University Of California, San Francisco

NIH Research Projects · FY 2026 · 2026-05

The recent FDA approvals (Lutathera, Azedra, Pluvicto) and the swell of promising experimental agents in clinical trials underscore the surging enthusiasm to investigate molecularly targeted radiotherapy (TRT) as a treatment modality for many cancers. However, the clinical experience shows that tumor responses to TRTs are often transient and/or variable among patients. Thus, there is an urgent unmet need to develop new strategies to maximize the therapeutic benefit of TRT for cancer patients. We have approached this challenge by developing a new class of radiopharmaceuticals termed “restricted interaction peptides” (RIPs) which are low molecular weight (MW) peptides that are internally cleaved by a tumor endoprotease to unmask a radiolabeled membrane binding peptide. After RIP proteolysis, the membrane binding peptide adopts a helical conformation and immediately attaches to a nearby plasma membranes in the tumor. Using PET, we have found that RIPs may have several properties advantageous for TRT. we hypothesize that RIPs may be a mutually safe and effective platform for TRT. During this project, we will test this hypothesis over three Specific Aims. During Aim 1, we will perform antitumor assessment studies with a radiolabeled RIP targeting human kallikrein 2 (hK2). We are prioritizing hK2 as the kallikreins are selectively produced by prostate cancer cells in patients with metastatic castration resistant prostate cancer (mCPRC), it is a highly efficient serine protease, and it is more highly and broadly expressed than PSMA. A promising lead (termed KRIP2.1) has been developed, validated as an hK2 substrate, radiolabeled with Cu-64, and confirmed via PET to target prostate cancer xenografts with no off target activation. During Aim 1, DOTA-KRIP2.1 will be conjugated to a representative β- (Lu-177) or alpha (Ac-225) emitter and its antitumor effects will be studied in mice bearing various tumor types with endogenous hK2 expression. During Aim 2, we will ask whether patient imaging with 64Cu-KRIP2.1 is feasible. A first in human study will be performed in 6 subjects (3 male, 3 female) to assess the safety, dosimetry, and pharmacokinetics of 64Cu-KRIP2.1. During Aim 3, we will ask whether tumor imaging with 64Cu-KRIP2.1 is feasible. Two cohorts representing patients with castration sensitive prostate cancer (n = 20) or mCRPC patients (n = 20) will receive 64Cu-KRIP2.1 PET/CT and the rate of detection will be benchmarked against anatomical imaging and immunohistochemical analysis for hK2 expression in biopsies. This project represents the first use of a conditionally activated membrane binding probe for TRT, which may overcome the well documented and significant shortcomings of conventional RLT. We are optimistic the data from these studies will provide a compelling rationale to initiate a drug trial for radiolabeled KRIP2.1 as well as to expand this platform to treat tumors overexpressing other extracellular endoproteases.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY The prevalence of type 2 diabetes (T2D) is increasing in adolescents, and metformin, the first-line FDA-approved therapy for T2D, often fails to achieve durable glycemic improvement. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) such as semaglutide have transformed the treatment landscape, offering substantial benefits, including weight loss, glycemic improvement, and β-cell preservation. However, their unintended effects on skeletal muscle loss and eating behaviors in adolescents remain poorly understood. Understanding these benefits is crucial for optimizing treatment safety and efficacy during adolescence, a key developmental period. To address this unmet medical need, Sujatha Seetharaman, MD, proposes a study through this career development with the following aims (1a) assess changes in body composition and functional outcomes over six months of semaglutide therapy in adolescents with T2D (1b) examine how the rate of weight loss with semaglutide relates to changes in muscle mass in adolescents with T2D (2) investigate the effect of semaglutide on the risk of disordered eating and internalized weight stigma in adolescents with T2D. She will enroll 50 adolescents (ages 12–17.99 years) with new-onset T2D from UCSF Diabetes Clinics, treated with metformin for at least 3 months, and initiating semaglutide per their routine clinical care. In aim 1, she will assess changes in fat mass using magnetic resonance imaging, skeletal muscle mass using the D3 creatine dilution method, muscle quality, strength, and function at baseline and 6 months. In aim 2, she will calculate the rate of weight loss over 6 months and correlate it with skeletal muscle mass loss, strength, and function. In aim 3, she will examine changes in eating attitudes and internalized weight-related stigma at baseline and at 6 months to identify individuals who are at risk for disordered eating. Results from this proposal will inform an R01 in which targeted interventions such as an integrated exercise program and eating disorder prevention strategies will be tested in a large randomized controlled trial and expanded to include emerging dual/triple agents in adolescents with T2D. Dr. Seetharaman’s long-term career goal is to become an independently funded clinician-investigator advancing research that integrates novel pharmacotherapies with tailored interventions to improve health outcomes in adolescents with T2D. In this career development award, her career goals are to gain targeted training in body composition analysis, become proficient in advanced biostatistical methods, become proficient in utilizing person-reported outcome metrics, gain experience in conducting pediatric clinical trials, and engage in career development activities in preparation for R01 funding. She will accomplish these goals with the advice and mentoring from a world-class multidisciplinary mentoring team, participation in relevant didactic coursework, and hands-on research experience, all necessary for future independent success. This project aligns with NIDDK’s mission to improve the health and well-being of individuals affected by diabetes and related conditions.

