University Of California, San Francisco

NIH Research Projects · FY 2026 · 2026-03

This proposal aims to design proteins from scratch that can undergo intramolecular allosteric regulation, a process crucial to central metabolism, genetic regulatory networks, and biological sensing. If we truly understand the molecular biomechanics behind allosteric regulation, then we should be able to design proteins that use remote binding of a ligand to control small molecule release. Recent work has demonstrated the possibility of changing remote protein conformation through fold switching or domain displacement. Researchers from my postdoctoral training lab have shown that designed proteins can bind small molecules with sub-nanomolar affinity, designed enzymes can use a remote binding event to suppresses reactivity, and designed membrane proteins acting as part of a protein complex can transmit information from one binding event to influence distant kinase activity. Building from these recent advances in protein design, as well as the wealth of experimental data on signal transduction in helical bundle proteins such as G-protein coupled receptors and histidine kinases, the proposed research aims to develop new helical bundle proteins where binding of a ligand at one site increases the population of protein in a strained conformation, causing small molecule release at a second site. The capacity to design targeted proteins capable of small molecule delivery in response to changes in ligand concentration would give rise to powerful new capacities for biotechnology, and this proposal aims to explore release of two drugs for which de novo protein binders have been recently designed. In Aim 1, I will design a protein that releases the anti-cancer drug rucaparib upon binding of the pro-tumor metabolite itaconate. In Aim 2, I will design a protein that releases the anti-cancer drug apixaban following itaconate binding. Binding sites for the allosteric ligand and releasable molecule will be incorporated onto protein scaffolds built from stable helical bundles in combination with loops and kinks generated from diffusion-based probabilistic models. The resulting proteins will be expressed and purified, their binding will be assayed using fluorescence spectroscopy, and their structures will be determined using X-ray crystallography and NMR spectroscopy. Once successful allosterically regulated proteins are designed, new ligand binding sites will be positioned increasingly distal to the active site to explore progressively more remote strain transduction. Demonstrating intramolecular allosteric regulation within a single protein monomer will extend our understanding of a longstanding problem in protein biophysics. The proposed research project will advance my training goals as I integrate computational protein design, molecular biology and biochemistry techniques for cloning, protein expression and purification, and biophysical characterization. Combining my existing experience in physical chemistry with the skills developed during the proposed research will prepare me for an independent research career using proteins and synthetic macromolecules to understand and intervene in strained biological macromolecules.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY/ABSTRACT Behavioral variant frontotemporal dementia (bvFTD) is a devastating neurodegenerative disorder characterized by early and profound social cognitive deficits, including impairments in theory of mind, emotion reading, and empathy, which cause significant distress and burden for caregivers. While research has traditionally focused on cortical degeneration in bvFTD, mounting evidence highlights the cerebellum’s critical role in cognitive and social processing. Despite comprising 80% of the brain’s neurons and demonstrating early atrophy in bvFTD, the cerebellum’s contributions to social cognition and its potential as a biomarker for disease progression remain underexplored. This study aims to address this gap by investigating the cerebellum’s influence on social cognitive deficits and its value for predicting clinical trajectories in bvFTD. Leveraging cross-sectional and longitudinal neuroimaging and clinical data from the University of California San Francisco (UCSF), Memory and Aging Center and the multisite ARTFL-LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study, this project is structured to achieve two primary aims. Aim 1 will use cross-sectional data from UCSF to characterize the relationship between social cognition and cerebellar structure and function in bvFTD across disease stages, using neuroimaging to identify compensatory and degenerative mechanisms. Aim 2 will use longitudinal data from ALLFTD to assess the predictive value of early cerebellar atrophy for later social, cognitive, and psychiatric decline, enhancing understanding of the cerebellum’s impact on clinical outcomes. This research is poised to fill critical gaps in our understanding of bvFTD by highlighting the cerebellum’s involvement beyond traditional motor functions, thereby offering new insights into brain network dynamics and their clinical implications. Findings from this study have the potential to enhance diagnosis and inform novel intervention strategies targeting cerebellar circuits, ultimately enhancing patient management in bvFTD. This project supports Dr. Chen’s career development goals of becoming an independent researcher specializing in advanced quantitative neuroimaging and neuropsychology in individuals with neurodegenerative disease. The K99 phase will provide training in cognitive neuroscience, interpretation of social cognition testing, and multimodal neuroimaging, enhancing her ability to integrate clinical and neuroimaging data to study neurodegenerative disease mechanisms. The R00 phase will support the establishment of her research program at a leading academic institution, leveraging advanced neuroimaging techniques to address key questions in dementia diagnosis, disease monitoring, and intervention. Dr. Chen’s training will take place in a highly collaborative, resource-rich environment at UCSF, which offers cutting-edge neuroimaging facilities, access to a well- characterized dementia cohort, and mentorship from experts in neurodegeneration, social cognition, and imaging analytics. This comprehensive training will position her to lead an impactful independent research program that advances our understanding of bvFTD and related neurodegenerative disorders.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY/ABSTRACT The objective of this proposal is to develop a quantitative understanding of how the biophysical properties of antibodies impact their capacity to evolve affinity to divergent SARS-CoV-2 spike variants. Though there is substantial evidence that mutations acquired during affinity maturation impact antibody expression, affinity for distinct viral variants, and self-reactivity, we lack a quantitative understanding of (1) how mutations impact these biophysical properties and (2) how these properties, and trade-offs between them, collectively determine the fate of the corresponding B-cell lineage. Here, we propose three Aims to test our hypothesis that mutations differentially impact antibody expression, affinity, and self-reactivity, resulting in biophysical trade-offs that constrain the evolution of antibodies that bind divergent SARS-CoV-2 spike variants. In Aim 1, we quantitate the biophysical effects of mutations in anti-SARS-CoV-2 spike antibodies, using high-throughput mammalian cell- display methods we recently developed. By measuring the expression, affinity, and self-reactivity for millions of anti-spike antibodies, including broadly neutralizing antibodies (bnAbs) that bind divergent spike variants, their evolutionary predecessors, and systematically mutagenized antibody sequences, we will unveil biophysical constraints that shape affinity maturation to rapidly evolving viral antigens. In Aim 2, we evaluate the contributions of antibody biophysical properties to B-cell fitness, or proliferation, using longitudinally-sampled patient B-cells following exposure to divergent strains of SARS-CoV-2. This approach will reveal the relative importance of distinct antibody biophysical properties in driving B-cell evolutionary dynamics in human repertoires and enable development of quantitative models for predicting the outcomes of affinity maturation. In Aim 3, we define the impact of selection pressure during affinity maturation on the biophysical properties of the resulting antibodies, focusing on selection regimes known to favor the maturation of bnAbs that bind distinct spike variants. To this end, we leverage a B-cell directed evolution platform that mimics the mutagenic load of somatic hypermutation, enables fine-tuning of the antibody selection conditions, and supports longitudinal B-cell sampling to profile the evolutionary dynamics of the B-cell response and the biophysical properties of the corresponding antibody lineages. The resulting data will be used to define the impact of the selection regime on the biophysical determinants of B-cell fitness. Successful completion of these Aims will yield quantitative insight into (1) how antibody biophysical properties change during affinity maturation, (2) how they collectively determine B-cell fate in human repertoires, and (3) how their relative importance varies across distinct selection regimes. Thus, this work will advance our fundamental understanding of the biophysical mechanisms that shape antibody affinity maturation to rapidly evolving pathogens like SARS-CoV-2, supporting efforts to design and elicit antibodies that bind existing and novel viral variants.

