University Of California, San Francisco

NIH Research Projects · FY 2025 · 2024-06

ABSTRACT Genomic data can provide an invaluable source of information to understand pathogen evolution, identify patterns of transmission, and characterize phenotypes such as drug resistance and immune escape. For eukaryotic pathogens, larger genomes, sexual recombination, and complicated transmission dynamics including polyclonal infections have historically limited the use of genomic data for many of these applications. However, recent laboratory developments, including multiplexed targeted sequencing, have rapidly increased the pace of genomic data generation for eukaryotic pathogens. Fundamental differences in the biology and transmission of infections caused by these pathogens render many of the genomic data and analysis tools developed for other organisms (primarily humans, viruses, and bacteria) difficult or impossible to use. As a result, many research efforts have needed to rely on bespoke methods for processing and analysis, limiting the reusability of data, the accuracy and reproducibility of results, and more generally the productivity of scientists studying eukaryotic pathogens. There is a need to develop software and computational tools to process, store, share and analyze these data in a way which sets standards, encourages innovation, and facilities scientific discovery. We will develop a suite of data standards and robust software including a) bioinformatic pipelines including tools to facilitate the sharing and storage of these data, b) a modular software toolkit to conduct downstream statistical analyses relevant for epidemiologic and population genetic research, and c) work within a community of advisors and experts in the analysis of genomic data for eukaryotic pathogens to develop approaches that meet the needs of community and encourage broader uptake. The proposed work also includes harmonizing and developing standards for genomic, epidemiological, and clinical data. We will initially focus on Plasmodium falciparum, a species of parasite that causes malaria infections, as an organism of direct application which exhibits key complexities of eukaryotic pathogens (recombination, polyclonal infections). As such, standards and software developed during this proposal will have relevance beyond this single organism to other eukaryotic pathogens where similar biological and transmission complexities limit the use of existing tools to leverage genomic data to answer scientific and public health relevant questions. The expected outcome of the proposed research is computational software able to analyze targeted amplicon sequencing data for eukaryotic pathogens. By developing these approaches, with clear engagement within the broader research community, this work will help change the landscape of analyses possible with complex genomic data.

NIH Research Projects · FY 2024 · 2024-06

SUMMARY The menopausal transition is a time of extensive hormonal and physiological changes for women in midlife. Unfortunately, it is often accompanied by a worsening of cardiovascular and metabolic disease risk factors, such as increases in plasma cholesterol levels, central adiposity, and blood pressure, and women have greater coronary heart disease, stroke, and mortality risk after menopause. To date, scientists only have a limited understanding of the molecular level changes that are set into motion as ovarian follicle supplies dwindle and estradiol levels fall with menopause, especially in non-reproductive tissues. We hypothesize that extensive, tissue-specific transcriptomic changes occur during and after the menopausal transition, leading to metabolic reprogramming in cardiometabolic tissues. Here, our first aim will be to use a chemically-induced, ovarian follicle depletion mouse model of the menopausal transition to identify menopause-induced changes in chromatin accessibility and gene expression in mouse liver, adipose, and aorta tissues. In addition to “menopausal” female and control-treated male and female (estrous cycling) mice, there will also be groups of “menopausal” mice implanted with estradiol versus placebo tubing. This experiment will allow comparisons between female follicle- depleted (“menopausal”) and cycling mice, between follicle-depleted mice implanted with E2 and control tubing, between female cycling mice at distinct stages of the estrous cycle (high E2 vs. low E2), and between male and female mice. Our second aim is to identify elements of women’s omics profiles associated with menopause status and time since menopause. To do this, we will compare transcriptomic, metabolomic, and proteomic profiles between premenopausal and postmenopausal women in studies with enough premenopausal and postmenopausal samples. Completion and integration of these aims will help to identify factors driving the increase in cardiovascular disease risk during the menopausal transition, their downstream targets, and the impact of estradiol hormone therapy on reversal of the changes. Clinically, this could help to optimize the timing and type of interventions that could be used in the future to control cardiovascular disease risk in midlife women.

NIH Research Projects · FY 2025 · 2024-06

PROJECT SUMMARY This study focuses on understanding the complex nature of chronic pain by investigating the communication between distinct brain circuits. We aim to unravel the mechanisms by which somatosensory, cognitive, and affective information is integrated to produce the percept of pain. By studying network dynamics across key brain regions using direct intracranial recordings and graph theory approaches, we will elucidate spatiotemporal activity patterns that underlie the affective and cognitive dimensions of pain. Previous studies have identified specific brain regions, such as the anterior cingulate cortex (ACC), medial prefrontal cortex (mPFC), insula, sensory and medial thalamus, periventricular grey matter, and primary sensorimotor cortices, as crucial hubs involved in regulating chronic pain traits. However, the dynamic functioning of these networks in influencing the fluctuating nature of chronic pain, which can vary over minutes to days, remains less understood. To bridge this knowledge gap, the study proposes the use of direct intracranial recordings from patients with chronic pain and combines them with graph theory approaches to analyze network dynamics. We aim to study pain circuits in the laboratory and naturalistic environments by investigating the impact of expectation and mood on descending circuits and determining if they influence pain through similar mechanisms. The hypothesis is that brain stimulation relieving pain engages descending control mechanisms similar to positive mood or expectation, while a breakdown in corticothalamic functional connectivity is associated with episodes of elevated pain. The study proposes three specific aims. Aim 1 involves analyzing intracranial recordings from chronic pain patients to track changes in functional connectivity within corticothalamic networks during spontaneous pain and pain-relieving brain stimulation. Aim 2 focuses on examining the interaction between ascending and descending circuits during a cognitive pain-expectation task using recordings from patients with DBS electrodes. Aim 3 investigates the role of affective state on pain perception and descending pain circuits during a mood modulating task. Our group aims to identify patterns of functional connectivity and coherence between key brain hubs, such as the ACC, medial prefrontal cortex, insula, and thalamus, and understand their relationship with pain perception. By clarifying the underlying mechanisms of chronic pain and the effects of brain stimulation, mood, and expectation, this study has the potential to contribute to the development of novel diagnostic tools and more effective treatments for chronic pain disorders.

