University Of California, San Francisco

NIH Research Projects · FY 2025 · 2024-09

The WISDOM Study, that includes 45,000 women in the US, is the first large-scale study of a risk-based approach to breast cancer screening. Its goal is to determine if risk-based screening is as safe, less morbid and preferred by women. The ‘WISDOM 1.0’ cohort, enrolling since 2016, began with a risk model that integrates clinical risk factors, race/ethnicity, breast density, polygenic risk score (PRS), and sequencing for moderate- and high-penetrance germline mutations. However, in the past 7 years there have been significant advances in breast cancer risk assessment, such that we have models that, for the first time, allow us to predict the type of cancer a woman is likely to develop. Breast cancer is not one disease and women have different risk factors. Thus, it is the hypothesis of this P01 that tailoring screening and prevention recommendations to an individual’s risk as well as the type of cancer for which she is at risk, can improve the efficacy and efficiency of breast cancer screening, improve the healthcare value of screening and ultimately reduce breast cancer mortality, incidence, and screening burden. The four Projects proposed represent a comprehensive research program to advance the science and evaluation of subtype-specific risk-based breast cancer screening and prevention. In Project 1, we extend enrollment of the WISDOM Study for 5 years, applying a subtype-specific risk assessment and screening that delineates risk for fast-growing and slow-growing cancers, and assigns commensurate screening and prevention recommendations. An additional 50,000 women will be enrolled via an expanded site network. While Project 1 evaluates our initial fast vs. slow-growing risk models, Projects 2 and 3 will work to improve subtype risk assessment in two ways, utilizing 5 large, diverse study cohorts with >200,000 women and >14,000 breast cancer cases, with available imaging and germline data. Project 2 aims to develop improved PRS for subtype-specific breast cancer risk, building on our preliminary predictor of fast-growing cancer. Project 3 will apply deep-learning artificial intelligence models for subtype-specific risk based on 2D and 3D mammographic imaging, and integrate with PRS from Project 2. Project 4 will take the best integrated subtype- specific risk models and associated screening strategies from Project 3 and determine their impact on the efficiency and efficacy of screening and prevention of slow growing cancers. We will work in collaboration with the well-established MISCAN/CISNET modeling team to determine the potential impact for individuals as well as the population of women in the US. The goal is to find the optimal risk classification schema, based on reduction in cancer death as well as screening’s potential harms and improvement in overall healthcare value. Our long-term goal is to iteratively reduce breast cancer mortality, while demonstrating that the WISDOM study can ultimately serve as a continuous quality improvement platform for breast cancer screening and prevention. Four cores support this extraordinary effort to bring smarter screening to women in the US.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY/ABSTRACT Insulin resistance is a driver of type 2 diabetes (T2D). Despite viral suppression, people living with HIV (PLWH) have concerningly high rates of both insulin resistance and T2D. In determining what underlies this, we have focused on the fact that whereas obesity is a common trait in humans, T2D risk is increased by “metabolically unhealthy obesity” (MUO). Emerging observations highlight two factors promoting MUO in the general population: 1) reduced mitochondrial content and fewer mitochondria-enriched “brown/beige” adipocytes in the subcutaneous fat (SCAT) and 2) development of SCAT fibrosis. Interestingly, limiting brown/beige fat biogenesis in mice promotes SCAT fibrosis and insulin resistance, whereas increasing it remarkably blocks fibrosis and improves insulin sensitivity. With this in mind, we and others have observed that PLWH have dramatically increased SCAT fibrosis, prompting us to wonder whether PLWH also have suppressed brown/beige fact activity, and what factors dictate this. To this end, we recently identified a subset of adipogenic precursor cells (APCs) expressing signature markers (Lin–: PDGFRa+: CD81+) that control a reciprocal balance between beige fat biogenesis and SCAT fibrosis. Specifically, CD81+ APCs give rise to mitochondria-rich brown/beige adipocytes, whereas CD81 deficiency leads to both SCAT fibrosis and insulin resistance. These data highlight the intriguing possibility that CD81+ APCs in the SCAT may influence the development of MUO in PLWH. Beige/brown fat is also a metabolic sink for branched-chain amino acids (BCAAs), the circulating levels of which are linked to human insulin resistance. Activating brown/beige fat biogenesis either pharmacologically or by cold exposure clears circulating BCAAs in humans; indeed, BCAA clearance is a noninvasive indicator of brown/beige fat activity. However, BCAA catabolism has not been assessed in PLWH. We hypothesize that a reduced capacity of CD81+ APCs to maintain normal SCAT beige/brown function, reflected by both SCAT fibrosis and impaired BCAA clearance, drives insulin resistance in PLWH, and that reversing this may improve metabolic health. Leveraging an innovative cohort of PLWH and uninfected controls, including those with MUO, we propose to test this hypothesis by A) examining the extent to which loss of CD81+ APC abundance, proliferative capacity, or differentiation potential predicts SCAT fibrosis and insulin resistance in PLWH (Aim 1); and B) evaluataing BCAA catabolism, alongside cutting-ege PET-CT quantification of brown/beige fat activity, as a determinant of glucose homeostasis in PLWH (Aim 2). These studies will be coupled to aligned mechanistic studies in the HIV viral accessory protein (Vpr) transgenic mouse model, which is interestingly prone to both insulin resistance and impaired brown/beige fat thermogenic function. By validating a mechanistic index of SCAT health (CD81+ APCs, fibrosis, BCAA clearance) that predicts MUO, we may reveal ways to prolong the metabolic healthspan of PLWH.

NIH Research Projects · FY 2026 · 2024-09

PROJECT SUMMARY Cells are the building blocks that comprise and pattern multicellular organisms from plants to humans, and many types of cells themselves exhibit complex shapes and patterns. While we understand many of the molecular components of cells, we know much less about how they are assembled to create patterns at the cellular scale. RNA regionalization, or spatially distinct localization of transcripts, is known to contribute to cellular morphology and function in various cells such as neurons. Several diseases that arise in the brain, from depression to Alzheimer’s, may also partly be explained by mislocalized RNA. To understand how cells are patterned via RNA regionalization, we must also understand how the genome is spatially organized as nuclear architecture and chromatin structure both influence gene expression. My proposal leverages the strengths of a unicellular system, Stentor coeruleus, that possesses a complex cellular architecture including a mouth and tail, and is capable of regeneration when damaged. Stentor cells also harbor a transcriptionally active macronucleus that spans the 1 mm long axis of the cell with a unique beads-on-a-string configuration and contains more than 50,000 copies of the genome. These properties enable microsurgery to physically separate regions of the cell and its nucleus along a defined axis for sub-cellular and sub-nuclear analyses of RNA and genome regionalization by sequencing, which is not possible in traditional model systems. First, I will examine two independent models for cellular patterning by RNA regionalization. With RNAi and RNA- sequencing in bisected cells, I will determine whether RNA transport promotes cellular asymmetry by defining the cytoskeletal elements and associated motors required for RNA regionalization. With RNA-sequencing in individual ‘nodes’ of the macronucleus, I will also determine if gene expression is regionalized, thereby reducing the distance RNA must travel before it reaches its destination. Then, with chromatin profiling and whole-genome sequencing, I will determine whether the genome is regionalized by spatial chromatin regulation or differential localization of genes themselves and establish whether these are associated with RNA regionalization and ultimately cellular patterning. To conduct this work, I will receive training in cell biology and imaging, chromatin biology and genomics, as well as in tool development in emerging model organisms. This innovative work will serve as the foundation for my independent research program, which aims to advance our understanding of the consequences of disrupted cellular patterning in development and disease.

