University Of California, San Francisco

NIH Research Projects · FY 2026 · 2026-04

Project Summary/Abstract Interorgan communication between the brain and peripheral tissues maintains a range of adaptive responses that can degrade with aging. Using mouse models, we found a powerful neural circuit that simultaneously motivates spontaneous activity and overrides spinal reflexes that control bladder and colonic function. Our preliminary findings show a strong direct neural circuit between estrogen-responsive neurons in the hypothalamus and the major micturition center in the hindbrain that controls urination, the Pontine Micturition Center (PMC) or Barrington’s nucleus (BAR). When activated, this VMHvl-BAR monosynaptic circuit blocks all voiding, even when animals have been pre-loaded with saline; when inhibited, urine release increases. Similarly, when a glass bead is inserted into the colon, excretion of this pellet takes up to fifteen times longer (20 minutes versus 5 hours) if chemogenetics is used to activate this neurocircuit. In vivo cystometry results confirm the potency of this hypothalamic-hindbrain circuit in modulating urine and fecal release. Here, we will define how neurons in BAR override normal spinal reflexes in the pelvic region. We outline three independent aims to: 1) identify the molecular nature of the inhibitory neurons in BAR responsible for this change in urinary and colon function and map projections from BAR to the spinal cord controlling the bladder or colon, 2) determine the sufficiency of VMHvl-BAR circuity components in urine release, and finally, 3) determine the initiating signals in the hypothalamus that control this voiding and defecation neurocircuit. This last aim will bring us closer to translating our preclinical research to human health. Our research program adds to emerging work on brain-body physiology to advance strategies for improving health and blends the team’s expertise in neuroendocrinology and neurocircuits. We are using state-of-the-art methods to pursue hypothesis-driven questions to decode a robust neuroendocrine circuit that controls two essential processes—urination and defecation. Both functions degrade with aging, especially in older women. Eventually, we wish to translate these preclinical studies to mitigate the loss of pelvic control in the older adult US population.

NIH Research Projects · FY 2026 · 2026-04

ABSTRACT: On any given day, nearly 2 million people are incarcerated in the US. People of color, disabled people, LGBTQ people, and people from lower socioeconomic statuses are incarcerated at much higher rates than white, able bodied, cis, straight, economically privileged people. This population experiences high rates of chronic illness and infectious disease prior to incarceration and continue to experience worse health during and after incarceration. The level of healthcare provided in correctional facilities varies, but in all cases when the medical need of a patient exceeds the capabilities of the institution, they are transferred to the community setting for care. While incarcerated patients are entitled to many of the same decision-making and privacy rights as non-incarcerated patients, little is known about how patients form relationships with their care team and make healthcare decisions while incarcerated, particularly in the community hospital setting. While most hospitals have policies on shackling, police presence, and other security measures, our preliminary research indicates that many clinicians are unaware of these policies and even more clinicians are unclear how to navigate care decisions within a complex policy landscape, perpetuating systemic inequities in care delivery. We will use the San Francisco General Hospital as a case study to examine how institutional, local, state, and federal policies converge and the conflicts that may arise as providers and correctional staff implement said policies with a diverse and vulnerable patient population. We will interview local and institutional policy makers from the hospital, the jail, and the sheriff’s department (N=45) and survey clinicians (N=500) about their knowledge, understanding, and utilization of existing policies (Aim 1). Through institutional ethnography, including participation observation and interviews with clinicians (N=50), patients (n=50), and correctional staff (N=25) we will develop a multifaceted understanding of care delivery, models of consent and decision making, and ethical challenges for incarcerated patients in the hospital setting (Aim 2). We will then use methods of Human Centered Design, within a Participatory Action Research framework, to translate empirical research findings into community driven policy and practice solutions (Aim 3). We are intentionally involving people with lived experiences of incarceration in all phases of the research (as co-investigator, research staff, advisory council members, and partners in policy development). We will engage in community-led co-learning of research best practices for collaboration with people impacted by the criminal legal system. Through this research, we will generate the needed evidence to develop community-based policy and practice recommendations to improve care, consent, and decision making for incarcerated patients in the hospital setting, advancing health equity and extending the research capacity of people with lived experience of incarceration. We will advance new understandings of the ethical principles of autonomy and justice for incarcerated patients while removing structural barriers to research through community-led efforts.

NIH Research Projects · FY 2026 · 2026-04

This project will develop and apply computational tools for assessing the risk that diseases with episodic transmission become established in the general population. Our project is relevant to emerging zoonoses, re-emerging vaccine-preventable diseases, and healthcare-associated infections. Timely identification and control of such diseases could have significantly altered the course of mpox, SARS-CoV-2, and antimicrobial resistance. It is therefore important to have methods available to monitor and fully elucidate the transmission patterns of infectious diseases that can develop increased burden through pathogen evolution, reduced population immunity, or other sociodemographic changes. Any such method needs to consider patchy surveillance and differences in risk among those who are exposed to the disease. Furthermore, diseases that cause episodic outbreaks might require specific control strategies that are different from those that apply to epidemic or endemic diseases. Existing models that explore some of these aspects typically omit key factors, rely on untested assumptions, or are validated in a circular fashion using simulations based on the same assumptions they aim to test. This limits their reliability for real-world applications. To address this gap, we will combine statistical inference with simulation approaches to address key questions in quantifying and mitigating the risk from infectious diseases. We will extend methods for inference using branching process models to take into account imperfect observations and heterogeneity in both transmission and susceptibility. We will apply these methods to a range of applications to improve our ability to learn from data describing sporadic infection clusters. We will also use mobility and demographic data to construct synthetic populations representing situations where infections cause occasional outbreaks. This will permit stress-testing of inference methods and evaluation of control strategies. Our iterative approach will allow us to refine model assumptions, improve inference robustness, and identify the most informative data types for public health surveillance and control. The work will result in a greater understanding of how public health agencies can best use data from episodic disease transmission and computational tools for applying this understanding to coming threats. To demonstrate the breadth of applicability, we will apply our methodological advancements to (1) quantify the transmissibility of H5N1 influenza, (2) determine the probability of large measles outbreaks occurring annually, and (3) evaluate control strategies for reducing transmission of virulent, healthcare-associated MRSA strains. To promote scientific reproducibility, we will produce user-friendly software that integrates with existing packages and share synthetic population data. Our team is well-positioned to conduct this work since we have developed many existing tools and paradigms for analyzing episodic transmission, including branching process models and outbreak simulations in synthetic populations. By advancing the science of disease transmission and equipping public health agencies with actionable results, this work will reduce the risk of future pandemics.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY: In this R03 application, “Development of a Humanized IL33 Mouse” we plan to engineer and characterize a mouse strain in which the human IL33 gene sequence from ~28 kb (including the 20 kb asthma-associated region) upstream of exon 1 to ~21 kb downstream of exon 8 of human IL33 gene will be cloned into intron 1 of ROSA26 locus in the mouse. This strategy uses a bacterial artificial chromosome (BAC) to insert all of the human regulatory regions which have been associated with allergic disease into the mouse. The targeting strategy uses the PiggyBac technology to deliver a single copy of the transgene into the specific integration site. The strategy includes the upstream regulatory regions because they confer localization of the human IL33 gene expression to the bronchial epithelial cells and the endothelium. That is in contrast to the mouse Il33 gene expression which is located in the lung type 2 alveolar epithelial cell. The mouse will also have lox-p sites introduced into exon 5 which can be used to conditionally delete IL33 expression. Finally, the human IL33 locus will drive an IRES-Citrine reporter that can report on the expression of the human IL33 promoter. This mouse will be crossed to the Il33cherry mouse which is a knock-in/knock-out (mcherry reporter) so that the resulting mouse will only have human IL-33 protein (which is biologically active in mice) from the human IL33 promoter along with a human IL33 Citrine reporter and a mouse Il33 cherry reporter. This mouse will then be compared to wildtype mice in an acute lung allergen challenge model to determine how localization of expression to different lung cell types (bronchial epithelium/endothelium vs type 2 alveolar epithelium) alters the location of lung type 2 infiltrates and the degree of bronchial epithelial remodeling. This proposal will utilize novel spatial transcriptomic technologies to ask important questions about how IL-33 localization alters the architecture of lung type 2 inflammation. This mouse has great potential to advance our understanding of human genetics since the asthma-associated genetic architecture (upstream of the human IL33 gene) will be introduced into the mouse.

