University Of California, San Francisco

NIH Research Projects · FY 2025 · 2025-09

Summary/Abstract: Since 2020, the NIAID R25-funded TB Research And Mentorship Program (TB RAMP) demonstrated that a dedicated robust scientific research and mentoring program in TB positions early stage investigators (ESIs) to pursue innovative research and launch successful careers as independent investigators, and adds significant value to the larger research community at UCSF and UC Berkeley. In TB RAMP II, we retain core elements of TB RAMP and further innovate the didactic, research, and mentoring offerings applied to address TB. In TB RAMP II scientific core competencies imperative to working in TB are paired with research skill-building and an innovative career development program that includes critical activities of importance for this ESI career stage, including grant-writing, presentation practice, networking opportunities. TB RAMP II provides ESIs with tangible scientific and academic skills to enhance their own research and compete successfully for pilot awards and NIH grants, while also developing a strong network of ESIs and mentors conducting research aligned with NIAID’s strategic mission, assuring sustained success of program participants. Specific Aim 1: TB RAMP Interactive Learning Series. These interactive didactic seminars and modules bring together core UCSF and UC Berkeley mentors with an array of TB expertise including basic scientists, clinical researchers, epidemiologists, clinical trialists to focus on the core scientific concepts and methodologies of TB research and discovery. TB RAMP scholars will meet twice a month for scientific seminars with leading experts in TB research and for professional development focused on critical academic areas such as career advancement, publishing, and priority setting. We enhance these offerings with two new innovative didactic modules: 1) ‘Communicating Research Impact,’ focused on effective communication strategies for disseminating research findings; and 2) ‘Emerging Research Technologies’ covering innovative tools like AI and big data analytics to accelerate TB research. Specific Aim 2: Grant Writing and Pilot Awards. The goals are to: 1) provide rigorous, individual training on grant writing, 2) train on grant reviews including standing up mock study sections, 3) offer rigorously peer-reviewed seed funding opportunities. Specific Aim 3: Enhanced Mentoring Activities. TB RAMP II will provide TB-specific, high- quality, sustained mentoring for all scholars. In addition to their research mentor, scholars will have annual career mentoring meetings with the Program Directors. Monthly, scholars will participate in Works in Progress (WIP) sessions to present their research and actively provide peer mentoring as a cohort and with TB RAMP faculty. Monthly, ‘Bay Area TB Science’ (BATS) meetings are offered where scholars present to a wider academic and industry audience. We host a day-long BATS Symposium (September) and World TB Day event (March) where scholars present and network. In TB RAMP II we enhance these offerings with two new mentoring modules: 1) ‘The Mentoring Academy’ for TB RAMP faculty and alumni, to strengthen the pipeline of mentors; and 2) ‘Building Equitable Research Partnerships’ for the TB RAMP community to examine best collaborative research practices.

NIH Research Projects · FY 2025 · 2025-09

Project Summary/Abstract Within the last decade, immune checkpoint inhibitors (CPIs) have changed the landscape of cancer care, but also heightened risk for a range of endocrinopathies. While CPI treatment has led to tremendous benefits in a subset of cancers, they also have led to new-onset autoimmune disease (also known as “immune related adverse events” or “irAEs”) that can involve almost every organ. Within endocrine organs, insulin dependent autoimmune diabetes (CPI-DM) is highly morbid and potentially lethal. With this proposal Dr. Quandt plans a multipronged approach to address the mechanistic understandings of CPI-DM as examples of provoked autoimmunity. In Aim 1, Dr. Quandt will address genetic predisposition to CPI-DM. In Aim 2, Dr. Quandt will use an unbiased high throughput assay for novel autoantigen discovery to elucidate the specificity of the immune response in CPI-DM. In Aim 3, Dr. Quandt will use single cell methodologies to identify cellular phenotypes, activation, and differential gene expression contributing to a transcriptional signature critical to CPI-DM development. These studies will contribute to mechanistic understanding of CPI-DM with hope that they may lead to identification of actionable targets that could be used in the prevention or treatment of type 1 diabetes mellitus (T1DM), both in the setting of cancer immunotherapy and conventional disease. Dr. Quandt’s goal is to become a translational physician-scientist specializing in the immunology of T1DM and endocrine related aspects of cancer care, including endocrine irAEs. Bridging the divide between patient care and bench science is critical to furthering medical knowledge in both these novel and well-established autoimmune diseases. Dr. Quandt will advance her current experience in endocrinology, epidemiology and biostatistics through further training in wet lab approaches and bioinformatics including genetic analysis and computational immunology. This experience will anchor her understanding of translational methods to match her clinical research expertise. Her team of mentors, scientific advisors and collaborators are leaders in their respective fields. This training plan and scientific team will be coupled with the exceptional environment provided by the University of California, San Francisco, ensuring that Dr. Quandt will successfully advance to meet her career goal and transition to independence.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY The ability to maintain the viability and function of organs outside the body (ex vivo) at body temperature (normothermia) is an emerging field of innovation. Normothermic ex vivo perfusion systems have been developed to maintain hearts, lungs, and livers in this fashion for up to several days and have been a valuable tool in transplantation medicine to extend the longevity of donor organs. The potential for these technologies to be utilized in other ways is now also being recognized. Normothermic ex vivo kidney perfusion (NEVKP), in comparison, has been more challenging to develop. The kidney is highly susceptible to damage from the products of red blood cell (RBC) degradation that are generated by machine perfusion. Because of this, existing NEVKP systems cannot reliably sustain the viability of kidneys beyond 24 hours. The goal of this project is to investigate whether this challenge can be overcome using a promising RBC alternative: the naturally acellular hemoglobin (erythrocruorin) of the earthworm Lumbricus terrestris. We aim to use this novel oxygen carrier to extend the duration of NEVKP, making it a more viable tool for kidney disease research. L. terrestris erythrocruorin (LtEc) has many properties suggesting it would be an ideal oxygen carrier for NEVKP. Having evolved to transport oxygen in an extracellular environment, LtEc is molecularly stable in a wide range of temperatures, has a low oxidation rate, and does not scavenge nitrous oxide (NO), an important vasodilator. Its size (30 nm) is favorable for perfusing the kidney as it would likely not get lost to glomerular filtration (6-8 nm cutoff) but remain able to perfuse vasoconstricted capillaries that are inaccessible to RBCs (8 µm). Together with preliminary results from our lab demonstrating that LtEc can sustain respiration in NEVKP, these properties strongly justify investigating the utility of LtEc in NEVKP. In this proposal, we will first evaluate LtEc by testing different LtEc concentrations in an NEVKP system against autologous porcine RBCs as a control. We will investigate the ability of LtEc to support kidney function and viability while monitoring adverse effects including oxidative stress, inflammation, and kidney injury. These experiments will help determine the concentration that best supports respiration and minimizes toxicity during NEVKP. LtEc will also be evaluated against other HBOCs to determine whether the advantageous molecular properties of LtEc confer an empirical benefit in NEVKP. We will then attempt to maintain NEVKP for up to 7 days using an LtEc-based perfusate. Optimizing the use of LtEc for NEVKP of porcine kidneys could result in two major breakthroughs: 1) the development of long-term NEVKP, a tool that would enable many avenues for novel discovery in kidney disease; and 2) the validation of LtEc as an effective and sustainable oxygen carrier in a mammalian organ, the impact of which could be relevant to numerous fields across medicine.