NIH Research Projects · FY 2025 · 2024-09

Summary Sphingosine-1-phosphate lyase insufficiency syndrome (SPLIS) is an ultra-rare, devastating, often lethal inborn error of metabolism recognized just five years ago. Most affected children exhibit a rapidly progressive form of nephrotic (protein spilling) syndrome which leads to kidney failure, the main cause of death. Affected children may also exhibit adrenal insufficiency, hypothyroidism, skin and neurological defects, and immunodeficiency. Although kidney transplantation may be lifesaving, there is no cure for SPLIS. SPLIS is caused by recessive mutations in SGPL1, which encodes sphingosine-1-phosphate (S1P) lyase, a vitamin B6-dependent enzyme responsible for catabolism of the bioactive lipid S1P in the final step of sphingolipid metabolism. SPLIS is a member of a new family of non-lysosomal sphingolipid disorders about which relatively little is known. Despite the dismal outcome in SPLIS, targeted therapies are rapidly being developed. Some children with milder forms of the condition may respond to supplementation with vitamin B6, the enzyme’s cofactor. Studies in a mouse model of SPLIS have provided proof-of-concept for the use of adeno-associated virus-mediated SGPL1 gene therapy as a universal and potentially curative treatment for SPLIS. Clinical trials testing these two therapeutic strategies are on the horizon. Although we have made rapid progress in methods of SPLIS patient finding, biomarker development, and therapeutics, achieving two additional goals will enhance our readiness to undertake SPLIS clinical trials: a) providing a comprehensive understanding of the natural history of SPLIS including the full spectrum of clinical presentations, disease subgroups, and natural progression; b) developing a method to identify SPLIS patients before irreversible kidney damage has occurred. We are now in a pivotal position to achieve both these strategic goals. We hypothesize that specific disease features and biomarkers will predict quality of life and survival in SPLIS patients. To confirm our hypothesis and achieve our goals, we propose three Aims: 1) Characterize the spectrum of SPLIS clinical presentations and their natural progression over time; 2) Determine how biomarker endpoints reflect or predict functional change over time in SPLIS patients; 3) Establish a screening strategy for early detection of SPLIS based on blood S1P levels. In achieving these Aims, we will develop a deeper understanding of the spectrum, sequence, and timing of onset of SPLIS manifestations, and will identify predictors of disease outcomes that are meaningful to patients and families and that will be critical for patient selection for clinical trial enrollment. Our project will create useful tools for measuring outcomes in SPLIS, providing quantifiable endpoints to be used in clinical trials. Overall, revealing the natural history of SPLIS will lay the foundation for evaluating the impact of targeted interventions in clinical trials. Developing early detection methods will open a therapeutic window in which treatments to prevent death and the need for kidney transplantation can be administered. Creation of biospecimen collections and stem cell lines will facilitate deeper investigation into the pathophysiology of SPLIS and its related sphingolipid disorders.

NIH Research Projects · FY 2024 · 2024-09

PROJECT SUMMARY Mass treatment of preschool children with azithromycin (AZ) and routine administration of seasonal malaria chemoprevention (SMC), have been effective in reducing infections and mortality among children.5,22 However, it is not clear how concomitant use of sulfadoxine in SMC and AZ affects child morbidity and mortality. As mass distribution of AZ in sub-Saharan Africa is being scaled-up, research is needed to determine whether routine SMC administration enhances the effect of AZ and whether administering AZ in SMC or no SMC seasons is more beneficial for reducing child morbidity and mortality. Additionally, previous studies show healthcare access and utilization lower with increasing distance from facilities and with increasing community poverty, suggesting that mass treatment with antibiotics maybe more beneficial for communities with potentially less access to healthcare and less treatment/antibiotic exposure.13 Further research is needed to examine whether the effect of AZ varies by distance to healthcare facilities and community wealth and whether distant and poorer communities with less access to treatment would benefit more from AZ. The goal of the proposed research is to examine factors that may modify the effectiveness of AZ in reducing child morbidity and mortality. The study will examine whether the administration of SMC modifies the effect of AZ on child mortality and morbidity (Aim 1A and 1B) and assess whether distance from health facility (Aim 2A) and community wealth (Aim 2B) modify the effects of AZ on infectious morbidity and mortality among children. Analyses will use data collected from a cluster randomized trial (CRCT) of treatment with AZ vs placebo, along with primary healthcare surveillance, pre-census data and Burkina Faso’s National Malaria Control Program (NMCP) data. The proposal will provide valuable and timely insight on heterogeneity of the effect of AZ to help guide how, where and when to implement MDA AZ programs, which is a current research gap.17, 36 By providing insights on how to maximize the benefit of interventions that improve child health, knowledge gained from this research will advance the NICHD’s mission of increasing children’s survival and potential to live healthy and productive lives free from disease. The proposed training, guided by an exemplary mentorship team, will enhance the applicant’s expertise in infectious disease and social epidemiology, methods, and analyses of CRCT and surveillance data, and statistical methods for studying heterogeneity and interactions between interventions as well as principal component analysis. The methodological skills, research competency, and content expertise Elisabeth will gain will prepare her for a career as a future independent academic researcher focused on strategies to reduce infectious diseases and mortality among children.

NIH Research Projects · FY 2025 · 2024-09

ABSTRACT Tobacco use causes one third of cancer-related mortality. Decades of tobacco control progress are threatened by the promotion and popularity of e-cigarettes (colloquially called “vaping”) by adolescents. Almost a decade ago, e-cigarettes became the most common tobacco product used by adolescents. In 2022, 2.55 million U.S. middle and high school students currently used e-cigarettes. Recently new “pod vape” devices have increased in popularity; they are highly discreet and deliver high levels of nicotine increasing addictive potential. Adolescent vaping is associated cigarette smoking initiation, and e-cigarette use increases risk of asthma, adverse cardiovascular effects, and is likely to increase risk of lung cancer. To address this problem, flexible, scalable evidence-based interventions are needed to help adolescents quit. However, there are few adolescent interventions for e-cigarette use with rigorous evaluation data. To the best of our knowledge, no vaping cessation programs are delivered on social media. In 2022, 62% of adolescents used Instagram, and 50% of adolescents used it at least once a day. We developed the program, “Quit the Hit” that takes place in direct message groups on Instagram to support cessation among mid to late-stage adolescents aged 13-21. The program was co-created with hundreds of adolescents and has been evaluated in a randomized controlled trial. Preliminary data show significantly higher end of program abstinence rate in the intervention arm than in the control (52% vs. 35%). Quit the Hit is promoted using social media advertising and it is administered by expert facilitators. To expand the reach and assess the effectiveness of the Quit the Hit, we propose to develop and evaluate a scalable version, the Quit the Hit Toolkit (QTHT) that can be implemented by school districts, community organizations, and other groups. We propose three Aims. Aim 1. Adapt the Quit the Hit Toolkit (QTHT) for implementation by youth serving organizations, assessing organizational needs and capacities to implement the program, training materials and supports for providers, and resources and guides for promotion and adoption. Aim 2. Evaluate the effectiveness of the QTHT implemented with community partner organizations in a parallel-arm randomized controlled trial. Aim 3. Document and Assess the implementation of the QTHT including treatment fidelity and adaptations, organizational capacity, facilitators/barriers to implementation, and types of technical assistance needed to sustain the intervention. We will evaluate the implementation using the RE-AIM framework. We will use a Type 1 Hybrid Effectiveness/Implementation Design that speeds translation from research to practice by enabling us to test the intervention’s effectiveness while also gathering information on its potential for large scale implementation in diverse settings. We have established partnerships with state health departments, the California State Board of Education, and the Stanford Tobacco Prevention Toolkit which has reached over 2.7 million youth for future dissemination.