NIH Research Projects · FY 2026 · 2026-04

SUMMARY Chlamydia trachomatis (Ct) is the leading cause of bacterial sexually transmitted infections (STI) worldwide. About 128M Ct cases are estimated to occur annually according to the WHO and 1.6M in the US. The Western Pacific Region (WPR) has over 61M of these global infections with a prevalence of ~35-40% among adolescents and young adults under the age of 25 years. About 50% of men and 80% of women are asymptomatic. Syndromic management—the reliance on signs and symptoms of STIs to determine the need for antibiotics—is often practiced in this region but is imprecise, leading to unchecked transmission to partners. Complications from these infections include infertility, pre-term birth and proctitis in addition to an increased risk of HIV and other STIs. Studies of Ct STIs focus primarily on female urogenital infections and rectal infections among men who have sex with men (MSM) with few studies of urethral infections among men who have sex only with women (MSW). While the US Centers for Disease Control (CDC) recommends annual Ct screening for women under 25 years and those at high risk (e.g., multiple partners), screening for MSW is not recommended, This leaves a gap in our knowledge about MSW urethral Ct infections and transmission dynamics to and from female partners. Our unifying hypothesis is that Ct infection, transmission and disease pathogenesis are driven/perpetuated by the interaction of male urethral and female partner endocervical, vaginal and rectal microbiomes and host immune responses that are influenced by Ct infections. For the proposed research, we will study a large cohort of male- female partners with a high prevalence of Ct in the male urethra and female endocervix, vagina and rectum. The microbiomes of these sites will be characterized by metagenome shotgun sequencing (MSS), the host immune responses by quantitative protein assays, and the Ct genomic characteristics by whole genome sequencing (WGS) and the respective analyses. Resistomes (i.e., antibiotic resistance genes (ARGs) or mutations conferring resistance to antibiotics) that are part of the microbiome will also be interrogated. Given our unique samples and metadata on all partners in this cohort, we aim to: 1) Evaluate the association between male urethral microbiomes and presence or absence of Ct; 2) Correlate male urethral microbiomes and Ct strains with similar data from female partners; 3) Model how microbiomes, including the resistome, host immune responses and Ct strains predict transmission, infection risk and disease pathogenesis. This study will create the most extensive dataset on male urethral microbiomes, resistomes, and host immune responses to date, providing a valuable resource for the medical and scientific community. Further, given the growing number of Ct STIs in the US and worldwide, the proposed research provides a unique opportunity to study male-female partners and within-host transmission to identify microbiome/resistome//inflammatory profiles that may promote Ct transmission and infection and how these data can be translated into Ct prevention and control strategies. These strategies may include identifying sentinel sites for targeted Ct screening and developing beneficial microbial therapeutics for topical therapy.

NIH Research Projects · FY 2026 · 2026-04

ABSTRACT Radiation plays an important role in treating primary and secondary liver tumors. Stereotactic body radiation therapy (SBRT) has become a standard treatment in the model era. However, toxicity-inducing doses to the normal liver often accompany the high biologically effective dose to the tumor, so radiation-induced liver disease (RILD) is a common complication that can be fatal to patients. As patient survival rates rise and therapeutic options expand, SBRT aims not only to ablate tumors but also to reduce radiation exposure to functional liver voxels, thereby decreasing treatment-related toxicities to maintain hepatic function and support future interventions, such as liver transplantation. Functional Avoidance SBRT (FA-SBRT) has been proposed. Researchers have created FA-SBRT plans using commercial planning systems. However, it was concluded there was insufficient data to confirm efficacy. The inability to establish the efficacy can be attributed to the following reasons: the lack of clinically accessible methods to assess voxel-level liver function, the lack of quantifiable liver function metrics for treatment planning, and the severe limitations of commercial planning systems in achieving a more significant level of functional liver sparing. We pioneered the development of a Multi-Tasking (MT) MR imaging sequence and advanced non-coplanar 4π planning method. The convergence of cutting-edge imaging and plan optimization strategies presents an unparalleled opportunity to optimize treatment delivery, reduce radiation-induced liver toxicity, and augment therapeutic outcomes. The proposal directly responds to PAR-25- 145, Clinical Characterization of Cancer Therapy-induced Adverse Sequelae and Mechanism-based Interventional Strategies. The three proposed aims are 1. To develop and optimize the MR multi-tasking abdominal integrated imaging (MT-AI2); 2. To create a functional avoidance SBRT planning strategy using advanced 4π optimization; 3. To conduct a phase II clinical trial to test efficacy. The project’s success will demonstrate the effectiveness of integrating cutting-edge imaging and therapeutic methods to maximally preserve liver function for future treatment options.

