University Of California, San Francisco

NIH Research Projects · FY 2026 · 2024-02

Project Summary In-hospital cardiac arrests (IHCA) occur in over 350,000 adults in the United States each year, or one IHCA every two minutes. Despite advances in management, patient survival rates with favorable neurologic function remain low. Ventricular tachycardia (VT) is the most common initial shockable cardiac rhythm identified at the onset of an IHCA and the most important determinant of survival is defibrillation in <3 minutes. While, continuous electrocardiographic (ECG) monitoring is the non-invasive gold standard method used to identify VT, false alarms are extremely common. False VT not only impedes immediate identification of true VT and lifesaving defibrillation, but contributes to alarm fatigue in clinicians. A widely held belief is that poor skin electrode contact and/or default monitor settings cause false VT. As a result, clinical scientists have tried a variety of interventions (e.g., customize alarm settings; daily skin electrode changes; disposable lead wires; education) to decrease the number of false alarms. However, we found that fewer than 10% of false arrhythmia alarms were due to poor signal quality (i.e., unanalyzable due to excessive noise, baseline wander, leads off). Rather, our prior research shows that the vast majority of false alarms are due to poorly designed VT algorithms. At the heart of the problem, are outdated databases used by monitoring manufacturers to develop and test VT algorithms for use in bedside ECG monitors. Therefore, improvements to VT algorithms for use in 21st century bedside monitors has been stalled for decades. Recently, our group completed a multi-tiered, multi-expert, ground truth, manual annotation, with three-person ascertainment of VT events testing a new VT algorithm created by our group. The UCSF VT database represents the single largest human annotated database in an intensive care unit (ICU) cohort in existence. We now aim to move these extensive efforts forward to augment our original VT algorithm using a data driven artificial intelligence approach and increase the generalizability of our VT algorithm by including step-down/telemetry unit patients. The specific aims are: Aim 1. Leverage our human annotated VT database and machine learning (ML) approaches to identify novel ECG features to create an “optimized” VT algorithm to predict VT associated and IHCA. Aim 2. Compare the following VT algorithms: (1) v1 (signal processing); (2) ML/AI (Aim 1), and the hospital-based ECG monitors (i.e., ICU and step-down/telemetry unit) using prospective data in 5,000 ICU (50% of total) and step- down/telemetry patients (50% of total). Designing and testing clinically relevant VT algorithms that both improve identification of true VT and forecast associated IHCA has important implications for reducing preventable morbidity and mortality, reducing alarm fatigue, improving patient safety, enhancing nursing care and ECG monitoring systems.

NIH Research Projects · FY 2026 · 2024-02

Project Summary/Abstract Most tumors are not homogeneous, but rather comprised of highly distinct and heterogenous cancer cell populations. Adjacent cells within a tumor may harbor different genetic alterations and have different phenotypes. Thus, complex tumors are more 'than the sum of their parts', which contributes to aggressiveness, metastatic potential, and drug resistance. This complexity of intratumor heterogeneity is a major challenge in cancer therapy. In contrast to normal cells in which chromosome segregation is tightly controlled to maintain a diploid chromosome set, cancer cells are frequently aneuploid. Indeed, abnormal gains or losses of chromosomes are amongst the most common characteristics of cancer cells with nearly all solid cancers exhibiting some type of aneuploidy. A high degree of tumor aneuploidy also correlates with poor clinical outcomes. Although this strong correlation between aneuploidy and cancer is well known, causal relationships are incompletely understood. Especially in normal tissues and during early stages of carcinogenesis, chromosome segregation errors are rare and transient events that are notoriously difficult to study. To advance our understanding how chromosome segregation errors drive cancer initiation, development, evolution, and heterogeneity and enable novel types of model systems to, for example, explore aneuploidy as a therapeutic target in patient-derived cancer organoids, this pilot project proposes to develop a molecular and imaging toolkit to observe and manipulate chromosome segregation dynamics with high spatial and temporal accuracy in three-dimensional model and patient-derived cancer organoids. In Aim 1, we develop methods to identify, count and track specific chromosomes during multiple cell divisions in cancer organoids. Two proposed approaches involve endonuclease-deactivated dCas9 combined with gRNAs to create unique chromosome-specific spectral barcodes or using dCas9 imaging of repetitive DNA sequences to generate chromosome-specific fluorescence patterns, with the long-term goal of enabling "live karyotyping" in cancer organoids using deep learning networks. In Aim 2, we develop three alternative strategies to control chromosome dynamics and integrity using optogenetics. The proposed optogenetic actuators include a light-controlled kinetochore-microtubule interface, an optogenetic chromosome trap to immobilize specific chromosomes during cytokinesis, and photoactivated Cas9 to produce acentric chromosome arms or induce chromothripsis. The effectiveness of these strategies will be evaluated in mammary epithelial and breast cancer models, with the goal of understanding how acutely induced segregation errors or chromothripsis of specific chromosomes affects cancer cell dynamics and tumor evolution.

NIH Research Projects · FY 2026 · 2024-02

Abstract Systemic lupus erythematosus (SLE) is an autoimmune rheumatic disease with elevated prevalence in women and individuals of Asian, African, and Hispanic ancestries. SLE patients present a broad range of symptoms across multiple organ systems and differentially respond to treatments. Our central hypothesis is twofold: 1) genetic drivers of SLE affect gene regulatory mechanisms in specific cell types and activation states, and 2) cellular drivers responsible for disease initiation and exacerbation may exhibit transcriptional regulatory states (e.g., epigenomic states) poised to respond to environmental disease triggers. To test this hypothesis, we will use highly innovative multiplexed multimodal single-cell sequencing to map cell-type-specific epigenomic, transcriptomic, and surface protein features that stratify patients. When integrated with SLE GWAS data, we will further fine-map SLE-associated variants and annotate the cellular contexts by which associated variants act through. Finally, utilizing a novel strategy to sequence capillary blood, we will characterize circulating immune cells in SLE patients during flare, resolution, and response to discrete treatments. 3