NIH Research Projects · FY 2025 · 2025-09

Women in rural areas face challenges to using contraception. Our and others’ studies emphasize the key facilitating role of positive peer support for helping women navigate myriad challenges when they desire pregnancy prevention. Despite such documented benefits, tested approaches to deploying experienced contraception users to provide social support to other women are lacking. We developed the “I-CAN” intervention to train and deploy experienced users of contraception as “mentors” who provide tailored informational, instrumental, appraisal, and emotional support to other women (“mentees”) on contraception. I-CAN was co-developed with community advisory boards and health officials in rural areas via participatory human-centered design. I-CAN mentors are local women with experience with multiple contraceptive methods, including self-injection (a novel yet underused self-care method). Underpinned by multiple theories, I-CAN is designed to increase women’s contraceptive knowledge, agency over contraceptive decision-making, and ability to access contraception, resulting in our primary objective of increasing women’s ability to overcome barriers to contraceptive use. Mentors are trained to provide neutral support and respect women’s decisions about contraception without being directive. After promising findings in our pilot study, we propose to build on our strong, ongoing partnership to test I-CAN on a larger scale. In Aim 1, we will test the effectiveness of I-CAN in a hybrid (type 2) effectiveness-implementation cluster-randomized controlled trial, randomizing 52 rural areas 1:1 to receive I-CAN or not. We will compare contraceptive use (primary endpoint), contraceptive agency, method satisfaction, and use of self-injection after 24 months between arms. Data will be collected via repeated cross-sectional household surveys (N=1,560 each time). In Aim 2, we will examine the process of implementing I-CAN, guided by the PRISM/RE-AIM framework. In Aim 3, we will estimate the incremental cost-effectiveness ratio of I-CAN relative to standard of care using each of our primary and secondary endpoints as effectiveness measures and measuring costs from an implementation perspective. I-CAN holds promise for helping women overcome contraceptive use barriers.

NIH Research Projects · FY 2026 · 2025-09

PROJECT SUMMARY/ABSTRACT This K23 career development award aims to support Dr. Rowan Saloner in acquiring the expertise to become a leading clinical researcher focused on unraveling the neurobiological underpinnings of clinical progression in frontotemporal lobar degeneration (FTLD), Alzheimer's disease (AD), and other related dementias (ADRD), Dr. Saloner is a clinical neuropsychology postdoctoral fellow transitioning to faculty at the University of California, San Francisco, Memory and Aging Center (MAC), This K23 will focus on large-scale proteomics, clinical characterization, and bioinformatics to identify fluid biomarker signatures of FTLD and their relationship to disease progression. Through the enriched multidisciplinary training environment at the MAC, Dr. Saloner aims to accomplish the following training goals: 1) clinical integration of deep molecular phenotyping of ADRD; 2) big data/bioinformatics; and 3) scientific leadership, Dr. Saloner will translate his K23 experience into future R01 efforts to integrate high-dimensional biological tools with detailed clinical phenotyping to refine personalized biomarkers for diagnosis, prognosis, and therapeutic target engagement in ADRD. Dr. Saloner has assembled an exemplary mentorship team with expertise in neurobehavioral aging (Primary Mentor Dr, Kaitlin Casaletto ), ADRD fluid biomarkers (Co-Primary Mentor Dr. Adam Boxer), proteomics (Co-Mentor Dr, Nicholas Seyfried), biostatistics (Co-Mentor Dr. John Karnak), disease progression modeling (Collaborator Dr. Adam Staffaroni), FTLD biology (Advisor Dr. Jennifer Yokoyama), and professional development (Advisor Dr. Joel Kramer). The central rationale is that the most potent therapeutics for ADRD will modify molecular targets that change early in disease and have downstream effects on neuron loss and cognitive decline. Cutting-edge proteomic platforms that measure thousands of proteins in a single biospecimen sample have advanced understanding of AD biology in living humans. However, far less is known regarding the molecular evolution of FTLD, a common cause of young-onset dementia for which there are no effective therapies. The proposed study will leverage large-scale proteomics in cerebrospinal fluid (CSF) and plasma to identify protein signatures that precede and predict brain atrophy and cognitive decline in carriers of autosomal dominant FTLD mutations, who represent an ideal population to study early ADRD biomarkers. Antemortem CSF and plasma proteomic data in sporadic, pathology-confirmed FTLD will also be leveraged to determine the degree to which genetically-derived protein signatures translate to sporadic FTLD, which represents the majority of FTLD cases. Examining deep molecular screening tools in relation to FTLD progression strongly aligns with Actions 1.B.1 ("Expand research to identify the molecular and cellular mechanisms underlying Alzheimer's disease and related dementias") and 1.C, 1 ("Identify imaging and biomarkers to monitor disease progression") of the 2022 National Plan to Address Alzheimer's Disease. Successful completion of study aims will advance discovery of early FTLD biology in humans and identify targets for the development of urgently needed FTLD biomarkers and treatments.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT - modifying treatments become available. Traditional diagnostic methods, primarily episodic memory assessments, are often inadequate in the early stages, missing subtle cognitive shifts that occur years before clinical symptoms are apparent. Language impairments, such as difficulties with word retrieval, emerge as early markers of AD, yet remain underutilized in clinical settings. Automated speech analysis offers a non-invasive, scalable, and cost-effective approach to detecting these early signs by analyzing spontaneous speech patterns. The objective of this project is to develop and validate an AD-specific speech profile using automated speech analysis to improve early detection and monitoring of AD. Leveraging existing and newly collected longitudinal speech samples from culturally and educationally diverse populations, we will use cutting-edge machine learning algorithms to identify key linguistic and acoustic features indicative of cognitive decline. Our large and diagnostically diverse cohorts will enable us to distinguish between different stages of AD and differentiate AD from other neurodegenerative diseases such as primary progressive aphasia and frontotemporal dementia. Aim 1 focuses on developing a sensitive and specific AD-speech profile to classify clinical diagnoses and predict the transition from preclinical to clinical AD. Aim 2 investigates the clinical validity of the AD-speech profile by correlating it with established neuroimaging biomarkers (e.g., amyloid-PET, MRI) and cognitive measures while accounting for sociodemographic influences. Aim 3 aims to establish the reproducibility and generalizability of the speech profile by externally validating it with an independent cohort. This multidisciplinary project brings together expertise in neurology, linguistics, neuropsychology, biostatistics, and digital health to create an accessible, objective tool that enhances early detection and monitoring across racially and ethnically diverse populations. By focusing on subtle changes in language patterns, the project lays the foundation for automated speech analysis as a clinically viable and equitable method for early AD diagnosis and disease monitoring.