NIH Research Projects · FY 2026 · 2026-02

Project Summary & Abstract Developing efficient gene therapies and biologics can unlock new cures for neurological diseases, but is hindered by inefficient delivery, especially to the central nervous system (CNS). Traditional delivery vehicle discovery and validation pipelines rely on cellular and animal models that often fail to predict CNS delivery in patients. What is needed is to assess delivery efficacy in humans at the beginning of the discovery process. We propose to revolutionize the field by discovering and validating vectors in physiologically maintained deceased (PMD) human cadavers. Delivery vector performance in a PMD cadaver will provide confidence in their efficacy in humans and greatly reduce the reliance on preclinical animal discovery research, ultimately increasing the success of clinical trials. Our ethics-informed PMD platform will provide a blueprint for the safe, ethical, and just use of human donors in discovery research. Our discovery platform will help future researchers and clinicians find the most effective vectors to enable gene and biologic therapies that could be used to treat millions of patients with CNS indications.

NIH Research Projects · FY 2026 · 2026-02

SUMMARY Pathological aggregation of the protein tau is a hallmark of Alzheimer’s disease and several related dementias, collectively referred to as tauopathies. Familial tauopathies caused by coding mutations in tau and experimental model systems support a causal role for tau aggregation in these diseases. Based on these findings, tau-lowering therapies using anti-sense oligonucleotides or antibodies are currently in clinical trials. However, potential drawbacks of these approaches are that the therapeutic modalities are expensive and would therefore be challenging to deploy in the large population of AD and tauopathy patients. Furthermore, therapies lowering total tau levels have the caveat that we insufficiently understand the physiological roles of tau, and lowering total tau may have detrimental effects. Therefore, therapies selectively targeting pathological forms of tau using small- molecule drugs remain a significant unmet need. Endogenous protein homeostasis mechanisms that lower pathological tau species may represent an attractive therapeutic target in AD and tauopathies. In previous work, the lab of MPI Dr. Kampmann used a genome-wide CRISPRi screen in human neurons to systematically uncover such mechanisms. The UFMylation pathway was an important class of hits in this screen, where knockdown reduced tau oligomers. In follow-up studies, Kampmann and collaborator Dr. Li Gan confirmed that inhibition of the UFMylation pathway lowers pathological tau species in different human neuron and mouse models of tauopathy. However, the underlying molecular mechanisms that link UFMylation to tau proteostasis are unknown. MPI Dr. Kopito has previously elucidated the mechanisms and targets of the UFMylation pathway using biochemical and structural approaches. His work established that the 60S ribosomal subunit is the target of UFMylation and that this modification is essential to dislodge terminated ribosomes from SEC61 translocons in the endoplasmic reticulum (ER). In unpublished findings, his lab uncovered that failure of UFMylation to recycle ribosomal subunits specifically activates adaptive signaling through the ER proteostasis sensor IRE1 and activation of the transcription factor XBP1s to drive a transcriptional program of protective stress response effectors. We hypothesize that this response serves as a feedback loop to ensure levels of available SEC61 translocons, while also upregulating other protein homeostasis factors that facilitate clearance of pathological states of tau. The proposed research will (1) Define the molecular mechanism by which disruption of UFMylation and translocon homeostasis activates protective IRE1 signaling in the absence of unfolded proteins, (2) Elucidate the mechanism by which protective IRE1 signaling suppresses tau aggregation, and (3) Validate the mechanism and therapeutic potential of IRE1 activation in tauopathy mouse models.