NIH Research Projects · FY 2026 · 2024-02

PROJECT SUMMARY/ABSTRACT Angiogenesis is crucial for tissue homeostasis and growth. Despite extensive studies, it remains unclear how angiogenesis is spatially and temporally regulated to drive therapeutic neovascularization or conversely to block vascularization of tumors. Initiation of angiogenesis is a symmetry breaking process across scales: at tissue level, a blood vessel must asymmetrically generate a new vessel; at cellular level, a polarized endothelial “tip” cell must break symmetry by remodeling its cell-cell adhesions to initiate migration towards an angiogenic stimulus. This symmetry break is carefully regulated, as a tip cell must maintain sufficient vascular endothelial (VE)-cadherin-based adherens junctions with follower “stalk” cells to generate a continuous neovessel. VE- cadherin remodeling is largely mediated by (1) VE-cadherin endocytosis and recycling and (2) remodeling of junction-associated actomyosin. As these two processes closely regulate each other, it remains unclear what initiates and regulates the break in symmetry that permits tip cell migration. To identify new molecular regulators of VE-cadherin remodeling, VE-cadherin interactors were profiled using unbiased proximal biotinylation (BioID) and mass spectrometry in Preliminary Studies, revealing Scribble (Scrib). Mice with germline Scrib loss in literature exhibit developmental vascular defects; however, the subcellular endothelial role of Scrib in human vascular development remains unclear. Preliminary studies show Scrib localizes at adherens junctions in primary human microvascular endothelial cells, and this localization is regulated by angiogenic stimuli. Scrib knockout 3D organotypic microvessels exhibit aberrantly increased sprouting. Mechanistically, Scrib regulates VE- cadherin turnover and junctional actomyosin. The central hypothesis of this proposal is that Scrib regulates angiogenic symmetry breaking through limiting VE-cadherin remodeling, and this regulation is exerted through stabilization of junctional actomyosin. This hypothesis will be tested by two Aims: (1) Determine how Scrib regulates angiogenesis across endothelial tissue and cell scales, and (2) Elucidate molecular mechanisms by which Scrib regulates VE-cadherin remodeling and endothelial symmetry breaking during angiogenesis. These Aims leverage engineered vascular models, CRISPR-Cas9 genome editing of primary human endothelial cells, and advanced live microscopy to capture unappreciated mechanisms underlying angiogenic initiation. These research goals will be conducted alongside a comprehensive training plan at the University of California, San Francisco, including structured conceptual and technical mentorship from primary sponsor Dr. Matthew Kutys, an expert in endothelial cell-cell adhesions, morphogenesis, and engineered vascular models. Co-sponsor and physician-scientist Dr. Dean Sheppard will provide further conceptual, translational, and career mentorship. The applicant will gain additional training by participation in the Cardiovascular Research Institute at UCSF and structured shadowing experiences with physician-scientists in vascular biology. Altogether this work will provide invaluable training for an aspiring physician-vascular biologist.

NIH Research Projects · FY 2026 · 2024-02

PROJECT SUMMARY/ABSTRACT This is a research grant application for a study being undertaken in the laboratory of Dr. Aras Mattis, a Scientist at the University of California, San Francisco (UCSF). This grant will provide support for the Mattis lab to conduct this research over the five-year term of this project. Differentiation of patient induced pluripotent stem cells (iPSCs) to hepatocytes (iPSC-Heps) has incredible value for modeling and experimental treatment of human hepatic disease. My lab has significant expertise in the differentiation of iPSCs to human hepatocytes and therefore modeling of liver diseases. The major goal of this project is to use iPSC-Hep cell lines that we have developed from a single family of patients with NASH and matched controls to study modeling of NAFLD in vitro and the relationship of novel genes we uncovered to the disease process. First, we will use the iPSC-Hep model to test a set of genes with unknown function for involvement in NAFLD. We uncovered these genes by sequencing this family with severe and penetrant NASH. Furthermore, we will test loss of function knockouts of these novel genes in control iPSC- Heps, for their ability to cause steatosis, endoplasmic reticulum (ER) stress, and/or inflammatory pathway activation. Finally we will test a set of genes we uncovered as potentially therapeutic targets. The specific experimental aims of this project are to 1) Identify NAFLD pathways modeled in patient 7017 familial NASH iPSC-Heps, 2) Establish contribution of known SNPs and novel genes for involvement in NAFLD Phenotypes, and 3) Test our previously identified genes as therapeutic targets in 7017 iPSC-Heps. This project follows the mission of the NIH to support medical research on hepatic diseases with the potential for clinical translational use.

NIH Research Projects · FY 2025 · 2024-02

Project Abstract The heart is an obligate aerobic organ, making it one of the highest oxygen consumers of any organ in the body. Cardiac dependence on oxidative metabolism makes the heart particularly vulnerable to oxygen insufficiency, which is observed in many diseases including ischemic heart disease and heart failure, as well as pulmonary pathologies such as chronic obstructive pulmonary disease. These constitute the leading causes of morbidity and mortality in the world. The heart retains some ability to adapt to mild hypoxia, indicating that protective pathways exist that could be harnessed to improve cardiac function in patients with chronic hypoxia pathologies. Cardiomyocytes (CMs)—the parenchymal cell type of the heart—are metabolically flexible and can shift their fuel source preference in response to hypoxia. This plasticity suggests that interventions that rewire CM metabolic pathways can reduce tissue damage. However, our ability to design such interventions is currently limited by our understanding of the molecular mediators of these metabolic changes. This proposal aims to gain a systems-level understanding of the pathways that facilitate adaptive and maladaptive metabolic changes in CMs in response to hypoxia, with the long-term goal of targeting these pathways as novel therapeutics. To accomplish this, I have developed a functional genomics platform in iPSC-CMs. In a preliminary genome-wide CRISPRi survival screen in iPSC-CMs in chronic hypoxia, my initial findings paradoxically suggest that suppressing excessive accumulation of intracellular glucose may be protective in hypoxia. Interestingly, a related clinical phenomenon supports this general concept – hyperglycemia at the time of ICU admission has been shown to correlate with worse outcomes following MI or cardiac arrest, independent of diabetes status. These findings suggest that shifting fuel sources is a central component of the (mal)adaptive hypoxic response. I hypothesize that modulation of hypoxia-responsive fuel rewiring can serve as a therapeutic strategy to restore CM function during cardiac pathologies caused by oxygen deprivation. I will test this hypothesis through three separate aims. First, I will systematically identify the regulators of cardiomyocyte survival in pathological hypoxia using a functional genomics screen. By creating nutrient limiting conditions, I will determine the pathways that enable substrate switching in hypoxia. Second, I will determine the metabolic fates of glucose during CM hypoxia using isotope tracer studies. Third, I will target glucose uptake and processing pathways genetically to restore CM survival and electrophysiology during pathological hypoxia. These experiments will identify novel therapeutic targets related to fuel rewiring in CMs and will provide mechanistic insights into cardiac glucose toxicity to enable a further understanding of the pathophysiology of cardiac hypoxia.