NIH Research Projects · FY 2025 · 2024-06

Abstract We have identified a highly tumor specific cell surface antigen, ALPPL2 or ALPG, that is not expressed in any normal tissue except for the placenta. ALPPL2 is expressed in a number of cancers including mesothelioma, ovarian, lung, gastric, pancreatic, endometrioma, and testicular cancer. ALPPL2 is one of those rare cell surface antigens that are genuinely tumor specific as opposed to tumor associated. The exquisite tissue specificity makes ALPPL2 an attractive target for developing cancer therapies that require a high degree of specificity. We propose to develop an ALPPL2-targeted bispecific T cell engager for treatment of ALPPL2 positive cancers. Target specificity is the hallmark of our new therapy development effort. In addition, we will engineer the CD3 arm: (1) a low affinity CD3 arm has the potential of reducing target independent cytokine release and thus gaining a wider therapeutic window; (2) tumor killing and cytokine release are mediated by two thresholds that can be differentially impacted by CD3 arm engineering. A mild or minimal on-target cytokine release is desired. Another important variable that affects developability and therapeutic window is the molecular architecture on which the bispecific is constructed. In this proposal, we will address the three critical issues, i.e., target specificity, CD3 arm optimization, and molecular architecture, and use a system engineering approach to identify an optimized T cell engager with matching components and forms that impart it with an excellent developability and a wide therapeutic window, enabling translation to clinical testing. In Aim 1, we will generate ALPPL2 BiTEs with engineered CD3 arm variants in forms compatible with clinical translation. In Aim 2, we will study tumor-specific cytotoxicity and cytokine release of system-engineered BiTEs targeting the true tumor specific antigen ALPPL2. In Aim 3, we will determine efficacy in vivo and identify a lead ALPPL2 BiTE for clinical translation. Impact: Successful completion of the proposed study will lead directly to clinical translation of a novel bispecific T cell engager with unprecedented tumor targeting specificity in multiple incurable cancer types with dire clinical needs.

NIH Research Projects · FY 2026 · 2024-06

PROJECT SUMMARY/ABSTRACT Dr. Melanie Molina is an Assistant Clinical Professor of Emergency Medicine at the University of California, San Francisco (UCSF) whose long-term goal is to become an independent investigator studying how to leverage health information technology to improve care for patients experiencing social disadvantage. To achieve this goal, she will develop critical skills in clinical informatics, human-centered design, and implementation science by: 1) completing formal coursework in SQL and Clarity data model fundamentals, human-centered design, and designing individual-level implementation strategies, 2) attending structured didactics, research group meetings, journal clubs, and works-in-progress sessions, and 3) performing goal- directed training activities in data query, retrieval, and analysis, contextual inquiry and focus group design, and intervention implementation and pilot data collection. The research infrastructure and resources at UCSF, including the Center for Clinical Informatics and Improvement Research and the Clinical and Translational Science Institute, will provide Dr. Molina with all the support necessary to complete the work proposed in her career development application. Dr. Molina has assembled an exceptional mentorship team: Dr. Laura Gottlieb (primary mentor) is a Professor of Family and Community Medicine with expertise in social determinants of health, Dr. Julia Adler-Milstein (co-mentor) is a Professor of Medicine and Chief of the Division of Clinical Informatics with expertise in electronic health record (EHR) data, and Dr. Courtney Lyles (co-mentor) is a Professor in the Department of Public Health Sciences at UC Davis with expertise in human-centered design and implementation science methodologies. The overarching goal of this proposal is to integrate patient social risk information into an existing EHR- based clinical decision support (CDS) tool to facilitate ED-initiated, social risk-informed opioid use disorder (OUD) medication treatment and ultimately improve treatment adherence and follow up. Dr. Molina will start by extracting metadata from Epic’s reporting database capturing whether discrete social risk data were documented and/or reviewed by ED clinicians for OUD-related ED encounters (Aim 1). Using insights from Aim 1—in addition to a human-centered design approach with semi-structured qualitative interviews of key ED staff and patient stakeholders—she will integrate patient social risks into an existing CDS tool for OUD treatment, creating a prototype that provides social care-enhanced OUD treatment recommendations (Aim 2). She will then evaluate the feasibility and acceptability of the social care-enhanced CDS tool at the UCSF ED as an intervention to increase treatment adherence and follow up using a mixed-methods, before-after approach (Aim 3). This proposal fulfills the National Institute of Drug Abuse research priority of understanding how to adapt existing services into more patient-centered models of care.

NIH Research Projects · FY 2025 · 2024-06

Project Summary/Abstract Cerebral aneurysms occur in about 6% of the population and have a very high morbidity and mortality rate if they rupture. Fortunately, most unruptured intracranial aneurysms (UIAs) rarely cause symptoms and do not require an invasive treatment that may itself causes severe cerebrovascular disorders. However, it is very difficult to predict which UIAs will rupture. Recent evaluations of the hemodynamic features of UIAs, using 4D Flow MRI (4DF), have shown promising results that suggest specific hemodynamic variables may have a great impact on aneurysm growth or rupture. However, the clinical applicability of these hemodynamic variables in predicting UIA growth has not yet been realized due to the lack of robust methods for gathering them, and also for describing their relationship to UIA growth. To fill in the gaps, the proposed research aims to develop a comprehensive statistical and computational framework to predict: (a) the growth of UIAs at the 24th month (b) their growth trajectory over a five-year period. Our goal is to develop a statistical framework to improve the UIA growth prediction that, in turn, will improve the UIA rupture risk assessment. Toward achieving this goal, we will develop a unique tensor regression machine learning framework that will (1) enhance 4DF resolution (2) predict the UIA growth at the 24th month and (3) predict the longitudinal UIA growth trajectory. Successful completion of the proposed research will provide a comprehensive computational system that can assist physicians when deciding whether a patient with UIA needs treatment, or follow-up imaging, as well as the time interval for the surveillance imaging.

NIH Research Projects · FY 2026 · 2024-06

Project Summary/Abstract Interorgan communication between the brain and peripheral tissues maintains a range of homeostatic responses. Efforts to identify new facets of interorgan crosstalk remain sparse. Missed opportunities exist because of the siloed nature of physiological research, especially between the brain and body. Cracking the molecular code in the brain-body dialog is also technically challenging and requires time-consuming, interdisciplinary preclinical in vivo studies. We previously discovered that eliminating ERa in a subset of hypothalamic neurons leads to a massive increase in trabecular bone mass and strength that persists with aging in female mice. Our focus on a brain-bone interaction that influences bone mass and bone fat underscores the potential role of select neurons to significantly alter peripheral tissues. Here, we will ask how this brain- derived factor increases bone mass while permanently decreasing bone fat, two opposing features of skeletal aging. In new data, we find that the high bone mass in our mutant mouse model system results from humoral rather than neuronal cues. An essential first step toward translating this work will be to identify this circulatory anabolic bone factor. While this goal is simple in principle, it is extremely difficult to achieve. We were fortunate to discover that this high bone mass phenotype reverses with a dietary challenge. High-resolution genomic approaches then allowed us to identify and test the most promising candidates through gain-of-function and loss-of-function approaches. Using in vitro, ex-vivo, and in vivo model systems, we provide the first molecular and cellular insights into how the brain influences bone mass, bone fat, and skeletal stem cell function. We will elucidate how and why this brain-derived anabolic bone factor increases bone formation. Our team brings together expertise in neuroendocrinology, bone and skeletal stem cell biology, and the clinical practice of treating metabolic and bone disorders. We are using state-of-the-art methods to pursue hypothesis- driven questions aimed at decoding a powerful dialog between the brain and bone. Eventually, we wish to translate these preclinical studies to skeletal and metabolic disorders that are associated with or accelerated in human aging. Our research program fits squarely within this new NIA mandate to transform our understanding of interorgan interactions and advance strategies for improving age-related decline in skeletal health, especially in women.