NIH Research Projects · FY 2026 · 2026-02

ABSTRACT In the US alone ~200,000 patients present yearly with Idiopathic Pulmonary Fibrosis (IPF), a relentlessly progressive disorder with average survival of 3-5 years that is strongly linked to aging. No FDA approved drug improves lung function or well-being, underscoring the medical need for new therapeutics. The central premise of this research program is that development and progression of metaplastic alveolar epithelial cells are the principal drivers of disease and poor outcome in IPF. In addition to a body of prior work on IPF risk, two recent discoveries by our group support this claim and are the basis for this R35 application: (1) Human alveolar type II cells (AT2s) are much more plastic than previously known and capable of transdifferentiation not only to normal alveolar type 1 cells (AT1s) but also pro-fibrotic alveolar basaloid/basal cells and lining cells of respiratory bronchioles. Spatial transcriptomic analysis of IPF respiratory bronchioles suggests they expand and create basal cell-like microcystic structures characteristic of IPF. Accumulation of these microcysts and alveolar basal cells both correlate with poor outcome for IPF patients. These findings provide a well-developed alternative to the long-held belief, termed bronchiolization, that accumulation of alveolar basal and other airway cells in IPF derive from airway cells. (2) Transdifferentiation of human AT2s to basaloid/basal cells is strongly age-dependent, tracking with the well-known advanced age of IPF onset. A central hypothesis of the program is that epigenetic and transcriptional regulators of AT2 cells operate to bias AT2 differentiation under injury/stress conditions with age toward basal cells at the expense of AT1 renewal. The core regulation of basaloid/basal cell transdifferentiation has two elements: the first is age-dependent epigenetic accessibility of basal cell gene promoters. We will pursue preliminary data that a key driver of the aged epigenetic landscape is AT2 cells expressing inflammatory mediators. Once accessible, the second element is assembly of transcriptional drivers of Krt5 mRNA expression including tp63 and Hif1a. Assembly of these drivers on the Krt5 gene also inhibits AT1 Rage transcription leading to marked age-dependent basal cell bias and impaired lung regeneration. We believe a more mechanistic and accurate understanding of IPF epithelial cytopathology will advance the fibrosis field by providing a better rationale for new therapeutic leads. Indeed, as part of the R35 mechanism, based on our recent findings, we will undertake a HTS small molecule screen using iPSC- derived iAT2 cells to identify compounds that reverse the basaloid/basal state.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY/ABSTRACT This proposal outlines a five-year career development program to investigate neural circuit mechanisms that lead to impaired memory consolidation after sleep loss in a corticothalamic circuit. The candidate, Dr. Jessica Jimenez, is currently a Clinical Fellow in Neurology at UCSF in the division of Sleep Medicine. This proposal builds on Dr. Jimenez’s previous research experience in neural circuits mediating learned and innate fear behaviors, by allowing her to obtain new expertise in sleep dependent memory consolidation under the guidance of her primary mentor, Dr. Karunesh Ganguly. The proposed experiments, advisory team, and didactics will provide Dr. Jimenez with the skillset needed to transition to independence as a physician scientist and leader in the field of sleep neurology. Sleep disturbances have detrimental effects on learning and cognitive function, and are a cardinal feature of many chronic diseases, including stroke, neurodegenerative diseases, and depression. Despite these observations, the mechanisms by which sleep loss impairs learning and memory are not well understood. The goal of this proposal is to understand how sleep loss impairs sleep microarchitecture after learning. This will ultimately enable the development of targeted therapies that restore the features of sleep that are critical for memory consolidation. To accomplish this, this proposal aims to investigate how dynamics during non-rapid eye movement (NREM) sleep between the medial prefrontal cortex (mPFC) and thalamus become altered after learning and sleep loss. Specifically, this proposal will assess how slow oscillations (SOs) and delta waves, which are generated by the cortex, become temporally coupled to spindles, which are generated by the thalamic reticular nucleus (TRN). A large body of work has causally shown that the temporal coupling between SOs and spindles during NREM sleep is necessary for memory consolidation, while the coupling of delta waves to spindles weakens memory strength. Still, how corticothalamic inputs modulate the generation of spindles to facilitate spindle coupling to SOs and delta waves after learning and sleep loss is unknown. This proposal hypothesizes that after learning, the mPFC drives SO-spindle coupling and memory consolidation during NREM sleep. Moreover, this proposal predicts that sleep loss impairs this process by altering the balance of SOs and delta waves, thereby desynchronizing mPFC inputs to the TRN and resulting in forgetting. To test this hypothesis, Aim 1 will assess mPFC-TRN circuit dynamics during NREM sleep after learning via chronic in vivo Neuropixels electrophysiological recordings. Aim 2 will employ closed-loop optogenetic silencing of mPFC axon terminals within the TRN to determine if mPFC-TRN input is necessary for SO-spindle coupling after learning. Aim 3 will then assess how mPFC-TRN dynamics become altered after sleep deprivation. The work outlined in this proposal will increase our understanding of how NREM corticothalamic circuit dynamics facilitate memory consolidation after learning and reveal potential therapeutic targets to restore aberrant activity after sleep loss.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY/ABSTRACT Tuberculosis (TB) is the leading cause of death worldwide from a single infectious agent, Mycobacterium tuberculosis (Mtb). Despite the development of effective multidrug regimens, many persons with pulmonary drug-susceptible (DS)-TB disease do not achieve durable cure at the end of treatment. The aim of this proposal is to define host immunological and transcriptional factors associated with treatment outcomes. We will use the time to stable culture conversion (TTSCC) as an endpoint to define these factors. TTSCC is the duration of treatment it takes a person with DS-TB to achieve two consecutive negative Mtb cultures from sputum samples. We will leverage existing samples and datasets from two seminal trials: the Predict TB (NCT02821832) Phase 2B and Study 31/A5349 (NCT02410772) Phase 3 trials, as well as samples from a prospectively recruited cohort of participants with DS-TB from the A5409/RAD-TB (NCT06192160) Phase 2 trial. These trials offer a unique opportunity to identify pathways linked to TTSCC across all treatment regimens or specific to certain regimens. In the first aim, we will use transcriptional profiling of whole blood to define pathways, and the genetic regulatory networks that govern them, that are associated with shorter TTSCC. We will validate the top candidate hits associated with TTSCC by assessing Mtb sterilization in CRISPR/Cas9- edited primary human macrophages compared to their isogenic counterparts in the presence of antibiotics. In the second aim, we will define the abundance and functional profiles of immune subsets in the blood that predict TTSCC in the A5409/RAD-TB clinical trial. We will also use a novel measure of Mtb sterilization, which is the modeled change in the time to positivity of serial sputum cultures over the first two months of treatment. This measure is a novel early efficacy endpoint being used in A5409/RAD-TB and several other clinical trials registered with the U.S. Food and Drug Administration. The data from these analyses will help identify (i) novel treatment strategies, potentially adding adjunct host-directed therapies to reduce time to Mtb sterilization and improve treatment outcomes, and (ii) inform the development of biomarkers to triage persons with DS-TB to different treatment regimens and duration. These findings will have a significant impact on changing the ‘one size fits all’ treatment paradigm for DS-TB, which renders many persons with TB at a high risk of unfavorable treatment outcomes or risk of overtreatment and toxicity. The Division of HIV, Infectious Diseases, and Global Medicine and the Division of Experimental Medicine at the University of California, San Francisco are an ideal setting to conduct the proposed activities due to their depth of content expertise and collaborations in the control of TB.