NIH Research Projects · FY 2025 · 2024-09

Summary Idiopathic pulmonary fibrosis (IPF) is a severe age-related lung disease that affects millions of people worldwide. It causes progressive lung dysfunction leading to death, usually within a few years of diagnosis. Two targeted drugs are available to treat IPF, but they merely slow lung function decline. The only cure for IPF is lung transplantation. Thus, new treatments with potential to cure IPF are direly needed. A growing body of evidence implicates the bioactive sphingolipid sphingosine-1-phosphate (S1P) in the pathophysiology of IPF. S1P promotes inflammation and fibrosis by activating a family of G protein-coupled receptors (S1PRs), thus stimulating signaling pathways that interact with TGFa multifunctional cytokine with a central role in fibrosis. Drugs targeting S1PRs are already on the market or in clinical trials for treating autoimmune diseases. Although targeting S1P appears to have a promising future in treatment of fibrotic diseases, chronic S1PR antagonism and the immunosuppression it causes increase the risk of cancer and neurodegenerative disease, especially in older patients. Thus, alternative S1P-targeting approaches may be needed in the context of IPF. S1P lyase (SPL), encoded by SGPL1, catalyzes the final step of sphingolipid metabolism in which S1P is irreversibly degraded. We find that endogenous lung SPL plays a protective role in pulmonary fibrosis. Further, we demonstrate that augmenting SPL activity by intravenous delivery of an adeno-associated virus 9 expressing human SGPL1 (AAV-SPL) to mice 10-14 days after bleomycin treatment attenuates lung TGF signaling and pulmonary fibrosis. Our findings have led us to hypothesize that AAV-SPL represents a novel single-dose IPF treatment that acts by reducing lung S1P and downstream profibrogenic signaling. It does so without causing immunosuppression, thus providing an S1P targeting approach superior to S1PR antagonists. In this proposal, we will confirm our hypothesis and advance AAV-SPL as a therapeutic agent for IPF. In the R61 phase of this award, we will rigorously validate the efficacy of AAV-SPL in IPF and confirm the cellular target for AAV-SPL. In Aim One, we will measure the impact of AAV-SPL on lung fibrosis: a) in a mouse IPF model in which the Trf1 gene encoding a telomere-specific protein is disrupted specifically in lung alveolar type II cells, and b) in cytokine-stimulated and IPF precision cut lung slices. In Aim Two, we will create a lung epithelial cell-specific Sgpl1 knockout mouse and demonstrate that it develops pulmonary fibrosis. In the project’s R33 phase, we will begin to characterize AAV-SPL’s pharmacological characteristics. In Aim Three, we will optimize AAV-SPL performance by comparing potency, bioavailability, and early safety profile after intravenous versus intratracheal delivery in murine models of IPF. The R33 phase will culminate in completion of Aim Four, in which we will plan next steps in development of AAV-SPL by submitting an INTERACT meeting request to the Food and Drug Administration. By completing this project and with guidance from our accelerator partner, we will be positioned to establish AAV-SPL as a first-in-class gene therapy for IPF.

NIH Research Projects · FY 2025 · 2024-09

Project Summary/Abstract Craniofacial morphogenesis involves a multitude of cell behaviors, including mesenchymal cell movements that change the physical properties of tissues, culminating in changes in tissue shape. During secondary palate morphogenesis the palatal shelves undergo a dramatic transformation in tissue shape that includes outgrowth, extension, elevation, adhesion, and fusion to form a continuous structure. Cleft palate, occurring in 1:1500 live births, can result from the failure of any step in this process, however, our understanding of the mesenchymal cell behaviors that regulate tissue shape changes during secondary palate development is limited. My lab’s previous research Indicates that Efnb1 is a key regulator of mesenchymal cell position and embryonic boundary formation in multiple contexts, but how these changes cause a cleft palate phenotype is not clear. Our preliminary data indicate that loss of function of the Shrm4 gene genetically interacts with Efnb1 loss, resulting in more severe craniofacial dysmorphology and a dramatically increased incidence of cleft palate. This proposal aims to establish the interplay between Efnb1 and Shrm4, and their impacts on the dynamic cell behaviors involved in secondary palate tissue shape change. My proposal takes advantage of mouse genetics expertise in my sponsor lab and three-dimensional imaging and quantitative analysis approaches that I have developed to understand mesenchymal cell behaviors, as they relate to secondary palate shape change normally and upon loss of Efnb1. I will test the hypothesis that EPHRIN-B1 and SHROOM4 regulate the actomyosin cytoskeleton to control palatal shelf shape change. Through these studies, I aim to improve understanding of the regulation of palatal outgrowth, mesenchymal organization, and tissue shape during normal and cleft palate morphogenesis. This is highly relevant to the etiology of CFNS, which is caused by mutations in the EFNB1 gene, and which includes cleft palate in its spectrum.

NIH Research Projects · FY 2025 · 2024-09

Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. Alcohol is the most commonly consumed drug in the world. Atrial fibrillation (AF) is the most common arrhythmia. In the original R01, we conducted a randomized trial of intravenous alcohol versus placebo to demonstrate an acute change in atrial electrophysiology expected to render the atria more prone to fibrillate and demonstrated a near-term risk of AF associated with alcohol consumption in an observational, case-crossover, study of ambulatory patients. Those findings coupled with a recent randomized trial showing that abstinence reduces AF burden along with an NIH priority to study utilization of digital health to promote alcohol abstinence in these patients motivate our revised Aim 1. In Aim 1, we will employ human-centered design in collaboration with AF patients and experts in behavioral change, alcohol use, technology, and implementation research to construct a smartphone-based mobile application purpose-built to promote alcohol abstinence specifically in AF patients. We will leverage our Eureka Digital Research Platform, our previous research findings, and recent integrations with commercially available smart watch-detected AF episodes to craft a starting framework for this Digital Intervention, including 1. Messaging; 2. An individualized visualization of alcohol-AF relationships; and 3. Real-time abstinence encouragement triggered by geofencing of establishments that sell alcohol. The Digital Intervention will be compared to a control condition in a randomized trial, with outcomes of AF burden and durable abstinence measured by self-report and objective assessments. In Aim 2 of this revised submission, we also seek to fill an important gap remaining in the study of alcohol and AF: definitive, randomized controlled trial evidence that alcohol consumption immediately heightens the risk of a discrete AF episode. New preliminary data ramifies the continued import of such information to AF patients, evidence of such a causal relationship would bolster the utility of the proposed Digital Intervention in Aim 1, and simultaneous assessments of physiology will provide mechanistic information also of priority per a recent NIH statement. In Aim 2, ambulatory paroxysmal AF patients will be fit with a continuously recording ECG, a transdermal alcohol sensor, and a Fitbit and will then receive randomization instructions daily to abstain or not abstain from alcohol. We are powered to detect clinically meaningful associations among AF patients drinking within guideline-acceptable limits, making this especially pertinent to the great majority of individuals who consume alcohol. Aim 2 participants will receive an individualized visualization of AF episodes versus their randomization assignments, and, with subsequent encouragement to avoid alcohol, will then be evaluated for durable abstinence using the same methods as those employed in Aim 1. This research offers a rigorously developed and evaluated digital tool to promote abstinence that is imminently scalable while elucidating a critical gap pertinent to immediate causal relationships between alcohol consumed within guideline-acceptable limits and discrete episodes of AF.