NIH Research Projects · FY 2025 · 2024-06

PROJECT SUMMARY AND ABSTRACT Alzheimer’s disease (AD) is a heritable and debilitating progressive neurological disease and the most common form of dementia. Among the AD risk loci identified by decades of AD genetics research, the APOE locus encoding for Apolipoprotein E, specifically the APOE4 isoform, is the strongest known genetic risk factor for sporadic AD (sAD). Thus, APOE4 represents a prime therapeutic target. However, APOE4 is differentially penetrant across genetically-defined ancestral populations, increasingly so across African (AFR), Non-Finnish European (NFE) and East Asian (EAS) ancestries. This suggests that other common genetic factors may modify its penetrance and therefore protect or predispose certain individuals to its pathological effects. Yet, the definitive sources of these differences remain undefined. This highlights a crucial gap in our understanding of sAD heritability that will be essential to effectively prognosticate, stratify, and treat diverse patient populations. Recent trans-ancestry transcriptional profiling suggests that APOE4 expression in the AD brain differs across ancestries and thus could be a key modifier of AD risk from APOE4. These expression differences could be attributed to noncoding genetic variants within the APOE locus that influence cis-regulatory element activity, leading to context-specific transcriptional dysregulation of APOE that drivies cell type- and state-specific molecular phenotypes. Indeed, increased APOE expression has been linked to sAD phenotypes. Further supporting this, reporter assays in cell lines suggest a subset of variants nearby APOE are functional. However, it is yet to be definitively confirmed which, if any, of these APOE locus noncoding variants underlie differential penetrance across AFR, NFE and EAS ancestries. This work aims to pinpoint functional ancestry-specific genetic modifiers of APOE4 penetrance in human cells. Massively parallel reporter assays in iPSC-derived brain cell types will functionally prioritize from a comprehensive set of 10,661 analytically-nominated variants (Aim 1). Transcriptomic and epigenomic profiling of ancestry-diverse iPSC-derived brain cell types will create ancestry- and cell type-specific gene-regulatory maps of the APOE locus necessary to functionally interpret prioritized variants (Aim 2). In turn, employing scarless genome editing in iPSC-derived models will determine the sufficiency of analytically nominated high-priority variants to alter gene expression in the APOE locus (Aim 3). This proposed work will accompany training goals centered around structured coursework in bioinformatics, leadership and management training, and improving science communication towards leading an independent research group in the future. Presenting this work at both broad and specific meetings will foster interdisciplinary crosstalk core to these goals. All experiments and training will be jointly guided by sponsors Dr. Ryan Corces and Dr. Yadong Huang in the Gladstone Institute for Neurological Disease. The unique combination of relevant scientific expertise, structured training environment, and core resources at both UCSF and the Gladstone Institutes will provide the necessary groundwork for successful training and research.

NIH Research Projects · FY 2025 · 2024-06

ABSTRACT We will address a critical problem in clinical oncology, namely how highly heterogeneous, drug resistant tumor cell populations develop, and how they can be targeted. Most tumors develop resistance to almost every type of therapy, including targeted-, radiation-, chemo- or immunotherapy, ultimately leading to cancer deaths. It is essential to develop novel methods to understand the processes leading to drug resistance under complex in vivo conditions where stromal and immune elements interact with malignant cells. We will study squamous cell carcinomas (SCCs), a major contributor to human cancer burden and one of the most common solid tumor types that arise in a range of tissues including head and neck, lung, esophagus, bladder, and skin. We will use a well-established multistage, carcinogen-induced, cutaneous SCC mouse model and credential its’ representation of human cancer drug resistance. Mouse cSCCs display many genetic alterations seen in human SCCs, including mutation of Ras, PI3 Kinase and Notch pathways. The model also incorporates the critical role played by non-mutagenic tumor promoting factors as cancer drivers. This proposal will build on our previous work, accessing our extensive in-house mouse tumor genomics and transcriptomics databases. In Aim 1, we will use single cell analyses of primary papillomas, carcinomas and metastases induced by chemical carcinogenesis in situ and analyzed before and during chemo- or immunotherapies. We will use our novel biocomputational Metagene approach to identify rewiring of transcriptomic networks within single tumor cells after therapy. Single cell analyses, namely scRNAseq, CyTOF, MIBI, and FISH, will be combined with our in- house developed analytical tools, to identify high plasticity state tumor cell populations enriched or depleted in response to therapy and their molecular and spatial relationship to other cells and structures within the tumor. In Aim 2, we will test the fidelity of the chemical carcinogenesis model as a robust representation of human cSCC biology by undertaking longitudinal validation studies of fresh human cSCC tissue collected before and during chemo- or immuno-therapy and analyzed using the same technology. In Aim 3, we will empirically test the function of candidate genes (Metagene components) expressed in the high plasticity state, for their contribution to drug resistance. CRISPRi/dCas9 and CRISPR/MultiCas12a technology will be used to test gene activities during drug therapy by single or combinatorial gene knockdown in syngeneic tumor models in vivo. Our strategy will credential the use of the skin chemical carcinogenesis system to model features of human cancer drug resistance. The project is responsive to PAR-23-281, as it undertakes cross-species discovery of the molecular basis for development of drug resistant tumor cells. The knowledge to be gained will contribute to discovery of biomarkers and therapeutic targets for this drug resistant cell population. Our computational methodology and our extensive transcriptomic data from hundreds of tissue and tumor samples will be shared with the Oncology Models Forum NCIP Hub.

NIH Research Projects · FY 2025 · 2024-06

Project Summary/Abstract This proposal’s objective is to determine whether genetic mutations that alter the transcriptional activity of the basic helix-loop-helix (bHLH) transcription factor Achaete-scute complex 1 (ASCL1) contribute to the etiology of organ-specific autoimmunity in humans. Transcription factor mutations that result in the misregulation of gene expression are particularly potent drivers of human disease. Studies of individuals and families with suspected monogenic forms of autoimmunity provide a unique opportunity to understand novel pathways in human immune biology and have revealed mutations in thymic transcription factors as potent drivers of autoimmunity. For example, mutations in the Autoimmune Regulator (AIRE) gene cause a spectrum of organ- specific autoimmune conditions such as hypoparathyroidism, hypothyroidism, Addison’s disease (adrenals) and type 1 diabetes (pancreas). AIRE is a transcriptional activator that drives the expression of tissue- restricted self-antigens (TSAs) in medullary thymic epithelial cells (mTECs) to enable the deletion of autoreactive T cells, a process termed “central tolerance”. While AIRE is critical for central tolerance, the severity and spectrum of organ-specific clinical disease among AIRE patients, including siblings with identical AIRE mutations, underscores the existence of disease-modulating variables, including perhaps organ-specific disease-promoting and/or ameliorating genetic elements that modulate AIRE expression, activity or function. ASCL1, an established bHLH transcription factor that orchestrates the proliferation, specification and differentiation of neural progenitors, was recently reported to be expressed in three human medullary thymic cell subpopulations: two known to be critical for central tolerance, 1) AIRE+ mTECs and 2) their developmental precursors (AIRE- mTECs); and 3) a novel subpopulation of thymic neuroendocrine cells. The role of ASCL1 in immune biology and autoimmune disease is completely unknown. We have also identified one individual and two siblings in our UCSF patient registry with suspected monogenic autoimmunity and ASCL1 mutations. The individuals tested negative for known genetic causes of autoimmunity and have rare/predicted deleterious ASCL1 mutations that are adjacently positioned within the transactivation domain of the protein. The novel discovery of ASCL1 expression in the thymus coupled with the identification of suspected ASCL1 monogenic autoimmune patients leads to the general hypothesis for this project. We hypothesize that ASCL1 mutations that alter its transcriptional activity disrupt the development, function, and/or microenvironment of AIRE+ mTECs, resulting in autoimmunity.