NIH Research Projects · FY 2026 · 2026-02

ABSTRACT The second annual RISE UP (Revolutionizing Investigations to StEp Up Prevention) for Breast Cancer conference will bring together practitioners, scientists, and advocates across women’s health specialties and leverage what we know about breast cancer biology, treatment, and hormonal management to better approach breast cancer prevention and treatment. RISE UP was conceptualized in 2023 by Dr. Laura Esserman. The first meeting was held in November 2024 with over 300 attendees across a variety of disciplines. Our goal is to build on the momentum of the first meeting and concentrate on the following aims for 2026: 1) highlight novel and standard agents that can be applied in the context of response-predictive subtypes in the early-stage setting to eradicate tumors; 2) highlight results from personalized screening programs and the opportunity to personalize both risk reduction and screening; 3) explore opportunities to pair breast cancer risk reduction in interventions across a woman’s life stage to both optimize for breast cancer prevention and improve treatments and quality of life for breast cancer survivors. The conference will include general sessions (including debates, keynote speakers, abstract presenters, and panel discussions) as well as poster sessions to foster cross disciplinary learning, highlight new research, and spark ideas and action. General sessions will be designed to educate attendees about opportunities to improve the health and well-being of women from prevention to treatment of breast cancer. Our goal is to bridge the critical gap in knowledge of breast specialists and gynecologists to make breast cancer management better, engage the gynecologic and primary care community in improvements in breast cancer screening and prevention, and to rethink hormonal control across the continuum of a woman’s life with an eye toward prevention. The conference is designed to foster questions, collaborations, and overall generation of new ideas and ways of thinking about breast cancer. There will be no overlapping sessions so that all attendees will gain the knowledge and ability to improve their practice and upend the way we think about breast cancer prevention. The conference will be held February 19- 21, 2026, at the Hotel Nikko in San Francisco. We aim to bring new energy and novel perspectives to the challenge of breast cancer prevention. The final session of the conference will be a “shark tank” like challenge, with a competition to integrate breast cancer risk reduction into health care products used during a woman’s life course. Last year we awarded four “SPARK” awards to foster early-stage ideas and collaborations, and the winners will present during the meeting and report on their progress. We plan to partner with more investors this year to award both SPARK and IMPLEMENTATION (later stage development ideas) prizes.

NIH Research Projects · FY 2026 · 2026-02

Neuroscience research is critical to the advancement of treatment of neurosurgical disorders. However, the pipeline of future neurosurgeons and neurosurgeon clinician-scientists may be impacted before medical school, as factors such as the presence of a neurosurgery residency program and accessibility to research experiences play a significant role in the recruitment of individuals into neurosurgery. Nearly 1/3 of medical schools accredited by the Liaison Committee on Medical Education do not have an affiliated neurosurgery residency program or neurosurgery departments, and the chances of becoming a neurosurgeon scientist are under 5% if one trains in this environment. Therefore, medical students experience barriers to becoming neurosurgeon scientists because they need exposure based on where they train for medical school. The exclusion of these students creates disparities in the diversity of neurosurgeon researchers. Thus, there is a critical need to diversify the exposure to neurosurgery research for medical students learning in programs without home neurosurgery programs. This gap in neurosurgical exposure exacerbates existing disparities in the field. Our long-term goal is to create a program to improve exposure to and recruitment into neurosurgery and research among medical schools without a home neurosurgery residency program. Aim 1 allows medical students at schools without a home neurosurgery program to participate in a 9-12 week neuroscience research methods-based curriculum during the summer between their first and second years of medical school. Aim 2 includes the implementation of a year-long grant, abstract, and scientific paper writing curriculum to provide participants with mentorship, exposure, and expanded neurosurgical knowledge. Aim three will monitor the research productivity of participants, both short and long-term. Through this, we intend to evaluate the success of this program in attracting students into neurosurgery and the pursuit of neurosurgical research and assess barriers faced by this cohort to pursuing research experiences.