NIH Research Projects · FY 2025 · 2024-02

PROJECT SUMMARY/ABSTRACT The psychological symptom cluster is a common problem that impacts women receiving breast cancer treatment and is associated with several negative outcomes, including reduced functional status and quality of life. Unfortunately, the mechanism(s) that underlie this cluster are unknown which limits the development of targeted interventions. Mounting evidence suggests that individual (e.g., age, education) and community-level determinants of health (e.g., neighborhood deprivation, pollution) increase psychological symptoms in women with breast cancer. While exercise can improve psychological symptoms in women with breast cancer, it is unknown if individual or community-level factors impact this relationship. Given that exercise, individual, and community-level factors can alter DNA methylation, evaluation of epigenetic regulation may provide new mechanistic insights. Investigation into the epigenomic, individual, and community-level factors associated with a psychological symptom cluster in women with breast cancer within the context of a randomized clinical trial for a moderate-intensity aerobic exercise intervention will clarify these relationships and inform the development of targeted interventions. The overarching goal of this research is to alleviate symptoms in cancer patients, which is a research priority of the NCI’s Division of Cancer Prevention. The aims of the K99 study are to (1) test the hypotheses that epigenomic, individual, and community-level factors are associated with psychological symptom cluster severity profiles in women with breast cancer prior to the start of aromatase inhibitor therapy; and (2) test the hypotheses that epigenomic, individual, and community-level factors are associated with worsening psychological symptom cluster severity profiles following six months of aromatase inhibitor therapy in women with breast cancer, while exercise and epigenomic factors mitigate this effect. The candidate will extend this line of research to immunotherapy, which is rapidly emerging as an adjuvant therapy for breast cancer. The detailed training plan, exceptional team of mentors, and research-intensive environment of the University of Pittsburgh will provide the candidate with the mentored training, support, and research experience needed to conduct this research. Through this training plan, the candidate will develop: proficiency in epigenomics; competency in analysis and bioinformatics of longitudinal epigenomic data; proficiency in the evaluation of social determinants of health in symptom science; expertise in the mechanisms of immunotherapy-related symptoms; and knowledge and skills for professional career development. The aims of the R00 study are to: (1) identify symptom cluster profiles of women with breast cancer receiving immunotherapy over time; and (2) evaluate for epigenomic, individual, interpersonal, community, and societal- level factors associated with symptom cluster severity profiles of women with breast cancer receiving immunotherapy over time. Findings from these projects will provide new knowledge to guide clinical assessment and the development of targeted interventions to mitigate the severity common symptom clusters.

NIH Research Projects · FY 2026 · 2024-02

ABSTRACT - In the United States, one in three older adults dies with or from Alzheimer's Disease and Related ADRDs (ADRD). The Medicare Hospice Benefit is considered the gold standard for end-of-life palliative care, offering interdisciplinary care in all settings for 52% of Medicare decedents. Yet the role of hospice for ADRD is complex. Our research indicates half of older hospice enrollees have ADRD and home- and community- dwelling people with ADRD who enroll in hospice have higher end-of-life care quality and lower costs than those not enrolled. On the other hand, access to hospice is restricted to a prognosis of 6 months or less, which for ADRD is difficult to estimate. Standard palliative care models are also not tailored for ADRD-specific needs such as managing behavioral symptoms. Moreover, there are inequities in access to and quality of end-of-life care for underserved populations of racial and ethnic minoritized people with ADRD. (To highlight the effect structural racism has had in producing underserved populations, we use “minoritized”). Black, Latinx, and Asian American people are less likely to enroll in hospice, particularly with ADRD. Efforts to reduce inequities in hospice and palliative care are limited by a lack of understanding of how racism impacts access, quality, and fit of hospice care for racial and ethnic minoritized people with ADRD. We aim to address these knowledge gaps and improve hospice, palliative, and supportive care for Black, Latinx, and Asian American people with ADRD. We will convene community and scientific advisory councils to partner with our team in refining study design, execution, and dissemination. Our aims are: (1) To identify Black, Latinx, and Asian American care partner definitions of high-quality ADRD end-of-life care. Interviews with 90 people will ask about experiences with provision of hospice care and other types of supportive care, often in home-based settings. (2) To document hospice organizational practices and policies that influence care for racial and ethnic minoritized people with ADRD. We will conduct case studies of 24 organizations using multiple qualitative methods, including organizational surveys, observations (including of home-based clinical and symptom management), document analysis, and interviews with providers and staff. (3) To develop a community-prioritized set of recommended services, clinical practices, and policies for improving hospice care for ADRD. We will use 6 focus groups (n=30) and a 3-stage modified Delphi process (n=60) with care partners, policy makers, clinicians and researchers with expertise in hospice, palliative care, ADRD, equity. Knowledge gained from this proposal will facilitate the development of professional and ethics guidelines, and policy and regulatory recommendations, to improve end-of-life care and equity in hospice care for racial and ethnic minoritized populations with ADRD. Improving end-of-life palliative care for ADRD aligns with NIA strategic directions for 2020-2025 to support research that improves our understanding of ADRD, informs policy decisions, and supports the goals of the National Plan to Address Alzheimer's Disease.

NIH Research Projects · FY 2026 · 2024-02

ABSTRACT Inherited retinal dystrophies (IRDs) cause progressive, irreversible vision loss and most are currently untreatable. Pathogenic variants in over 300 genes are implicated in IRDs, and variants within a single gene can cause diverse retinal phenotypes, which makes therapeutic development challenging. As an alternative to genetic strategies which are disease-specific, we propose that gene agnostic approaches using small molecule drugs have the potential to treat multiple IRDs independent of their genetic etiology. Our studies on mouse models of IRDs have identified cholesterol and ceramide as common pathogenic drivers of retinal pigment epithelium (RPE) dysfunction that culminates in retinal degeneration. Accumulation of these lipids facilitates complement- induced mitochondrial injury in the RPE, infiltration of microglia into the sub-retinal space, and eventually photoreceptor loss. Here, we will evaluate therapeutic efficacy of two small molecule drugs, a clinically approved bisphosphonate that inhibits cholesterol biosynthesis and ceramide generation (Aim 1) and a pan-adiponectin receptor agonist that stimulates ceramidase activity and promotes mitochondrial biogenesis (Aim 2), in mouse models of Stargardt disease and Batten disease. We will test the hypothesis that these drugs act as “triple threats” by lowering cholesterol and ceramide and protecting RPE mitochondria, thereby preventing microglial activation and retinal degeneration. We will use cutting-edge techniques such as intravital imaging of drug distribution, super-resolution imaging of mitochondrial dynamics in the living mouse retina, lipidomics, transcriptomics, and noninvasive evaluation of retinal structure and function to establish the ability of these drugs to safeguard the RPE and retina in disease models. These drugs have documented safety profiles and reach the retina in therapeutically effective concentrations after systemic administration, circumventing the need for invasive delivery. Therefore, they hold immense promise as novel, powerful, gene-independent therapeutics for IRDs.

NIH Research Projects · FY 2023 · 2024-01

ABSTRACT The goal of this highly interdisciplinary project, which draws on epidemiological, hydrological, and biostatistical expertise, is to use spatial data linkage to connect drinking water arsenic data (or model predictions) to cardiometabolic health outcomes in the REasons for Geographic And Racial Differences in Stroke (REGARDS) Study. The REGARDS Study is a biracial (African American and white) cohort with participants recruited from across the United States, with emphasis on the Southeastern United States. The large sample size and geographic variation in this cohort make it an ideal resource for spatial drinking water arsenic epidemiology. This proposed work will support the development and refinement of a novel data analytic pipeline, which will allow integration of multiple data streams (community water system public supply water quality data, and groundwater predictions relevant for private wells) to give epidemiological inferences about drinking water arsenic and cardiometabolic health outcomes. The primary outcomes of the study are blood pressure at the REGARDS Study baseline visit, hypertension prevalence at the REGARDS Study baseline visit, and incident ischemic stroke among participants in the REGARDS Study at risk of incident ischemic stroke at baseline. The study will consider potential differences in response to arsenic according to putative effect modifiers (e.g., sex, race). Successful completion of the project aims will not only address significant knowledge gaps about drinking water arsenic’s potential salience to cardiometabolic health in the United States, but also provide a highly innovative data analysis pipeline that can be the foundation for future drinking water health research in the United States.