NIH Research Projects · FY 2025 · 2024-06

Dentists may be the first and only care providers for intimate partner violence (IPV) survivors, as a significant percentage of IPV incidents involve injuries to the face/mouth/teeth. IPV has severe consequences for survivors, impacting their physical, mental, and oral health, and leading to long-term societal and economic repercussions. Despite recommendations from the American Dental Association, dentists face barriers such as limited time, training hindering their ability to effectively screen for IPV. Evidence shows that 2-50% of care providers screen for IPV. To streamline IPV screening for dentists, Dr. Banava will employ state-of-the-art machine learning techniques to develop a clinical decision support to deliver the right information, to the right person, in the right intervention format, through the right channel, and at the right time within the workflow provide ("five rights" approach). Using an integrated data-driven IPV-specific clinical decision support tool will improve patient outcomes, and reduce missed cases. The specific aims are: Aim 1: Identify Prevalence, Patterns and Correlates of IPV-related Orofacial Injuries and Conditions in Electronic Health Records. Dr. Banava will leverage standard IPV-related orofacial injury and condition terms to conduct a comprehensive search within the UCSF structured electronic health record (EHR) database Epic (APeX), which encompasses electronic dental records as well. Next, Dr. Banava will extract embedded IPV-related data from notes, manually annotate, and validate with patient chart review and actual diagnosis (gold standard). Later, Dr. Banava will apply NLP techniques, such as Named Entity Recognition, to annotate the same set of notes and evaluate their precision, recall, and F1 score. Additionally, Dr. Banava will leverage advanced Large Language Models (LLMs) within the NLP framework to further enhance the annotation process. Aim 2: Develop an IPV-Specific Clinical Decision Support Tool and Assess its Feasibility and Acceptability. Dr. Banava will collaborate with the UCSF APeX Enabled Research team to develop a prototype of an IPV-specific clinical decision support tool, leveraging generated data. Adopting a human-centered design approach, Dr. Banava will engage domain experts and conduct iterative focus groups to ensure the tool's user-friendliness, alignment with clinical workflows, and effectiveness in decision-making and case management. The focus groups, following a mixed methods research design, will take place during both the development and post-development phases of the project. Additional groups may be included if information saturation is not achieved. To evaluate the feasibility and acceptability of the developed tool, Dr. Banava will use the Technology Acceptance Model and incorporate prompts accordingly. A comparison will be made between the tool and a standard IPV screening approach. The primary objective of the K23 Award is to provide Dr. Banava with structured training in advanced quantitative statistical analyses and modeling techniques, health informatics, natural language processing, and mixed methods research. This award will empower Dr. Banava to bridge knowledge gaps and streamline IPV screening for dentists, ultimately leading to improved patient outcomes.

NIH Research Projects · FY 2025 · 2024-06

PROJECT SUMMARY Complications from preterm birth are the leading causes of global mortality in children under the age of five. The failure to mount appropriately-timed maternal-fetal immune tolerance is associated with preterm delivery. However, our current understanding of the humoral immune system in this process has been limited to a handful of examples of pathogenic antibodies that occur with pregnancy complications in humans. To fill this knowledge gap, it is essential to obtain a comprehensive portrait of autoimmune repertoire dynamics during normal and complicated pregnancies. The long-term goal of this work is to leverage serological autoantibody profiles for development of non-invasive predictors for preterm delivery and identification of key targets for preventative immunomodulatory therapeutics. In Aim 1, Dr. Rackaityte will chronicle the autoimmune changes across the time course of pregnancy using phage display immunoprecipitation and sequencing to generate machine learning models predictive of gestational age. Completed during the K99 phase, this high-resolution timeline of autoreactivity during pregnancy will build the foundation for understanding the roles, both protective and pathogenic, of these critical humoral immune adaptations. In Aim 2, Dr. Rackaityte will dissect antibody- antigen interactions specific to preterm pregnancy to discover contact points that lead to functional inhibition of the targeted protein. In the K99 phase, a suite of patient-informed recombinant antibodies will be generated through an evolution-driven antibody phage display system, and these will be tested in the R00 phase for their ability to inhibit target protein function. This will provide the framework for future studies to interfere with antibody-antigen interactions to prevent preterm delivery. In Aim 3, Dr. Rackaityte will develop murine models of inflammation during pregnancy that will be employed to determine the in vivo consequences of maternal autoantibodies on pregnancy outcome. This will deliver a validated model for interrogating the in vivo role of autoantibodies that lead to labor progression, a unique opportunity to mechanistically dissect observations made in humans for targeted therapeutic development. Dr. Rackaityte’s goal is to develop an independent research program in translational reproductive immunology, which is highly complementary to the mission of UCSF geared towards facilitating direct interactions between basic scientists and clinicians. To accomplish her goals, Dr. Rackaitye will receive guidance from her scientific advisory committee and her primary mentor, Dr. Joseph DeRisi. To complete her training and build a foundation of skills for her independent laboratory, she will develop expertise in recombinant antibody generation (with Dr. Charles Craik), mouse model development (with Drs. Tippi MacKenzie and Mark Anderson), and clinical metadata analysis of reproductive disorders (with Dr. Marcelle Cedars). She will attend UCSF and MOSAIC UE5 sponsored programs to gain skills in grant writing, leadership, and lab management as well as targeted coursework to prepare her successful transition to an independent career.