NIH Research Projects · FY 2026 · 2026-02

Project Summary/Abstract As young adults with autism spectrum disorder (YAASD) transition out of the academic supports provided by school, they can experience a degradation of social skills over time. This increases their risk of poor social, academic, vocational, and health outcomes. YAASD require continuous and ongoing skill development in order to maximize their potential; however, there are few services available to YAASD to develop and maintain their skills. While interventions exist in early childhood, mid-childhood, and adolescence, few programs have focused on improving resilience among YAASD. Resilience in ActionTM (RiA): Assessing the behavioral target mechanisms of the RiATM curriculum in young adults with autism, is a proposed research study that will be delivered in both community and academic settings to address the ‘adult world’ needs of YAASD who have exited out of secondary education. RiATM has been pilot-tested with YAASD and found to be highly acceptable (with 100% course completion and high course satisfaction), and contributed to YAASDs’ improved resiliency measured pre/post the course. In the proposed study, we will test the RiA curriculum developed in the San Francisco Bay Area, into 2 new sites (Boston, Massachusetts, and Baltimore, Maryland) – In Aim 1, we will conduct a randomized waitlist control trial with 288 YAASD (between 19-26 years of age) to examine the effectiveness of the RiA curriculum on resiliency targets (e.g. self- determination, self-efficacy, social confidence, emotional regulation). In Aim 2, we will examine whether resilience targets are associated with improvements in mental health and explore the impact on emotional regulation, vocational outcomes, and quality of life over a 12-month follow- up. Aim 3 will focus on studying the implementation of the RiA curriculum across the different sites using an expanded RE-AIM Framework. The proposed study would be the first to test resilience as a mechanism of action of the RiA curriculum for YAASD, and whether resiliency gained contributes to improved mental health and social outcomes in a multi-center trial of community-based partnerships across the US. This study will add to the science of how resiliency interventions can improve YAASD’s mental health, social, educational, and health- related outcomes.

NIH Research Projects · FY 2026 · 2026-02

Abstract Malaria is a leading killer of children worldwide, and existing WHO-recommended vaccines offer only modest protection that is of short duration. Malaria vaccine innovation has been impeded by our limited knowledge of the antigens and epitopes targeted by T cells and the characteristics of malaria-specific CD4 T cells that are most critical for immune protection. We will address these critical gaps by identifying hundreds of novel P. falciparum CD4 T cell epitopes and using innovative T cell assays to characterize epitope-specific T cells at the individual cell level. P. falciparum has a complex life cycle, and the human immune response differs according to the stage of parasite development. The most successful malaria vaccine strategies identified to date require vaccination with live attenuated sporozoites, which infect hepatocytes but undergo developmental arrest at the liver stage and do not establish blood-stage parasitemia. Evidence from both human and animal studies of sporozoite vaccination indicates that CD4 T cells targeting liver-stage parasites are critical for this protection, but the antigens targeted by protective T cells are almost entirely unknown. In preliminary studies, we have developed a bioinformatic strategy to identify P. falciparum antigens transcriptome-wide that are highly and selectively expressed during the liver stage of infection. In the first aim, we will use a novel assay to generate large DNA-barcoded P. falciparum peptide libraries, including geographically relevant sequence variants, and perform highly multiplexed screens to identify peptides that bind HLA-DRB1 allotypes common in East Africa. We will then test the recognition of candidate epitopes using samples from a large cohort of highly malaria- exposed Ugandan children. In the second aim, we will use the peptide:HLA binding data to build a 1000-plex DNA-barcoded multimer probe-set to label cells for single-cell sequencing, which will enable us to simultaneously discern the epitope specificity, HLA restriction, full transcriptomes, and TCRα:β sequences of P. falciparum-specific CD4 T cells. We will use this novel genomic assay platform to compare the transcriptional and functional phenotype of CD4 T cells targeting liver- vs. blood-stage epitopes in children residing in a highly malaria-endemic region of Uganda. Lastly, we will use a unique set of samples from a randomized trial of childhood chemoprevention to test the hypothesis that selective suppression of blood-stage infection by antimalarial drugs fosters the development of a broader and more functionally robust CD4 T cell response to liver-stage antigens. Together, these novel assay platforms will enable us to identify hundreds of novel P. falciparum epitopes recognized by malaria-exposed Ugandan individuals and characterize the responding CD4 T cells in unprecedented detail to uncover the functional and phenotypic features critical for T cell-mediated protection.