NIH Research Projects · FY 2025 · 2025-09

ABSTRACT: Seasonal availability of nutrient constitutes a major driver of organismal physiology that has produced extreme phenotypes such as hibernation, but also seasonal variation in body weight, blood-glucose control, peripheral tissue transcription, and sleep in humans. A central theme of these adaptations is the tradeoff between energy conservation and energy harvesting that drives circannual patterns in feeding and sleeping behavior. The circadian clock segregates sleep and feeding behaviors to distinct phases of the day in coordination with the environmental light/dark cycle, yet little is known about how clock regulation of sleep/feeding adapts to seasonal variation in nutrient and light. My previous postdoctoral research uncovered a phosphorylation event on PER2- S662 that regulates circadian nutrient sensing and synchronization with seasonal photoperiods. My new preliminary data reveals sleep, feeding, energetic, and hypothalamic signaling defects in PER2-S662 phospho- mutant mice that recapitulate seasonal adaptations observed in nature. The overarching goal of this research is to interrogate the role of the clock in seasonal sleep and feeding adaptations. I hypothesize that light and nutrient cues that occur during the summer will drive food intake at the expense of sleep by increasing PER2-S662 phosphorylation. Understanding the mechanisms whereby organisms adapt to the seasons is key for gaining insight into the etiology of disease as humans in modern society are exposed to year-long unhealthy diets and long photoperiods as a result of modern supermarkets and electronic devices. These cues, therefore, signal a constant state of summer that is predicted to disrupt sleep and drive development of obesity. The research and training programs that I have proposed will allow me to establish a novel niche at the intersection of sleep, circadian rhythms, and seasonality that will fuel a productive independent research program into the future.

NIH Research Projects · FY 2025 · 2025-09

7. PROJECT SUMMARY The goal of this Exploratory/Developmental project is to develop a way of assessing mechanical failure of bone matrix using the same material used to evaluate bone formation in vitro. Mechanical failure (fracture) of bone is the primary clinical concern in bone disease. Pharmaceutical interventions to prevent mechanical failure of bone focus on increasing bone size or density (i.e. bone quantity and BMD). These approaches are successful, but their long-term use either has diminishing returns and/or increased risk of adverse effects. The mechanical properties of bone extracellular matrix are a major contributor to bone fragility but are only indirectly addressed by existing therapeutics. A major roadblock to identifying modifiable factors that influence bone matrix is the effort required for early-stage discovery of factors influencing bone matrix: Screening for factors that enhance bone formation can be performed using cell modified and cultured in vitro (weeks of effort). In contrast, detecting a change in mechanical failure of bone matrix (fracture toughness, strength) requires specimens as large as whole mouse bones, necessitating the development of a transgenic mouse (months of effort). To overcome this challenge, we propose using micropillars (~5-10 um diameter) generated by focused ion beams to evaluate mechanical failure in bone matrix in bony nodules generated by in vitro culture. Encouraged by PRELIMINARY STUDIES demonstrating high repeatability of micropillars in bone and the feasibility of generating micropillars from bony nodules, here we establish the micropillar in the context of deficiency of the heterotrimeric G protein Gs in mice, a condition that results in severe bone fragility. The project has one aim: determine the effects of deficiency of GS on the fracture toughness of bone matrix using bony nodules formed in vitro and bone matrix formed in vivo and includes mechanical testing of bony nodules generated by precursor cells in which GS is removed in vitro, bone matrix from the GS deficient mouse and osteoprogenitors reprogrammed from human fibroblasts in which GS is removed in vitro. In addition to addressing the rate limiting factor to identifying factors that influence bone matrix mechanical properties, the proposed technique will have broad applications including localized measures of matrix strength at localized areas including within a fracture callus or the peri-implant space.

NIH Research Projects · FY 2025 · 2025-09

People with HIV (PWH) are at increased risk for type 2 diabetes (T2D) due to both disease-related and treatment-related factors. MicroRNAs are regulatory elements of transcription of mRNAs to amino acids and regulate many physiological processes, including in adipose tissue. There is promising but extremely limited evidence for the role of specific microRNAs and their mRNA targets in the dysregulation of adipose tissue related to HIV infection and risk for T2D. We propose to evaluate microRNA expression in adipose tissue from PWH who do and do not have T2D and to investigate whether there are corresponding changes in target mRNA expression that might provide insights about the functional impacts of HIV on adipose tissue and risk for T2D. We will also explore whether circulating microRNAs in plasma may be novel signals for these underlying adipose tissue perturbations and might have clinical implications as biomarkers of risk for T2D in PWH. Knowledge gained from this project has the potential to inform future hypothesis-driven studies into specific molecular targets to diminish the harmful impact of HIV on adipose tissue physiology and risk for T2D and as potential biomarkers to detect latent risk in PWH who are at greatest risk for T2D.

NIH Research Projects · FY 2026 · 2025-09

Project Summary/Abstract My research is about creating the tools, insights and capabilities needed by the field of structural biology to understand structure-function relationships, including catalysis, enzyme-substrate interactions, and structure- based drug design. In the next five years this field will face new challenges as accurate structure prediction generates a firehose of testable hypotheses, shifting the focus of experimental efforts to the “last Angstrom” between predicted and actual atomic positions. This short distance is where the puzzle pieces of biology and chemistry fit snugly together, and it is the details on this scale that are vital to understanding the structure- function relationship. The experiments of the near future must reveal accurate, high-resolution, and damage- free 3D images. Remarkably, the data used to train current prediction models already contain yet-to-be- unlocked information. Single-electron changes can be visible in Macromolecular Crystallography (MX) data at resolutions as low as 3.1 Å, but structural models must be far more accurate to reveal such features. To enable this robust interpretation of experimental data, I will develop simulation-based models that are minimally restrained but still faithfully reproduce observed average-image and diffuse-scatter data. These improved, multi-conformational models will enhance understanding of how macromolecules transmit forces through their interior and how they influence and interact with other molecules. Deducing these intramolecular communication networks requires solving the topological problem of simultaneously satisfying observed density and prior knowledge of chemical geometry. Solving this problem will be made easier by comparing related structures. This will arise from current technologies for correction of non-isomorphism in real space, which I will migrate into reciprocal space, enabling merging of incomplete data such as XFEL stills and parametric structure frameworks. These low-dimensional frameworks will allow selection from a continuum of 3D molecular structures like a marionette by dialing in desired parameter values, such as temperature, pH, or other reaction progressions. I will test these framework models against the thousands of non-isomorphous data sets collected at my beamline and report on best practice. Radiation damage will be the final barrier, so to move towards damage-free data from a synchrotron, we will implement a new kind of data collection called "painting with X-rays," leveraging modern fast-framing detectors and small X-ray beams to extract the full information content from each sample and extend zero-dose extrapolation to the single-photon level. Collectively, I expect the benefits of bridging the gap between prediction and reality to be transformative to both methods development and functional studies using complementary structural techniques, such as CryoEM, SAXS, tomography electron diffraction, and especially hybrid methods that combine structural data from multiple sources.