NIH Research Projects · FY 2026 · 2026-05

Project Summery/Abstract Amid a public health crisis driven by antibiotic-resistant pathogenic bacteria, bacteriophages (phages), which naturally infect and kill bacteria, represent a promising alternative as antimicrobials. However, a significant challenge is posed by diverse bacterial immune mechanisms that resist phage infections. Overcoming this obstacle requires phages equipped with robust anti-immune capabilities. In this context, ΦKZ-like jumbophages (genomes > 200kb) have an exceptional ability to counter various bacterial nucleolytic immune systems throughout infection, with numerous family members targeting key Gram-negative pathogens. The jumbophage ΦKZ is a broad host range killer of the multi-antibiotic-resistant pathogen Pseudomonas aeruginosa and serves as the leading model phage for this family. Immune evasion is largely achieved through the assembly of a bacterial membrane lipid derived compartment termed the “Early Phage Infection Vesicle” (EPIV), which I co-discovered during my postdoctoral work, and a phage-encoded proteinaceous compartment called the “phage nucleus,” which shields the replicating phage genome. The long term goal of this study is to understand three unexplored aspects of jumbophage biology related to the biogenesis and functioning of the EPIV. The EPIV houses early transcription, but the phage has to solve a fundamental challenge not previously solved in bacteria–mRNA export from a lipid-bound compartment and successful docking with ribosomes, which are unusually uncoupled from transcription in this case. I hypothesize that a novel mRNA export channel, analogous to the eukaryotic nuclear pore complex, is assembled by injected ΦKZ proteins to export mRNA to ribosomes. I will uncover this complex using cryo-ET, mass spectrometry and genetics. I will additionally examine the role of EPIV assembly in enabling ‘pseudolysogeny’ in jumbophage infections. This process of phage quiescence was observed in jumbophages long ago but lacks a mechanistic understanding. I hypothesize that the EPIV has the potential to be a stable pseudolysogenic entity inside an infected bacterium that I will test herein with my multidisciplinary approach. Finally, I will attempt to elucidate the mechanism of EPIV biogenesis – it remains entirely unknown how this massive membrane-bound organelle is rapidly assembled within bacteria and how its formation is conserved across diverse jumbophage infections. To answer these questions, I will combine genetic dissection and c-ET to reveal the key participants and early assembly events of this unique phage-driven prokaryotic organelle formation. Overall, my studies stand to uncover fundamentally fascinating bacterial-phage cell biology in addition to innovative and potentially transferable mechanisms to enhance phage success in combating pathogenic bacteria. This research will be conducted at UCSF, which hosts state-of-the-art facilities and a highly intellectual and collaborative research community. It will also provide me with the training in genetics and structural biology that I need to fulfill my postdoctoral training goals and pioneer an independent research program in bacterial-phage interactions.

NIH Research Projects · FY 2026 · 2026-05

Project Summary / Abstract Enduring social bonds are essential for human health and well-being, yet their underlying neural mechanisms remain elusive due to limitations in traditional model organisms. Prairie voles, which naturally form lifelong pair bonds, offer a powerful system for investigating how the brain encodes stable social states. The medial amygdala (MeA) is functionally connected to a broad network of brain regions that collectively governs social behavior. Specifically, the MeA relays pheromonal cues that are critical for guiding context- appropriate behavior selection, yet how this region contributes to the behavior transition from a naïve to a bonded state in prairie voles is unknown. This proposal investigates how molecularly defined circuits in the MeA contribute to the emergence and maintenance of attachment behavior. Using single-cell RNA sequencing, I identified a sex-biased neuronal population that downregulates the neuropeptide gene Tac1 following pair bond formation. Intriguingly, the mouse equivalent of this population drives both affiliative and aggressive behaviors, and Tac1 itself has been linked to aggression control. In prairie voles, a bonded animal exhibits selective affiliation toward its partner and aggression toward all other opposite-sex conspecifics – a behavioral dichotomy that may be orchestrated by this population. I propose to characterize how this population is integrated into broader brain circuits of prairie voles and to monitor its activity during the formation of a pair bond. These experiments will clarify whether and how this population might serve as a neural substrate for the internal state of bondedness. Ultimately, this research may shed light on fundamental principles of social attachment and offer insight into how disruptions in such processes contribute to psychiatric illness. In addition to the proposed research, this application outlines a comprehensive training plan to prepare Dr. Wang for an independent career as a neuroscientist and psychiatrist. She will be mentored by Dr. Dev Manoli (UCSF), an expert in the molecular genetics and social behavior of prairie voles, and co-mentored by Dr. Michael Brainard (UCSF), a leader in the neurophysiology of complex behavior, and Dr. Vikaas Sohal (UCSF), who specializes in quantitative neural data analysis and circuit-level manipulations. Dr. Wang will also receive guidance on advanced molecular tool development from Dr. Nadav Ahituv (UCSF) and Dr. Josh Huang (Duke). Her career development is strongly supported by the UCSF Department of Psychiatry and Behavioral Sciences, which is committed to transitioning her to a full-time faculty position.

NIH Research Projects · FY 2026 · 2026-05

SUMMARY Nearly 40 million people globally and 1.2 million people in the United States are living with HIV. Although antiretroviral therapy (ART) has transformed HIV from a fatal disease to a manageable chronic condition, lifelong treatment poses substantial challenges, and ART does not cure the infection. Based on data in humans and non- human primate models linking high quality CD8+ T cell responses with low viral loads, there is strong rationale for targeting HIV-specific CD8+ T cells to promote control of HIV. However, due in part to limitations of existing CD8+ T cell assays, the field currently lacks a mechanistic understanding of which features of the CD8+ T cell response might drive effective control of HIV rebound. The overarching goal of this project is to comprehensively define the mechanistic features of CD8+ T cell responses that most strongly relate to control of HIV after stopping ART. To do this, we will study peripheral blood samples collected before analytic treatment interruption (ATI) and longitudinally after rebound in participants from ATI sub-studies within the San Franscisco SCOPE cohort, including several who maintained low viral loads (<2,000 copies/mL) for several months after stopping ART. We recently developed a novel nanoparticle class I peptide:Human Leukocyte Antigen (pHLA) pool assay that enables simultaneous measurement of pHLA specificity, T cell receptor (TCR) avidity and breadth of peptide recognition, and transcriptional signature at a clonotype level from up to 1000 HIV-specific CD8+ T cell responses per sample. In Aim 1, we will use this tool to identify features of HIV-specific CD8+ T cell clonotypes that respond as HIV reactivates during viral rebound. In Aim 2, we will apply newly-developed single-copy sequencing methods to plasma HIV sequences in order to characterize the development of HIV escape to autologous CD8+ T cell responses during and after rebound. Finally, to connect these distinct but inter-related data types, in Aim 3, we will utilize mathematical models that describe viral dynamics and evolution simultaneously to model dynamic CD8+ T cell-virus interactions that promote control of HIV after ART is stopped. This highly collaborative project with clinical, immunology, virology, and mathematical investigators will identify the mechanistic properties of CD8+ T cell responses required for successful control rebound HIV across a large group of post-treatment controllers. Our work will provide a target for the next generation of immunotherapies for HIV cure and inform T cell-based therapeutics for other chronic infections and cancers.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY/ABSTRACT Although effective therapeutics that target the dysregulated kinase activity of BCR::ABL1 have been developed for patients with chronic myeloid leukemia (CML), acquired resistance remains an important clinical issue. Additionally, problematic side effects plague a considerable proportion of patients who are expected to require lifelong therapy. The first five approved tyrosine kinase inhibitors (TKIs) for CML target the ATP binding pocket of BCR::ABL1 (“orthosteric” TKIs). Asciminib is the first active “allosteric” TKI for CML and was recently approved as a frontline therapy based on high response rates and excellent tolerability. Asciminib is rapidly being adopted as a preferred treatment in all lines of therapy. We have demonstrated that several mutations that confer resistance to orthosteric TKIs unexpectedly confer in vitro and/or clinical resistance to asciminib. We have further demonstrated that a clinical variant of BCR::ABL1 lacking ABL1 exon 2 is uniquely and highly resistant to asciminib. Notably, these isoforms retain asciminib binding affinity, thereby invoking a novel molecular mechanism of resistance. Our central hypothesis is that asciminib will be vulnerable to multiple resistance- conferring mutations that disrupt its allosteric effect on kinase conformation, in addition to a limited number of mutations that impair its ability to bind BCR::ABL1. Our rationale is that pioneering work on orthosteric TKI resistance mechanisms in CML have informed kinase conformational dynamics, optimal CML patient management, development of next-generation TKIs and successful prediction of TKI resistance mechanisms in several other malignancies. We propose to (i) employ orthogonal approaches to identify and validate single point mutants in BCR::ABL1 that can confer resistance to asciminib, and compound (≥2 on one DNA strand) mutants that arise following subsequent orthosteric TKI therapy, (ii) assess their sensitivities to a novel active investigational allosteric inhibitor, combinations of TKIs, and a novel bitopic TKI, (iii) determine mechanisms of resistance through computational and structural studies, (iv) define residues necessary for adoption of the closed ABL1 kinase conformation, and (v) assess the ability of asciminib-resistant mutants to pathologically activate ABL1 kinase activity. The proposed research is significant due to its potential to rapidly impact clinical investigation and optimize patient management, inform understanding of kinase regulation and other malignancies. The proposed research is innovative because it applies state-of-the-art methodologies to comprehensively define and characterize a novel mechanism of resistance to a first-in-class highly clinically active allosteric TKI and thereby establish a new paradigm. Additionally, it will assess the promise of emerging agents, TKI combinations, and an innovative bitopic TKI with best-in-class features for treating asciminb-resistant single and compound mutants.