NIH Research Projects · FY 2026 · 2024-09

PROJECT SUMMARY/ABSTRACT One in 10 births results in preterm delivery, and preterm birth is a significant source of childhood morbidity, mortality, and healthcare utilization.1 Black families are at highest risk for preterm birth and adverse child health due to structural racism.2-4 Addressing social drivers/determinants of health (SDH) as sequela of structural racism as well as predictors of poor health outcomes can improve pediatric health outcomes.5-7 Several professional organizations recommend addressing social needs in pediatric settings to reduce racial inequities in health outcomes.8-11 However, there is a lack of evidence to inform strategies to effectively address SDH to promote the long-term health of Black preterm infants. Dr. Karvonen's long-term goal is to become an independent researcher who develops, implements, and disseminates SDH interventions that improve the long-term health of Black preterm infants. Centering this population, her overall objectives are to identify the relationships between neighborhood-level SDH, prematurity, and long-term health; identify family-prioritized SDH and related interventions; and evaluate the feasibility and acceptability of a novel intervention that addresses SDH. The central hypothesis of her work is that addressing SDH at birth will improve the positive health and neurodevelopment of Black preterm infants. The rationale is that understanding the critical components of SDH interventions to impact long-term health is crucial for developing an effective, scaled, and evidence-based SDH intervention for this population. To pursue her objectives, Dr. Karvonen will pursue these specific aims: (1) To determine associations between neighborhood-level SDH and long-term health among Black children using extant data from a large, national, longitudinal cohort; (2) To identify family-prioritized SDH and preferred approaches to interventions that address SDH using semi-structured interviews; and (3) To determine the feasibility and acceptability of a novel SDH intervention designed for the general pediatric population among Black preterm infant-caregiver dyads. The proposed work is innovative in its use of (1) a novel outcome, child positive health, in addition to more traditional health outcomes (2) centering the priorities of Black families with preterm infants, and (3) a novel intervention that addresses SDH. It is significant as findings will inform a future intervention specifically designed to address SDH to improve the long-term health of Black children born preterm, a NIMHD priority population. This work exemplifies the NIMHD priorities to "enhance the scientific knowledge base and design interventions to improve health outcomes to reduce and ultimately lead to the elimination of health disparities". To successfully pursue her proposed specific aims, Dr. Karvonen will receive training in advanced statistical methodology, qualitative research, and implementation science through didactic courses and experiential studies at the University of California, San Francisco. She will also be guided by a multidisciplinary mentorship team of leaders with strong expertise across her training goals.

NIH Research Projects · FY 2025 · 2024-09

Project Summary/Abstract The Primary Immune Deficiency Treatment Consortium (PIDTC) was founded in 2009 to bring together immunologists, bone marrow transplant (BMT) physicians, and cell/gene therapists to improve treatments and outcomes for patients with inborn errors of immunity (IEI). The PIDTC has aggregated data from 49 sites across the US and Canada to address key questions related to the treatment and outcomes of the most severe, life- threatening IEIs including Severe Combined Immune Deficiency (SCID), Chronic Granulomatous Disease (CGD), Wiskott- Aldrich Syndrome (WAS), and Primary Immune Regulatory Disorders (PIRD). The PIDTC database, along with the associated tools that have been built to facilitate acquisition of detailed longitudinal data across a diverse network of clinical sites, and the aggregate experience of the involved clinical and scientific experts, has become an indispensable resource for research, treatment planning, and clinical care advancement within the IEI community. We propose that the data, materials, and expertise of PIDTC now be organized and made available as a resource to the entire IEI community with key enhancements that will empower the community to easily access and use the PIDTC Resource, and simultaneously ensure the continued growth and sustainment of the PIDTC Resource. We will expand the PIDTC Resource to increase its utility and improve the power to answer further questions related to the treatment of IEI's including particular genotypes or clinical subtypes of disease. We will consolidate and build tools and infrastructure to accelerate standardized data collection from ongoing and future studies and trials that are contributing data to the PIDTC Resource. We will provide tools to make the PIDTC data more readily accessible to the broader IEI community including researchers, clinical care providers, patient advocacy groups, patients, foundations, and consortia. This expansion and transformation of the PIDTC into an open resource will enable diverse users to take advantage of unparalleled IEI datasets to increase understanding and develop better health outcomes for patients as well as conduct new studies with the support of the PIDTC Resource database, expertise and infrastructure. Together, we will further propel the PIDTC's mission to study therapeutic outcomes in IEI and improve the outcomes of patients with IEI.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY / ABSTRACT – OVERALL Prostate cancer is the second leading cause of cancer deaths of men in the United States and places a significant health burden on society. The overarching goal of the UCSF Prostate Cancer SPORE is to address this burden by reducing the morbidity and mortality associated with prostate cancer, through leveraging a deep understanding of the disease to translate biological findings into clinical impact. The SPORE team will approach this mission with transdisciplinary research that is highly collaborative and translational, through four specific aims: A) Investigate molecular drivers of aggressive prostate cancer; B) Develop biomarkers to guide treatment of patients with advanced prostate cancer; C) Target therapeutic resistance in metastatic castration resistant prostate cancer (mCRPC), which is the lethal manifestation of advanced disease; and D) Accelerate translational research across the spectrum of prostate cancer. To address these aims, the UCSF Prostate SPORE proposes three scientific projects, each investigating aggressive prostate cancer from a mechanistic, biomarker, and therapeutic perspective: Project 1: Combination immunotherapy with radioligand therapy for metastatic prostate cancer Project 2: Investigating Clinical and Biological Implications of a Novel Hypermethylated Subtype of mCRPC Project 3: Deciphering the Role of the Translational Oncogenic Program in Prostate Cancer These proposed studies will be aided by horizontal collaborations with other Prostate SPORES, NCI initiatives, and molecular diagnostics companies, as well as vertical collaborations with the National Clinical Trials Network (NCTN), DOD Prostate Cancer Clinical Trials Consortium (PCCTC), and pharmaceutical companies, among other organizations. Additionally, these projects will be complemented by strong, ongoing institutional commitments of money and space, well-resourced Career Enhancement and Developmental Research Programs, and three cores: Administration, Biostatistics/Bioinformatics, and Pathology/Tissue. The infrastructure outlined under this SPORE application is designed to encourage and promote translation of innovative, impactful ideas by supporting promising new projects, providing access to critical resources for bench-to-bedside transitions, sponsoring interdisciplinary collaborations, and providing an effective framework for mentoring/nurturing the next generation of translational scientists. By bringing together a diverse and multi- disciplinary group of investigators, this Prostate Cancer SPORE will accelerate highly impactful translational research with the potential to significantly improve clinical outcomes for men with aggressive prostate cancer.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY/ABSTRACT The World Health Organization estimates that 80% of blindness worldwide is avoidable. However, in resource-limited settings progressive eye diseases such as glaucoma, diabetic retinopathy (DR), and age-related macular degeneration (AMD) often go undiagnosed until it is too late. New approaches that detect progressive eye diseases before they cause irreversible vision loss could help reduce visual impairment of communities. One such approach is community-based eye disease screening. The Village Integrated Eye Workers Trial II (VIEW II) is an ongoing cluster-randomized trial in which communities in Nepal receive visual acuity screening and are subsequently randomized to receive either a community-based eye disease screening intervention consisting of optical coherence tomography (OCT) and intraocular pressure (IOP) assessment, or to no intervention. The goal of the screening intervention is to detect cases of glaucoma, diabetic retinopathy, and age-related macular degeneration—all of which are progressive and cause irreversible vision loss if left untreated—and refer these cases to the local eye hospital for management. A door-to-door census is performed four years after starting the screening intervention to determine the effectiveness of screening for reducing vision impairment relative to communities not receiving the screening intervention. This is a proposal for the extension of the VIEW II trial, maintaining the original randomization and continuing the same screening intervention in the study clusters except that fundus photography is also included in the screening intervention and that the targeted age group is expanded to those ≥50 years. The specific aims of the proposal are (1) to determine if the screening intervention is effective for preventing vision loss at the community level over 7 years, (2) to compare text messages versus community volunteers for improving linkage to care, and (3) to determine the natural history of OCT measurements over time in a population-based study. Glaucoma, DR, and AMD are slowly progressive diseases, and given interruptions to study activities caused by the COVID-19 pandemic, the originally planned 4-year endpoint in the original VIEW II trial may not be long enough to observe the full effect of the screening intervention. Extending the trial will provide a more accurate assessment of any benefit of screening. Extending the trial also allows for repeated OCTs in a population-based sample, providing much needed data on the natural history of OCT parameters to help clinicians better determine what constitutes progression. This research is significant because it will provide the strongest type of evidence to guide national eye health programs – results from a randomized controlled trial. Ultimately, this trial will benefit blindness prevention programs worldwide in deciding how to allocate limited resources to optimally detect eye disease.