NIH Research Projects · FY 2026 · 2026-02

ABSTRACT Sub-Saharan Africa's (SSA) 400 million adolescent girls and young women (AGYW, age 15-24) face disproportionate rates of HIV acquisition and suboptimal HIV care engagement. Despite the widespread availability of oral PrEP at public health facilities, uptake is impeded by low awareness, socio-cultural and access barriers, provider bias, and user dissatisfaction. Moreover, among PrEP-aware AGYW, uptake and continuation of PrEP is low due to side effects, fear of being seen with medicines, and low adherence support, undermining PrEP's preventative effects and leaving AGYW in need of critical HIV prevention. Our team and others have demonstrated that AGYW are interested in PrEP, especially newer modalities such as injectables, and that they prefer to seek HIV care at locations that foster privacy, are convenient, and are girl-friendly. Given the growing recognition that pharmacies, staffed by health workers who can be trained to provide expanded services, outnumber health facilities, can promote beneficial health behaviors, bridge gaps in health services, and mitigate health workforce shortages, we aim to expand this body of research to conduct an implementation science study on potential implementation models of pharmacy-based PrEP provision and adherence support for AGYW. In Uganda, the Community Retail Private Pharmacy Drug Distribution Point (CRPDDP) already provides pharmacy-based anti-retroviral therapy (ART) to over 48,000 clients across 160+ pharmacies (and increasing). Given the Uganda Ministry of Health's interest to expand this pharmacy-based differentiated service delivery model for increased reach and extended prevention offerings, we propose a mixed-methods study to garner foundational evidence to evaluate how this cadre of pharmacies already providing ART refills to PLHIV can include PrEP services generally and specifically tailored to AGYW. We hypothesize that these pharmacies can be well-equipped to reach AGYW with PrEP, given the critical role they already play in the community providing expanded care. As such, we propose to conduct formative research among CRPDDP pharmacies and their AGYW clients to advance implementation of pharmacy-based PrEP and adherence support. Guided by participatory processes of human-centered design, including in-depth interviews with AGYW who are potential PrEP users, pharmacists, and focus groups with pharmacy and youth advisory boards and MOH stakeholders, we will conduct formative research to understand barriers, facilitators, and desires for pharmacy-based PrEP to inform a discrete choice experiment (DCE) (Aim 1). We will then evaluate a series of implementation science outcomes—willingness, acceptability, feasibility, and readiness—among CRPDDP pharmacists (n=~160) (Aim 2), and conduct parallel DCE surveys among CRPDDP pharmacists and their AGYW clients (n=300) to evaluate preferences for pharmacy-based PrEP implementation models (Aim 3). By the end of the study, we will understand how a potentially ready platform of pharmacies can be expanded to provide PrEP care to a key population, and will have identified potential implementation gaps from user, provider, and policy perspectives .

NIH Research Projects · FY 2026 · 2026-02

Project Summary/Abstract Progressive supranuclear palsy (PSP) is a rare neurodegenerative motor disorder affecting approximately 20,000 people in the U.S. Clinical hallmarks of PSP are early loss of balance and falls, together with impairment in saccadic eye movements. Additional features often mimic Parkinson’s disease (PD), but PD treatments provide little to no therapeutic benefits in PSP. Histopathologically, PSP is characterized by the presence of insoluble aggregates of the microtubule-associated protein, Tau. While disease-causing mutations to the Tau- encoding MAPT gene have been described, the majority of PSP cases are idiopathic. Postmortem analysis of PSP patient brains show Tau pathology in several motor control regions, such as the basal ganglia (e.g. striatum, subthalamic nucleus, substantia nigra) and midbrain eye movement nuclei. Recent findings indicate basal ganglia output nuclei, such as the substantia nigra, are among the first sites of neuronal pathology. Tau pathology in these regions may lead to physiological dysfunction of motor circuits, in turn driving motor symptoms seen in PSP. To test this hypothesis, we recently repurposed a previously described Tau transgenic mouse and determined that Tau pathology in the mice was sufficient to mimic two key clinical aspects of PSP: gait and eye movement abnormalities. Using custom-built gait and eye movement recording systems, we observed that Tau hP301S mice had impaired coordination and vertical eye movements. Furthermore, we find these phenotypes correlate with pathology in many PSP-associated motor control regions, such as the substantia nigra and mesencephalic locomotor region. We also find that expressing mutant Tau specifically in the substantia nigra is sufficient to mimic these same abnormal phenotypes. In this proposal, I will use these two new mouse models to test my central hypothesis that Tau pathology leads to behavioral deficits via physiological abnormalities in midbrain motor regions, the substantia nigra pars reticulata and the mesencephalic locomotor region. I will use a combination of in vivo electrophysiology, ex vivo patch-clamp recordings, and quantitative measures of eye movement and gait to identify these links between pathology, physiology, and behavior. Understanding these mechanisms may help focus future work on both the underlying mechanism of PSP and identify new treatment strategies. The experiments proposed in this study expands upon my prior ex vivo slice electrophysiology training and adds training in in vivo electrophysiology and complex behaviors. In addition, I have assembled an expert mentoring team to provide guidance in my career development with the goal of launching a career as a successful independent investigator at a biomedical research institution.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY Dementia, including Alzheimer’s disease (AD) and frontotemporal dementia (FTD), are major contributors to mortality, morbidity, and worldwide healthcare expenditure. FTD is fatal and incurable and represents 10-20% of all dementia cases. Approximately 9% of all FTD cases are caused by MAPT mutations (FTD-tau). Given that there are no effective treatments for FTD (an Alzheimer’s-related dementia), novel therapeutic strategies are urgently needed. Targeting the MAPT gene itself by CRISPR/Cas9 genome editing may provide a curative intervention. We have established a novel dual sgRNA strategy, which can excise the mutant MAPT allele in patient-derived induced pluripotent stem cells (iPSCs). The excision preserves expression from the non-diseased allele. In Aim 1, we will maximize efficiency of our gRNA strategy by identifying sgRNA pairs that excise the MAPT transcription and translation start sites on the mutant allele with high efficiency and no side effects in patient iPSCs and post- mitotic patient-derived neurons in vitro. We will then deliver our optimized editing reagents to an FTD mouse model (PS19) via AAV PhPeB, which cross the blood brain barrier and achieve brain-wide distribution. In Aim 2 we will optimize AAV dosing and determine whether CRISPR editing can reverse pathologic hallmarks of FTD- tau or only prevent their onset. In Aim 3 we will determine how three genes embedded in MAPT affect normal and pathologic tau expression, potentially providing new therapeutic targets, and in any case a useful context for any therapy that aims to alter tau expression or the MAPT locus. With the successful completion of these studies, we will have optimized a candidate gene editing strategy that targets the MAPT mutation, and reaches the highest therapeutic efficacy in human neurons in vitro. We will also determine the therapeutic window in vivo. Our editing strategy will then be ready to pair with human-specific delivery reagents that we and others are developing as they become available. We will have additionally addressed a number of open questions in the field, including whether editing efficiencies in post-mitotic neurons differ from mitotic cells, how to deliver CRISPR/Cas9 with multiple sgRNAs widely throughout the mouse brain, whether it is possible to reverse or arrest clinical phenotypes in symptomatic mice, and the impact of embedded genes on MAPT physiologic and pathologic function. This work will inform our understanding of normal MAPT function and provide proof-of-concept and IND-enabling studies for a novel MAPT CRISPR therapeutic. Our approach is likely also applicable to sporadic FTD-tau and other tauopathies, including progressive supranuclear palsy (PSP), Alzheimer’s disease (AD) and corticobasal degeneration (CBD). Our overarching goal is to accelerate genome editing for neurodegenerative diseases toward the clinic.