NIH Research Projects · FY 2026 · 2026-05

Project Summary/Abstract Common forms of human obesity have a polygenic genetic basis, highlighting the importance of understanding different genetic variants in body weight regulation. Multiple Genome-Wide Association Studies (GWAS) have linked Ankyrin Repeat and SOCS Box Containing 4 (ASB4) to human obesity, but how ASB4 regulates energy homeostasis is not well understood. Our preliminary experiments show that ASB4 is expressed in mouse brain regions that are crucial for feeding regulation. ASB4 deficiency leads to increased meal size and food intake following a fast, and ASB4 is required for the anorectic effects of CalcR agonists or long-acting amylin analogues. ASB4 deficiency also results in heightened consumption of dietary fat at the expense of dietary carbohydrates when two diets are offered. These preliminary findings strongly suggest that ASB4 is important for meal termination and food choice. In this application, we will determine the site of action and cellular mechanism by which ASB4 controls meal termination. We will investigate if ASB4 engages the brain reward system to regulate food choice. If successfully completed, this study will establish ASB4 as a pivotal regulator of homeostatic and hedonic feeding. As ASB4 is highly conserved between mice and humans and is linked to obesity by GWAS, this study will provide mechanistic insight into how ASB4 may regulate food intake in humans.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY/ABSTRACT Long-acting (LA) antiretroviral therapy (ART) has emerged as a paradigm-shifting approach for treating HIV by addressing adherence challenges, a critical barrier to achieving viral suppression (VS). While clinical trials demonstrated high efficacy among people with HIV with VS on oral ART, real-world implementation has expanded to include those with active viremia and adherence difficulties. The UCSF Ward 86 Clinic and the Emory Ponce de Leon Clinic pioneering LA ART programs have shown remarkably high rates of VS on LA ART, even among initially viremic patients with significant comorbidities, informing recent guideline changes in the U.S. that now permit LA ART for those with viremia. However, critical knowledge gaps remain regarding predictors of treatment outcomes in real-world populations, including pharmacokinetics (PK) and the reservoir. This study will establish the relationship between LA ART drug concentrations and virologic outcomes in a real- world clinical setting with a focus on populations not well-represented in clinical trials (e.g. those with initial viremia and adherence challenges). We hypothesize that specific threshold levels of cabotegravir, rilpivirine, and lenacapavir in hair and plasma will predict blips, persistent low-level viremia, and virologic success, with other patient-level factors, such as body mass index (BMI), age, sex, modifying these relationships. Finally, the frequency of blips on LA ART has raised concerns that these drugs may fail to achieve complete VS, meriting deep investigation of how LA ART affects the active and latent viral reservoirs. Ward 86 in San Francisco and Ponce Clinic in Atlanta have now collaborated in this application due to having the two largest LA ART programs in the country (~1100 on LA ART combined). We will: 1) enroll patients from our two LA ART programs into a cohort with PK sampling, demographic data, and clinical outcomes (Aim 1); 2) assess the relationship between drug levels and viral suppression using validated assays for cabotegravir, rilpivirine, and lenacapavir in both hair and plasma (Aim 2); and 3) compare the active and latent viral reservoir among those starting LA ART with or without viremia, and compare this reservoir data to a contemporaneous cohort of people on oral ART (Aim 3). Our two sites are well poised to conduct these aims and the inclusion of a site in the South will allow for sex differences to be evaluated due to the higher prevalence of women in the region. The UCSF Hair Analytical Laboratory has performed drug level monitoring for two decades, and our team is experienced in measurement of the HIV viral reservoir within a large preexisting cohort on oral ART. By study completion, we will have determined factors that predict virologic success on LA ART and established drug levels necessary for VS in real-world settings so that LA ART can be optimally dosed for individuals and intensified, depending on reservoir findings. Our findings will address the 33% gap in viral suppression in the U.S. and provide guidance for optimizing LA ART implementation. These results will directly inform clinical practice and interventions to optimize LA ART outcomes, particularly among those with adherence challenges.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY Over 930 million people worldwide are estimated to be living in fragile and conflict-affected settings (FCAS) – characterized by recurrent violence, conflict, or war – and experiencing food insecurity and mental distress. The detrimental effects of violent political events on food insecurity, and separately, on mental health are well documented. However, the impact of non-violent political events on food insecurity in FCAS is lesser explored. Furthermore, little is known about the differential cumulative impact of repeated political events – ranging from violent events (e.g., military assaults) to less extreme non-violent events (e.g., agreements) – on the relationship between food insecurity and mental health in FCAS. Quantifying the cumulative impact and capturing the intensity and severity of violent and non-violent political events is especially important in the context of protracted FCAS, where individuals endure prolonged exposure to violent and non-violent events, and stressors, such as food deprivation and insecurity, are likely to accumulate through time and impact mental health outcomes. We will leverage a longitudinal, geo-location political events dataset and three waves of repeated cross- sectional, representative household and corresponding individual survey datasets from a protracted conflict- affected setting, the occupied Palestinian territories (oPt); together, these data are uniquely positioned to permit examination of the relationships between political events, food insecurity, and mental health, and their intervening pathways. We reason that each discrete political event may function as a stressor and contribute to feelings of insecurity (across varying needs and including food) and mental distress. We expect that repeated occurrences of even non-violent, low extremity political events (e.g., establishing a political headquarter) each year can add up and exert its cumulative impact on food diversity, food insecurity experience, and on mental distress in a FCAS. Understanding the cumulative impact of violent and non-violent political events on food insecurity, incorporating individual behavioral changes and coping mechanisms, and mental health, will inform evidence- based interventions in FCAS. The evidence can allow for rapid response and improve the efficacy of humanitarian interventions during time of crises. This information is especially important given the recent increase in conflict and political events worldwide.