NIH Research Projects · FY 2026 · 2024-01

PROJECT SUMMARY/ABSTRACT Anarthria, a loss of the ability to articulate speech, can be a severe symptom of neurological conditions, including paralysis, stroke, and motor neuron disease. Invasive speech neuroprostheses that decode cortical activity into intended speech have potential to restore naturalistic and rapid communication to patients with anarthria and paralysis by bypassing diseased motor pathways. Speech decoding has expanded rapidly in recent years. Multiple studies have demonstrated that English phrases may be decoded from cortical activity in participants with anarthria. While these are critical milestones, an ideal speech neuroprosthesis would fully restore communication to any person living with paralysis, regardless of their language background. Currently, over half the world is bilingual with proficiency in at least two languages. Extensive qualitative and quantitative research has demonstrated that bilingual speakers use each language in distinct social contexts and report that their two languages contribute unique dimensions to their overall personality and worldview. Despite this, prior speech decoding studies have exclusively focused on monolingual decoding. A key challenge in developing a bilingual speech neuroprosthesis is decoding the intended language of the user in addition to specific phrase content. Prior neuroscientific studies of bilingual speech have not provided a clear consensus on the representation and localization of cortical activity patterns that are language-specific or shared across languages. Thus, to develop a bilingual neuroprosthesis, we must first understand the basic cortical mechanisms that underlie bilingual speech. Based on our preliminary data and prior literature, we hypothesize that lexical access is language-specific and supported by higher-order speech regions (i.e., inferior frontal gyrus) whereas vocal-tract articulation is shared and supported by the speech sensorimotor cortex (SMC). We hypothesize that these representations will be sufficient to decode both intended language and specific phrase content in participants with anarthria. SMC articulatory activity, specifically, may facilitate rapid generalizability of decoders across languages. To test these hypotheses, we propose studying bilingual speakers and bilingual participants with anarthria, using high spatio-temporal resolution electrocorticography (ECoG). In aim 1, we will record cortical activity while bilingual speakers produce a large set of unique English and Spanish phrases, allowing us to assess whether shared or language-specific cortical activity underlies bilingual lexical access and articulation. In aim 2, we will develop algorithms, in bilingual participants with anarthria, to decode cortical activity into intended language and phrases. Finally, in aim 3, we will explore which cortical representations and regions allow content decoders to rapidly generalize across languages, reducing training times for system users.

NIH Research Projects · FY 2025 · 2024-01

Project Summary / Abstract Interstitial lung diseases (ILD) are disorders in which lung inflammation and scarring cause reduced lung function. When seen in the context of connective tissue disease (CTD), ILDs are treated with generalized immune suppression as mechanisms driving disease remain poorly understood. COPA syndrome is a monogenic autosomal dominant autoimmune disease causing CTD ILD that often progresses despite immune suppression, with several patients with this rare disease requiring lung transplant. Importantly, this syndrome provides a model for identifying disease pathways driving CTD ILD. Studies from the laboratory of Dr. Anthony Shum (my sponsor) defined COPA syndrome and determined that disease is caused by failed retrieval of stimulator of interferon genes (STING) from the Golgi to the Endoplasmic Reticulum (ER) by coatomer subunit α (COPA). STING, a key innate immune adaptor, can only signal from the Golgi, and our group and others have shown that the pathogenic mechanism causing COPA syndrome is constitutive STING activation and signaling. COPA syndrome has a non-penetrance rate of ~30%, with unaffected carriers showing no signs of disease. As STING drives pathogenesis of COPA syndrome, we hypothesized that STING alleles might act as genetic modifiers impacting disease penetrance. Remarkably, we found perfect co-segregation of diseases non- penetrance with heterozygosity for the common R71H-G230A-R293Q (HAQ) STING allele in 25 carriers of pathogenic COPA mutations. As such, we propose HAQ STING as a suppressor allele for COPA syndrome. This proposal seeks to define the mechanisms by which HAQ STING is protective in COPA syndrome. STING is an ER-localized signaling hub for innate immune activation in response to cytosolic DNA. STING activation results in interferon signaling and multiple other outputs including NFkB activation, autophagy, senescence, and cell death. While HAQ STING has been shown to have impaired interferon signaling, this allele is highly prevalent (over 30% of non-Africans have at least one copy) and is thus likely to be competent for some but not all STING roles. How HAQ STING confers protection in COPA syndrome will be determined at many levels. Differences in HAQ STING in the presence or absence of pathogenic COPA mutations will be established at the mRNA and protein expression levels, through intracellular localization in resting and stimulated cells, and via interferon dependent and independent read outs of STING activation. With STING implicated broadly in ILD and other forms of lung inflammation, these studies hold potential for identifying novel therapeutic approaches for COPA syndrome and other forms of ILD. Discovery of additional disease modifying approaches is critically needed as ILDs have limited treatment options, resulting in high morbidity and mortality.

NIH Research Projects · FY 2026 · 2024-01

Project Summary/Abstract This project is designed to develop a new approach to monitor and predict treatment response in patients with pancreatic ductal adenocarcinoma (PDA) using hyperpolarized (HP) 13C pyruvate MR molecular imaging. PDA is among the deadliest cancers and is anticipated to become the 2nd leading cause of cancer-related death in the US by 2030. Most PDA patients present with nonresectable disease where systemic therapy is the only life- prolonging treatment. In the minority of patients (~30%) who present with localized, potentially resectable disease, neoadjuvant therapy (NAT) followed by surgery is an emerging approach to improve patient survival but is only beneficial if the selected NAT is effective. For all PDA patients, effective systemic therapy is the single most important factor influencing their survival. However, current response assessment tools, including MRI, CT, and the serum tumor marker CA19-9 provide poor early assessment of response in patients with rapidly lethal advanced PDA, and are suboptimal for selecting patients most likely to benefit from a highly morbid surgery after NAT. Therefore, there is a critical unmet need for more timely and accurate indicators of therapy response in PDA to 1) promptly discontinue ineffective treatments and switch to alternative treatments with potentially better efficacy, and 2) better guide clinical decisions regarding surgery following NAT. Metabolic reprogramming towards increased glycolysis is a hallmark of PDA. In particular, the over-expression of lactate dehydrogenase A and monocarboxylate transporter 1 and 4 results in high levels of pyruvate conversion to lactate, which plays a central role in PDA progression and therapy resistance. Such reprogrammed glycolytic metabolism can be noninvasively interrogated using HP 13C pyruvate MRI, an emerging molecular imaging method that provides dynamic and pathway-specific metabolic information not available with current imaging methods including [18F]fluorodeoxyglucose positron emission tomography (FDG-PET). Our preliminary patient studies demonstrate reprogrammed glycolytic metabolism in PDA using HP 13C pyruvate MRI, with increased conversion to lactate and reduced conversion to alanine in tumors compared to normal pancreas. Our preliminary results also suggest that early metabolic changes measured by HP 13C pyruvate MRI can predict tumor response to therapy. Building on these exciting results, we propose to investigate for the first time the value of HP 13C pyruvate MRI for therapy response monitoring in PDA patients. In Aim 1, we will develop and refine HP 13C pyruvate MRI acquisition, post- processing, and analysis strategies optimized for PDA metabolic evaluation. In Aim 2, we will monitor early therapy response using this imaging approach in patients with advanced/nonresectable PDA. In Aim 3, we will determine whether HP 13C pyruvate MRI can predict response to NAT through correlation with pathologic response in patients with resected PDA. Successful completion of this project will provide the first data on HP 13C pyruvate metabolism of PDA in response to therapy, with the overarching goal of better guiding clinical decision making to improve survival for patients with this deadly disease.