NIH Research Projects · FY 2025 · 2025-09

PROJECT ABSTRACT / SUMMARY: Fatty acids (FAs) are essential signaling molecules that induce cellular metabolic reprogramming in addition to their conventional roles as energy fuel. Elevated FA during fasting is the primary fuel for the body and an essential substrate to generate an alternative energy source, ketone bodies. However, excessive plasma FA levels in obese or diabetic patients are associated with inflammation, insulin resistance, and cardiovascular diseases. Consequently, understanding the functional role of FAs in cells will uncover novel physiological mechanisms in the health and pathogenesis of metabolic diseases, leading to new therapeutic approaches for disease prevention and treatment. Our compelling preliminary data reveal a novel signaling role for FAs in regulating a specific translation network to induce the synthesis of proteins that are important for ketogenesis upon fasting and inflammation in hyperlipidemia. Fasting can lead to wide-ranging health benefits, including weight loss, improved insulin sensitivity, enhanced brain function, and even offer protection against cancer. Fasting triggers the body to switch its source of energy from glucose to ketone bodies (KBs). KBs are an alternative energy source that is mainly generated in the liver from fatty acids stored as fat. Despite decades of work, how fasting signals elicit changes in gene expression at the level of the proteome to establish metabolic programs that underlie lipid catabolism and production of ketone bodies remain unknown. Our findings remarkably show that while global translation is downregulated during fasting, hepatocytes selectively remodel the translatome to sustain lipid metabolism and ketogenesis. We uncovered a new signaling pathway, induced by FAs directly binding to the AMP-activated protein kinase (AMPK), that upregulates the translation of hundreds of mRNAs, that are under pervasive translational regulation that was missed by conventional transcriptomics analysis. In this pathway, we found the rate limiting enzyme of ketogenesis, Hmgcs2 and the master regulator of lipid metabolism and ketogenesis in the liver, peroxisome proliferator-activated receptor alpha PPARa to be under translational control. We mechanistically uncovered that the phosphorylation of the major cap binding protein, eukaryotic translation initiation factor (P-eIF4E) is induced during fasting and is essential for regulating ketogenesis and ketone body production. Interestingly, our published and unpublished findings have further also demonstrated that P-eIF4E is activated during high fat diet and is critical for lipid accumulation and inflammation upon a high fat diet. Thereby P-eIF4E is a node of convergence downstream of changes to fatty acids both in nutrient deprivation such as fasting as well as nutrient overload. In this grant, we will investigate three outstanding questions: 1) What are the molecular mechanisms that establish a specific tailor-made translation program underlying fasting? 2) What is the signaling pathway responsible for fatty acid-induced activation of eIF4E during fasting, and the molecular mechanism underlying FA induced AMPK activation? 3) We will leverage our expertise in polysome sequencing and genome wide translation control to characterize the metabolic programs that are regulated at the translation level downstream of P-eIF4E during the development of fatty liver (NAFLD) and nonalcoholic steatohepatitis (NASH). The results from these experiments in combination with our ability to pharmacologically target P-eIF4E will provide new therapeutic interventions for metabolic dysfunctions.

NIH Research Projects · FY 2025 · 2025-09

PROJECT ABSTRACT Black and Hispanic patients are less than half as likely to be preemptively waitlisted or receive preemptive kidney transplantation compared to their non-Hispanic White (NHW) or Asian counterparts. Black and Hispanic patients are also less than half as likely to receive peritoneal or home hemodialysis compared to their non-Hispanic White (NHW) or Asian counterparts. To date, a few trials have tested interventions aimed at reducing the known racial and ethnic inequities in access to preferred kidney replacement therapy (KRT) modalities such as kidney transplantation and home dialysis, but these interventions have had minimal impact and even when efficacious, are often difficult to adopt in real-world practice due to the resource investment needed and the absence of insurer support for these interventions (e.g., patient navigation or home education). In addition, prior studies have focused primarily on patient-related barriers to accessing home dialysis and preemptive waitlisting or kidney transplantation. Less attention has been paid to provider-related factors that may be contributory, such as how and which providers discuss kidney replacement therapy (KRT) options with patients, and when such discussions begin. The lack of granular data collection on how provider interactions with patients may mediate racial or ethnic disparities in access to preferred KRT modalities represents a significant and critical gap in the literature and likely stems from the fact that such granular data are not typically available in large national registries. Our objective is to leverage unstructured data in provider documentation embedded within electronic health record systems to understand how provider communication about KRT options may vary across different racial and ethnic groups (Aim 1), and whether such variations in patient-provider communication about KRT associates with or mediates the differential access of patients to preemptive waitlisting, transplantation, or home dialysis (Aim 2). To accomplish Aims 1-2, we will use harmonized data from diverse healthcare systems that have been centralized at UCSF to complete our analyses. To complement the data available within provider documentation, in Aim 3, we propose to innovatively review transcripts of clinic encounters focused on discussions of KRT options. We will apply qualitative inductive analyses and review these transcripts to identify factors and themes in patient-provider communication that may vary by patient race/ethnicity. We will then compare these themes to quantitative data on patient knowledge about KRT, satisfaction with the KRT education they received, and preferences as it relates to KRT after their clinic encounter. If successful, our study will identify best practices in patient- provider communication about KRT options that are amenable to simple interventions that could address the known long-standing inequities in access of racial and ethnic minorities to preferred KRT modalities.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Tuberculous meningitis (TBM) is one of the most devastating forms of tuberculosis (TB), with mortality rates as high as 50%. Despite dismal outcomes, few data are available on optimizing the approach to treatment of TBM. While several interventional TBM trials are underway, they face tremendous barriers that could impede the knowledge gained from these essential studies. First, TBM is exceptionally difficult to diagnose, which directly impacts selection of the right trial population on which to test treatment regimens. Second, although the host immune response may be a major driver of poor outcomes in TBM, our understanding of the immunopathogenesis of TBM and how it may be targeted with host-directed therapy is in its infancy. Third, dedicated resources to develop and sustain research capacity are often limited in low- and middle-income countries (LMIC) where TB is endemic and where data-driven treatment strategies for TBM are urgently needed. In this ancillary study, we propose 3 scientific aims and a capacity-building plan designed to address these major challenges. We will perform a secondary analysis of the ACTG IMAGINE-TBM (Improved Management with Antimicrobial AGents Isoniazid rifampiciN LinEzolid for TBM) trial, a phase II randomized trial comparing a 6-month regimen of high dose rifampin, high dose isoniazid, linezolid, and pyrazinamide with a 9-month standard of care regimen in participants at 17 sites in 12 LMIC across 3 continents. In Aim 1, before deploying our previously developed host transcriptomic machine learning classifier (MLC) to diagnose TBM in the diverse IMAGINE-TBM trial population, we will use integrated host gene expression data from stored cerebrospinal fluid (CSF) from two successfully completed TBM trials, TBM-KIDS and ALTER, to retrain and revalidate the MLC. In Aim 2, we will use a combination of direct pathogen detection with CSF metagenomic next generation sequencing (mNGS) and the optimized host transcriptomic MLC developed in Aim 1 to reclassify 300 IMAGINE-TBM participants as definite versus not definite TBM, after which we will re-analyze the efficacy of the investigational regimen versus standard of care. In Aim 3, we will use a case-control study design nested within IMAGINE-TBM to determine if host gene expression profiles differ between participants who have a poor versus good outcome. This study will leverage stored biologic specimens and existing data to augment the knowledge gained from IMAGINE-TBM. By re-analyzing the trial after re-classifying participants using mNGS and host transcriptomics, we could detect a benefit of the investigational regimen that would otherwise be missed. In addition, findings from the study will provide critical insights into immune pathways implicated in TBM pathogenesis and response to treatment, which could support the use of targeted host- directed therapies. In conjunction with the scientific aims, to strengthen capacity for sustainable TBM research programs based in epicenters of the TB epidemic, we will partner with the Chan Zuckerberg Biohub to support training in metagenomics and bioinformatics at 3 regional training hubs in India, Kenya, and Peru.