NIH Research Projects · FY 2026 · 2026-05

Project Summary/Abstract Vision loss is a devastating medical problem as it can lead to reduced productivity, lower quality of life, and loss of independence. Glaucoma affects over four million Americans and 76.0 million people worldwide, making it the second leading cause of irreversible blindness globally. The disease is characterized by retinal ganglion cell degeneration with consequent loss of the axons that connect the eye to the brain and progressive damage to the optic nerve. Pharmacological and surgical interventions that lower intraocular pressure can slow or even stop retinal ganglion cell degeneration. However, many patients do not seek medical attention until the disease is advanced and others continue to experience disease progression despite treatment, ultimately resulting in the widespread loss of retinal ganglion cells and profound vision loss. Unfortunately, the human retina has minimal regenerative capacity and cannot replace lost retinal ganglion cells, making vision loss in these patients permanent. The candidate’s long-term career goals are to advance our understanding of gene regulatory networks directing retinal ganglion cell differentiation during development and to apply these insights to formulate strategies for regenerating retinal ganglion cells from dormant progenitor cells in the adult retina. The proposed career development and training plans will allow the candidate to acquire further expertise in retinal development and regeneration. By learning additional cutting-edge experimental techniques, the candidate will also enhance the scientific rigor and impact of their research program. In the first specific aim, the candidate will investigate the role of transcription factor Pou2f2 in retinal ganglion cell development using conditional gene deletion, as well as gain-of-function by in vivo electroporation of postnatal progenitors. In the second and third specific aims, the candidate will perform an in vivo screen of more than 40 candidate transcription factors to identify a combination capable of reprogramming Müller glia into retinal ganglion cells. Further studies will focus on characterizing induced retinal ganglion cell morphology, laminar position, axon extension, electrophysiology and gene expression. Adaptive optics will be used to longitudinally image the reprogramming process in vivo. Lastly, the candidate will investigate survival and circuit integration of these newly generated retinal ganglion cells in mouse models of glaucoma. Because retinal ganglion cells are widely used as a model for axonal regeneration in vertebrates, these studies have broader implications for regeneration of central nervous system neurons and pathways. The candidate will conduct the proposed research in collaboration with co-mentors Dr. Yvonne Ou and Dr. Xin Duan, and the other members of the advisory committee. Experiments will take place in Rock Hall, where the candidate has dedicated laboratory space in close proximity to all collaborators. The UCSF Department of Ophthalmology is a leading center for vision science research, providing the candidate with access to NEI P30 funded core facilities and extensive university-wide resources. The candidate will also benefit from interactions with the broader neuroscience and stem cell research communities at UCSF.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY/ABSTRACT Across sub-Saharan Africa, approximately one-third of new HIV infections occur among men. Men in highly mobile occupations, such as fishing, are particularly vulnerable to poor HIV prevention engagement. Fisherfolk (men and women who work in the fishing industry) are the largest key/priority population in Kenya. Despite significant declines in HIV incidence in other populations in sub-Saharan Africa, fishermen have persistently high rates of HIV acquisition. Kenya has been a leader in scaling up biomedical HIV prevention, including oral tenofovir-based pre-exposure prophylaxis (PrEP), a daily pill that is highly effective with sufficient adherence. However, efforts to improve daily oral PrEP use have not been effectively deployed to address the unique barriers experienced by mobile fishermen, particularly as new HIV prevention technologies and regimens are introduced such as long-acting injectable PrEP (e.g., CAB-LA; injection every 2 months and lenacapavir; injection every 6 months), event- driven PrEP (oral PrEP taken before and after sexual contact), and post-exposure prophylaxis (oral PrEP taken after potential HIV exposure). Without tailored delivery strategies, these innovations risk reproducing the same access and adherence challenges that have limited the impact of existing prevention tools in this population. Evidence-based approaches tailored to the needs of mobile fishermen are urgently needed to optimize their engagement in biomedical HIV prevention. Evidence-based approaches such as differentiated and patient- centered service delivery for HIV prevention have been endorsed by the WHO, yet these service delivery models have not yet been effectively harnessed to improve mobile fishermen’s uptake and adherence to biomedical HIV prevention. Meaningful engagement of community members in tailoring evidence-based HIV interventions is recognized as an approach that may increase sustainability, ownership, and acceptance of interventions. However, established methods to effectively engage mobile populations, including fishermen, in research are limited. Community-led, participatory approaches in global HIV research have infrequently been utilized with priority populations such as mobile fishermen yet may be vital to addressing prevention gaps. The proposed research uses community-engaged and participatory approaches to identify factors influencing fishermen’s engagement in HIV prevention (Aim 1) and to co-design an evidence-based intervention in collaboration with fishermen (Aim 2). The co-designed intervention will then be piloted to evaluate its implementation and client outcomes (Aim 3). Completion of the proposed training and research plan will provide me with an expanded skillset in community-engaged research, intervention design, and implementation science approaches. I will be mentored by a team of experienced Kenyan and UCSF mentors. A future R01 will evaluate the co-designed intervention at scale.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY The goal of this K08 Career Development Award is to train Dr. S. John Liu, a second year Assistant Professor in Residence at UCSF, in the skills he will need to become an independently funded physician-scientist capable of basic and translational investigation in neuro-oncology. Dr. Liu proposes to investigate the role of DNA-PKcs, a kinase well described in DNA repair but relatively underappreciated in non-canonical functions such as tumorigenesis and tumor-immune signaling. The proposal is an extension of his previous work on developing and implementing single cell functional genomics tools to identify and validate genetic regulators of radiotherapy resistance, which is a major problem in the treatment of patients with glioblastoma (GBM). Dr. Liu has shown through unbiased genome-wide CRISPR screens, in vivo perturb-seq experiments, intracranial xenografts, and spatial transcriptomics of patient tumors that inhibition of DNA-PKcs combined with radiotherapy results in decreased pro-growth gene expression and remodeling of the tumor immune microenvironment in GBM. In Aim 1, Dr. Liu will investigate the tumor cell-intrinsic mechanisms of how DNA-PKcs drives resistance to radiotherapy and cell survival in GBM, focusing on transcriptional regulation through chromatin binding and interactions between DNA repair and interferon signaling. In Aim 2, Dr. Liu will investigate how DNA-PKcs regulates the tumor immune microenvironment in syngeneic animal models of GBM. He will then determine the role of the cGAS/STING pathway in the anti-tumor effects of DNA-PKcs inhibition, followed by therapeutically targeting this pathway through STING agonism. In Aim 3, Dr. Liu will validate tumor immune microenvironment reprogramming using patient tumor biospecimens from a clinical trial of DNA-PKcs inhibition and radiotherapy for GBM. This proposal uses vertebrate animals because understanding glioblastoma, a complex disease that involves tumor, stromal, and immune cells, requires experimentation in mice in which the tumor immune microenvironment cannot yet be entirely recapitulated in vitro. Dr. Liu’s career development and research plans include a combination of formal coursework tailored to fill his specific knowledge gaps, national workshops, international conferences, and intensive hands-on research experience that will take place at UCSF, a leading NCCN Comprehensive Cancer Center with an excellent track record in basic and translational neuro-oncology research. Dr. Liu’s training plan specifically focuses on areas that are underdeveloped in his research skillset, specifically (1) molecular biology and radiobiology research methods, (2) tumor immunology knowledge and research methods, (3) translational research skills in neuro-oncology, and (4) leadership and laboratory management skills to achieve and sustain independence. This project will be mentored by David Raleigh, Associate Professor of Radiation Oncology, Neurological Surgery, and Pathology at UCSF who is an experienced mentor well suited to train Dr. Liu in these key areas. Dr. Liu has a highly distinguished but available advisor committee possessing synergistic expertise spanning basic, translational, and biostatistical sciences to guide his research and career trajectory. Successful completion of this proposal will train Dr. Liu for independence and also provide mechanistic understanding of RT resistance in GBM, while elucidating rationally informed combination therapy strategies that may improve outcomes for patients with GBM.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY Chronic pain affects one out of four Americans and is often refractory to any treatment including medications, injections or surgery. Deep brain stimulation (DBS) involves implanting electrodes in key brain regions and holds promise as a new option for therapy, but we currently lack the technology to reliably achieve long-term pain symptom relief. A “one-size-fits-all” approach of continuous, 24/7 brain stimulation has helped patients with some movement disorders, but the key to reducing pain may be the activation of stimulation only when needed. This is called closed loop stimulation which may help to reduce side effects and keep the brain from adapting to stimulation effects. Further, because we know that an individual’s pain experience is processed by many brain regions and no single target works for all patients, DBS that targets these many regions may serve more patients and pain syndromes then just targeting one or two brain regions. We aim to develop a new brain stimulation device platform using personalized brain targets for hard-to-treat chronic pain and to improve technology that will enable the delivery of stimulation only when pain signals in the brain are high. This device platform provides a form factor and ease of use that addresses needs expressed to our team by previous patients and includes necessary technical capabilities that exceed any existing device. We will then test whether personalized stimulation, possible with this device, leads to reliable symptom relief for chronic pain patients over extended periods of time.