NIH Research Projects · FY 2026 · 2026-01

Abstract The ultimate success of immunotherapy for brain malignancies, such as malignant glioma, will require integration of in-depth understanding of immunology with solutions for the following long-standing challenges: 1) paucity and heterogeneous expression of glioma-specific antigens; 2) on-target off-tumor toxicity and exhaustion of therapeutic T lymphocytes, such as chimeric antigen receptor (CAR) T-cells; 3) immunological privilege of the CNS and 4) immunosuppression involving tumor, neuronal, and immune cells. My laboratory has contributed to critical discoveries in these areas and integrated our findings into novel immunotherapy clinical trials for glioma patients. In the current proposal, I will enhance my research by mobilizing multiple immune mechanisms. To this end, I will collaborate with an outstanding group of investigators whose diverse expertise in multi-disciplinary areas complements my own in brain tumor immunology as the central component and apply a wide variety of resources available at UCSF and collaborators to one overarching program. I will evaluate the overarching hypothesis that the integration of novel cell-engineering and antigen-targeting approaches will allow us to develop safer and more effective immunotherapy strategies by overcoming heterogeneous expression of antigens and unique challenges in brain immunology. I will evaluate the following strategies: 1. Develop neo- junction-targeting T-cell receptor (TCR)-T cell-based immunotherapy. We will leverage our highly reliable and valuable pipeline for T-cell epitope prediction, which we established during the current funding cycle, to discover novel neoepitopes derived from tumor-specific alternative splicing events (neojunctions). 2. Develop novel cell therapies using allogeneic induced pluripotent stem cells (iPSCs) and in vivo transduction approaches. While my current NINDS R35 award allowed me to implement the first-in-human phase I study of Synthetic Notch (synNotch)-CAR T-cell therapy in patients with glioblastoma, inherent and logistical challenges associated with the use of autologous T-cells motivate us to develop these novel and alternative approaches. 3. Enhance “epitope spreading” to overcome the antigen heterogeneity. While the novel synNotch-CAR approaches are promising, one major inherent challenge is that targeting a few or several antigens by CARs or TCRs may not adequately cover the marked antigenic heterogeneity of tumors. We will enhance the effects of low-intensity pulsed ultrasound with microbubbles (LIPU/MB) to induce adaptive immune responses against heterogeneous tumor antigens. 4. Investigate the glioma-neuronal circuit-induced immune regulation. We will delineate essential mechanisms on our recent discovery of neuronal activity-driven immunosuppression as a previously unrecognized resistance mechanism of cancer immunotherapy for gliomas. These 4 strategies will be logically integrated into combination approaches. As expected per the purpose of the NINDS R35 mechanism, these strategies may involve high risks. However, based on our preliminary proof-of-principle data, we will persistently pursue our goals with long-term support from the R35 mechanism and adopt new technologies flexibly and swiftly.

NIH Research Projects · FY 2025 · 2026-01

Project Summary/Abstract Tuberculosis (TB) remains a significant global health threat, causing approximately 1.5 million deaths annually, with treatment complicated by the rise of drug-resistance Mycobacterium tuberculosis (Mtb) strains. A common target for antibiotics is the bacterial ribosome, and mycobacterial ribosomes have unique features and functions, which may be exploited to development more effective treatments. One such example is the prevalence of so- called leaderless mRNAs, (lmRNA) which lack the 5’ untranslated region and Shine-Dalgarno sequence used during canonical protein translation initiation. This project seeks to develop an understanding of the mechanism of lmRNA translation in mycobacteria and understand how this form of translation is regulated. I hypothesize that there are unique structures in the mycobacterial ribosome that allow for efficient translation of lmRNAs and that lmRNAs are of particular relevance during stress or infection conditions. Aim 1 will use reverse genetics to screen candidate regulators of lmRNA translation in mycobacteria using a pair of orthogonal reporters for leaderless translation. Regulators validated by both reporters will be further investigated by ribosome profiling. Aim 2 will use forward genetics in the form of a CRISPRi screen to identify unknown regulators of lmRNA translation in mycobacteria using a leaderless sacB reporter. Hits from the screen will be validated using an orthogonal fluorescent leaderless translation reporter, and confirmed hits will be further analyzed using ribosome profiling. Aim 3 will leverage cryoEM to identify structural components of the mycobacterial ribosome that contribute to effective leaderless translation, first by isolating and comparing structures of the ribosome on canonical and leaderless mRNA transcripts and later by solving structures of ribosomes lacking promising validated hits from Aims 1 and 2. This work will allow for the identification of novel therapeutic targets on the mycobacterial ribosome, supporting the broad NIH mission to reduce the burden of infectious diseases. This project combines my research interests in infectious disease, protein translation, and bacterial genetics while increasing my familiarity with structural biology. This award will support my long-term career development into an independent academic researcher, and I will supplement it with continued mentoring and teaching, as well as taking advantage of the career and professional development programs available at UCSF.