NIH Research Projects · FY 2025 · 2025-09

1 PROJECT SUMMARY 2 Organoids derived from stem cells are valuable tools that have potential to unlock cellular-based regenerative 3 medicine applications for otherwise incurable illness. Severe liver dysfunction, which affects millions of people 4 and is the 10th leading cause of death in the United States per year, can only be treated with a liver transplant, 5 but a critical shortage of organ donors means many patients die while on the transplant waiting list. Creating 6 functional and transplantable bioengineered liver tissue that can treat severe liver dysfunction would address a 7 critical unmet need in modern-day medicine. Achieving closed system operation and effective cryopreservation 8 in tissue culture are critical requirements for producing clinical grade bioengineered tissue that meets 9 regulatory requirements. With the goal of producing highly functional bioengineered liver tissue for cell-based 10 regenerative medicine applications, we developed a custom bioreactor to biomanufacturer induced pluripotent 11 stem cell (IPSC)-derived liver organoids in the simulated microgravity of low shear rotational suspension 12 culture. Our custom bioreactor, Tissue Orb, supports isochoric supercooling cryopreservation and is the 13 world’s first isochoric supercooling chamber that can support sterile tissue culture. Isochoric supercooling uses 14 constant volume to maintain aqueous solutions in a liquid state at sub-zero temperatures without the harmful 15 formation of ice. Importantly, the constant volume confinement has been shown to impart stability to the 16 supercooled condition, which decreases the need of toxic cryoprotectants that are required in other 17 cryopreservation methods. Furthermore, isochoric supercooling is simple to implement, involving a rigid 18 container with no moving parts, and was recently demonstrated to be a promising cryopreservation method 19 that can be easily translated to clinical or research settings to preserve biological material. Our lab is the first to 20 apply isochoric cryopreservation to liver organoids. We are now combining this technology with simulated 21 microgravity tissue culture in efforts to produce high quality liver organoids for regenerative medicine therapies. 22 The objective of this proposal is to improve isochoric supercooling protocols for liver organoids and complete 23 the design of the Tissue Orb to allow tissue culture and cryopreservation to occur in a single, closed system 24 and is a critical step towards achieving scalability and repeatability that is needed for high quality, clinical grade 25 products. We will expand on our prior work through a biological aim which looks to improve the protocol for 26 isochoric supercooling of liver organoids (Aim 1) and an engineering aim which looks to complete the design 27 for the heat exchange system to allow integrated isochoric supercooling in the Tissue Orb (Aim 2). The 28 proposed aims will result in information and technology that can lead to substantial improvements in our ability 29 to produce and preserve liver organoids, which, in turn, can drastically increase the availability of high-quality 30 bioengineered liver tissues to researchers and healthcare facilities around the world.

NIH Research Projects · FY 2025 · 2025-09

SUMMARY/ABSTRACT We first discovered that the rate of sudden cardiac death (SCD), the most feared manifestation of cardiovascular disease, is substantially higher in people with HIV (PWH). We established the POstmortem Systematic InvesTigation of Sudden Cardiac Death (POST SCD) study, a prospective medical examiner-based cohort using autopsy to refine presumed SCDs to true cardiac causes, with banked tissue and data on PWH and uninfected control cases. ~80% of HIV+ SCDs were on ART, thus this a one-of-a-kind resource to study the direct myocardial tissue effects of treated HIV. HIV POST SCD showed that the increased SCD risk in PWH is attributable to higher levels of myocardial fibrosis, a known substrate for fatal arrhythmias, and our updated incidence analysis confirms a significant, 2-fold higher rate of arrhythmic death in PWH (IRR 2.001, 95% CI 1.02- 3.93, p=0.044). Yet, the mechanisms by which HIV leads to myocardial fibrosis or other tissue processes to cause non-CAD SCD are poorly understood. We have generated expression, immunohistochemical, and viral persistence data in myocardial tissue sampled at the time of SCD from 20 PWH, matched to >40 HIV- control SCDs that demonstrate: (1) hearts from PWH, most on ART, exhibit higher immune activation and cardiac ion channel dysregulation; (2) PWH on ART have downregulated expression of acute heart failure (HF) genes, suggesting that SCD in PWH is less related to HF and may be due to a distinct arrhythmogenic substrate or other inflammatory process; and, (3) the level of myocardial immune upregulation in PWH on ART is comparable to the highly inflammatory myocardial state triggered by traumatic injury. Via regional digital spatial profiling, we demonstrate the first direct tissue evidence of HIV RNA in myocardial-resident macrophages (MΦ) and that HIV may preferentially affect the epicardium, a known frequent source of VT/VF triggers, in the ART-suppressed heart, suggesting a regional myocardial specificity to the effects of HIV. Our central hypothesis is that HIV- induced MΦ activation in myocardium of PWH on ART, with particular augmentation in the arrhythmogenic epicardium, leads to chronic cardiac inflammation, interstitial fibrosis, ion channel dysregulation, and disruption of normal electrical coupling. Together, these process exert a direct myocardial tissue effect beyond the vascular space, to ultimately result in arrhythmic substrate that underlies increased SCD risk due to fatal arrhythmias in PWH. Our aims are to test the following hypotheses: 1A) myocardium from PWH on ART with SCD vs. HIV- SCDs and trauma controls have a higher burden of HIV-infected or infiltrating/inflammatory MΦ, which in turn correlates with levels of myocardial inflammation, fibrosis, and electrical remodeling; 1B) myocardium from PWH on ART with SCD vs. HIV- SCDs and trauma controls demonstrate chronic immune activation and tissue remodeling specific and distinct to the highly arrhythmogenic and inflammatory epicardial layer, including its adipocytes; and 2) chronic immune activation promotes fibrosis and decreased electrical coupling in specialized conduction tissues from PWH on ART with SCD vs. HIV- SCDs and trauma controls.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Meningiomas comprise 40% of primary intracranial tumors and approximately 1% of humans will develop a meningioma in their lifetime. Meningioma treatments are largely restricted to surgery and radiotherapy (RT), and systemic therapies remain ineffective or experimental. The World Health Organization (WHO) has historically graded meningiomas according to histological features. According to WHO criteria, many grade 1 meningiomas can be effectively treated with surgery or RT, but many WHO grade 2 or grade 3 meningiomas are resistant to treatment and cause significant neurological morbidity and mortality. Approximately 30% of WHO grade 1 meningiomas develop recurrences that cannot be predicted from histological features, and some WHO grade 2 or grade 3 meningiomas are unexpectedly well controlled with surgery and RT. These data indicate that improvements in meningioma risk stratification are needed, but limited understanding of meningioma biology and the misconception that all meningiomas are “benign” has encumbered medical advances for patients. Postoperative RT improves local control of meningiomas, but the benefits of meningioma radiation must be weighed against long-term toxicities, which can include neurocognitive deficits and secondary cancers. Most meningioma patients survive 5 years or more after diagnosis and are therefore at risk of long-term side effects of ionizing radiation on the normal brain, including white matter change, microvascular damage, and cognitive deficit. In recognition of the controversies surrounding meningioma risk stratification and treatment, clinical trials in North America and in Europe currently randomize patients with newly diagnosed WHO grade 2 meningiomas to postoperative surveillance or postoperative RT after gross total resection. Thus, there are unmet needs for improved risk stratification and prediction of postoperative RT responses for meningioma patients. To address this, we performed molecular profiling on 1856 frozen or formalin-fixed paraffin-embedded meningiomas from 12 institutions across 3 continents to develop a predictive 34-gene expression biomarker that outperforms all other risk stratification systems and identifies tumors that benefit from postoperative RT. The clinical and analytical validity of this biomarker were established in external cohorts and archival samples from NRG/RTOG 0539, the only successful prospective study of RT for meningiomas in North America. Despite these advances, all our meningioma gene expression profiling was performed in research laboratories, and our biomarker calculations largely relied on a hybridization and barcode-based platform for transcript quantification that is not widely available in the clinic. Our central hypothesis is that gene expression profiling will enable biomarker detection in clinical meningioma samples in a CLIA/CAP-certified setting. To test this, we will deploy two platforms for transcript quantification that rely on hybridization and barcoding, or on RNA sequencing, to test archival (Aim 1) or prospective (Aim 2) meningiomas. Successful completion of this proposal sets the stage for biomarker-stratified clinical trials that are currently under development for meningiomas through NRG Oncology.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Rac1, a member of the Rho GTPase subfamily, regulates essential cellular functions including cytoskeletal arrangement, cell motility, cell cycle progression, and proliferation. Dysregulation of Rac1, such as through the oncogenic P29S mutation or the expression of the alternative splice variant Rac1b, is common in cancer and contributes to tumor progression, metastasis, and drug resistance. While Rac1 gain-of-function mutations, amplification, or increased activity of activating proteins are necessary for driving tumorigenesis, the Rac1b variant alone has also been shown to promote oncogenicity. While Rac1 and Rac1b differ by only a 19- amino acid insertion after Rac1b's Switch II pocket, this alteration changes the Switch I and II dynamics of Rac1b, resulting in changes in cellular activity and promotion of tumorigenesis. Furthermore, distinguishing the roles of these variants in cellular signaling and disease is challenging due to their sequence and structural similarity, coupled with the scarcity of selective chemical tools for effectively targeting these proteins in cellular systems. Current inhibitors of Rac1 reversibly target the conserved GEF binding pockets or compete with GDP/GTP for the conserved Switch I/II region, resulting in compounds with low potency and lack of specificity to Rac1. Given the differences in the dynamics of the Switch I and II pockets among Rac1 variants, I hypothesize that targeting these regions will lead to the development of Rac1 variant selective inhibitors. My preliminary data demonstrates that Switch II pocket inhibitors can exhibit selectivity for Rac1 isoforms, aiding in understanding their distinct roles in cancer progression. For Aim 1, I will utilize structure-based design to optimizing selective and cellular active Switch II pocket inhibitors towards Rac1/Rac1b G12C. To assess the potency and selectivity of these compounds in a cellular system, I will introduce the Rac1/Rac1b G12C mutation in immortalized cancer cell lines via CRISPR Prime editing. To create therapeutics towards oncogenic Rac1 variants, Aim 2 of this proposal focuses on developing covalent inhibitors targeting the conserved cysteine in the Switch I pocket of Rac1 GTPases. This strategy will exploit Rac1 P29S and Rac1b fast-cycling phenotype and low affinity for GTP to create inhibitors that outcompete GTP for binding the Switch I pocket. In conjunction with the Arkin lab, I have identified fragments from a disulfide tethering screen with affinity for the Switch I pocket, which will be optimized for binding Rac1 P29S and Rac1b. Since Rac1 P29S and Rac1b have different Switch I conformations and lower affinity for GTP than Rac1 WT, I hypothesize that these identified covalent Switch I pocket binders will preferentially inhibit GTP binding of these oncogenic variants over Rac1 WT. This project aims to create selective chemical tools to elucidate Rac1 isoforms’ role in oncogenesis and provide therapeutic inhibitors for selectively targeting oncogenic Rac1 variants in cancers. By continuing my training in integrating chemical genetics and cell biological techniques and leveraging the expertise and collaborative environment provided in the Shokat lab, I have the tools to successfully complete this project.