NIH Research Projects · FY 2026 · 2026-05

ABSTRACT The goal of this project is to enable scientific discovery and advances in biomedical research through the development of cutting-edge software tools that provide integrated visualizations and analyses of molecular structures and related biological information. Our tools can be applied to diverse types of biomolecular data, including atomic-resolution coordinates, 3D cryo-EM and cryo-ET density maps, and protein and nucleic acid sequences, annotations, and networks. During the next five years we will continue our emphasis on the unmet software needs for basic and applied biomedical research using highly trained and talented staff, with excellent interdisciplinary knowledge and specialized, state-of-the-art expertise in software engineering, computer graphics, and data analysis. Our primary focus will be on the interactive visualization and analysis of structures of molecules, molecular assemblies, and sequence-structure relationships. These areas are critical for addressing important and highly relevant biomedical problems such as identifying the molecular bases of disease, identifying targets for drug development, designing drugs, and engineering proteins with new functions. The tools we develop and disseminate will enable scientists to understand, analyze, and illustrate to others the important principles of molecular structure, function, and interactions. Our tools such as ChimeraX are widely recognized as works of the highest quality, and are available for free on our website as executable applications and in source-code form through our GitHub repository. We fully support and maintain these tools, and provide detailed documentation and tutorials. Our technological developments are disseminated widely via scientific publications, lectures, software distribution, and web-accessible videos.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY Juvenile idiopathic arthritis (JIA) is the most common rheumatologic condition in children, and 12-38% of patients with JIA develop chronic asymptomatic anterior uveitis, typically within 4 to 7 years of arthritis onset. JIA- associated uveitis can cause significant morbidity, with as many as 1/3 of all patients developing substantial visual impairment and up to 15% becoming legally blind. The anti-tumor necrosis factor (TNF) human monoclonal antibody adalimumab has shown efficacy in treating JIA-associated uveitis but is associated with a risk of serious adverse events, including opportunistic infections and malignancy. Furthermore, long-term treatment with adalimumab is expensive and causes a significant financial burden for the patient and healthcare system. The Adalimumab in Juvenile Idiopathic Arthritis (JIA)-associated Uveitis Stopping Trial (ADJUST), an NEI-funded, double-masked, randomized controlled trial recently conducted by our team, revealed 64% cumulative failure among patients with previously stable JIA-associated uveitis at 24 weeks after stopping adalimumab. The rate of recurrence of inflammation when stopping adalimumab was high, even when over 70% of the patients had over two years of controlled uveitis. Encouragingly, all patients who relapsed regained control upon restarting treatment. Collectively, these reasons contribute to a growing interest in developing evidence-based guidelines for reduction in adalimumab dose frequency once control of inflammation has been achieved. We propose to conduct a multicenter, parallel-treatment, observer-masked, randomized trial to generate an adalimumab regimen-response curve with rates of treatment failure in patients with controlled JIA-associated uveitis across a range of adalimumab injection frequencies. (Aim 1). 160 patients across eighteen clinical centers will be randomized to one of four regimens: 1) injections administered every 2 weeks (standard of care) 2) injections administered every 4 weeks 3) injections administered every 8 weeks 4) injections administered every 12 weeks. Additionally, we aim to identify the optimal range of drug exposure for adalimumab that maintains JIA-associated uveitis disease remission. (Aim 2). A comprehensive investigation of the clinical pharmacology of adalimumab will enhance our understanding of the association between drug levels and optimal immunosuppression and provide more effective but convenient dosing strategies for long- term disease control. Results from this clinical trial can be used to guide the counseling of patients and families who want to optimize treatment. Therefore, reduced-frequency dosing strategies for adalimumab may be a promising alternative strategy to stopping adalimumab.