NIH Research Projects · FY 2026 · 2026-04

Abstract In the past few decades, enormous progress has been made in our knowledge of basic, translational and clinical pharmacology in healthy and diseased adult populations. In marked contrast, few studies have focused on basic, translational, and clinical pharmacology in pediatric populations and in pregnant and lactating mothers. The primary goal of the proposed five-year series of symposia is to identify and address critical gaps in our understanding of drug safety, efficacy and individual therapy for pregnant women, fetuses and children. Our secondary goal is to foster collaborations in pediatric pharmacology and women’s health primarily during pregnancy and lactation. Multi-disciplinary researchers across a range of topics throughout the maternal-child health continuum will be invited to give presentations. The conference will feature interactive panel and roundtable discussions to facilitate audience participation, and include a poster session. This unique conference will bring together for the first time national and international researchers who are working in these highly understudied areas of pharmacology. The specific objectives of our proposed symposium are to: (1) Advance translational pharmacological research in pregnant and lactating women as well as in children across the developmental stages; (2) Promote and support implementation science in pediatric pharmacology through discussions ranging from pharmacokinetic sampling methods, pediatric clinical trials, and translating pharmacologic evidence into clinical guidelines and practice; and (3) Foster synergy between U.S. and international teaching and research ecosystems, emphasizing competency-based, practice ready and inclusive education frameworks. Through scientific discourse and networking, this unique, first of a kind, two-day conference will be held at the University of California, San Francisco in the first year. In subsequent years, the conference will be held at other sites and will provide an in-depth examination of critical topics in child and maternal pharmacology. Through scientific exchange, the conference will provide a blueprint for research, education and implantation sciences to enhance the discovery, development and therapeutic use of medications in these highly understudied populations.

NIH Research Projects · FY 2026 · 2026-04

Project Summary/Abstract Over the past 20+ years, our group and others have worked to make multiparametric (mp) MRI a valuable tool for detecting prostate cancer (PC) and guiding diagnostic & treatment decisions. While mpMRI provides a whole gland assessment with a high patient-level sensitivity, it still misses clinically significant PC in up to 20% of patients with a negative mpMRI (12). Furthermore, the Prostate Imaging Reporting & Data System (PI-RADS), which is qualitative in nature, is associated with significant inter-reader variability and generally poor correlations with tumor grade. Radionuclide FDG or PSMA PET are not clinically reliable in the setting of localized PC. These limitations, together with the increased use of focal therapies for intermediate risk disease, highlight the need for improved and quantitative biomarkers of aggressive PC especially for guiding biopsies and treatment planning. This resubmission project is designed to translate new safe, non-radioactive hyperpolarized (HP) 13C dual-agent molecular MRI techniques with ~10x higher sensitivity to guide prostate biopsies in PC patients in order to address the unmet clinical need of reliably detecting aggressive prostate cancer for improved patient care. HP pyruvate-to-lactate conversion rates (kPL) have been shown to provide quantitative metabolic measures that correlate with prostate cancer aggressiveness (Figure 1). Also, HP 13C-urea MR, using a small molecular weight (0.08 of Gd contrast), metabolically-inert, safe, endogenous, positive-contrast stable-isotope probe, has been shown in preclinical animal studies (and in an initial human study) to provide unique tissue/tumor perfusion information that is altered with aggressive prostate cancers (Figures 1-3). HP 13C-urea detects decreased tumor urea distribution volume and perfusion that are hallmarks of high-grade disease (Figure 2-4), providing unique information synergistic with HP 13C-pyruvate MRI for detecting aggressive PC. HP [1-13C]pyruvate+urea MRI was able to detect clinically occult prostate cancer not seen on conventional multiparametric MRI (Figure 3). This novel project, improved in response to the prior critiques, is designed by highly experienced academic- industry PC MRI researchers to translate new dual agent HP acquisition & analysis methods and integrate this new "biomarker-driven" guided biopsy approach into a 1H & HP 13C mpMRI exam with: A) Specialized hardware and methods for novel, cost-effective high-concentration HP urea+pyruvate contrast-agent sterile doses and greatly-advanced HP 13C MR acquisition & analysis techniques (Aim 1), B) Pre-prostatectomy studies with correlations of the non-invasive biomarker of tumor tissue-perfusion & metabolism, kUR, with “gold standard” step-sectioned histopathology, immunohistochemical staining and genomic sequencing to correlate the imaging markers to histological and genomic signatures of aggressive cancers with associated highly proliferative, lethal phenotypes (Aim 2), and C) Specialized kinetic modeling and MRI-TRUS fusion biopsy-guidance methods (Aim 3) to provide a novel solution to a significant & persistant challenge in PC clinical research & management, constantly faced by our urologists & oncologists, namely, the accurate detection of aggressive tumors.

NIH Research Projects · FY 2026 · 2026-04

Project Summary/Abstract Precise delivery of biomolecules to specific cell types is essential for elucidating cellular functions and advancing precision molecular therapies. While viral vectors have achieved significant advances in targeted gene delivery through capsid engineering and cell-type-specific promoters, they are limited by immunogenicity, restricted cargo capacity, and scalability challenges. Non-viral lipid nanoparticles (LNPs) offer advantages such as high payload capacity, low immunogenicity, and scalable production. However, achieving the cell-type specificity inherent to viral systems remains a critical challenge. This proposal seeks to advance gene delivery by integrating the scalability and versatility of LNPs with the precise cell-type targeting of viral vectors. We introduce two innovative strategies: (1) Bio-inspired design of LNPs to enhance transfection efficiency and specificity, and (2) Development of programmable RNA sensors that enable cell-type-specific expression of transgenes. We will employ a multidisciplinary approach combining nanotechnology, synthetic biology, and systems neuroscience. We will develop novel LNP formulations and characterize their physicochemical properties and cellular interactions using advanced imaging and biophysical techniques. In parallel, we will design and screen RNA sensors that respond to endogenous cell-specific transcripts, encapsulate them in optimized LNPs, and evaluate their specificity and efficacy both in vitro and in vivo. The development of scalable, precise gene delivery platforms will transform our ability to manipulate and study cellular functions in the central nervous system and peripheral organs, paving the way for next-generation precision therapies.