NIH Research Projects · FY 2026 · 2024-06

SUMMARY Untreated and inadequately treated pain has substantially increased as a problem in the US over at least the last 20 years. Increasing fears around prescribing opioids have also contributed to inadequate analgesic treatment. Importantly, often chronic pain and major depressive disorder (MDD) are comorbid. Therefore, discoveries of previously unknown neural circuits that can be targeted to address not only nociceptive discomfort but also the affective component of chronic pain and its interactions with depression remains an important area of focus for research. We recently showed that the lateral habenula (LHb) is a brain region that contributes to both acute nociception and the aversiveness of chronic pain. The LHb also plays a role in behavioral models of depression in rodents and has been targeted for deep brain stimulation to treat MDD in humans. LHb neurons generally fire more in response to noxious stimuli and aversive behavioral states. We recently found that a glutamatergic input from the lateral preoptic area of the hypothalamus (LPO) to the LHb is activated by noxious stimuli, and inhibiting LPO → LHb neurons relieves the mechanical hypersensitivity induced by a neuropathic pain model (spared nerve injury, SNI) in male rats. Inhibiting LPO → LHb also generated a conditioned place preference in male and female animals with SNI, but not the control animals. This suggests that targeting this circuit should have less abuse liability compared to agents that act on neural circuits that produce reward in control animals. Here we propose to investigate the projections out of the LHb that transmit the pain signal compared to the projections that modulate depression-model-related changes in behavior. While many have studied the direct and indirect projections from the LHb to the dopaminergic systems and dopamine systems contribute to pain and relief signaling, the LHb also sends a direct excitatory projection to the parabrachial nucleus (PBN), an important component of the pain processing circuitry. The PBN receives nociceptive inputs from the dorsal horn of the spinal cord and transmits pain signals to the central nucleus of the amygdala. Therefore an LHb input to the PBN is a direct route for the LHb to have a strong impact on both sensory and affective components of pain. The LHb also projects to the dorsal raphe nucleus (DRN), which is strongly implicated in MDD in humans and depression models in rodents. Our preliminary findings show that the projections to the PBN and DRN are from mostly non-overlapping sets of LHb neurons, making interactions possible but not necessary. Here we propose to systematically investigate the contributions of the LHb → PBN and LHb → DRN to nociception and motivated behaviors at the anatomical, neurophysiological, and behavioral levels. We will make these measurements in control animals, animals with SNI, and animals treated with repeated aversive restraint stress (a model for inducing depression-related behavioral changes). Together this proposed research provides an opportunity to examine the neural circuit basis for the clinically established relationship between pain and depression and to determine how to modulate these circuits for therapeutic effect.

NIH Research Projects · FY 2026 · 2024-06

Project Summary Aging is associated with age-related impairments in cognitive function and is the number one risk factor for a series of neurodegenerative disorders, including Alzheimer’s disease. However, aging is not isolated to the brain, but is instead a system wide process affecting multiple tissues and organ systems. A growing body of work has demonstrated that exposure to an aged circulatory system, which connects all organ systems that face age- related decline, drives hippocampal-dependent cognitive impairments during aging. Interestingly, there are known age-related changes in the peripheral immune system, which constitutes an integral portion of the aging circulatory system. T cells, a component of the adaptive immune system, are one of the immune cells most detrimentally affected by age. In addition to a decrease in the ability to respond to infections and increases in inflammatory cytokine secretion in the periphery, there is an emerging role posited for T cells in age-related brain dysfunction. While studies have identified an increase in T cell infiltration into select areas of the aged brain, the effect of age-related changes in circulating T cells on hippocampal-dependent cognitive function has not fully been explored. Therefore, I sought to delineate the role of peripheral, aged CD8+ T cells in driving age-related cognitive decline. Using single cell RNA sequencing, I identified age-associated CD8+ T cells, marked by elevated expression of Granzyme K (GZMK), in spleens of cognitively impaired aged mice and young mice exposed to an old circulatory system via heterochronic parabiosis. Interestingly, levels of secreted GZMK are increased in the plasma of aged mice. Functionally, adoptive transfer of aged CD8+ T cells into young mice resulted in cognitive deficits in hippocampal-dependent learning and memory, underlain by synaptic and neuronal changes. To explore the rejuvenating potential of targeting aged CD8+ T cells, I selectively depleted circulating CD8+ T cells in aged mice and observed amelioration of age-related impairments in learning and memory. Interestingly, bulk RNA sequencing identified differentially expressed genes enriched in neurons and endothelial cells. Consequently, this study aims to test the hypothesis that peripheral, age-associated CD8+ T cells are drivers of cognitive impairments in the aging hippocampus. In Aim 1, I will determine the molecular and cellular changes elicited by aged CD8+ T cells in the aged hippocampus. As depletion of circulating CD8+ T cells is sufficient to ameliorate cognitive decline, in Aim 2, I will investigate the role of CD8+ T cell-derived factors in promoting hippocampal-dependent cognitive decline, focusing on the pro-aging effects of GZMK. This study aims to identify molecular mechanism by which circulating aged CD8+ T cells drive cognitive impairments with age and identify potential therapeutic targets to counter aging-associated cognitive decline and dementia-related neurodegenerative disorders, such as Alzheimer’s Disease.

NIH Research Projects · FY 2026 · 2024-06

PROJECT SUMMARY Intimate Partner Violence (IPV) is a major public health problem. Globally, an estimated 30% of women report physical or sexual violence by an intimate partner in their lifetime. IPV is a well-established social driver of mental health problems and doubles the rate of depression and PTSD. Interventions like cognitive behavioral therapy (CBT) can improve depression after women experiencing IPV exit abusive relationships. However, despite ongoing violence, many young women are less likely to divorce or separate from their husband. But ongoing IPV severely limits mental health recovery and increases the risks of suicide. Another important factor is that young women often live in extended, multi-generational households, where studies have shown that mother-in-laws (MILs) play a critical role in young daughter-in-laws (DILs) autonomy and freedom of movement, substantially affecting her mental health. The pathways via which multiple family members and ongoing IPV affect young women’s mental health is very poorly understood. There is an urgent need to study interventions that: a) improve mental health and reduce IPV; b) engage husbands and MILs, and not just women experiencing IPV; and c) elucidate pathways via which IPV-related drivers affect mental health. Our Nepal-US collaborative team has pilot-tested a novel Multi-component family Intervention to Lower depression and Address intimate Partner violence (MILAP, meaning unity and reconciliation in Nepali) among young women in Nepal. MILAP’s first component engages DILs and their MILs by establishing them as allies in addressing IPV and improving DIL’s empowerment and freedom of movement. In MILAP’s second component, the DIL and her husband participate in behavioral couple’s therapy (BCT) to improve communication skills, increase caring behaviors, and enhance trust in the marital relationship. This approach was acceptable, feasible, and safe. It resulted in substantial reduction in proportion of people with moderate depression (PHQ-9>9) (baseline: 46%, 3 months: 4%). Based on this pilot study (n=75; 25 triads), we now propose to conduct a fully-powered RCT of MILAP to: a) establish effectiveness by conducting a 12-month RCT with 300 triads (young women reporting IPV, their husbands, and their MILs), b) understand mechanism of intervention impact, and c) conduct a costing analysis. Our team has a 16-year history of successful global health collaborative research in Nepal. If successful, this study will deliver an effective family intervention and a better understanding of its mechanism to address two complex challenges (IPV and depression) that lead to a massive public health burden among young women living in Nepal, and other countries and regions where women live in multi-generational households and have limited options to leave abusive relationships.