NIH Research Projects · FY 2026 · 2025-09

PROJECT SUMMARY/ABSTRACT This proposal emerges from the discovery that the D1 family of dopamine receptors, a class of G protein coupled receptor (GPCR), long considered to only signal from the plasma membrane, also signal from the Golgi membranes. This subcellular and compartmentalized signaling challenges some of the basic paradigms of signaling regulation. D1 dopamine receptors are the main GPCR in the midbrain and regulate functions such as locomotion, cognition, attention and impulse control. Several pathological conditions including Parkinson's disease, schizophrenia and addiction are due to dysregulation of this signaling pathway. Many drugs of abuse promote dopaminergic transmission within the midbrain by increasing the release of dopamine and activating D1 dopamine receptors, D1DRs. This increased activity of midbrain dopaminergic neurons results in increased locomotor activity and motivational behaviors such as craving and drug-seeking. In all of these studies, it has been assumed that functions of D1DRs are mostly limited to the plasma membrane. Our data challenge this assumption. We show that these receptors signal from both the plasma membrane and the Golgi in the midbrain neurons relevant to locomotor and motivational effects regulated by dopamine. We have found that signaling from each compartment has distinct effects on the molecular and cellular consequences of D1DR activation. Importantly, we have found that D1DR signaling from the Golgi plays a critical role in the molecular mechanisms associated with dopaminergic signaling events related to addictive behaviors. The overall goals of this proposal are to elucidate the molecular, cellular and physiological consequences of D1DR signaling from the PM and the Golgi compartments in primary medium spiny neurons, MSNs. We have developed or adapted state-of-the-art tools such as a light-controlled nanobody recruitment system and photoactivatable bacterial adenylyl cyclase to selectively modulate D1DR signaling at a given subcellular location. We will combine these tools with molecular and cellular readouts of neuronal activity as well as a high throughput phosphoproteomics approaches to identify the consequences of signaling from each compartment. We will then apply these tools in zebrafish, an established animal model to study the significance of D1DR compartmentalized signaling in regulating dopaminergic-mediated behavior. This project brings together conceptually and technically innovative approaches in cells and in intact animals as well as high throughput methods to identify downstream targets and potentially new therapeutic targets for countering the effects of mis-regulation of dopaminergic signaling.

NIH Research Projects · FY 2025 · 2025-09

Project Summary/Abstract Recent years have seen the simultaneous eruption of the field of cancer neuroscience and the expansion of the role of intraoperative neurophysiological monitoring to guide safe maximal neurosurgical resection of intracranial pathologies, including gliomas. This enables an unprecedented study of the effects of tumors on the electrophysiological correlates of human cognition. Breakthrough translational technologies such as microelectrode arrays and the Neuropixel probe have only improved our investigations' granularity, narrowing the capabilities gap between rodent and human researchers. Despite the nascent ascendancy of cancer neuroscience as a field, we know very little, in humans and generally, about the electrophysiologic mechanisms by which gliomas affect neuronal information processing on either population or single neuron levels and how this is affected by tumor grade and pathology. We do, however, clinically observe that cognitive dysfunction is present in most glioma patients, which is an independent predictor of worsened outcomes, highlighting the pressing need better to understand glioma cells’ functional integration into cortical circuits. Thus, by answering the central question of our project proposal – what are the population and single neuron level mechanisms by which various gliomas affect cognition? – we can potentially satisfy the dual purpose of the NINDS, furthering our fundamental understanding of neurophysiology and generating ideas for potential novel therapeutics for gliomas. We aim to accomplish this by administering a newly developed somatosensory discrimination task to patients with gliomas undergoing awake brain surgery for resection while recording brain activity with both macroelectrode grids and microelectrode arrays. We will then employ established and novel electrophysiologic techniques to probe the electrophysiologic signature of the glioma-neuron interface. Our institutional environment is uniquely positioned to answer these questions due to its status as an international referral center for glioma surgery and its current nation-leading efforts in translating novel recording technologies for human intraoperative experimentation. During my fellowship, I will participate in fine-tuning intraoperative data acquisition and have the personnel and computing resources to perform electrophysiological analyses on the recorded signals. This will advance my understanding of lab management, novel electrode technology, and data science, with the end goal of increasing my capabilities of running my own lab as an independent surgeon-scientist in the near future.