NIH Research Projects · FY 2025 · 2024-09

Project Summary/Abstract Peripheral artery disease (PAD) is a public health crisis, affecting 20 million Americans and 200 million people worldwide, and continues to grow due to aging and the epidemic rise of diabetes and renal metabolic disorders. Vascular calcification (VC) is accelerated in these conditions, particularly in a distal pattern of medial artery calcification (MAC) in the lower leg and foot. In chronic limb-threatening ischemia (CLTI) — the most advanced form of PAD — we have shown that MAC poses a significant challenge to lower extremity revascularization and is a major risk factor for limb amputation. However, there remains no effective treatment for VC, and both the pathologic characteristics and mechanistic drivers of MAC in PAD are poorly understood. Emerging data suggest that Klotho — a regulator of insulin signaling and phosphate homeostasis — is lost in diabetes and renal disease, which may play an important role in osteogenic pathways promoting MAC. We hypothesize that Klotho is a central regulator in the pathogenesis of MAC, and its loss under conditions of hyperglycemia, hyperphosphatemia and low shear stress promotes VSMC osteogenic transdifferentiation and VC. This hypothesis will be rigorously investigated via two innovative and complementary central aims: Aim 1 takes a clinically-oriented approach to define molecular and cellular calcific changes occurring in the serum and vasculature of patients with CLTI. Pedal artery tissue and serum samples from patients with CLTI will be analyzed, focusing on the relationship between Klotho arterial tissue expression, serum Klotho levels, clinical pedal artery calcium burden (pMAC score), and VSMC phenotype. Aim 2 approaches the hypothesis from a basic science angle, using 3D human engineered vessels in culture to characterize de novo molecular alterations occurring in response to conditions of hyperglycemia, hyperphosphatemia and low shear stress. I will carry out this work with the close support of my mentors Dr. Michael Conte, an accomplished vascular surgeon-scientist and global leader in the field of PAD, as well as Dr. Matthew Kutys, who is an expert in state- of-the-art microfluidics and 3D vascular modeling. Both the Conte and Kutys labs are embedded within the rich UCSF research environment and provide access to the resources needed to execute my project. This investigation builds upon my career goal to become a vascular surgeon-scientist focused on the field of vascular calcification — a highly impactful area that remains a critical barrier to improving clinical outcomes in PAD. My prior research has laid important groundwork in this area, quantifying the problem of pedal artery calcification and establishing its impact on outcomes in CLTI. The proposed work provides an innovative opportunity to develop my unique investigator profile by delving translationally into the mechanisms governing MAC, leveraging the expertise of my mentors and my background in MAC clinical research and 3D tissue culture. The overarching objective of this fellowship will be to grow my technical skill set and topic expertise, while providing important advancements to identify potential targets for therapy.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY Nature has evolved dynamic proteins that act as sensors, detecting changes in the environment and producing signals that allow the cell to adapt and respond accordingly. For this function, signaling proteins must adopt multiple conformations, affording switch-like behavior between “on” and “off” states. The specific mechanisms by which states are switched or maintained often remain elusive due to a lack of biochemical and structural information. Herein, I propose that protein design and engineering offer a unique approach to deconvolute these complex biomolecular processes. Specifically, I aim to use protein design to generate minimal, tunable versions of modular signaling subdomains and engineer them into wild-type signaling protein scaffolds. This allows for direct assessment of thermodynamic or conformational signaling mechanisms by allowing us to measure the effect of design changes on signaling outputs. For this proposal, bacterial histidine kinases offer a promising test system due to 1) their highly modular scaffold that is amenable to chimera engineering and 2) the coiled-coil core through which signal transduction is propagated, as coiled-coils are highly designable. In my preliminary efforts, I have demonstrated for the first time that a histidine kinase can be re-wired with a de novo designed sensor domain, allowing signal transduction to be initiated from a de novo part. The proposed research expands upon this by applying protein sequence design to vary sensor domain stability, enabling insight into how sensor stability (and thus, the thermodynamic gap between sensor domain “off” and “on” states) affects signaling output (Aim 1). Moving down the histidine kinase scaffold, I then propose to use hyperstable de novo designed helical bundles to drive the geometry (conformation) of the catalytic domain (Aim 2). By systematically varying the geometry of the de novo bundle, I can force the kinase domain to adopt a related geometry. Then, by measuring kinase activity of the de novo/kinase chimeras, I aim to identify geometric parameters at which the kinase domain switches activity states. Finally, I propose to apply multi-state design to generate de novo linker domains that can adopt multiple conformations (Aim 3). Engineering of de novo/natural chimeras and experimental characterization of multi-state designed candidates will shed light on the sequence diversity that enables accommodation of multiple conformations. Together, these efforts will provide significant mechanistic insight into how histidine kinases undergo signal transduction while pushing the boundaries of function-guided protein design.