NIH Research Projects · FY 2026 · 2026-04

Background: T cell therapies have been transformative for certain leukemias and lymphomas, however solid tumors have proven far more difficult due to challenges such as poor infiltration, harsh metabolic environments, and a myriad of suppressive factors in the tumor microenvironment (TME). Most large-scale genetic screens in human T cells have been performed in vitro, which fail to capture many solid tumor-specific barriers. However, performing large-scale screens in vivo has been impractical due to the low recovery of T cells from tumors, which significantly limits screening throughput. To overcome these limitations, we developed a novel screening platform that allows engagement of human CD4+ and CD8+ T cells with any polyclonal repertoire and achieves significantly higher T cell recovery from tumors, enabling genome-wide screens in relatively few mice. Preliminary Data: Using this system, we performed two genome-wide CRISPR loss-of-function screens for gene targets that enhance T cell abundance within tumors as well as effector function in tumors based on interferon- γ production. We uncovered many genes with known roles in T cell fitness, as well as many novel gene targets, including from two GPCR signaling pathways that regulate (1) T cell resistance to TME-mediated suppression and (2) T cell trafficking and infiltration into tumors. The PTGER4-GNAS (Gαs) signaling pathway was enriched in our screens and has been previously shown to induce dysfunction in mouse T cells in the TME in response to suppressive cues. Our preliminary data suggest knocking out GNAS in human T cell therapies can robustly enhance tumor control and survival. Our screens and preliminary validation data also identified P2RY8-Gα13 signaling, a pathway previously characterized in B cell migration, as a major regulator of human T cell trafficking into tumors. Research Strategy: In Aim 1, we will investigate the genetic disruption of GPCR-Gαs-PKA signaling to enhance T cell resistance to TME suppression. We will test the efficacy of GNAS KO in TCR- and CAR-T cells in multiple solid tumor models and we will dissect the dominant upstream GPCRs as well as key downstream PKA targets driving these effects. In Aim 2, we will establish the P2RY8-Gα13 GPCR signaling pathway as a novel regulator of T cell trafficking and immune exclusion. We will use a combination of in vivo and in vitro competition assays to assess how this pathway affects T cell migration into tumors, as well as functional genetics and microscopy approaches to evaluate its role in immune exclusion. We will test whether the P2RY8 ligand, S-geranylgeranyl-L-glutathione, is a repulsive cue used by tumors to block T cell infiltration. In both aims, in addition to our studies in healthy T cells, we will test the relevance of these pathways in tumor- infiltrating lymphocytes from solid tumor patients. Expected Results and Impact: These studies will rigorously test whether targeting key GPCR signaling pathways nominated by our screens can enhance T cell infiltration and durable effector function. Our findings will provide novel strategies for engineering more effective T cell therapies for solid tumors and establish a new standard for in vivo functional genomics screens in human T cells.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY/ABSTRACT Our brain generates sensory perceptions by integrating externally (bottom-up) and internally (top-down) driven representations of the world. The bottom-up pathways provide information originating from the sensory periphery about the physical properties of the stimulus. The top-down pathways provide inferential or predictive information about the nature of the stimulus based on its context and on the organism’s experience. Imbalances between the bottom-up or top-down driven representations result in profound perceptual abnormalities, leading to various psychiatric disorders. However, the mechanisms that enable our brain to establish and maintain a balanced integration of bottom-up and top-down information streams during sensory processing is unknown. Specifically, the mammalian sensory cortices are composed of a diverse array of neuronal types classified by their transcriptomes. It is unclear which types receive inputs from the bottom-up, top-down, or both sensory streams. Additionally, while sensory neurons exhibit varying responses to the same stimuli depending on the context within which the stimuli are presented, it remains unclear whether this variability is influenced by how these neurons are integrated in the bottom-up and top-down pathways. Furthermore, the timeline for when bottom-up and top- down integration matures is largely unknown, as is the impact of experience on this developmental trajectory. I propose to address these questions using the mouse primary visual cortex (V1) as a model system. V1 receives visual information that ascends from the eyes through the dorsolateral geniculate nucleus of the thalamus (dLGN) and descends from higher-order visual areas, including the lateral posterior (LP) nucleus and cortical higher visual areas (HVAs). I hypothesize that V1 neurons receiving bottom-up or top-down inputs from the dLGN, LP or HVAs represent largely distinct transcriptomic categories with distinct laminar profiles and response properties to visual stimuli. Furthermore, I hypothesize that visual experience is necessary for the development of bottom- up and top-down integration in V1. To test these hypotheses, I will implement a combination of a newly developed anterograde transsynaptic tracing technique, spatial transcriptomics and in vivo two-photon imaging to carry out the following experiments. In the K99 phase, I will first determine the molecular identities of neurons receiving bottom-up or top-down inputs in the adult mouse V1. I will then characterize the response properties of adult V1 neurons in relation to the origins of inputs they receive and to their molecular identities (K99 + R00). In the R00 phase, I will determine the developmental time course and the role of visual experience in the development of bottom-up and top-down integration in V1. These experiments will allow us to provide the first mapping of the two major streams of visual information, the bottom-up and the top-down, to V1 onto molecularly defined neuronal types. We will also reveal, for the first time, the logic of neuronal responses to sensory stimuli in relation to the two major pathways that impinge on these neurons. Furthermore, we will uncover fundamental principles of the development of bottom-up and top-down integration in V1.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY/ABSTRACT African American individuals face a disproportionately higher risk of tobacco-related cardiovascular diseases (CVD) than other races, a disparity not fully explained by traditional and socioeconomic risk factors. Despite lacking approval from the U.S. Food and Drug Administration (FDA) for their safety, e-cigarettes (e-cigs) have become increasingly popular, particularly among youth, and are now among the most commonly used tobacco products alongside traditional cigarettes. Approximately half of African American individuals carry at least one of two genetic variants (G1 and G2) of the apolipoprotein L1 (APOL1) gene, which are exceedingly rare in other populations. APOL1 is widely expressed, particularly in the vasculature. We have shown that carriers of APOL1 G1 and G2 variants have increased susceptibility to tobacco-related CVD, including stroke and coronary heart disease. Dysfunction of vascular endothelial cells (ECs) is a critical precursor to CVD. EC dysfunction also plays a key role in APOL1-associated pathology, including exacerbated renal issues and increased susceptibility to sepsis and severe COVID-19. Recent research indicates that, similar to cigarettes, both e-cigs and menthol—a flavor popular in the African American community—independently impair endothelial function. While studies, including those using induced pluripotent stem cell (iPSC)-derived ECs, demonstrate these effects, the specific impact of APOL1 risk variants on vascular health in African American tobacco product users remains unknown. The goal of the proposed research is to determine the effects of e-cigs, with and without menthol, on endothelial health, compare them to the effects of cigarettes, and identify potential molecular markers and pathways associated with CVD in African American users, with a focus on the APOL1 genotype. As such, this application aims to expand my background and expertise in modeling the CVD risk from tobacco products and to provide specific training in tobacco product-related in vitro assays, iPSC methodology, gene editing, and computational techniques. Building on my prior work in human studies, this research extends to the cellular level to address significant gaps in knowledge regarding the adverse effects of the most popular tobacco products, with and without menthol, among the African American population—a demographic long targeted by the tobacco industry marketing. To achieve this goal, I will use a robust in vitro platform of human iPSC-ECs to address the following aims: Aim K1) to determine the effect of e-cigs and cigarettes on markers of EC dysfunction in G1/G1 iPSC-ECs, Aim R1) to determine the effect of e-cigs and cigarettes on endothelial function in G2/G2 iPSC-ECs, and Aim R2) to determine the effect of e-cigs and cigarettes on inflammatory markers and lipid mediators of inflammation in G1/G1 and G2/G2 iPSC-ECs. This project will deepen our understanding of the adverse effects of widely used tobacco products on vascular health in the CVD-burdened African American population. It also aims to identify molecular markers of cardiovascular injury in this high-risk group, providing insights into the mechanisms of tobacco-related cardiovascular damage and supporting the development of targeted interventions.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY The Developmental Origins of Health and Disease framework has illuminated that maternal factors during pregnancy, such as exposure to elevated stress, increase children’s risk of mental health problems, via prenatal and postnatal mechanisms. Thus, there is a critical public health imperative to conduct research in this area to understand and ultimately prevent the development of psychopathology. Fetal exposure to elevated maternal inflammation during pregnancy (PMI) increases risk for child psychopathology via placental mechanisms, however, evidence from animal and human models suggests that heightened PMI may also disrupt maternal parenting behaviors. Via a phenomenon called “sickness behaviors,” high levels of inflammation can cause social withdrawal, depression-like feelings, and problems understanding social situations. Although social withdrawal and depressive tendencies may be potentially adaptive, energy- conserving responses that facilitate fighting an infection, affective and social difficulties may impair parents’ ability to recognize and respond optimally to their baby’s signals. Critically, the direct and indirect associations among PMI, parenting, and child mental health have not yet been tested in humans. In this proposal, I will fill critical training gaps in prenatal immune biology, advanced longitudinal statistical modeling, and multidisciplinary intervention research to test 3 Aims. First, I will leverage my primary mentor’s deeply-phenotyped, sociodemographically diverse longitudinal pregnancy cohort of mother-child pairs (n = 1303) to test the novel hypothesis that parenting partially accounts for positive associations between PMI and childhood mental health problems (Aims 1 and 2). Mentored training and findings will inform a pilot intervention study in which I partner with a well-established clinical research program to bridge Aims 1-2 findings with applied solutions (Aim 3). This program delivers an evidence-based intervention targeting traumatic stress exposure (Perinatal Child-Parent Psychotherapy) to pregnant Latina women. In this study, I will collect repeated measures of PMI as well as observations of parenting and infant behavior (n = 20). Preliminary findings from associations among intervention-related changes in PMI, parenting, and infant behavior will validate the mechanism tested in Aims 1 and 2 and lay the groundwork for a follow-on R-34 intervention study testing effects of prenatal psychological intervention on PMI, parenting, and child mental health. Investigating associations between PMI, parenting, and child mental health will elucidate the etiology and maintenance of child psychopathology, as well as mechanisms for targeting prenatal prevention and postnatal intervention. Addressing these potential determinants and solutions are public health and NIMH priorities. Mentored training from this K23 proposal will support my transition to an independent interdisciplinary clinical science career investigating and preventing the intergenerational transmission of stress and psychopathology.

