prior to synapsis via the assembly of the synaptonemal complex (SC). Failure of this pairing process can result in aneuploidy. Much of the effort to understand meiosis has focused on determining genes involved in homology recognition and recombination, but the physical process by which chromosomes come together inside the densely packed nucleus remains poorly understood. In order to pair successfully, chromosomes must carry out a huge number of homology tests while avoiding interlocks that would prevent complete pairing. Meiotic chromosome movement is facilitated by forces, generated by the cytoskeleton and motor proteins, that in turn are coupled to telomeres through the nuclear envelope (NE), leading to large-scale active telomere-led motions. But these telomere motions are randomly directed, raising the question of how exactly they facilitate pairing. In addition to random telomere movement, the meiotic nucleus can undergo an extensive re- organization, including clustering of telomeres to form a bouquet, coupling of centromeres between non- homologous chromosomes, and pre-meiotic homolog alignment, depending on the organism. Here we will investigate the cellular mechanism of meiotic pairing by testing a set of hypotheses regarding the role of telomere-led active motion and nuclear re-organization in increasing the fidelity of pairing, reducing the extent of homology searching, and avoiding or reducing interlocks between chromosomes. Our work uses live-cell imaging combined with genetic manipulation in budding yeast as a model system.

NIH Research Projects · FY 2025 · 2025-07

Major Depressive Disorder in older adults, or Late life depression (LLD), is characterized by mood symptoms and is also often further complicated by motor frailty and cognitive dysfunction. Additionally, LLD is also one of the strongest identified risk factors for accelerated cognitive and functional decline. The factors contributing to motor frailty and cognitive dysfunction in LLD are currently poorly understood which prevents the early identification of individuals most at risk for poor outcomes. The combination of mood, frailty, and cognitive disturbances in LLD implicates dysfunction within specific networks of monoamine- and cholinergic brainstem and basal forebrain nuclei that together make up the neuromodulatory system. The widespread subcortical and cortical projections of the neuromodulatory system control the brain’s activity state and thus behavioral responses to incoming internal and external information. Of note, neuromodulatory system abnormalities are often already present in the preclinical or very early stages of other neurodegenerative diseases before higher order cortical and subcortical structures become affected. These abnormalities therefore have the potential not only to become an early marker of LLD but also risk for poor outcomes. However, the neuromodulatory system is a compex structure made up of densely packed and often not well-delineated fiber tracts and small nuclei that are not discernible on conventional structural 3T MR and thus is understudies in LLD. New multi-contrast based segmentation approach imaging processing methods have developed to address this challenge. The goal of this project is to evaluate the association of depression severity, cognition, and motor frailty with specific components of the neuromodulatory system and to demonstrate that structural and functional abnormalities within this system are more strongly linked to baseline severity and longitudinal progression of these symptoms than abnormalities within their higher cortical and subcortical target structures. Specifically, it will be demonstrated that: 1) Structural and functional abnormalities within the dopaminergic and serotoninergic brainstem and forebrain nuclei will be more strongly associated with depression severity than their cortical and subcortical projection areas, 2) Abnormalities within the noradrenergic locus coeruleus as well as the brainstem and forebrain nuclei connected to it will be more strongly associated with cognition than those within their cortical and subcortical projection areas, and 3) Abnormalities within the brainstem and forebrain motor system will be more strongly associated with motor frailty in LDD than abnormalities within the higher motor centers. This goal will be accomplished in a longitudinal study over 24 months with 100 LLD and 50 age and gender matched non-depressed participants (ND). All participants will undergo a standardized evaluation of mood, cognition, and frailty and structural and functional imaging at 3T at baseline. Longitudinal evaluations will include depression assessments at six month intervals and cognition and frailty assessments will be conducted annually (months 12 and 24).

NIH Research Projects · FY 2025 · 2025-07

DGAT1 deficiency is a rare lipid metabolism disorder that results in congenital diarrhea with protein losing enteropathy and prolonged parenteral nutrition dependence. Despite its discovery over a decade ago, DGAT1 deficiency remains under-recognized and incompletely understood. The DGAT1 Deficiency Symposium, to be held virtually on Sunday, November 9, 2025, seeks to address the crucial question: how do we change the course of the disease? The conference will bring together patients and families, health care providers, investigators, and industry partners, to foster collaborative learning and innovation. The aims of the project are particularly relevant to the missions of NCATS, which focuses on translating research observations into practical solutions for patients, and of NICHD, which focuses on improving the health and well-being of children affected by genetic disorders: Establish a disease registry. Initiate a prospective longitudinal study of DGAT1 deficiency. Engage basic science and translational researchers in elucidating the mechanism of lipotoxicity induced enterocyte dysfunction in DGAT1 deficiency, providing further insight into genotype-phenotype correlations, and identifying therapeutic targets. Disseminate best practice guidelines to healthcare providers and share resources with patients and families. Facilitate early diagnosis. Identify and address the unmet needs of patients and families affected by this disorder.