NIH Research Projects · FY 2025 · 2024-06

Project Summary This Ruth L. Kirschstein National Research Service Award Individual Predoctoral Fellowship will provide the trainee, an Epidemiology PhD student at UCSF, with mentored training essential achieving the applicant’s career goal of becoming a perinatal epidemiologist with expertise in health policy and health services research. Her training goals are to gain expertise in perinatal epidemiology and outcomes research, advanced quasi- experimental approaches for health policy research, and methods to measure effects on health disparities. To improve maternal and newborn outcomes, several US states have implemented numerous state-level initiatives and policies in recent decades. One set of initiatives were focused on reducing rates of early-term elective deliveries (EEDs) – non-medically indicated labor inductions and c-sections occurring before 39 weeks gestational age. EEDs are associated with significant increases in the risk of several newborn complications and neonatal intensive care unit admission. Studies thus far have found mixed results on the effects of initiatives on newborn outcomes, and frequently exclude endpoints for maternal outcomes and disparities in outcomes. Studies thus far are also hindered by data sources that misclassify EEDs and methodologic limitations that do not allow for generalizability or comparison between EED initiative types. The goal of the proposed research is to leverage a robust dataset to rigorously evaluate the effects of EED initiatives on maternal and newborn outcomes. Building on the applicant’s previous perinatal outcomes research and experience with the proposed dataset, this study will investigate and compare the effects of different state-level EED initiatives on healthcare utilization and perinatal (maternal and newborn) outcomes (Aim 1) and effects of these EED initiatives on disparities in outcomes, including by maternal race and ethnicity (Aim 2). Evidence and methodologic advancements from this study will inform further implementation and evaluation of state-level perinatal care initiatives. The proposed research is an ideal opportunity for the applicant to receive mentored training on recent innovations in quasi-experimental designs that will help overcome limitations of previous studies. The proposed training plan includes mentorship from experts and leaders in the in fields of perinatal epidemiology and outcomes research, comparative effectiveness studies, health services and policy research, social and structural determinants of perinatal outcomes, and clinical care. Research and training in this fellowship proposal are feasible and appropriate for the applicant’s current expertise and future goals. This fellowship will provide the applicant with the content knowledge, methodologic skills, and hands-on mentored experience to lay the foundation for an independent research career focused on holistically evaluating the effects of health services and policy changes on maternal and newborn outcomes. This training is critical to the applicant’s long-term goal, and NICHD priorities, to conduct research that helps to improve pregnancy outcomes and ensure lifelong wellness for mothers and their infants.

NIH Research Projects · FY 2025 · 2024-06

PROJECT SUMMARY/ABSTRACT Primary care is the first point of contact for most people experiencing cognitive concerns, and its providers are a critical workforce for dementia care. Timely and equitable diagnosis of Alzheimer’s disease and related dementias (ADRD) in primary care is a key national priority and enables primary care providers (PCPs) to identify treatment opportunities and to support patients and their caregivers in planning ahead and making decisions about safety, medications, management of comorbid conditions, and caregiving. Yet, missed and delayed diagnosis of ADRD in primary care is a persistent problem, occurring in over 60% of affected persons, impeding these key care functions, and is especially common among racial/ethnic minorities and socioeconomically disadvantaged populations. Early, equitable detection and diagnosis in primary care will be crucial as new disease-modifying therapies become available, but workforce studies indicate that there are insufficient specialists to make these diagnoses, especially in low-resource settings. Therefore, the overall goal of this project is to build on strengths and overcome barriers in the primary care workforce that contribute to missed and delayed diagnosis of ADRD, particularly among patients impacted by health disparities. To do so, this study will take place in 7 primary care practices (safety net, community, academic) that serve diverse populations in both urban and rural locations. We will use comparative ethnography to ascertain how the most efficacious PCPs do successfully and proactively identify and diagnose dementia in diverse primary care settings, and we will also identify drivers of disparities and barriers to timely diagnosis. Comparative ethnography, an innovative lens we will bring to this persistent health system challenge, is a qualitative approach used to holistically determine how social and cultural processes and individual and structural contexts impact healthcare. Our Specific Aims are: (1) Assess the diagnostic journeys of people with ADRD across diverse clinical settings and analyze their interactions with the primary care workforce to identify ways social, cultural, and structural contexts impact the ADRD diagnostic process; (2) Analyze how PCPs, their practice cultures, and available resources across these contexts strengthen or impede the ADRD diagnostic process; and (3) a) Identify systems and policy-level factors that impact the ADRD diagnostic process, b) Triangulate and compare findings across sites and domains, and c) Develop intervention targets, towards future translation. We will identify how patient/caregiver factors, clinician and practice culture, and policies and health systems strengthen or impede PCP engagement in the ADRD diagnostic process. A Stakeholder Advisory Board will partner with the research team to help identify intervention targets for future studies. The results will inform development of practice and policy intervention targets to achieve equitable workforce management and outcomes for the growing population of older adults with cognitive decline. These will be testable in future interventions to improve the primary care workforce’s approach to ADRD diagnosis.

NIH Research Projects · FY 2026 · 2024-06

Unhealthy alcohol use is very prevalent (22-30%) among persons with HIV (PWH), impairs adherence to antiretroviral therapy (ART), and fuels inflammation, HIV non-suppression, coinfections (e.g., tuberculosis), and noncommunicable diseases (NCDs) that are common among PWH. There is an urgent need to reduce unhealthy alcohol use, especially in Uganda which has high prevalence of HIV, unhealthy alcohol use, and HIV comorbidities. Brief (up to 4 hours) alcohol-focused interventions (BI) can reduce alcohol use in PWH, but their effect sizes have been modest. This is also true for screening and brief (5-15 minutes) interventions (SBI) that are being rolled out within HIV clinics in Uganda. BIs rely on self-reported alcohol consumption for assessment, personalized feedback, goal setting and monitoring, which are key for readiness and motivation for behavior change, but may be limited by impaired self-awareness and under-reporting. We hypothesize that alcohol biomarker testing and results communication, with a biomarker such as phosphatidylethanol (PEth), can improve the efficacy of BIs by increasing readiness and motivation for change via increased self-awareness and improved personalized feedback based on an objective measure, and by objectively measured goal setting and monitoring, similar to targeting a HbA1c level in diabetes, viral suppression in HIV, or tenofovir adherence in ART and HIV pre-exposure prophylaxis via recently developed urine testing. PEth is correlated with total prior month alcohol consumption and is sensitive and specific for unhealthy alcohol use; a low-cost PEth immunoassay is being validated, and a point-of-care test will likely soon follow. We propose the Phosphatidylethanol Results Communication (PERC) Study, that builds on our long-standing US/Uganda collaboration in alcohol/HIV research. Our long-term goal is to determine whether PEth can be used to boost the efficacy of alcohol BIs. Our short-term goal for this R34 is to develop the strategies to provide PEth results in BIs, and examine their acceptability, appropriateness, and feasibility, before proceeding to a larger trial. Aim 1 is to elicit input via a series of focus group discussions (FGDs) including theater testing and role playing, with several groups of stakeholders (patients, clinic staff, community, and government), and conduct field testing and in-depth interviews (IDIs) with PWH who engage in unhealthy alcohol use. Aim 2a is to conduct a pilot randomized controlled (RCT) trial (n=80), with PWH who engage in unhealthy alcohol use randomized to receive either PEth-boosted BI or the standard BI that is being rolled out in HIV care in Uganda. Our primary measures will be acceptability, appropriateness, and feasibility of the intervention, measured quantitatively and qualitatively. We will explore changes in readiness for alcohol reduction and changes in PEth at three months, by study arm. Lastly, we will share these results in FGDs with the stakeholders from Aim 1, and elicit input on whether we should proceed to a full-scale trial. This work is relevant for a broad range of alcohol BIs for PWH and others, and for other behavioral interventions that might benefit from new point-of-care testing.