NIH Research Projects · FY 2024 · 2024-09

Project summary and abstract Approximately 80% of patients with ovarian cancer and 30% of patients with uterine cancer are diagnosed with advanced disease. In the absence of effective screening, many patients present with severe functional decline from symptomatic burden from chronic malnutrition due to obstructed bowels, hypoalbuminemia with ascites, and muscle wasting due to fatigue and physical inactivity. The average age of diagnosis is 62 years old, however patients present with accelerated physiologic aging because of these catabolic diseases. Furthermore, as the population continues to age the number of older adults with these gynecologic cancers will significantly grow. Options for symptomatic relief and potential prolonged survival require intensive treatment including months of poorly tolerated chemotherapy and morbid abdominal surgery. The choice of treatment and timing is predominantly age-based and dependent upon subjective assessments by surgeons, and the balance of over- and under-treatment of prolonging survival against the harms of aggressive surgery and chemotherapy may be better achieved through objective frailty assessments. Furthermore, older adults report that quality of life and functional independence are as important as traditional oncologic measures, yet few researchers have examined these essential patient-centered outcomes. The purpose of this study is to 1) objectively assess physical frailty in this patient population and quantify the associations with perioperative (90-day healthy days at home after surgery) and oncologic adverse events (relative dose intensity of chemotherapy) and 2) characterize and identify predictors of functional recovery and quality of life at 3 and 6 months after presentation. To accomplish these aims, we will utilize an existing research infrastructure of a prospective multi-center cohort (“Promoting gynecologic cancer patients with frailty to achieve functional recovery cohort” aka “PROOF cohort” NCT06089083). We will perform repeated functional and quality of life assessments in patients 50 years and older after presentation of advanced ovarian or uterine cancer on 100 patients. This is an innovative prospective study with longitudinal physical frailty and quality of life measures, including functional recovery, that are not currently available in existing datasets. This proposed project focuses on an understudied group who are particularly vunlerable as the majority of these women are older adults with significant symptom burden. The overall goal is to create a rapid, novel physical frailty tool specific to this paient population that will improve the ability of our field to assess the risks of over- vs under-treatment and make objective treatment decisions in the use of surgery and chemotherapy that align with outcomes important to older adults. The GEMSSTAR award is crucial to continuing the important work we have laid the foundation for and will support the PI in becoming a leader bringing the field of aging research to gynecologic oncology to improve patient centered outcomes in older adults.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY Mammalian genomes are organized into loops and topologically associated domains by the cohesin protein complex. The formation of these structures has suggested models for how DNA regulatory elements, such as enhancers and promoters, are spatially arranged to coordinate gene expression. However, testing these models and their implications in cellular function and fate has been challenging due to the lack of systems for interrogating the activity of cohesin in vivo. Using mouse olfactory sensory neurons and serotonergic neurons from the raphe nuclei, post-mitotic cells in which the role of cohesin in genome function can be uncoupled from its role in sister chromatin cohesion, we recently uncovered that cohesin and its unloader WAPL play a critical role in the development of the central nervous system by regulating the expression of clustered Protocadherin (Pcdh) genes. In this proposal, we aim to leverage the Pcdh gene cluster as a new paradigm to study the molecular underpinnings of cohesin activity and its dynamics in governing the generation of neuronal cell surface diversity during brain development. Specifically, we propose to understand the role of auxiliary proteins to the cohesin complex in regulating cohesin dynamics and Pcdh gene expression in vivo. Finally, we aim to link the molecular operations of cohesin and its protein regulators to neural wiring and neural circuit assembly. The findings from our proposed studies are poised to generate new hypotheses for how genome architecture is coupled to gene expression in mammalian cells. They will provide an unprecedented view of neural wiring across scales, linking cell-type-specific regulation of genome structure to neural wiring during brain development. Finally, they will generate insights into developmental and intellectual disorders known as cohesinopathies, where dysregulation of the Pcdh genes is linked to improper cohesin actions.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY There is significant evidence of cancer-type specific patterns of sex hormone receptor expression and signaling in many central nervous system (CNS) tumors, often correlating with their high sex-specificity. This supports the hypothesis that sex hormone receptors play tumorigenic and pathologic roles across many CNS cancers. However, their mechanistic functions in CNS tumors remain largely unknown. This proposal seeks to address these knowledge gaps in 2 of these cancers: meningioma and glioblastoma (GBM). In Aim 1, I explore the mechanism underlying progesterone receptor (PR) expression and signaling in meningiomas, the most common primary intracranial tumors. Meningiomas are 2.7 times more common in females than in males, can arise in the setting of exogenous female hormone therapy, and 70% express high levels PR, suggesting female sex hormones may drive meningioma tumorigenesis. Using human meningioma xenografts in mice treated with clinically relevant doses of synthetic progestins, I developed a model of female sex hormone-driven meningioma. The data presented in this application suggest progestins induce PR expression, increase tumor growth, and reduce survival through a positive feedback mechanism that requires progesterone membrane component 1 (PGRMC1), a non-classical hormone receptor with pathologic roles in breast and endometrial cancers. The central hypothesis of my doctoral dissertation project is that progestin ligand activates PGRMC1 to drive expression of PR in meningioma through regulation of NFB transcriptional activity, and that PR drives meningioma growth through cytoplasmic activation of MAPK signaling and transcriptional activation of TNFSF11, TGFA, and IRS2. Through the remainder of my graduate work I will (i) validate the pathway through which PGRMC1 drives PR expression through ChIP-QPCR, luciferase reporter, and loss-of-function validation models, (ii) identify hormonal cofactors involved in PGRMC1 signaling, (iii) validate the roles of PR downstream targets in driving growth and proliferation in meningioma through gain- and loss-of-function models, and (iv) incorporate human proteomic data to define expression levels of proteins implicated in PR and PGRMC1 signaling pathways in human patients. In Aim 2, I outline the proposed direction of my postdoctoral studies, the characterization of sex hormone signaling pathways in GBM. The most malignant primary brain tumors in adults, GBM are often marked by high expression of androgen and estrogen receptors, yet limited and often contradictory functional data for these receptors in GBM has impeded the development of sex hormone-targeted therapeutics. For this project, I plan to (i) perform integrated proteomic and phospho-proteomic characterization of hormone signaling networks in GBM, (ii) characterize and mechanistically validate the pathways through which sex hormone signaling influences GBM pathology, and (iii) develop combination therapies targeting these signaling axes. Taken together, these projects will integrate genetics, biochemistry, and proteomics to characterize therapeutically vulnerable signaling pathways in meningioma and GBM.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY Tuberculosis (TB) and common mental disorders (CMDs) are both leading causes of death and disability worldwide and are intertwined health states that often co-occur but are rarely addressed together. People with TB and diagnosis of at least one CMD have double the risk of loss to follow-up, treatment failure, or death along with increased odds of non-adherence to TB treatment. Thus, there is an urgent need to identify and assess evidence-based interventions to address CMDs as part of routine TB care to improve wellbeing and TB treatment outcomes among people with TB. The overall objective of this application is to identify and adapt an intervention to address CMDs among people being treated for TB. The central hypothesis is that an existing mental health intervention for CMDs is appropriate for and can be adapted and integrated into routine TB care. The central hypothesis will be tested by pursing three specific aims: 1) examine the relationship between CMDs and associated factors with TB treatment adherence and treatment outcomes during the TB treatment period to identify the most critical timing and type of intervention needed, 2) adapt and explore barriers and facilitators for implementation of an evidence based CMD intervention for integration into routine TB treatment services, and 3) pilot an intervention aimed at improving TB treatment outcomes among individuals with CMD symptoms. The results of this work will provide critical preliminary data for an NIH R01 application evaluating effectiveness of the adapted intervention among people with TB on treatment. Dr. West’s career goal is to become an independent investigator focused on improving TB treatment outcomes in high-burden settings by addressing the mental health needs of people with TB. To support her path to independence, the proposed work will be paired with a dedicated, multidisciplinary mentorship team and training in longitudinal study design and conduct (Aim 1), implementation sciences (Aims 2 and 3), and interventional research (Aim 3). UCSF is an outstanding environment that is committed to junior investigators with extensive resources for research and career development. Thus, the K01 award will provide Dr. West with the critical mentorship, training, resources and experience to become an international leader in mental health research among people with TB.