NIH Research Projects · FY 2025 · 2024-01

PROJECT SUMMARY Glioblastomas (GBMs) are malignant primary brain tumors in adults. Standard of care involves maximal safe surgical resection, radiation, and chemotherapy with temozolomide. Novel therapies are also under development for GBM patients. However, physicians are hampered in their efforts to effectively treat GBM patients by their inability to reliably monitor tumor growth in vivo. Specifically, disease progression and treatment response in GBM patients are typically monitored by non-invasive magnetic resonance imaging (MRI) methods such as contrast-enhanced MRI. However, contrast enhancement reflects the integrity of the blood brain barrier rather than any intrinsic biological activity of the tumor. As a result, it becomes difficult to reliably determine response to therapy. Tumors reprogram their metabolism to generate the biosynthetic precursors needed for proliferation. Phosphatidylcholine is the main structural component of all cellular membranes, and its biosynthesis is upregulated in most cancers due to the high membrane turnover associated with uncontrolled proliferation. The dietary nutrient choline is converted to phosphocholine (PC), which is subsequently incorporated into phosphatidylcholine. Expression of the key enzyme in this pathway, choline kinase α (CKα), is elevated in tumors relative to surrounding normal tissues, including in GBMs. Non-invasive methods of imaging CKα activity will provide the unique opportunity to visualize tumor intrinsic biological activity in vivo. Deuterium magnetic resonance spectroscopy recently emerged as an innovative clinically translatable method of imaging the metabolism of stable, non-radioactive, deuterated molecules in vivo. Our goal is to determine whether mapping CKα activity using deuterated choline enables non-invasive assessment of GBM response to therapy in vivo. We will examine the ability of deuterated choline to spatially map CKα activity (Aim 1) and provide a readout of GBM response to therapy (Aim 2) in vivo at the clinical field strength of 3T. For both aims, we will use complementary biochemical assays to confirm our DMRS data and correlate it with tumor biology. Our proposal is innovative and impactful because it will validate deuterated choline as a specific, safe, non- radioactive tracer for imaging GBM growth in vivo. By doing so, our proposal will enable precision imaging that significantly improves outcomes and quality of life for GBM patients.

NIH Research Projects · FY 2026 · 2024-01

PROJECT SUMMARY/ABSTRACT There is a fundamental gap in the mechanistic understanding of the optokinetic reflex (OKR), used in the clinic to diagnose a variety of visual and neurological disorders. The OKR provides a unique system in which the visual system input, and eye movement output, are well-controlled and quantifiable, and the information bottleneck at dedicated ganglion cell types is accessible. The long-term goals are to reveal the mechanistic basis of the OKR from the molecular programming of circuit wiring to computations to stimulus (in)dependence and to translate this knowledge into diagnostics. The overall objective of this proposal is to determine how the individual and population properties of two specific ganglion cell types influence eye movements. This proposal’s focus is on the vertical OKR, which is subserved by up/Superior and down/Inferior preferring ON direction selective ganglion cells (Superior and Inferior oDSGCs). Preliminary work leads to a central hypothesis: The vertical OKR is influenced by properties that can be traced to retinal direction selective circuits and specifically, motion encoding in Superior and Inferior oDSGCs individually and as a population. Previous studies show that the OKR is contrast sensitive and asymmetric, with higher gain in the up vs. down directions. Differences in intrinsic properties, e.g., dendritic morphology, and synaptic inputs can explain these phenomena with contrast sensitive spike tuning curves and greater responses in Superior vs. Inferior oDSGCs. Recent single-cell sequencing supports the asymmetry with identification of differentially expressed genes in Superior vs. Inferior oDSGCs, including molecular guidance cues that could be integral to the development of direction selective circuits. We propose to examine the fundamental molecular and computational mechanisms that support and preserve the vertical OKR across diverse stimulus statistics. We will achieve this by (1) using mouse genetics to elucidate the molecular processes that construct and maintain direction selective circuitry, and (2) measuring oDSGC population responses and OKR in the context of stimulus perturbations including noise. (Aim 1) Identify essential signaling pathways for the development of direction selective circuits and the OKR, and (Aim 2) Elucidate the mechanisms of noise correlations among populations of oDSGCs and their impact on the OKR. The aims will be accomplished by using stimulus manipulations, genetic perturbations, cellular physiology, circuit mapping, and computational modeling to identify characteristics of the reflex, their potential mechanistic basis, and their stability or adaptability under different visual environments. The expected outcomes for Aim 1 will be a concise link between molecules, retinal circuits, and behavior, and for Aim 2 will be insight into how stimulus statistics, including noise correlations, influence behavior. The proposed work is significant because it will reveal—from molecules to behavior—how cells, circuits, computations, and their behavioral output operate in health and change in disease in an evolutionarily conserved system with the potential for clinical application of knowledge gained in this proposal.