NIH Research Projects · FY 2026 · 2024-06

ABSTRACT Pancreatic cystic lesions (PCLs) are the only radiographically identifiable precursor to deadly pancreatic carcinoma and they are detected in a million people annually in the U.S. Most patients with PCLs have “indeterminate” cysts in which both the type and histologic grade are clinically and radiographically uncertain. Currently used cyst fluid diagnostics suffer from poor accuracy and they typically require large volumes of fluid that are unavailable in ~50% of cases, leading to both missed cancers and unnecessary major surgery. In this proposal, we leverage our novel multiplex substrate profiling by mass spectrometry method combined with proteomics to refine target proteins and then validate our two-tier classifier for the identification of mucinous PCLs with high grade dysplasia or invasive carcinoma, together considered advanced neoplasia (AN). The final clinical assay requires only 5 µL of fluid. A micro-volumetric assay is expected to improve the diagnostic yield of cyst fluid testing from ~50% to >90% for patients who undergo routine invasive testing. The Tier-1 classifier identifies mucinous PCLs, which carry variable risk of malignant transformation, thereby potentially removing ~25% of patients with non-mucinous PCLs from the need for further surveillance or surgery. We will validate the Tier-1 classifier with PCL samples from the Early Detection Research Network (EDRN), a histologically diverse, well- annotated biorepository + untested samples from UCSF and UCLA. We will further test and refine our Tier-2 classifier for the identification of AN using untested banked mucinous PCLs from UCSF, and then validate it using external samples from the EDRN and prospectively collected samples from UCSF and UCLA to prioritize detection of AN while minimizing the burdens of overtreatment. We will also use our radiology search engine, mPower, to improve capture of “missed” patients with incidental clinically relevant PCLs, and we will thereby expand the racial and ethnic diversity of our Panc Cyst Registry. Our registry is a prospective longitudinal research resource that uses patient-directed input and includes demographic and lifestyle information. Together these novel tools are expected to make a significant impact on the management of “indeterminate” PCLs and improve the detection of early-stage pancreatic cancer, while reducing the burdens of overdiagnosis and overtreatment.

NIH Research Projects · FY 2025 · 2024-05

Project Summary/Abstract Asthma is a debilitating lung disease marked by reversible airway obstruction that affects over 5% of the US population and is growing in prevalence. In the majority of cases of asthma, allergic inflammation around the bronchial airways contributes to disease pathogenesis. A key pathway in the initiation of allergic immune responses is elicited by antibodies of the IgE isotype. In allergic individuals, IgE antibodies are produced with specificity for components of harmless environmental substances, termed allergens. However, the mechanisms responsible for the production of IgE specific for allergens inhaled into the respiratory tract (aeroallergens) remain poorly characterized. One of the major limitations in understanding the process of allergic sensitization through the respiratory tract has been technical difficulty in direct studies of IgE producing plasma cells and their B cell precursors. My laboratory has developed methodology enabling the sensitive identification of these rare IgE- expressing cells by flow cytometry and microscopy. The focus of this project is to apply this robust methodology to study the generation of IgE-expressing cells following aeroallergen exposure through the respiratory tract. In order to do a detailed analysis of tissues involved in respiratory tract immunity, we will study mouse models of allergic airway disease. The overall objective of this project is to study the cellular response leading to the production of IgE in allergic sensitization through the respiratory tract. The specific aims of this study are to: 1) characterize the generation and fate of IgE B cells and plasma cells and their tissue localization in different models of aeroallergen sensitization and 2) determine the relative abundance of allergen-specific IgE B cells and plasma cells compared with other isotypes (IgM, IgG, and IgA) and establish their clonal relationships. The results from these studies will provide important insights into IgE production after allergen exposure via the respiratory tract. More broadly, this study will increase our understanding of the ways in which we may develop sensitization versus tolerance to aeroallergens.

NIH Research Projects · FY 2026 · 2024-05

PROJECT SUMMARY/ABSTRACT Mounting evidence from our team and others suggests a potential bi-directional relationship between sleep and Alzheimer's disease and related dementias (ADRD) in older adults, in which sleep disturbances precede clinical ADRD, in addition to commonly occurring after disease onset. This bi-directional relationship has important implications for the early intervention of ADRD, yet it remains debatable whether sleep disturbance is a prodromal or modifiable risk factor of ADRD. Research to disentangle the role of sleep in ADRD requires the use of a life course approach to address the directionality of the association, particularly given the long neurodegenerative processes leading to ADRD before symptoms onset and the large variations in sleep disturbances across the life course. Our long-term goal is to develop preventive strategies for ADRD by addressing the role of sleep disturbances across the life course. The objective of this proposal is to determine the effects of objective and subjective sleep disturbances on age-related cognitive decline and risk of ADRD across the life course in diverse populations, and to elucidate mechanistic pathways contributing to this association at different stages of life. Our central hypothesis is that objective and subjective sleep disturbances over the life course are associated with life-course cognitive trajectories and risk of ADRD, with varying magnitude and different underlying pathways for each stage of life. We have an unprecedented opportunity to leverage data from six well-characterized longitudinal cohorts, two with 40-50% Black or Mexican American participants, to create a synthesized diverse cohort of ~35,000 (age 30-104) adults with objective (polysomnography and actigraphy) and subjective sleep measures, and cognition assessed regularly spanning up to 60 years. We will also perform replication analysis using data from the UK Biobank, a study of 500,000 UK adults aged 40-84 years. By applying an innovative life course approach both in the synthesized and each individual cohort, we will address the following aims: 1) Identify age trends in objective and subjective sleep disturbances and cognition from early adulthood to the oldest old; 2) Evaluate the longitudinal association between sleep disturbances at different stages of life and cognitive performance over the life course including incident ADRD; 3) Elucidate and compare novel pathways linking sleep disturbances to ADRD at different stages of life. The research is highly significant because it helps to address the timing of sleep disturbances in relation to cognitive aging over the life course and thus the directionality of the relationship. The creation of the first-ever synthesized diverse cohort of sleep and cognition across the life course will also develop foundational resources for future research to disentangle the bi-directional link between sleep and ADRD. This work has a large impact as a critical step towards elucidating the role of life- course sleep disturbance as a prodromal or modifiable risk factor for ADRD. This will directly inform the early detection of ADRD and the design of intervention trials, especially in establishing the optimal timing for sleep intervention to mitigate dementia risk, a topic with profound public health implications.