CIHR Grants and Awards · FY 202526 · 2025-09

In Canada, two-thirds of adults and one-quarter of children and youth are overweight or obese. Obesity is a disease that puts individuals at risk for developing other chronic diseases, such as type 2 diabetes, cardiovascular disease, and some cancers. As such, there is increasing interest in the development of appetite suppressing medications, such as semaglutide (commercially known as Ozempic® and Wegovy®) to reduce obesity rates. However, these medications have variable effects in patients and patients always regain their weight after discontinuing treatment. To better understand how these medications suppress appetite and to develop safe, effective, and lasting treatments for obesity, it is important to study the intricate signalling pathways in our brain involved in appetite and body weight regulation. Neurons in our brain have antennae-like structures called primary cilia, which are able to receive, integrate, and transmit signals. We have demonstrated that an essential receptor for body weight regulation localises to and signals via primary cilia. Using novel genetic tools, we will 1) test if ciliary signaling pathways are active upon receptor activation, and 2) test if inhibiting these ciliary signals results in increased food intake and obesity. These findings will provide insight into ciliary signalling pathways involved in body weight regulation and may identify new approaches to develop specific and lasting treatments for obesity. In general, this work offers a more comprehensive understanding of how neurons in the brain integrate and respond to signals in the context of normal physiological and disease states. Keywords: LEPTIN-MELANOCORTIN SYSTEM; NEUROPEPTIDE SIGNALLING; MELANOCORTIN-4 RECEPTOR (MC4R); NEURONS; PRIMARY CILIA; GENETIC TOOLS; G-PROTEIN COUPLED RECEPTOR (GPCR); STEREOTAXIC SURGERY; OBESITY

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ ABSTRACT Methamphetamine (MA) use has been increasingly recognized as a significant contributor to the worsening health outcomes of individuals with HIV (PWH), with severe comorbidities including immune dysfunction, cardiovascular disease, and pulmonary hypertension. Even in the presence of effective antiretroviral therapy (ART) that maintains viral suppression, MA use exacerbates HIV pathogenesis and complicates efforts to achieve an HIV cure. Despite the high prevalence of MA use among PWH, its direct effects on HIV cure efforts, particularly how it alters HIV reservoirs and immune function, remain poorly understood. The overarching goal of this proposal is to investigate the complex intersection of HIV, methamphetamine use, and immune dysfunction. In addition, this career mentorship award will provide protected time for Dr. Lee to expand her mentoring capacity of early-stage data science investigators in the interdisciplinary field of clinical translational HIV and substance use research. This proposal outlines a comprehensive, data-driven approach to investigate how MA exposure influences HIV reservoir transcription and host immune responses, with the goal of developing computational models that can predict the biological consequences of MA exposure, and ultimately, inform HIV cure strategies. The specific aims of this proposal will employ advanced statistical and computational methods to examine the causal relationships between MA exposure and immune dysfunction, quantify the pharmacologic effects of MA in individuals with HIV, and identify the genetic factors that mediate these effects. In Aim 1, we will apply causal inference methodologies to longitudinal data from Dr. Lee’s ongoing Effect of Methamphetamine on Residual Latent HIV Disease (EMRLHD) cohort. This analysis will focus on determining whether MA exposure causally influences host immune dysfunction, including the activation of the NLRP3 inflammasome and elevated IL-1β signaling, as well as whether it contributes to persistent HIV transcription in CD4+ T cells of individuals on ART. In Aim 2, we will use pharmacokinetic/pharmacodynamic (PK/PD) modeling to explore the dose- and host- specific effects of MA on HIV reservoir transcription and immune function. Using data from a randomized placebo-controlled trial of PWH on ART receiving oral MA, we will apply nonlinear mixed-effects PK/PD modeling to assess how varying doses of MA impact host immune responses (such as cytokine levels and gene expression) and HIV reservoir transcription. Finally, in Aim 3, we will prioritize genes that are functionally relevant to MA exposure using a transcriptome-wide association study (TWAS) approach, combined with machine learning algorithms, integrating genetic data with transcriptome data to identify genes whose expression is influenced by MA exposure. This work will address critical gaps in our understanding of how MA exposure impairs immune function and maintains HIV reservoirs, even in individuals on ART. Ultimately, this work will not only advance our understanding of MA’s role in HIV pathogenesis but also help lay the foundation for innovative, data-driven therapeutic strategies to address both HIV and substance use comorbidities in the future.

NIH Research Projects · FY 2026 · 2025-09

The proposed K01 Award will provide the candidate, Dr. Lauren Suchman, with 1 training and skills to achieve her long-term goal of becoming an independent investigator who enhances access to quality sexual and reproductive health (SRH) care across the lifespan. Dr. Suchman is an Assistant Professor at the University of California San Francisco (UCSF) with expertise in women’s health, SRH, and HIV with a strong foundation in qualitative methods. The tailored training and research programs described in this K01 application will enhance Dr. Suchman’s ability to conduct independent research in line with NIH’s new high-priority area outlined in NOT-OD-24-119: Research Opportunities Centering the Health of Women Across the HIV Research Continuum. She requires additional training to: 1) develop topical expertise in HIV and menopause with a focus on symptom management and its impact on health outcomes; 2) develop proficiency in clinical research and statistical methods; 3) obtain experience in participatory intervention design; and 4) develop professional skills for career advancement. She has assembled a mentorship team of experts in HIV and menopause, the epidemiology of brain health outcomes in aging women with HIV (WWH), biostatistical methods, and participatory intervention design. These mentors will support Dr. Suchman’s transition to independence through didactic coursework, one-on-one meetings and tutorials, access to adjacent research teams and working groups, and completion of an independent research project. Dr. Suchman’s program of research centers on the midlife health of WWH in the U.S. with a particular focus on the San Francisco Bay Area. Menopause is a critical inflection point in the health of midlife cisgender women, which disproportionately impacts WWH. The menopausal transition and severity of associated symptoms has also been associated with suboptimal engagement in HIV care and antiretroviral treatment. However, WWH are less likely to be offered efficacious treatments for menopausal symptoms and less likely to accept these treatments if offered compared to women without HIV. To address these gaps, the study for this K01 aims to understand how menopausal phase and symptom severity affect HIV outcomes in midlife WWH and determine how therapeutic management of menopausal symptoms can best be implemented in an HIV clinic. Study outcomes will serve as proof of concept for an R01 proposal to develop and empirically test a multi-level intervention for both providers and patients. Research and training will occur at UCSF and will leverage the Multicenter AIDS Cohort Study (MACS)/Women's Interagency HIV Study (WIHS) Combined Cohort Study (MWCCS) and the UCSF Women’s HIV Program. Research findings and skills obtained through this K01 award will facilitate Dr. Suchman’s transition to become an independent investigator who develops interventions aimed at improving SRH care for WWH as they age.