NIH Research Projects · FY 2026 · 2026-04

Project Summary There are demonstrated benefits of comprehensive, continuous, and coordinated primary care for older adults, ranging from higher rates of appropriate preventive care receipt to lower rates of hospitalization and mortality. However, the benefits of strong primary care are threatened by an impending primary care workforce crisis, exacerbated by prevalent trends of primary care physician (PCP) workforce attrition and clinical effort reduction. Partly in response to these trends, there is increasing representation of NPs and PAs, collectively referred to as advanced practice clinicians (APCs), in the primary care workforce. However, burnout, intent to leave, and intent to reduce clinical effort are also prevalent among primary care APCs. These trends across primary care clinicians (PCCs; comprising physicians, NPs, and PAs) may significantly threaten quality of and access to care for older adults. At present, there is limited evidence to inform healthcare leaders and policy makers about how primary care workforce disruptions impact access to and quality of primary care received by older adults. There is additionally insufficient information on the actionable factors associated with PCC turnover and PCC reductions in clinical effort. In this grant, we will leverage data from Medicare fee-for-service and Medicare Advantage, which together provide coverage for 93% of older adults, in order to: 1) quantify the number of Medicare patients impacted by PCC turnover and sustained reductions in billed clinical effort and identify factors associated with these work effort changes; 2) assess the impact of PCC turnover and PCCs’ sustained reductions in billed clinical effort on patterns of primary care receipt and non-primary care utilization, including emergency department visits and hospitalizations; and 3) assess the impact of PCC turnover and sustained reductions in billed clinical effort on quality of care for older adults. All analyses will be conducted for the overall population of older adults as well as for subgroups of more vulnerable older adults, including those with dementia, multiple chronic conditions, and from underserved groups (e.g., dually eligible for Medicaid). Additionally, analyses will be conducted for physicians and APCs separately, and for the overall study period and comparing the pre- and post-COVID periods. The results from this study will elucidate how changes in PCCs’ work patterns influence the care of the growing US population of older adults. They will provide actionable insights for leaders seeking to design clinical systems and policies that enhance primary care for older adults. Overall, this proposal will enhance the ability of clinical, operational, and policy leaders to maintain the effort of the primary care workforce and optimize care for older adults.

NIH Research Projects · FY 2026 · 2026-04

ABSTRACT: Prenatal surgeries to treat anatomic malformations have been life-changing for thousands of patients and their availability continues to expand. The field now includes molecular therapies to treat patients with severe, early-onset genetic conditions such as in utero enzyme replacement therapy (IUERT) for early- onset lysosomal storage disorders (LSDs). While such medical therapies are not yet curative, they have demonstrated the feasibility of diagnosing genetic conditions early enough to intervene and the technical safety of prenatal infusions into the umbilical vein. As patients with genetic conditions still need definitive cures, developing a prenatal somatic cell gene therapy (PSCGT) that is safe for both the mother and fetus would be transformative. AAV9 gene therapies have been life-saving for children with neurologic conditions like Spinal Muscular Atrophy and appear to have a favorable risk/benefit profile for use in prenatal therapy. While decades of small and large animal preclinical data support the safety and efficacy of prenatal AAV gene therapies, a clinical trial has not been performed. After numerous discussions with scientists, clinicians, patient advocates, ethicists, and the FDA, we think the field is ready to consider an IND application in the right disease setting. GM1 gangliosidosis may be the ideal condition for a first-in-human approach: it is a severe, fatal neurodegenerative LSD resulting from biallelic mutations in the GLB1 gene. Patients suffer from progressive neurodegeneration characterized by spasticity, deafness, blindness, and seizures, and medical care is limited to symptomatic management. There is evidence of prenatal onset of disease, particularly in the two early-onset subtypes: Type I (infantile) and Type IIa (late infantile). An ongoing postnatal phase 1/2 clinical trial of AAV9- GLB1 therapy (PI: Dr. Cynthia Tifft) that has demonstrated excellent safety and partial efficacy, although the benefits are limited due to irreversible damage from demonstrated prenatal onset of disease and even patients treated as infants succumb to disease. We hypothesize that administration of the same AAV9-GLB1 vector in patients with infantile GM1 could improve outcomes. We have submitted a pre-IND application and are now ready to perform IND-enabling studies. In this grant, we will perform a pharmacology/toxicology study of the clinical vector in the prenatal lamb model (Aim 1). We will also develop amniotic fluid assays to detect efficacy of the vector (expression of the GLB1 construct and decreases in disease-specific biomarkers) and to quantify inflammatory markers after prenatal intervention (Aim 2). We will engage with patients to understand their attitudes towards this new treatment protocol (Aim 3). We will also perform regulatory activities, including developing a clinical protocol and internal IRB application, culminating in submission of an IND protocol to start a phase 1 clinical trial in prenatal patients with infantile GM1 gangliosidosis. Successful completion of these aims will provide critical important regarding the safety and feasibility of PSCGT and could enable the development of similar therapies for patients with other severe genetic conditions.