NIH Research Projects · FY 2026 · 2024-09

ABSRACT Preconception micronutrient status (including anemia) is a critical determinant of maternal, newborn, and child health that remains undervalued in Nepal. However, providing micronutrient supplements (MMS) alone is not enough. In the Nepali context, the gap between marriage and the first birth is short and newly married women have the lowest household status. Addressing the intersectional barriers to health for newly married women, including inequitable gender norms and women’s empowerment, household relationships, nutrition knowledge and practices—is essential for improving maternal and infant outcomes in Nepal. To mitigate the community, household, and individual factors resulting in poor nutrition, our team developed and pilot-tested an educational group intervention (Sumadhur, meaning “Best Relationship”) for newly married women, husbands, and mothers-in-law triads. Sumadhur aims to provide information on nutrition and women’s health, address inequitable gender norms and practices, strengthen household relationships and communication, and improve the household status of newly married women. The pilot study of Sumadhur brought triads of several households together for 16 interrelated sessions over four-months. Findings suggest that participants (N=90) found the intervention to be highly feasible and acceptable and nutritional norms and practices improved. We propose to test the effectiveness of Sumadhur on maternal health and nutrition outcomes using a 2-arm cluster RCT (cRCT). The intervention participants will receive the Sumadhur group intervention and will be provided MMS directly at group sessions. In control villages who do not receive the Sumadhur group intervention, we will facilitate access to MMS at primary health centers. We will randomize 70 villages to each arm (with one group per village). Each village has one group of five women (total of 700 women). Newly married women, their husbands and mothers-in-laws (total=2,100), will be followed four times for 18 months post-intervention through surveys, hemoglobin tests and blood draws (women only). Our specific aims are to estimate the effectiveness of Sumadhur on women’s anemia and micronutrient status, including the cost-benefit of the intervention (Aim 1); explore the impact on intermediate outcomes such as gender norms, household relationships and eating practices and characterize the individual and household-level mechanisms of impact (Aim 2); understand triadic experiences and impact over time of Sumadhur (Aim 3). Accomplishing these aims will provide evidence for how to improve micronutrient and anemia status among women before they become pregnant—thereby ensuring that women are not deficient in the critical early phases of pregnancy. These findings will also advance the field by testing novel approaches (household and community level behavior and norm change intervention) that, when combined with supplements, may lead to better adherence, uptake, and, ultimately, health outcomes, and have additional longer-term benefits.

NIH Research Projects · FY 2026 · 2024-09

ABSTRACT This is a Mentored Research Scientist Career Development Award (K01) award for Dr. Sarah B. Garrett, PhD, a medical sociologist and Assistant Professor at the University of California, San Francisco (UCSF). Dr. Garrett is establishing herself as an investigator of healthcare facilities’ efforts to improve their patients’ maternity care outcomes. This K01 will provide Dr. Garrett with the support necessary to become an expert in this field and to lay the foundation for an independent research career focused on improving maternal health in the US. Dr. Garrett will be supported by an outstanding mentorship and advisory team with expertise in the proposed training areas: maternal healthcare, implementation science, and hospital-focused interventions. Co-Primary Mentors are: Dr. Daniel Dohan (UCSF), expert in health policy, institution-focused qualitative research, and medical culture; and Dr. Melissa Simon, MD, MPH (Northwestern), an obstetrician and NIMHD-funded clinician-investigator who has deep expertise in the application of implementation science to the design, evaluation, and scaling of impactful maternal health interventions. Co-Mentors will be Dr. Brittany Chambers, PhD, MPH (UC Davis), a preeminent scholar of maternal health-promoting interventions and community-based methods; and Dr. Melissa Rosenstein, MD, MAS (UCSF), a national leader in conducting and researching maternal health quality improvement. Scientific Advisors are: Dr. Christine Dehlendorf, MD, MAS (UCSF), an NIMHD R01-funded expert in reproductive health interventions and their implementation in large institutions; Dr. Hector Rodriguez, PhD (UC Berkeley), an expert in health system effects on patient care quality and outcomes; and Dr. Patience Afulani, PhD, MD, MPH (UCSF), an expert in measuring and improving patient experience of maternity care. Under the team’s close guidance, Dr. Garrett will gain proposed skills and knowledge via coursework, mentored tutorials, and practical experience. Hospitals recognize the need to improve the quality of maternity care, but there is inadequate evidence to guide them on how best to do so. Dr. Garrett proposes to use stakeholder guidance, implementation science, and theory-driven frameworks to investigate California hospitals' efforts to improve maternity care. Focusing on interventions intended to promote high-quality maternity care, she will: Aim 1) Characterize how a selection of California hospitals are working to improve maternity care for patients who tend to experience poorer outcomes; Aim 2) Identify drivers of practice change in facilities participating in a collaborative program to improve maternity care outcomes; and Aim 3) Generate actionable patient-centered guidance for hospitals seeking to implement interventions to improve maternity care. This implementation-focused K01 will provide evidence-based guidance for implementing maternity care improvement interventions. It will form the basis of an R01 to examine how maternity care interventions affect patient outcomes in hospital settings across the country.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY People living with HIV (PLWH) have an estimated 1.6-6.0 times increased risk of developing oropharyngeal cancer (OPC) compared with individuals in the general population. 70% of OPCs are caused by human papillomavirus (HPV), and PLWH also have an increased prevalence of oral HPV infection. Disparities by race/ethnicity exist. Whites have higher incidences of OPC than other racial groups, while people with OPC categorized as “Black” have worse survival rates than other groups. Disparities also include a later stage of diagnosis and less frequent cancer-directed treatment for members of ethnic minority groups. There are few data, however, on racial/ethnic differences in oral HPV infection, persistence of oral HPV infection, or progression of oral HPV infection to OPC among PLWH. Prospective studies are needed to identify risk factors, potential biomarkers, novel screening or prevention methods for OPC among PLWH. However, there are serious feasibility issues in performing prospective studies of oral HPV persistence. Oral HPV infection is rare, even among sexual minority men (SMM) living with HIV (LWH), who have the highest prevalence of oral HPV (5% HPV-16, 17% high-risk HPV). A prospective study with the ability to recruit and screen a race/ethnically diverse cohort would require screening thousands of men to identify the few with oral HPV infection. This would be costly and burden the participant with multiple clinic visits. A time and cost-saving alternative would be to conduct most of the screening for eligible study participants by mail. We propose to conduct a pilot study with 135 racially/ethnically diverse SMM-LWH to evaluate the agreement between at- home self-collected samples and clinic-collected samples for detecting HR-HPV. Participants will have HPV DNA sample collection kits sent to them through the USPS. They will be asked to collect one alcohol-based mouthwash oral rinse and gargle sample and one Foam Swab collected saliva sample applied to an FTA card and to return the two samples via FedEx refrigerated overnight shipping. A clinic visit will be within 7- 10 days of the home sample collection, and participants will have a similar ORG sample collected in the research office following gold-standard clinic procedures. We will also assess the feasibility, acceptability, and comfort of receiving oral HPV DNA sample collection kits in the mail, ease of understanding the instruction sheet, ease of collecting samples, and ability to package and mail the samples using refrigerated packaging within 24 hours of collection. The PI will use the pilot data collected through this funding mechanism for new investigators to design a future prospective cohort study among racially and ethnically diverse SMM-LWH investigating risk factors and salivary biomarkers for persistent oral HPV and early HPV- OPC. Her study directly addresses NIDCR’s initiative “Understanding Persistent Oral Human Papillomavirus and Human Immunodeficiency Virus co-infection and Its Role with Oropharyngeal Cancer Induction.”