NSF Awards · FY 2025 · 2025-09

With the support of the Chemistry of Life Processes (CLP) Program in the Division of Chemistry, Professors Michael Therien and David Beratan of Duke University and William DeGrado of University of California San Francisco are studying new approaches to design materials that direct, store, and release energy. Biology has developed numerous designs that carry out these functions; chemists, however, have yet to create energy harvesting, storage, and release systems from scratch that possess the sophistication of those seen in nature. Recent advances in protein design enable chemists to construct large molecules that capture and manage the flow of positive charges, negative charges, and energy. By designing protein-based materials that migrate and collect charges and energy, unique optical, electrical, and chemical functions will be realized. The experimental procedures used in this effort provide new tools to build proteins having innovative designed functions. This pursuit allow graduate students and postdoctoral fellows to acquire specialized training in synthetic chemistry, protein design, protein biochemistry, modern computational methods, and techniques to monitor fast processes that move charge and energy. The protein design methods developed are broadly applicable and enable construction of new biologically inspired materials that carry out novel functions not seen in nature. Outreach activities of this project introduce college and pre-college students to important new technologies and teach skills important for future careers in science and engineering. Biological energy transduction relies on protein-cofactor assemblies that possess physico-chemical functionality that far exceeds that realized to date through molecular and macromolecular design and synthesis. This effort designs redox proteins that transduce energy using bound cofactors, redox-active amino acids, titratable sidechains, and buried water molecules, to orchestrate the light-triggered flow of electrons, holes, and protons, elucidating rules and principles important for driving thermodynamically reversible reactions at low overpotential and engineering vectorial control over electron and proton currents. This project takes advantage of an integrated, multi-disciplinary approach that employs: (i) design and synthesis of light-harvesting and redox-active cofactors, (ii) de novo protein design using advanced computational methods to selectively bind cofactor units in precise, organized spatial arrangements, (iii) protein expression and characterization, (iv) state-of-the-art pump-probe transient optical methods and theoretical models that interrogate photo-induced electron and proton migration reactions, and (v) spectroscopic, potentiometric, and dynamical methods, high resolution protein structure, and predictions made by theory to provide insights into how atomic-level control of cofactor environments directs energy transducing function. Information from this study elucidate fundamental principles required to understand photosynthetic energy transduction and to design proteins that possess novel electro-optic function and can transduce energy via innovative pathways. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2025-09

Project Summary Cardiovascular disease is a leading cause of mortality in the United States. One hallmark of heart failure is the reactivation of a “fetal gene program” involving increased expression of genes related to contractility, calcium handling, and energy metabolism. Despite adopting fetal-like gene expression patterns, the failing adult heart lacks the regenerative potential seen in prenatal mammals or certain species, such as fish and amphibians. The lack of regenerative capacity in the adult heart means that tissue damage leads to maladaptive cardiac remodeling, fibrosis, and eventual organ failure, rather than regrowth of the lost cardiomyocytes. This proposed work aims to understand the loss of regenerative capacity in adult mammalian cardiomyocytes through the lens of evolutionary and developmental biology. My central hypothesis is that there is a core gene expression program enabling heart regenerative capacity that is active in fetal mammals as well as lower vertebrates. In Aim 1, I will compare fetal, healthy adult, and failing human hearts and the single-cell using both transcriptomic and open-chromatin data. This will enable me to identify genes that are not reactivated during heart failure, hindering the return to a proliferative state. My preliminary analyses of multiple single-cell transcriptomics datasets suggest that the differences between healthy and failing hearts are small compared to the differences between fetal and adult hearts, and furthermore, these gene expression differences map onto changes in chromatin accessibility. In Aim 2, I will compare single-cell transcriptomics of fetal and adult human hearts with the adult and embryonic hearts of multiple other vertebrate species. This will enable me to identify gene expression programs active in species capable of cardiac regeneration in adulthood but not in those incapables. Integrating single-cell transcriptomic data across multiple species presents its own unique challenges, but preliminary work indicates that it is feasible to obtain an integration that balances species-mixing and separation of shared cell types. Together, completion of this proposal will result in hypotheses for how the regenerative capacity of hearts is conserved across vertebrates and how it becomes inactivated in adult mammals, bolstering the search for improved therapeutic strategies for heart failure by reactivating regenerative potential.

NIH Research Projects · FY 2025 · 2025-09

Background: T cell therapies represent one of the most promising recent developments in oncology, with impressive responses in certain leukemias and lymphomas resulting in the FDA approval of six CAR-T cell therapies. However, it has become increasingly clear that there are numerous challenges to the successful application of these therapies to a broader spectrum of malignancies. One significant obstacle is the development of T cell dysfunction that can result from chronic tumor antigen stimulation. Preliminary Data: Our genome-wide CRISPR screens in primary human T cells subjected to the pressure of repeated tumor stimulation identified nearly every core subunit of the Cullin-5 E3 ubiquitin ligase complex as restraining T cell functional persistence. The Cul5 complex is upregulated and activated by TCR stimulation, suggesting that chronic stimulation may trigger excessive activity of this negative regulator. We showed that disabling the Cul5 complex enables therapeutic T cells to resist dysfunction from chronic antigen stimulation and maintain potent long-term effector function. Rationale: The Cul5 complex is a highly modular E3 ubiquitin ligase complex that can host approximately 40 different known substrate receptors, which act as adaptors that each bind a variety of different substrate targets for ubiquitination and proteasomal degradation. We hypothesize that by disrupting the Cul5 complex, loss of multiple key Cul5 substrate receptors results in preservation of key substrates that can collaborate to avert T cell dysfunction. In addition, a number of the Cul5 complex substrate receptors play known roles in negatively regulating cytokine signaling responses. Our preliminary data suggest that by knocking out Cul5, we are lowering the threshold for cytokine responsiveness (signal 3), which may avert T cell dysfunction induced by repeated antigen stimulation (signal 1). Research Strategy: In this proposal, we will build on our preliminary data in three specific aims. In Aim 1, we will identify the key Cul5 complex subunits driving human T cell dysfunction after chronic stimulation through comprehensive genetic and proteomic interrogation. In Aim 2, we will evaluate the therapeutic potential of manipulating this complex in human T cells through a variety of relevant preclinical models. In Aim 3, we will test how the loss of Cul5 complex subunits affects response to key cytokines and determine whether Cul5 complex editing can synergize with antigen- inducible synthetic cytokine circuits. Expected Results: These studies will rigorously test the hypothesis that the Cul5 complex is a central driver of T cell dysfunction due to chronic antigen stimulation and will map the functional network of key Cul5 complex interactors mediating these effects. We will also determine how to combine genetic manipulation of the Cul5 complex with antigen-inducible cytokine circuits to override signal 1 induced dysfunction by boosting signal 3. Altogether, our results will teach us how to reprogram the Cul5 complex for optimal functional persistence in future generations of CRISPR-engineered T cell therapies.