NIH Research Projects · FY 2026 · 2026-05

Project Abstract Glioblastoma outcomes have not improved substantially over the past decades, with median survival remaining at 12-15 months despite aggressive therapy. A major limitation in the current radiotherapy (RT) planning is it defines clinical target volumes (CTVs) using uniform geometric expansions around MRI-visible tumor boundaries. This conventional approach fails to capture GBM’s diffuse infiltrative spread and ignores patient-specific tumor biology. As a result, microscopic disease often extends beyond the treated field while normal brain is unnecessarily irradiated, leading to universal recurrences and treatment-induced toxicity. Although diffusion tensor imaging (DTI) can visualize white matter tracts, current tractography does not distinguish between tract pathways that facilitate tumor cell migration and those that are anatomically present but rarely involved in tumor spread. Additionally, molecular biomarkers such as MGMT methylation and TERT promoter mutations reflect distinct tumor progression patterns, yet these factors are not incorporated into RT target delineation. This project investigates DTI-based infiltrative risk mapping integrated with molecular biomarkers to improve glioblastoma progression prediction and RT CTV definition using a dataset of over 500 patients with pre-operative DTI, anatomical MRI, and molecular biomarker data. We will develop White Matter Infiltrative Risk maps by identifying population-level infiltration patterns across major white matter tracts and combining these with patient-specific fiber density maps. The infiltrative risk maps will be integrated with anatomical MRI, MGMT methylation and TERT promoter mutation status through a transformer-based deep learning framework with cross-attention mechanisms. Validation will be conducted via spatial accuracy assessment against ground truth progression, comparison with standard RT targets, and histopathological correlation using tissue samples with matched imaging coordinates from 298 patients. This fusion of advanced DTI mapping and genomics with state-of-the-art Artificial Intelligence modeling will produce voxel-level risk maps that reveal otherwise occult tumor infiltration pathways and can be directly incorporated into RT planning. This work will provide proof-of-concept for integrating infiltration pathways and biological factors into RT target definition and establish the foundation for future clinical trials testing personalized radiation therapy strategies. The goal is to transition from geometric margins to biology-guided targeting that improves GBM control while preserving healthy brain tissue.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY/ABSTRACT Leishmaniasis is a neglected tropical disease caused by over 20 protozoal species and transmitted by 70 species of sandflies, resulting in mucocutaneous, cutaneous, and visceral manifestations. Accurate species-level identification is essential for effective treatment and prognostication. Traditional microscopy lacks sensitivity and species specificity, whereas PCR, the most accurate current method, requires complex equipment and trained personnel in conventional laboratory settings. CRISPR-Cas direct detection technology, specifically CRISPR-Cas12, presents a promising alternative for species-specific diagnosis at the point of care. This technology detects DNA in vitro using a guide RNA that produces a fluorescent signal upon recognizing target DNA sequences, providing a faster and simpler alternative to PCR that could be used at the point of care. The objective of this research is to develop a CRISPR-based assay capable of speciating Leishmania, leveraging our expertise in CRISPR diagnostics for infectious diseases. This assay aims to enhance disease management by enabling accurate, rapid, and accessible species-level diagnosis. The project will achieve this by (1) identifying species-specific sequences for CRISPR-Cas targeting, and (2) developing and confirming Cas12 guides that can speciate Leishmania spp. DNA samples. These objectives will be accomplished through Cas12 guide design and selection, optimization of the CRISPR assay, and sample preparation to quantify parasite DNA spiked into blood. The anticipated outcomes include species-specific guides that be used for speciation, thereby informing treatment decisions. Additionally, the research will establish a pipeline for guide design applicable to further diagnostic research on Leishmaniasis and other neglected tropical diseases. The ultimate goal is to integrate this assay into a diagnostic platform suitable for low-resource settings, accelerating efforts to elucidate epidemiological patterns of leishmaniasis and guide treatment strategies aimed at disease elimination. These research objectives will be pursued in the context of a comprehensive research training program at the University of California, San Francisco, and Berkeley. This program encompasses structured technical and conceptual mentorship from the primary sponsor, Dr. Daniel Fletcher, an expert in diagnostics for neglected tropical diseases, and the co-sponsor, Dr. Dawn Wetzel, a physician-scientist expert in molecular parasitology. The applicant will receive additional training through structured preceptorships and regular advising sessions with physician-scientists specializing in the epidemiology and diagnostics of neglected tropical diseases, with a focus on pediatric care. This combination of experiences will provide invaluable training for an aspiring infectious disease physician-scientist.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY/ABSTRACT People with HIV (PWH) who experience challenges with antiretroviral therapy (ART) adherence are at increased risk for suboptimal treatment outcomes, including viral non-suppression and disengagement from care. Despite advancements in ART delivery options, personalized treatment approaches that integrate patient preferences remain underutilized, particularly among PWH facing psychosocial and documented barriers. Clinical decision support (CDS) tools offer a promising avenue to address this gap by tailoring treatment recommendations based on patient-specific needs and barriers. However, current CDS tools often fail to incorporate rich patient insights available from unstructured electronic health record (EHR) notes or systematically integrate directly reported preferences, limiting their potential to enhance adherence and outcomes. The proposed training and research plan for this K23 will enable José I. Gutierrez, Jr., PhD, FNP- BC, to acquire the expertise necessary to become an NIH-funded independent investigator who designs patient-informed CDS interventions that optimize HIV treatment delivery. Under the mentorship of an experienced multidisciplinary team, Dr. Gutierrez will use a mixed-methods approach to develop foundational components of a CDS prototype that integrates natural language processing (NLP)–derived EHR information with patient-reported preference data. Building on prior work in HIV treatment delivery and preference evaluation, he will pursue the following specific aims: (1) explore HIV treatment delivery preferences, barriers, and facilitators within EHR notes using NLP; (2) identify and quantify patient preferences, barriers, and facilitators using qualitative interviews and MaxDiff; and (3) develop the key features of a CDS prototype that generates tailored suggested actions informed by EHR and patient-preference data, and evaluate its acceptability, feasibility, usability, and intended adoption in a 9-month, cross-sectional, non-clinical user-testing study using standardized vignettes and de-identified/fictionalized cases (no live EHR). This research plan aligns with Dr. Gutierrez's career development goal to gain advanced skills in clinical informatics and NLP, qualitative and mixed-methods research, and patient-informed intervention design. Findings will provide the foundation for a subsequent NIH R01 to rigorously evaluate effectiveness in clinical settings, with the overarching goal of improving ART adherence and treatment outcomes among PWH. 1