NIH Research Projects · FY 2026 · 2026-04

ABSTRACT Pathogen transmission via indirect routes such as fomite, waterborne, and airborne transmission are hallmarks of both endemic and pandemic spread. Viruses such as Influenza, SARS-CoV-2, and measles are notable examples, in addition to deadly microbes such as Bordetella pertussis, Mycobacterium tuberculosis, and Coccidioides species. However, the rapid detection and analysis of airstreams as part of biosurveillance, public health monitoring, or epidemiological research remains challenging. Current state-of-the-art methods rely on bulky apparatuses for both the collection and detection of airborne agents; most of these methods are ill suited to rapid response point-of-testing within medical facilities, workplace locals, or public spaces. Further, these technologies are based on bulk Polymerase Chain Reaction (PCR) and Loop-mediated isothermal amplification (LAMP) methods that have limited quantitative accuracy. Thus, more portable and accurate platforms are needed to address the types of rapid response and ubiquitous monitoring that is required to minimize outbreaks in the 21st century. Towards this objective, this grant will address the need for an improved method of airborne pathogen detection through the development of the digital droplet Aerosol Capture & Quantification (ddACQ) system. The ddACQ system consists of two novel technologies, a filter particle array and a droplet buoyancy counter. The filter particle array allows for the capture of airborne pathogens or biological agents and generation of microfluidic droplets when mixed with an oil and water reagent solution. A phone-powered heat block then drives a one-step isothermal digital droplet reaction. Digital techniques have several key advantages over classical quantitative PCR and LAMP techniques, namely single molecule detection and direct quantification without a standard curve. Finally, the droplet buoyancy counter allows for smartphone based read out of the reaction immediately at the testing site in under an hour. Together, the innovations within and implementation of the ddACQ system represents a novel application of microfluidic principles and an enabling technology for both pathogen transmission research and public health monitoring applications.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY/ABSTRACT Our research aims to advance the understanding and diagnosis of Sjögren’s Disease, particularly its manifestation as dry eye disease (DED), which disproportionately affects women. By refining diagnostic capabilities, we intend to facilitate earlier detection and better therapeutic strategies, which could potentially improve patient outcomes and quality of life. We will utilize a comprehensive human proteome-wide programmable phage display to pinpoint autoantigen targets in tears collected at baseline from participants of the Sjögren’s International Collaborative Clinical Alliance (SICCA). By employing phage immunoprecipitation sequencing (PhIP-Seq), which integrates oligonucleotide library synthesis for encoding peptides in bacteriophages with high-throughput sequencing, to profile the entire antibody repertoire in tear samples. This technique allows for the high-resolution identification of autoantigens associated with Sjögren’s Disease, particularly focusing on distinguish Sjögren’s Disease from other causes of DED, especially female patients. We will also assess the persistence of specific autoantibodies identified at baseline in follow-up samples collected two years later from the SICCA cohort. This cohort includes over 700 participants with baseline and follow-up tear samples collected via Schirmer strips.

NIH Research Projects · FY 2026 · 2026-04

Project Summary/Abstract This application is submitted in response to RFA-HD-18-011, Child Health Research Career Development Award (CHRCDA) Program to provide K12 awards through the CHRCDA mechanism to young pediatric investigators. This new application requests resources to support three pediatricians each year who hold MD or MD/PhD degrees and have completed scholarship training in a clinical subspecialty. The rationale for the program is based on the well-documented and urgent need to support mentored career development for pediatricians to enable them to become fully independent and productive basic science researchers, and the fact that the department of Pediatrics at UCSF has the vision, experience and infrastructure to train the next generation of leaders in pediatric science. Our aims are to (1) offer a structured program for training academic pediatricians, (2) foster career development and promote retention of junior faculty, (3) expose promising early career pediatricians to the intellectual richness of UCSF research and (4) promote diversity in academic pediatrics. The scholars trained by this program will bring state-of-the-art approaches to bear on diagnosis, treatment and prevention of health problems in children as well as childhood onset of adult illness. The design of this program involves harnessing the expertise of world- class basic laboratory scientists who will serve as mentors for interdisciplinary training. The basic science training program is focused around eight scientific cores: cancer, cardiopulmonary medicine, developmental biology, genetics, immunology, neurobiology, stem cell biology, and our new computational sciences core. Each core has a Director, designated faculty, and a specific didactic curriculum. The scholars, in conjunction with their mentor and Core Director, will also participate in a program of additional discipline-specific course work dependent on both the prior experience and training of the applicant and the scientific theme of the trainee’s research, which may often overlap amongst different cores. In this application, we provide evidence that the Department of Pediatrics together with the broader UCSF research community comprise an exceptional environment for preparing young pediatricians who will receive support through the CHRCDA mechanism for successful careers as basic science researchers. There are > 1,200 research laboratories and > 2,200 active research projects at UCSF, and the faculty includes 5 Nobel laureates, 64 members of the American Academy of Arts and Sciences, 76 members of the Institute of Medicine, and 18 Howard Hughes Medical Institute investigators. This program is an investment in the future of children's health, as the diverse group of researchers we will train will harness advanced research strategies to address urgent problems that will result in new treatments to improve child health.