NIH Research Projects · FY 2025 · 2024-01

PROJECT SUMMARY/ABSTRACT The incidence of type 2 diabetes (T2D) is rapidly increasing in youth, particularly in youth of color, and if uncontrolled can lead to devastating complications as early as 10 years after diagnosis. Yet, there are limited medication options for youth, who have worse response to available therapies such as metformin compared to adults. There is therefore a critical need for the development of targeted and effective treatment approaches that utilize the most appropriate therapeutic option right from the onset of disease. T2D is a heterogenous disease with variations in mechanistic pathways related to insulin sensitivity, insulin deficiency, obesity and fat distribution that contribute to disease progression. Methods to subtype individuals with T2D have been developed using clinical and genomic machine learning based clustering approaches in adults. However, these clustering approaches have not been evaluated in youth of diverse racial and ethnic backgrounds and using clinical variables that are routinely measured in clinical practice. In K23 funded work, Principal Investigator Dr. Srinivasan is evaluating the genetic and pharmacological determinants of metformin response in youth with T2D. The proposed R03 work will broaden the scope of this work by evaluating the pathophysiological patterns associated with the development of complications and metformin response in youth, a framework that can be applied to other T2D medications beyond metformin. In this study, we propose to leverage existing pediatric T2D datasets and utilize complementary clinical and genetic machine-learning clustering techniques to identify groups of youth with T2D at highest risk for microvascular complications and most likely to fail metformin treatment, based on underlying biological mechanisms. In Aim 1, we will categorize 974 youth with T2D from the Treatment Options for Type 2 diabetes in Adolescents and Youth (TODAY) and SEARCH for Diabetes in Youth (SEARCH) studies into pathophysiological subgroups based on clinical clusters developed in adults and evaluate the association of cluster membership with T2D progression, development of microvascular complications and metformin response. Additionally, we will develop and evaluate novel youth clusters based on routine clinical variables using an unsupervised machine learning technique and will compare the performance with adult clusters. In Aim 2, we will construct individual level polygenic scores derived from genetic clustering of T2D loci and based on mechanistic pathways in TODAY and SEARCH to evaluate the association of genetic scores with the same outcomes proposed in Aim 1, both alone and in combination with clinical clusters. In Aim 3, we will validate youth-derived clinical and genomic clusters in a real-world electronic medical record-based youth dataset from the Boston Children’s Hospital Precision Link Biobank for Health Discovery. This proposal will generate a prediction model that leverages both routine clinical and genomic data to inform risk stratification and to improve metformin prescribing. These results, in combination with Dr. Srinivasan’s K23 work will directly inform a future R01 proposal evaluating precision dosing algorithms for metformin and other drug classes in youth.

NIH Research Projects · FY 2025 · 2024-01

Acute respiratory distress syndrome (ARDS) is a high mortality condition in which the lung epithelium is unable to mount its usual regenerative response to injury. Despite promising preclinical data showing that cell-based therapy, primarily adoptive transfer of mesenchymal stromal cells, can promote epithelial regeneration in acute lung injury, the mechanism behind these findings is unclear, and thus they have not been successful in clinical trials. Currently, there are no mechanism specific treatments for ARDS, even though the COVID-19 pandemic has increased the urgency of the need for ARDS treatments to tackle ongoing and future respiratory pandemics. In this proposal, we aim to develop cell-based therapy using a mechanistic approach with the goal of delivering growth factors that promote alveolar epithelial cell (AEC) proliferation to the injured lung. We will use engineering principles from the CAR T cell field and combine them with knowledge from in vitro and in vivo studies of lung epithelial injury response to develop a potent new model for delivering therapeutics. Hepatocyte growth factor (Hgf) and keratinocyte growth factor (Kgf) are known to stimulate AEC proliferation and protection from lung injury in mouse models and hence we will initially focus on delivering these growth factors as therapeutics. First, we will evaluate in vitro how to best design “sender” engineered T cells to secrete sufficient concentrations of growth factors to activate downstream signaling pathways in “receiver” cell lines or primary lung epithelial cells. Next, we will use mouse models of lung injury to compare delivery of intravenous recombinant Hgf and Kgf vs delivery of these factors via adoptive transfer of T cells. We will then confirm in vitro and in vivo that we can engineer synthetic notch receptors that activate an engineered transcriptional output (“payload”) when they bind to lung epithelium specific surface markers. The surface markers we have selected are membrane GFP expressed specifically on surfactant protein C expressing type 2 AECs (from an SFTPC-CreERT2; H11-lsl- mGFP mouse), Ager, expressed on mouse and human type I AECs, and Slc34a2, expressed on mouse and human type 2 AECs. Finally, we will combine these two systems to engineer T cells that deliver their “payload,” in this case Hgf or Kgf, only when they contact an AEC, thus activating the AEC specific synthetic notch receptor (AEC-SynNotch). We expect that we will see an increase in AEC proliferation after lung injury with adoptive transfer of these AEC-SynNotch-Hgf or AEC-SynNotch-Kgf cells and that we will also see improvements in physiologic and histologic measures of lung injury. The completion of this project will generate data that will provide a clearer understanding of how mechanistically engineered cell-based delivery of a growth factor compares to delivery of the same therapeutic in IV recombinant form. Our long-term plan is to apply these design principles to cells already being used in ARDS clinical trials (mesenchymal stromal cells and regulatory T cells) to improve efficacy, which will represent a new paradigm for designing cell-based therapies to deliver genetically encoded therapeutics to specific tissues.

NIH Research Projects · FY 2025 · 2024-01

PROJECT SUMMARY. Social attachments play a central role in every level of human interaction, from relationships between parents and children to enduring partnerships with mates. A major barrier to understanding the neural basis of this behavior is that mice and other traditional model organisms do not exhibit complex attachments. In contrast, prairie voles (Microtus ochrogaster) form social attachments and demonstrate enduring social monogamy between mates. Such attachments result in a preference for bonded partners and the robust rejection of novel conspecifics, both of which require social memory of specific individuals. This suggests that key regions such as the hippocampus contribute to the affective and behavioral responses to a given individual. Hippocampal areas CA2 and CA3, specifically, are implicated in social memory and the display of agonistic behaviors towards novel intruders in mice. Importantly, hippocampal CA2/3 is modulated by oxytocin, a key neuroendocrine mediator of attachment behaviors. However, how CA2/3 and oxytocin receptor (OxtR) signaling therein contribute to pair bonding is unknown. This proposal will delineate the molecular, cellular, and functional mechanisms by which neuroendocrine signaling in the hippocampus contributes to social attachment in the socially monogamous prairie vole. In the mentored phase of this research plan, we will identify sex- and species- specific spatial distributions of cell types and neuroendocrine receptors in the vole hippocampus. To do this, we will conduct single-nucleus RNA sequencing of the hippocampus in combination with multiplexed error robust fluorescence in situ hybridization (MERFISH). In the independent phase, we will test the hypothesis that CA2/3 and OxtR signaling therein mediate the rejection of novel, potential mates in the prairie vole. First, we will determine the hippocampal neuroendocrine cell types activated by exposure to a partner vs. a novel stranger using MERFISH with immediate early gene imaging in bonded prairie voles. Second, we will test CA2/3 ensemble responses to social interactions with partners and strangers across pair bonding using miniscope imaging. Third, we will test whether CA2/3 activity and CA2/3 OxtR function are necessary for pair bond maintenance by a) chemogenetically inhibiting CA2/3 or b) locally delivering an OxtR antagonist prior to assays for stranger rejection in pair bonded voles. These studies will provide novel insight into the neural mechanisms governing social attachment and their modulation by oxytocin, ultimately contributing to the BRAIN Initiative priority areas of identifying cell types, monitoring neural activity, and using interventional tools to understand the neural basis of complex social cognition. This work will be conducted at the University of California, San Francisco, a premier research institution with ample research and career development resources. I will receive training in transcriptomics, bioinformatics, and professional development. For this, I have assembled a mentorship team that will provide expertise for every aspect of my training and will help me to accomplish my goal of becoming faculty at a top institution.