NIH Research Projects · FY 2026 · 2026-05

Project Summary/Abstract Protein-small molecule interactions regulate protein function, signal transduction, and enzymatic catalysis in biological systems. Advances in protein engineering have enabled modifications of natural protein-small molecule interactions for diverse applications, including developing protein tags for fluorescence imaging and engineering enzymes for biocatalysis. However, designing de novo proteins to bind small molecules and catalyze reactions remains a significant challenge, often requiring extensive screening and experimental optimization. In my recent work, I developed a nature-inspired strategy leveraging weak protein affinities for non-primary substrates to create functional proteins. Using this approach, I designed Fluorescent ABLE (FABLE), a fluorophore-binding protein, and Kemp eliminase ABLE (KABLE), an enzyme for Kemp elimination. The initial Kemp eliminase design achieved an activity of 6600 M⁻¹s⁻¹ in just five attempts, surpassing previous computational designs by over an order of magnitude. Saturation mutagenesis produced a quadruple mutant with an activity of 600,000 M⁻¹s⁻¹, setting a new benchmark for base-catalyzed Kemp eliminase and outperforming mechanistically similar natural enzymes. These successes highlight the frontier of de novo protein design for specific ligand interactions. A deeper understanding of protein-small molecule interactions in de novo proteins is crucial for advancing both fundamental understanding of these interactions in Nature and practical applications in protein engineering, particularly in the development of protein tags for fluorescence imaging and the design of enzymes for biocatalysis. In this proposal, In this proposal, I aim to test my hypothesis that protein dynamics, particularly the enrichment of productive conformations, contribute to the enhanced rate of KABLE1.4 using a multidisciplinary approach that includes molecular dynamics, X-ray crystallography, and NMR (Aim 1). For fluorescence imaging, I will transform the proof-of-concept de novo protein (FABLE) into a set of ready-to- use protein tags by designing proteins that bind modern rhodamine fluorophores while equipping them with a predefined set of optimal features that no existing tool offers (Aim 2). Lastly, I propose engineering de novo proteins with covalent ligand interactions, allowing stable binding and a universal protein tag for various synthetic molecules without requiring sequence redesign (Aim 3). Harnessing de novo protein design will revolutionize the ability to engineer protein-small molecule interactions, driving transformative advancements in fluorescence imaging, enzyme catalysis, and broader applications requiring precise molecular recognition.

NIH Research Projects · FY 2026 · 2026-05

Project Summary/Abstract As malaria transmission declines, an increasingly large proportion of the parasite reservoir is imported, with transmission persisting in specific sub-populations with high exposure to malaria and barriers to accessing and utilizing malaria prevention. Epidemiological data alone are unable to establish transmission links between infections or distinguish those that arise from importation events, posing a key barrier to measuring progress toward elimination targets. The long-term goal of this proposal is to leverage the confluence of cutting-edge molecular methods, genomic data, and novel analytic approaches to improve malaria case classification, identify drivers of residual transmission, and understand the introduction and spread of antimalarial drug resistance mutations. The overall objective is to quantify the contribution of infections imported by agricultural populations—including those carrying antimalarial drug resistance markers—to transmission in Eswatini. The central hypothesis is that imported infections in agricultural populations disproportionately contribute to ongoing malaria transmission and the spread of antimalarial drug resistance mutations. The hypothesis will be tested by pursuing two specific aims: (1) To improve case classification using high-resolution genomic data. (2) To characterize transmission dynamics and patterns of drug resistance markers in relation to imported cases within agricultural populations. To achieve these aims, existing and new high-resolution parasite genomic data will be analyzed with epidemiological data from samples collected through complementary studies conducted in Eswatini between 2012-2017 and 2023. For the latter, contemporaneous genomic data from Mozambique in 2023 will be used as a source population to assess genomic connectivity and improve genomic case classification models. Genomic transmission networks will be constructed for each dataset in addition to probabilistic models of importation based on travel history. Temporal, spatial, and demographic characteristics of highly related clusters will be quantified, and epidemiological metrics will be inferred from reconstructed networks. Findings are expected to shed light on the contribution of malaria importation and agricultural work in ongoing transmission and detection of parasites harboring antimalarial drug resistance markers in Eswatini and serve as proof of concept for innovative genomic transmission network methods for case classification and estimates of transmission between subpopulations. These contributions will be significant in providing critical evidence of the role of cross-border movement and agricultural populations in maintaining transmission and spread of antimalarial drug resistance markers in Eswatini. In addition to generating key metrics to inform decision-making in Eswatini, findings will support the broader use of genomic data and transmission network models for case classification and drug resistance surveillance. Results will be used to develop future R01 clinical trials focused on targeted active surveillance and intervention strategies at agricultural worksites and inform strategies for global surveillance of resistant parasites that pose an immediate threat to U.S. travelers.