NIH Research Projects · FY 2026 · 2026-03

Project Summary / Abstract Nociception is the process whereby a subset of somatosensory nerve fibers (called nociceptors) detects noxious stimuli and transmits this information to the central nervous system, ultimately producing a percept of discomfort or pain. Nociceptors are faced with the complex task of recognizing disparate environmental and endogenous signals of both a physical and chemical nature; these include temperature, pressure, irritants, pruritogens, and inflammatory agents. Consequently, nociceptor activation elicits acute pain as well as injury-evoked pain hypersensitivity and can contribute to so-called ‘maladaptive’ processes underlying persistent pain syndromes. Our goal is to understand how nociceptors detect, integrate, and transmit these signals under numerous environmental and physiological conditions. This proposal is aimed at identifying and characterizing molecules, cells, and mechanisms that contribute to nociception in the context of acute (protective) or pathological (chronic) pain states. Our approach is multifaceted and ranges from structural biology to integrative physiology. At the most reductionist level, we will use biophysical, biochemical, and pharmacological tools to elucidate structural mechanisms underlying ion channel function, with an emphasis on identifying proteins and other cellular elements that physically and functionally engage with members of the TRP ion channel family that play key roles in nociception. We will also leverage cutting edge approaches in electron cryo-microscopy and tomography to visualize these channels and signaling complexes in cellular membranes and, ultimately, in their native environment of the primary afferent nociceptor. At a more integrative level, we shall probe mechanisms of intero-nociception by asking how primary afferent nociceptors interact with tissues to detect noxious signals and transmit this information to the spinal cord. We will focus on the intestine and joints, using mice as genetically tractable models for understanding mechanisms underlying chronic visceral or osteoarthritic (OA) pain. We will employ state-of-the-art techniques, such as genetically encoded neurotransmitter sensors and single cell sequencing, to characterize interactions between nociceptors and sensory epithelial cells in the gut or subchondral bone in joints. Because visceral and OA pain are more prevalent in women, we will ask if these interactions or other properties of resident nociceptors differ with sex or with age, which is also a significant factor contributing to OA. Models of OA or visceral hypersensitivity will be used to ask if genetic, functional, or anatomical characteristics of nociceptors change under maladaptive states. Visceral and OA pain remain poorly managed, reflecting our current lack of mechanistic insight into these common debilitating disorders. Together, these studies will help bridge this knowledge gap and facilitate the development of novel analgesic therapies.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY/ABSTRACT Summer Research Experiences in Neuroscience (SREN), developed and led by the Science & Health Education Partnership (SEP) at UC San Francisco (UCSF), will annually support 10 public high school students in neuroscience research internships. Interns’ research projects will focus on deepening our understanding of the brain and nervous system in order to reduce the burden of neurological disease. UCSF’s world-renowned departments of Neurology, Neurological Surgery, and Institute for Neurodegenerative Diseases offer an ideal backdrop to develop interns’ ability to conduct rigorous scientific research. The specific aims for this project are to: 1) develop students’ science skills, 2) build students’ awareness of neuroscience careers and identity as neuroscience researchers, and 3) foster college readiness. This project leverages UCSF SEP’s experience coupling authentic research experiences with co-curricular supports to prepare students to matriculate to and thrive in college, ultimately to increase participation in neuroscience careers. The short and long term impacts of SREN on its student cohort will be documented through surveys to track high school graduation, college matriculation, major selection and degree completion, as well as students’ self-reported gains in science confidence and researcher identity. Over the lifetime of the project, 50 students will be engaged in authentic neuroscience research projects and have the chance to leverage the support structures within SREN to propel themselves into a neuroscience career.