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY As the U.S. population ages, the number of people with Alzheimer’s disease and related neurodegenerative diseases (NDDs) that cause dementia will grow. Emerging disease-modifying treatments are/will be designed to address the specific biology of each form of dementia. They are likely to be most effective early in the course of illness, increasing the importance of prompt and accurate diagnosis. Specific identification of the cause of cognitive impairment is routine in Neurology and Psychiatry, but exclusive reliance on this limited workforce for assessment of cognitive and behavioral changes will result in treatment delays with meaningful clinical impact, particularly for medically underserved communities that face obstacles in accessing specialists. Early evaluation in the primary care (PC) setting can reduce delays, but PC practitioners (PCPs) identify time and a lack of confidence as barriers preventing them from assessing cognitive and behavioral complaints. Biomarkers can facilitate the identification of NDD, but expert guidelines stress that they must be paired with clinical findings to guide diagnosis. In addition, the available biomarkers only address some of the entities that cause NDD. The goal of this project is to support more thorough assessment of cognitive and behavioral complaints in PC by supporting PCPs to use a comprehensive diagnostic toolkit developed by the California Alzheimer’s Disease Centers. The toolkit includes a pre-visit questionnaire that can potentially shorten future assessments if the sensitivity of the questions can be established. This project will demonstrate first that assessment with this toolkit, in combination with regular expert-led case conferences, facilitates accurate distinction by PC providers of mild cognitive impairment and dementia likely due to Alzheimer’s disease from other, less typical NDD syndromes, and second, that the implementation of this approach is feasible and acceptable to PCPs, patients, and families. We will implement the model in five CA PC practices that work with medically underserved communities to facilitate the assessment of approximately 750 patients by at least 30 PC providers. Each participant will be re-evaluated at an expert center, where blood biomarkers of NDD will be collected. We will support PC practitioners to provide a biomarker-informed diagnostic disclosure to each patient. We will examine the accuracy of PCP diagnoses, using expert opinions and biomarkers as the gold standard, and evaluate the feasibility of toolkit use in the practices through surveys, interviews, and focus groups. To help address the sensitivity of pre-visit questions to atypical symptoms of NDD, we will also recruit 200 patients with atypical presentations at UCSF. Achievement of the project goals will establish an efficient model for earlier, etiologically-specific diagnosis of cognitive and behavioral changes due to Alzheimer’s disease and other NDDs.

NIH Research Projects · FY 2026 · 2024-09

PROJECT SUMMARY/ABSTRACT Black-White inequities in Alzheimer’s Disease and Related Dementia (ADRD) are a pressing public health problem: prevalence is almost double for Black adults aged 65-84. ADRD is a leading cause of death in the United States, affecting an estimated 5 million Americans. ADRD is a progressive disease impacting the parts of the brain that control thought, memory, and language. Unlike heart disease and cancer, death rates from ADRD are rising. ADRD prevalence is projected to decrease for White and increase for Black adults over time. Higher education is a strong social determinant of lower ADRD risk. However, large Black-White inequities in ADRD persist at the highest levels of education. Unfortunately, most nationally representative studies on ADRD are comprised of White adults. To address this disparity, we must consider risk factors that impact Black Americans uniquely as opposed to White experiences. Though structural racism is implicated as a fundamental cause of higher education gaps, little is known about if, and to what extent, uniquely Black college experiences influence ADRD risk in Black adults, specifically Historically Black Colleges and Universities (HBCUs). HBCUs are comprised of predominantly Black students (76%) and uplift Black individuals as well as Black communities through economic and cultural empowerment, increased social and political capital, and neighborhood revitalization and pride. Thus, early life exposure to HBCUs is a promising and unexplored mechanism that may improve later-life ADRD outcomes and inequities for Black adults. This K99/R00 study proposal leverages three large, well-established racially diverse national panel datasets to investigate the impact of early life exposure to HBCUs on vascular risk factors of ADRD, late-life incidence of ADRD, and all-cause mortality in Black adults; The Health and Retirement Study (HRS), Reasons for Geographic and Racial Differences in Stroke study (REGARDS), and Project Talent. We will apply quasi-experimental methods to evaluate the causal effects of (1) HBCU attendance and completion compared to a Predominantly White Institution (PWI), (2) early life HBCU proximity compared to a PWI through educational attainment, and (3) state and federal funding policy of HBCUs compared to PWIs during college-aged years. The research plan is complemented by an exceptional multidisciplinary mentorship team at the University of California San Francisco and training activities that build on the candidate’s background in racism-related research by providing new training in (1) life course determinants of ADRD, (2) data harmonization, and (3) causal effects of social and policy measures. The combined research and training plans will prepare the applicant for a successful independent epidemiology research career specializing in the study of structural racism as a social determinant of ADRD and inequities. This study aligns with NIA’s strategy for reducing health disparities and harmonizing population data. Findings from this proposal will provide critical insight into our understanding of uniquely Black college experiences as a source of cognitive resilience for Black adults. OMB No. 0925-0001/0002 (Rev. 03/2020 Approved Through 02/28/2023) Page Continuation Format Page

NIH Research Projects · FY 2024 · 2024-09

Stuttering is a disorder of speech fluency that affects 3.5 million people in the USA alone. The primary symptoms consist of involuntary repetitions and prolongations of speech sounds, but many individuals who stutter also experience negative effects on emotional and social well-being, academic and professional achievement, self-esteem, relationships, and overall quality of life. Thus, stuttering is a significant public health issue and there is a great need for increased efforts to translate recent discoveries from mechanistic neurophysiological studies into evidence-based treatment options with potential for continuous optimization and personalization. Most existing treatments for stuttering still use approaches that are purely behavioral in nature and that are applied in a relatively generic manner across individuals. Unfortunately, the relapse rate for behavioral treatments for adults who stutter has been estimated to be as high as 50-70%. We propose that there is a need for a clinical paradigm shift toward efficacious treatments based on contemporary insights from basic neuroscience. This requires, as a first step, carefully designed studies that identify key sensorimotor mechanisms that are amenable to realistic intervention strategies. For example, interventions ranging from experimental manipulations of the speaker’s auditory feedback to pharmacological agents that regulate dopaminergic activity are widely known to induce fluent speech, and such effects are supported by an extensive literature spanning several decades. Yet, in real-life clinical practice, the mechanisms of action of these methods are not understood and no progress has been made in improving their long-term clinical effects through empirically supported refinement and individualization. The current proposal is grounded in the premise that reaching the goals for any promising intervention for stuttering is facilitated by demonstrating direct effects on neural sensorimotor mechanisms underlying the disorder. The data from such studies can then form a much-needed translational link to develop subsequent full-scale clinical trials of the promising intervention. Recent research on the neuroscience of speech production has revealed atypical sensorimotor processing in children and adults who stutter (AWS). One set of processes that differentiate stuttering and nonstuttering speakers relates to the central nervous system’s reliance on sensory predictions for movement planning and execution. In AWS and adults who do not stutter (ANS), we will use magnetoencephalography (MEG) imaging after either aripiprazole or placebo to examine the following indicators of speech sensorimotor function - pre-speech auditory modulation (PSAM), speaking-induced suppression (SIS) and its modulation by speech variability, and centering. These indicators will be studied during unaltered-feedback speech, choral speech, and altered-feedback speech. The outcome of this work will lay the foundation for future studies on novel stuttering interventions that use pharmacological agents that regulate dopamine uptake either in isolation or in combination with existing behavioral treatments like fluency enhancement with auditory feedback manipulations or with future neuromodulation treatments. Project Summary/Abstract