NIH Research Projects · FY 2025 · 2024-05

ABSTRACT Bedaquiline is central to nearly all shorter, modernized all-oral regimens being evaluated and is revolutionizing rifampin-resistant tuberculosis treatment. Yet, despite extensive research activity in this space, a poor understanding of the genotype-phenotype correlation (i.e., the association between specific mutations (genotype) and the resulting spectrum of resistance) is the primary barrier to developing an accurate molecular diagnostic for bedaquiline. We propose accelerating discovery in this area using an unbiased, comprehensive mutational and screening strategy to determine the range and scope of all rv0678 mutations conferring bedaquiline resistance. We will construct a library of M. tuberculosis clones carrying single-nucleotide polymorphisms and specific indels, and we will screen this library in vitro and in a murine model. The success of our proposed work will provide a template to accelerate the discovery of resistance-conferring variants for all new and repurposed agents and help close the diagnostic gap, allowing for the development of tests to rapidly inform treatment decisions, regardless of resource setting.

NIH Research Projects · FY 2026 · 2024-05

Project Summary Candida albicans is a eukaryotic component of mammalian gut microbiota, where it exists in a commensal state, both benefitting from and acting upon the host environment without causing symptoms. C. albicans is also the most common cause of fungal infectious disease, which occurs upon overgrowth and escape to ectopic sites. Existing research on commensalism has largely ignored eukaryotes and is devoid of mechanistic detail. It is unknown how pathobiont commensals establish their niches, or what determines the transition from commensal growth to pathogenesis. As such, tools for the timely diagnosis and treatment of serious fungal infections are lacking. Our laboratory has taken unbiased genetic and hypothesis-directed approaches to identify fungal regulators of gut colonization. Using a library of >700 barcoded homozygous null mutants that we created, we identified 14 fungal transcription factors (TFs) that determine C. albicans fitness in a mouse model of gut colonization. We hypothesize that complex signals in local gut niches lead to TF activation, and activated TFs modulate the expression of the fungal effectors that directly foster commensalism. Recently, we implemented a C. albicans -Seq (CCS), which uses transposase-transcription factor fusion proteins to permanently mark genomic sites of transcription factor binding by transposon integration. Pairing CCS with transcriptomic analysis of mutants affecting three TFs (Efg1, Wor1, and Czf1), we captured the in-host activity of these regulators during active gut colonization. We then mined these datasets to predict and validate the first two commensal effector proteins to be described in this species, determining that the GPI-anchored cell wall chitinase Cht2 promotes commensal fitness, and that the secreted aspartyl protease Sap6 inhibits commensal fitness. - C. albicans commensal effectors; and (2) use host transcriptional responses to WT and mutant C. albicans lacking specific effector genes to capture the impact of fungal colonization on specific host cell types and to generate testable hypotheses for effector function.

NIH Research Projects · FY 2026 · 2024-05

ABSTRACT Dry eye disease (DED) is a major health problem. Reduced ocular surface hydration is a key pathology in DED, which causes symptoms and can lead to ocular surface inflammation and damage. Current FDA- approved treatments for DED include artificial tears and anti-inflammatory agents that have variable and limited efficacy. Here we propose a novel target for treatment of DED. The target is the extracellular Ca2+-sensing receptor (CaSR) that has well-known modulatory effects on epithelial ion transport in various tissues such as intestine and kidney. We found prominent CaSR expression in mouse and human corneal and conjunctival epithelial cells. CaSR activation in the ocular surface reduced CFTR-mediated Cl- secretion, confirming key roles of CaSR ocular surface ion transport. Importantly, we found that CaSR inhibition by NPS-2143 stimulates CFTR-mediated Cl- secretion in the ocular surface and increases tear fluid volume in mice by ~100%. Here we will perform key translational studies for CaSR inhibitors, by testing them in clinically relevant animal and human cell models of DED to advance them towards clinical testing (Aim 1). We will also study the roles and mechanisms of CaSR effect in ocular surface ion transport and health (Aim 2). The proposed studies can potentially lead to clinical testing of CaSR inhibitors for DED in the very near future. By identifying a novel treatment, these studies can ultimately reduce DED morbidity. Lastly, by identifying roles and mechanisms of CaSR in ocular surface, this project can also identify novel disease mechanisms for DED.

NIH Research Projects · FY 2025 · 2024-05

PROJECT SUMMARY Growing emphasis on the early diagnosis and treatment of Alzheimer’s disease and related dementias (ADRD) increases the demand for providers to make informed care decisions. Most of the care for people recently diagnosed with ADRD falls on primary care physicians (PCPs), as frontline providers for older adults. Many of the clinical decisions PCPs must make to care for patients with ADRD are not currently supported by robust evidence. Given the heterogeneity of ADRD, we cannot rely on randomized trials to provide evidence for clinical decisions across the range of conditions and unique patient/family considerations. Unclear guidelines on treatment strategies lead to large inconsistencies in how patients are treated, potentially causing harm and exacerbating health inequities. There is a large and growing need for evidence on best practices in early dementia care using accessible, timely data, and rigorous methods. This F31 career development proposal is designed to prepare the candidate for a career focused on this critical area, delivering much-needed evidence to guide common clinical decisions to provide the best possible care for individuals with early ADRD. The research plan evaluates three important clinical decisions commonly encountered by PCPs caring for patients experiencing cognitive decline. Aim 1 will evaluate whether referral to dementia specialty care delays onset of patient frailty using electronic health record (EHR) data from University of California, San Francisco (UCSF) primary care clinics. The candidate will use both traditional observational methods and an instrumental variable analysis with physician preference for referral as an instrument. Aim 2 investigates whether prescriptions of an antidementia drug (memantine) are associated with incident frailty using both traditional observational methods and an emulated target trial design analysis using UCSF EHR data. Finally, many conditions, including urinary tract infections (UTIs), are not specific to patients with ADRD but are more common among older adults with cognitive decline. In the context of emerging cognitive declines, inappropriate UTI management (especially if drug resistant) may be especially harmful. In Aim 3, we will examine whether early treatment of UTIs caused by drug-resistant E. coli is associated with reduced risk of incident ADRD and patient frailty using EHR data from UCSF and the San Francisco safety net public healthcare system. This proposal will demonstrate use of EHR data to evaluate the efficacy of current and future innovations in dementia care across diverse patients, with the goal of contributing to informed clinical guidelines for PCPs. This research will directly contribute to the NIA’s goal to provide evidence to delay ADRD progression. Guided by an interdisciplinary and expert mentorship team, the proposed training will enhance the candidate’s knowledge of clinical care for ADRD, advanced causal inference and econometric methods, and clinical informatics. Facilitated by the supportive training environment at UCSF, executing this F31 research and training plan will prepare the candidate to succeed in a career as an independent translational researcher in dementia epidemiology.