NIH Research Projects · FY 2025 · 2024-01

PROJECT SUMMARY The long-term goal of this project is to assess the utility of multi-ancestry polygenic risk scores (PRSs) in large real-world cohorts to predict health outcomes in clinical settings. PRSs represent a numerical summary of an individuals’ genetic risk for a trait or disease based on combined effects of genetic variants across the human genome. A PRS has many potential benefits such as efficient disease screening/prediction and therapeutic prevention/intervention and may be useful in saving many lives and resources. However, the application of PRS for risk prediction in clinical settings alongside non-genetic risk factors such as lifestyle and environmental risk factors remains largely unknown. A better understanding of PRS utility for clinical risk prediction, and limitations of PRS in real-world populations is needed to realize the potential benefits of the applications of PRS for all populations. This proposal encompasses a training and research plan to develop the candidate’s expertise in genetic epidemiology research. The specific aims are to 1a) Investigate the association of multi-ancestry blood pressure (BP) PRS with hypertension incidence and progression in individuals across their life course, 1b) Investigate the association of multi-ancestry BP PRS with incidence of BP-related health outcomes including stroke, cardiovascular disease (CVD), dementia, kidney disease, heart failure and all-cause mortality (F99 dissertation research. This proposed project will generate new knowledge and provide training for the candidate’s advancement to become an independent investigator focused on genetic epidemiology of complex polygenic diseases and traits. The research is relevant to NHGRI’s bold predictions by 2030, number 6 “The regular use of genomic information will have transitioned from boutique to mainstream in all clinical settings, making genomic testing as routine as complete blood counts”.

NIH Research Projects · FY 2025 · 2024-01

ABSTRACT – UCSF E-STaR OVERALL The aspirations of an integrated Learning Health System (LHS) are to deliver care that is of the highest quality, is safe, and is optimally efficient. These goals guide all UCSF-affiliated health systems, including UCSF Health, SF Health Network/Zuckerberg SF General and the SF Veterans Affairs Medical Center. The diversity of patient populations and delivery systems represented by UCSF-affiliated health systems, along with their evolution as integrated LHS, is a ripe, natural training environment for developing LHS scientists. To achieve greater impact, UCSF needs a larger workforce of LHS scientists from diverse backgrounds, working in teams with clinical operators, data stewards and informaticians, and engaged with multiple stakeholders (patients, caregivers, clinicians, institutional leadership) to co-produce real-time improvements in practice patterns, patient-centered outcomes, and health system performance. As an AHRQ/PCORI-sponsored LHS K12 Career Development Program and LHS Center of Excellence, UCSF has designed an outstanding research training and career development program for 8 individuals who have already demonstrated an impact. This UCSF E- STaR Center proposal will create and scale up LHS-specific training and research infrastructure: Aim 1. To establish multidisciplinary Cores that share resources and facilities with healthcare systems to support research and training for LHS scientists, particularly in areas of embedded research training, patient and stakeholder engagement, informatics, and outcome evaluation. The Administrative Core (AC) will provide overarching Center leadership, stakeholder engagement and coordination, recruitment, program evaluation, and internal and external communications. The Research Education Core (REC) will implement the Scholar training program; the Research and Data Analysis Core (RDAC) will provide consultation and services for study design and analysis, facilitating data access and dedicated IT support; Aim 2. To enroll Scholars from diverse backgrounds, and provide them with the research, engagement, and leadership skills necessary to pursue successful careers as LHS scientists. The AC and REC will coordinate recruitment, training, and retention activities. Performance and outcomes will be captured in the Program Evaluation; Aim 3. To enable embedded research that advances and continuously improves healthcare quality, equity, and patient-centered outcomes, and to disseminate results locally and nationally. RDAC will implement processes to systematically ensure patient-centered outcomes are measured, captured, and aggregated across embedded research projects. Expected Outcomes: At end of 5 years, the UCSF LHS E-STaR Center will have trained >60 Scholars across at least 6 unique health systems, and provided consultative LHS support to >100 additional scientists. Their research projects will increase the quality and health outcomes for patients of all backgrounds, with results disseminated through local health systems, publications in the medical literature, and presentations at national meetings.

NIH Research Projects · FY 2026 · 2024-01

Amyotrophic lateral sclerosis (ALS) and related motor neuron degenerative diseases affect more than 30,000 people in the US, and 90% of patients die within five years of diagnosis. Although ALS and ALS-like disease manifestation varies, all forms are characterized by progressive loss of motor neurons. These disorders have a strong genetic component, and although more than 50 genes involved in ALS have been identified, much still remains to be learned about the genes and mechanisms that contribute to ALS susceptibility and protection. Aberrant RNA metabolism and processing plays an important mechanistic role in neurodegeneration, and mutations in genes encoding RNA-binding proteins underscore several of the more common causes of ALS. The general idea that altered RNA metabolism and processing leads to neurodegenerative disease suggests that additional genes encoding RNA-binding or RNA processing factors are likely to be involved in the genetics of ALS and related neurodegenerative disorders. The ZNF106 gene encodes an RNA binding protein and maps to human chromosome 15q15.1, the site of an incompletely described rare form of juvenile onset ALS. Genetic inactivation of Zfp106, the mouse ortholog of ZNF106, results in an early onset, profound ALS-like neurodegenerative phenotype with a corresponding loss of motor neurons, suggesting that this factor plays a neuroprotective role in vivo and that its loss-of-function could be involved in ALS in humans. Zfp106 is expressed in the nucleolus and nuclear speckles in both motor neurons and skeletal muscle and its function is essential for maintenance of neuromuscular junctions in vivo. Zfp106 binds selectively to G-quadruplex-forming RNA molecules and strongly associates biochemically with other RNA binding proteins, including several with strong causative roles in ALS, further suggesting the possibility that Zfp106/ZNF106 might play a role in ALS. Consistent with this notion, unpublished work has identified two unrelated patients with a rare, homozygous variant in ZNF106 that is associated with adolescent onset ALS-like neurodegenerative disease. Introduction of the human disease-associated ZNF106 variant into mouse Zfp106 also results in profound juvenile onset ALS-like neurodegeneration similar to the disease observed in the patients and in Zfp106-null mice. This proposal will test the hypotheses that mutations in human ZNF106 cause or contribute to ALS-like neurodegeneration and that Zfp106 plays a protective role in maintaining neuromuscular junctions through its RNA binding function and its autonomous functions in either motor neurons or skeletal muscle. Studies proposed in this application will define the functional consequences ALS0associated ZNF106 variants by characterizing the ALS-like neurodegenerative phenotype in mice harboring knock-in of the variant and by determining the effect of the variant in cell culture-based and in vitro assays of ZNF106/Zfp106 protein function. These studies will also determine the cell autonomous requirement for Zfp106 in motor neurons and skeletal muscle using conditional genetic approaches in mice.