NIH Research Projects · FY 2026 · 2026-03

Replicative immortality is a hallmark of cancer that underpins tumor growth. Immortality is achieved by reactivating the Telomerase Reverse Transcriptase (TERT) gene. Without TERT, telomeres erode with each cell replication, limiting cellular lifespan. Heterozygous activating mutations in the TERT promoter (TERTp) are the most common non-coding mutations in cancer, but their activation mechanism is unresolved for most cancers. Understanding how TERTp mutations lead to reactivation and immortality is a central question in cancer research with major therapeutic implications. However, a cadre of regulators of the mutant TERTp has been proposed. The two hotspot mutations generate identical de novo E26 transformation specific (ETS) transcription factor binding motifs largely shared by the 28 members of the ETS family. We were the first to discover that one unique ETS factor, the multimeric GA-binding protein (GABP), activates the two hotspot mutations in TERTp mutant glioblastoma. In our preliminary data, we analyzed cell lines representing sixteen cancer types and six recurrent mutations and found that a B1L heterotetramer is responsible for activation in all cases. Surprisingly, TERT expression is maintained after B1L tetramer depletion. Further investigation revealed an underlying network of GABP transcriptional auto-suppression, the release from which drives the upregulation of the GABPB1S dimer or the alternative GABPB2 tetramer. We hypothesize that the B1L tetramer is the pan- cancer activator of the mutant TERT promoter, but it is replaceable exclusively by the upregulated B1S dimer or B2 tetramer. Based on this new regulatory model, we anticipate that targeting the common elements of the GABP complexes will reverse tumor cell immortality phenotypes and slow or eliminate further tumor growth. We devised three specific aims to evaluate our hypothesis and develop experimental tools to subvert immortality. We will use CRISPR knockouts and a biological proteolysis-targeting chimera designed to selectively degrade GABP. In TERTp mutant and wildtype cancer cells, we will use these targeting tools to resolve the temporal relationships between GABP targeting and tumor immortality phenotypes including TERT expression, telomere loss, and cell viability associated gene expression signatures at the bulk and single cell level (Aim 1). In Aim 2, we will discover vulnerabilities in domains shared among GABP complexes via in silico mutagenesis at an unprecedented scale with Artificial Intelligence tools AlphaFold and Struct-Evo, and validation experiments. This will allow us to refine and interpret the structure predictions of complete GABP complexes bound to the mutant TERTp at atomic resolution, to develop potent GABP degraders and potentially small molecule binders or inhibitors. In Aim 3, we will determine whether an inducible GABP-degrader can subvert immortality in vivo, including sensitization and rescue experiments. Targeting this core enabler of immortality could convert oncogenes into drivers of cell death and senescence. The results of our study will be applicable to a wide spectrum of adult and pediatric cancers. The AI-based mutagenesis and experimental validations may be applicable to many other cancer targets.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY Top-down signals from the prefrontal cortex have long been postulated to regulate hippocampal function as part of numerous cognitive and emotional processes, but the specific pathways mediating top-down control have been unclear. We have found a novel long-range GABAergic pathway from prefrontal cortex to hippocampus that represents a potential substrate for top-down control. Notably, this pathway seems to operate in an unusual manner: by inhibiting disinhibitory circuits. Our initial studies found that these prefrontal- hippocampal GABAergic projections can promote object exploration by enhancing hippocampal representations of object locations and associated network oscillations. However, two major questions remain unresolved. First, prefrontal GABAergic neurons which project to the hippocampus are heterogeneous and the significance of this is unknown. Second, the detailed circuit mechanisms through which long-range GABAergic projections from prefrontal cortex alter hippocampal information processing remain unclear. The goal of this project is to first and foremost, elucidate mechanisms through which long-range prefrontal-hippocampal projections shape computation in downstream circuits, and second, relate these to the heterogeneity of long- range GABAergic neurons. This project will specifically test our hypothesis that long-range GABAergic projections exert top-down control over the hippocampus by targeting disinhibitory microcircuits, thereby regulating how competing input regions recruit and entrain feedforward inhibition in the hippocampus. This could explain how hippocampal circuits switch between different information processing modes, each characterized by rhythmic synchronization with a different upstream region. Furthermore, we may identify different subtypes of long-range GABAergic neurons that each promote synchrony with a unique input region, elucidating organizational principles and functional implications for the heterogeneity of long-range GABAergic neurons.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY Mutations in two polycystin proteins called PC1 and PC2 cause Autosomal Dominant Polycystic Kidney Disease (ADPKD), which cause kidney and liver cysts. ADPKD is the most common monogenic cause of kidney failure, accounting for 10% of global kidney failure. PC1 and PC2 are essential subunits of a non-selective cation TRP channel. 80% of ADPKD-causing variants occur in PC1, but it is currently only poorly understood how such mutations impair physiological function. As a consequence, there are limited therapeutic interventions for this chronic disease. The central goal of this project is to functionally characterize and classify pathogenic missense mutations in PC1. The first aim quantifies the effects of PC1 variants on expression, trafficking and channel function. The second aim identifies the susceptibility of pathogenic variants within different domains of PC1 towards rescue, either by temperature shift or small molecules. The third aim will for the first time determine how small molecules restore defective polycystin function and affect cystogenesis using a kidney organoid system. Completion of this project will elucidate the fundamental principles by which pathogenic mutations in PC1 cause ADPKD. In addition, classification of variants by molecular mechanism will enable rationale development of therapeutics for ADPKD similar to the remarkable progress in cystic fibrosis.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY/ABSTRACT Behavioral variant frontotemporal dementia (bvFTD) is a devastating neurodegenerative disorder characterized by early and profound social cognitive deficits, including impairments in theory of mind, emotion reading, and empathy, which cause significant distress and burden for caregivers. While research has traditionally focused on cortical degeneration in bvFTD, mounting evidence highlights the cerebellum’s critical role in cognitive and social processing. Despite comprising 80% of the brain’s neurons and demonstrating early atrophy in bvFTD, the cerebellum’s contributions to social cognition and its potential as a biomarker for disease progression remain underexplored. This study aims to address this gap by investigating the cerebellum’s influence on social cognitive deficits and its value for predicting clinical trajectories in bvFTD. Leveraging cross-sectional and longitudinal neuroimaging and clinical data from the University of California San Francisco (UCSF), Memory and Aging Center and the multisite ARTFL-LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study, this project is structured to achieve two primary aims. Aim 1 will use cross-sectional data from UCSF to characterize the relationship between social cognition and cerebellar structure and function in bvFTD across disease stages, using neuroimaging to identify compensatory and degenerative mechanisms. Aim 2 will use longitudinal data from ALLFTD to assess the predictive value of early cerebellar atrophy for later social, cognitive, and psychiatric decline, enhancing understanding of the cerebellum’s impact on clinical outcomes. This research is poised to fill critical gaps in our understanding of bvFTD by highlighting the cerebellum’s involvement beyond traditional motor functions, thereby offering new insights into brain network dynamics and their clinical implications. Findings from this study have the potential to enhance diagnosis and inform novel intervention strategies targeting cerebellar circuits, ultimately enhancing patient management in bvFTD. This project supports Dr. Chen’s career development goals of becoming an independent researcher specializing in advanced quantitative neuroimaging and neuropsychology in individuals with neurodegenerative disease. The K99 phase will provide training in cognitive neuroscience, interpretation of social cognition testing, and multimodal neuroimaging, enhancing her ability to integrate clinical and neuroimaging data to study neurodegenerative disease mechanisms. The R00 phase will support the establishment of her research program at a leading academic institution, leveraging advanced neuroimaging techniques to address key questions in dementia diagnosis, disease monitoring, and intervention. Dr. Chen’s training will take place in a highly collaborative, resource-rich environment at UCSF, which offers cutting-edge neuroimaging facilities, access to a well- characterized dementia cohort, and mentorship from experts in neurodegeneration, social cognition, and imaging analytics. This comprehensive training will position her to lead an impactful independent research program that advances our understanding of bvFTD and related neurodegenerative disorders.

NIH Research Projects · FY 2026 · 2026-03

Project Summary/Abstract The rapid advancement of genomic medicine holds great promise for improving diagnosis, treatment, and health outcomes across diverse populations. However, the pace of progress has outstripped the ability of many healthcare providers to effectively integrate this knowledge into their practice, a challenge compounded by a limited genetic workforce. As a result, a widening gap has emerged between the potential of genomics and its practical application, particularly in underserved communities where access to genetic expertise is severely constrained. To bridge this divide, electronic consultations (eConsults) have emerged as a promising solution, enabling timely and cost-effective communication between referring providers and genetic specialists, thereby expanding access to critical expertise and support. The University of California, San Francisco (UCSF) proposes to address these gaps in care delivery by establishing the Western Regional Genomic eConsult Network (WestGEN), a comprehensive genomic medicine eConsult service for the Western United States available to both primary care providers (PCPs) and specialists, with an emphasis on supporting underserved populations. WestGEN will conduct studies to support the integration of genetic counselors into the eConsult service, and pilot AI solutions to augment genomic eConsults. The program incorporates research to optimize the delivery of genomic eConsult services and assess its adoption and impact. The specific aims are: 1) Deploy WestGEN across the Western U.S., initially to 239 primary care practices through an existing eConsult platform, and then extend to eConsult-naive practices; establish the role and scope of practice for genetic counselors; and evaluate genomic eConsult utilization and outcomes using mixed methods. 2) Support the expansion of regional genomic medicine eConsult programs nationwide by developing implementation tools and best practices for sustainability. 3) Evaluate an AI-assisted eConsult model to enhance efficiency and scalability. WestGEN brings together experts in genomics, implementation science, eConsults, and machine learning to create a scalable, evidence-based model for genomic medicine eConsults. The project will provide clear evidence on the impact of genomic eConsults on patient outcomes, generate tools for dissemination, and explore an AI-assisted model to improve efficiency and reach. By achieving its aims, WestGEN will enhance access to genomic expertise, provider knowledge, and quality of care, particularly for underserved populations, aligning with NHGRI's mission to implement genomics in clinical care to improve health equity and outcomes for all.