NIH Research Projects · FY 2026 · 2026-04

ABSTRACT Schizophrenia is a complex disorder characterized by positive, negative, and cognitive symptoms. Antipsychotic medications, which bind to dopamine D2 receptors (D2Rs), are effective at treating positive and negative symptoms. Adequate treatment for cognitive symptoms however, originating from aberrant hippocampal and prefrontal signaling, remains elusive. An emerging target in schizophrenia treatment is another member of the D2 family, the dopamine D3 receptor (D3R). Newly developed second-generation antipsychotics (SGAs) functioning as D3R agonists, such as cariprazine, show signs of cognitive symptom relief. Additionally, recent work from our lab has shown differential D3R signaling among different classes of SGAs in hippocampus CA1. Despite evidence implicating D3Rs in the treatment of schizophrenia cognitive symptoms, a clear understanding of hippocampal D3R expression and function remains unclear. Here I propose that within hippocampus CA1 dopamine D3Rs are the most widely expressed D2 family receptor and are a key mediator of hippocampal network function. Moreover, I will test the central hypothesis that D3Rs are the predominant D2 family receptor affecting hippocampal circuit function and that hippocampal D3R signaling is a core cellular mechanism of antipsychotic action. The effect of SGAs targeting the D2 family of receptors is often attributed to D2R action due to limited access differentiating between D2Rs and D3Rs. New pharmacology and in-situ approaches now allow for specific characterization of D2Rs and D3Rs. My preliminary data shows that significantly more CA1 cells express D3R transcripts than D2R. This indicates that D3Rs are the dominant D2 family receptor subtype in CA1, warranting further investigation of hippocampal D3R function. Indeed, my preliminary data demonstrates D3R agonism induces significant effects on excitatory and inhibitory synaptic transmission within CA1. Here, we will explore how D3Rs regulate both synaptic and intrinsic features of excitability in hippocampal circuits using electrophysiological and imaging approaches. Previous work from our lab has outlined a D3R specific mechanism of SGA axon initial segment calcium modulation in CA1 pyramidal cells. This modulation provides another avenue for D3Rs to alter CA1 spiking and hippocampal output in addition to changes in CA1 synaptic transmission. The diverse array of D3R mediated CA1 synaptic and firing properties could serve as potential sites for D3R specific SGA action. We will test this hypothesis through the pursuit of three aims. Aim 1: To determine the expression profile of SGA-targeted dopamine receptors in hippocampus CA1. Aim 2: To determine the mechanism by which dopamine D3 receptors regulate hippocampus CA1 function. Aim 3: To determine how SGAs affect dopamine D3 receptor-dependent hippocampus CA1 circuitry. We expect this work to uncover the cellular mechanisms of D3R activity in CA1 and the D3R specific actions of SGA treatment. This will not only advance our understanding of hippocampal dopaminergic signaling, but delineate cellular mechanisms of SGA action informing new therapeutic targets for treating schizophrenia cognitive symptoms.

NIH Research Projects · FY 2026 · 2026-04

Dysregulation of basal ganglia and cortical development in the forebrain is central to epilepsy, mental deficiency, autism and schizophrenia. During forebrain development, the medial ganglionic eminence (MGE) generates GABAergic projection neurons in the basal ganglia and GABAergic interneurons in the cortex and hippocampus. We aim to identify transcriptional and epigenetic mechanisms that control cell fate specification and neuronal differentiation of these forebrain GABAergic neurons - information that will lead to insights into how abnormalities in specific gene networks cause human neuropsychiatric disorders.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY/ABSTRACT Major Depressive Disorder (MDD) afflicts more than 280 million people worldwide and is the leading cause of life years lost to disability. Current treatments have important limitations in efficacy and, in the case of medication, substantial side effects. There is thus a compelling need for additional effective, well-tolerated treatments. Body heating practices, such as saunas, sweat lodges, and hot yoga, have rich traditions across cultures as healing practices. Additionally, recent basic and clinical research, as well as the investigative team’s pilot data, suggest that whole-body hyperthermia (WBH) holds promise for depression treatment. The investigative team therefore hypothesizes that WBH, a body-based heat treatment, may decrease depression symptoms. Additionally, pilot data suggest benefit from combining WBH and cognitive behavioral therapy (CBT), an established mind-based treatment for depression. The UCSF investigative team led an NCCIH- funded project testing WBH and CBT in adults with major depressive disorder and have found the combined treatment to be feasible and acceptable. Additionally, preliminary data from this project suggest a clinically meaningful and statistically significant reduction in depression symptoms. Despite promising initial data from such pilot studies, rigorous and well-designed clinical trials are required to evaluate the efficacy of depression treatments that include WBH. Before the investigative team can conduct a definitive efficacy trial, they must assess the feasibility of key study design components. This proposal will test the feasibility of a multi-site 2 x 2 factorial trial design that randomizes adults (N=60) with MDD to two treatment factors: WBH (yes/no) and CBT (yes/no). The three-site investigative team (University of California San Francisco, Cleveland Clinic Foundation, Massachusetts General Hospital) will capitalize on their established collaborative relationships to assess the feasibility of recruitment, enrollment, randomization, and retention (Aim 1), intervention fidelity and acceptability (Aim 2), and consistency of data collection (Aim 3). The study will include a 2-week screening period, a 10-week intervention period, and a 12-week follow-up period. During the intervention period, participants randomized to WBH will receive four biweekly sessions, and participants randomized to CBT will receive eight weekly sessions. If successful, the proposed multi-site feasibility R01 trial will lay key groundwork for a future multi-site 2 x 2 factorial efficacy trial that will test the effects of WBH, CBT, and their combination on depression symptoms. If successful, this program of research may yield novel non-drug treatment options for millions of individuals struggling with depression.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY The objective of my proposal is to apply a novel, interdisciplinary approach with its combination of spatial analysis, implementation science, and exposure assessment to understand respiratory health and gaps in resource availability in the San Francisco Bay Area. My proposal builds on my past and current expertise in environmental engineering to use a systematic approach to assimilate across multiple data source to detect wildfire smoke risk changes due to exposure reduction strategies. I seek additional training to develop and apply innovative spatial and exposure analytical and qualitative methods to better characterize respiratory risk due to wildfire smoke exposure across all populations and identify specific factors influencing the success or implementation of strategies designed to increase community resilience. Due to evolving climate trends, environments in the western United States (U.S.) as well as more broadly across Canada have become drier and warmer resulting in more frequent and intense wildfire fire events. Year after year, wildfire smoke and particularly, wildfire-specific fine particulate matter (PM2.5) remain significant contributors to the air pollution burden on population health in the U.S. and beyond. While numerous guidance documents exist, especially in California, it unknown whether these strategies are adopted and enacted across communities and specifically in those most vulnerable to respiratory health outcomes. Historical patterns have led some communities to face higher risk for adverse respiratory outcomes and therefore these communities must be the public health priority when examining respiratory health effects of wildfire smoke and identifying effective risk reduction strategies. This proposal will advance the field of environmental health by applying spatial analysis to examine the distribution of risk reduction strategies and the factors driving these patterns (Aim 1); identifying individual, organizational, and societal factors that influence the presence of wildfire smoke risk reduction strategies using implementation research methods (Aim 2); and quantifying the impact of these strategies on the association between wildfire smoke and respiratory outcomes, with a focus on how effectiveness may vary based on community characteristics (Aim 3).The K99 training will enhance my research expertise through targeted coursework, mentorship, and active engagement in: (1) advanced spatial analysis; (2) implementation science and community-based participatory research; (3) quasi-experimental methods and epidemiology; and (4) career development. The skills gained through this award are essential to achieving my long-term goal of advancing multidisciplinary statistical and methodological approaches to quantify the respiratory health impacts of air pollution and exposure reduction strategies. This work will generate new scientific knowledge to improve understanding of respiratory health disparities and resource distribution, while equipping me with the expertise to plan and execute independent, innovative studies on the health effects of hazardous air pollutants using multi- dimensional analysis techniques.

NIH Research Projects · FY 2026 · 2026-04

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