NIH Research Projects · FY 2026 · 2023-12

Project Abstract: The recent FDA approvals (Lutathera, Azedra, Pluvicto) and the swell of promising experimental agents in clinical trials underscore the surging enthusiasm to investigate molecularly targeted radiotherapy (TRT) as a treatment modality for cancers. However, tumor responses to TRTs are often transient and/or variable among patients. Thus, there is an urgent unmet need to develop new strategies to maximize the therapeutic benefit of TRT for cancer patients. For the past several years, the nuclear medicine field has prioritized developing low MW small molecule or peptide radioligands (RLTs) that rapidly exit the bloodstream to minimize host toxicity. However, tumoral responses to RLTs are limited by several factors, including heterogeneous target expression among tumors, dissociation or degradation of ligand/receptor complexes, and incomplete target saturation due to low mass doses and infrequent repeat dosing. Thus, exploring new strategies beyond RLTs for the tumoral delivery of radioisotopes is a worthwhile goal. We have approached this challenge by developing a new class of radiopharmaceuticals termed “restricted interaction peptides” (RIPs) which are linear and unstructured low MW peptides that are internally cleaved by a tumor endoprotease of interest to unmask a radiolabeled, helical membrane binding peptide. Once liberated, the radiolabeled helical peptide immediately and irreversibly attaches to a nearby phospholipid membrane in the tumor. Using PET, we have found that RIPs may have several properties advantageous for TRT, including catalytic amplification of tumor uptake and long persistence of the radioisotope in tumors due to the stability of the peptide/lipid membrane interaction. Thus, RIPs offer an unusual combination of the desirable safety profile characteristic of a low MW RLT with a high tumoral uptake more typical of a large MW TRT. Collectively, these findings provide a strong scientific rationale to test for the first time if radiolabeled RIPs can be effectively leveraged to treat tumors. Over three specific aims, we will evaluate the antitumor effects of a novel RIP termed “FRIP2” by coupling it to a representative β- (Lu-177) or alpha (Ac-225) emitter. Furthermore, we will translate 64Cu-FRIP2 into patients to test the safety, dosimetry, and pharmacokinetics of the platform while also evaluating the feasibility of tumor targeting. In summary, this project represents the first use of a conditionally activated membrane binding probe for TRT, which may overcome the well documented shortcomings of conventional RLT.

NIH Research Projects · FY 2026 · 2023-12

Project Summary/Abstract The NorCal-RCC (Regional Coordinating Center 13) leads a regional clinical trials network of centers committed to conducting high-quality clinical research to improve stroke prevention, acute stroke treatment, and recovery from stroke as part of the NIH Stroke Net clinical trials network. Investigators at the University of California San Francisco have partnered with multiple centers including Zuckerberg San Francisco General Hospital, the Veterans Administration Medical Center San Francisco, the Kaiser Permanente Northern California system, the Sutter Bay Hospitals network, Community Regional Medical Center, John Muir Medical Center, Salinas Valley Memorial Hospital, and Queen’s Medical Center to engage with diverse populations of stroke patients to advance and accelerate stroke clinical research through its support of high- impact clinical trials in the regional and national network and its support of training for the next generation of leaders in stroke clinical research.

NIH Research Projects · FY 2026 · 2023-12

ABSTRACT Fibrosis is the common endpoint responsible for liver failure in nearly every form of chronic liver disease, yet there remains no effective treatment for preventing the progression of fibrosis. Our preclinical studies identified a novel antifibrotic target, the enzyme acid ceramidase (aCDase). We demonstrated that depletion or inhibition of aCDase reduces HSC activation, the key step in hepatic fibrogenesis. Moreover, pharmacologic inhibition of aCDase or genetic knockout of aCDase in HSCs reduces fibrosis in mouse models for liver fibrosis as well as in precision cut liver slices from fibrotic rats and humans. The long-term goal of this project is to develop a potent inhibitor of aCDase for the treatment of hepatic fibrosis. Using structure-based drug design, we have recently discovered a novel series of covalent inhibitors with increased potency and metabolic stability. The objective of this application is to optimize this lead series towards the goal of oral, once-daily dosing for the treatment of hepatic fibrosis. In Aim 1, we will use structure-informed medicinal chemistry approaches to identify a covalent inhibitor based on the lead series with optimal potency, ADME profile, selectivity, and PK properties for oral delivery. In Aim 2, we will use mouse and human models of fibrogenesis to demonstrate the efficacy of the optimized compounds. We have assembled a team with expertise in hepatic fibrosis, medicinal chemistry, and antifibrotic drug development. This work is the first to target the aCDase pathway for the treatment of hepatic fibrogenesis. Our expected outcome is identification of a candidate compound that is ready for nomination for IND-enabling studies. This work is highly significant because it will facilitate a new treatment strategy for patients with hepatic fibrosis, for which no therapies currently exist.

NIH Research Projects · FY 2026 · 2023-12

ABSTRACT Of the 6,500 known rare diseases, only about 5% have U.S. Food and Drug Administration-approved treatments. In cancer, rare tumors account for approximately 20% of cancer incidence but often lack established therapeutic regimens. Hence, gaining a molecular understanding of rare tumors is key for development of effective therapies. This multi-investigator proposal investigates oncogenic mutations that activate protein kinase A (PKA) to promote defective cell signaling in rare endocrine and hepatic tumors. Targeted therapeutics have transformed care for patients with rare cancers by targeting oncogenic mutations in protein kinases. PKAc-driven cancers are challenging to target in this way because this broad specificity kinase controls myriad physiological processes. Consequently, selective PKAc inhibitors have been relegated to the role of tool compounds rather than clinically viable drugs. Thus, alternative strategies must be developed to treat PKAc-driven cancers. Our preliminary profiling of oncogenic PKAc mutants provide compelling evidence that PKAc engages downstream protein kinase cascades that impact translation in adrenal and hepatic tumors. We also observed increased mRNA translation as an emerging hallmark of these PKAc driven malignancies. These findings have forged a working hypothesis that PKAc-driven cancers can be treated by targeting downstream effectors such the RNA helicase eIF4A rather than globally blocking the catalytic activity of the kinase. Three specific aims will test this transformative premise. 1) Proteomic and transcriptomic profiling of cells expressing oncogenic PKAc variants that underlie Carney complex, Cushing’s adenoma and fibrolamellar carcinoma will elucidate downstream signaling elements that impinge on mRNA translation. 2) Molecular approaches will investigate new properties imparted by the DNAJ-PKAc-chimeric kinase in fibrolamellar carcinoma that may confer resistance to chemically induced apoptosis. 3) Clinically relevant compounds and novel bivalent inhibitors will dissect the mechanism of eIF4A dependence in PKAc-driven malignancies and patient derived (PDX) models of fibrolamellar carcinoma. This proposal not only builds on a solid foundation of PKAc research, but also affords an unparalleled opportunity to discover, develop and validate drug targets for a group of patients in dire need.