NIH Research Projects · FY 2026 · 2026-01

PROJECT SUMMARY / ABSTRACT Rehabilitation of central visual disorders like amblyopia and cortical visual impairment depends on synaptic plasticity, the changes in synaptic connections between neurons in the brain. A major regulator of synaptic plas- ticity is brain state - the moment-to-moment fluctuations in attention, arousal, emotions and other factors sep- arate from the actual content of experience - but brain states are generally left uncontrolled in treatment. Con- trolling brain state may be particularly important for brain stimulation therapies like repetitive transcranial mag- netic stimulation (rTMS), which mediate their effect through induction of neuroplasticity. The goal of this re- search proposal is to explore how attentional state - an experimentally tractable, well-understood, and disease- relevant brain state mechanism - regulates rTMS-induced neuroplasticity to the human visual cortex (Aim 1) and frontal eye fields (FEF, Aim 2). Changes in the steady-state visual evoked potential (ssVEP) contrast-response function following rTMS provide a high signal-to-noise neural readout of visual cortical neuroplasticity, while changes in psychophysical contrast discrimination sensitivity provides a perceptual readout of plasticity. During rTMS, subjects will orient attention to either the same or opposite retinotopic visual field to which rTMS is tar- geted, to determine how attentional state affects the propensity of rTMS to induce neuroplasticity. Powerful quantitative linking models will then be used to link rTMS-induced neural changes to perceptual changes, and to determine which neural changes most contribute to behavioral change (Aim 3). These experiments will pro- vide novel evidence that attentional state controls the neuroplasticity effects of brain stimulation. Moreover, they will help identify the cortical circuit mechanisms that are affected by rTMS and which of these mechanisms are most determinative of behavioral change following rTMS. Together this provides fundamental knowledge in hu- man visual cortical plasticity addressing NEI’s Area of Emphasis Biology and Neuroscience of Vision, and will inform the development of brain state control paradigms to augment the efficacy of rehabilitative neuromodula- tion therapies for visual disorders including hemineglect, cerebral scotoma, and amblyopia, in line with NEI’s core programs on Strabismus/Amblyopia/Visual Processing and Low Vision/Blindness Rehabilitation. In the process, the candidate will expand upon his background in in vivo synaptic plasticity and optical physiology in autism animal models to gain expertise in core methods of human neuroscience including rTMS, MRI, EEG, visual spatial attention paradigms, and computational modeling, learning from Stanford mentors who are au- thorities in these techniques (Dr. Nolan Williams, Dr. Tony Norcia, and Dr. Justin Gardner). He will take full advantage of Stanford’s vibrant intellectual environment, interacting with clinicians and researchers to bridge the gap between basic neuroscience bench and the clinic bedside. This training will allow the candidate to estab- lish a unique research niche at the interface of neuromodulation, neuroplasticity, and brain states and eventually lead a translational program to implement neuromodulation-assisted behavioral and rehabilitation therapies.

NIH Research Projects · FY 2026 · 2025-12

Proposed Approach: We will use a mixed methods study design to identify the components of emergency department (ED) pediatric readiness most predictive of short- and long-term survival among children. This project will help EDs prioritize implementation of ED readiness to save pediatric lives. We will use existing research infrastructure, data science methods, the ability to follow children to one year, novel analytics, and an interdisciplinary team to address this critical public health need. Importance: Injury and acute illness are the leading causes of death in children. We have recently shown that high ED pediatric readiness in US trauma centers and general hospitals is independently associated with improved survival, but the components of ED readiness driving survival are unknown. It is also unclear whether other organizational factors or ED processes of care improve survival among children. Answers to these questions will guide EDs in prioritizing the implementation of ED readiness, especially in smaller hospitals and rural settings with limited resources and budgets. This project is designed to inform the national trauma center verification criteria, the national field triage guidelines, the National Pediatric Readiness Project, and the Emergency Medical Services for Children program. Objectives: There are three specific aims: Specific Aim 1: We will build two multi-state cohorts of children receiving emergency care and use machine learning to identify the components of ED pediatric readiness predictive of short- and long-term survival. Specific Aim 2. Empirically develop a global measure of ED pediatric readiness and compare it to the weighted Pediatric Readiness Score for predicting short- and long-term survival in children. Specific Aim 3: Use a positive deviance approach to identify ED pediatric readiness factors and processes of care associated with improved survival among children receiving emergency care. Study Design & Setting: We will build two cohorts of children using emergency services from 1/1/2018 to 12/31/2022 in 928 EDs in 11 states (ED cohort) and 678 trauma centers in 50 states (Trauma cohort). We will link state vital statistics death records to the cohorts to track outcomes to one year and assess 152 unique components of ED readiness using machine learning methods. We will also conduct 150 interviews in 30 hospitals across the US using positive deviance methods as a complement to the quantitative analyses. Participants: Injured children 0–17 years using emergency services, including 15.6 million children with ED visits, 606,810 hospitalized children, and 264,865 children admitted to US trauma centers. Outcome measures: We will evaluate in-hospital mortality (primary) and 1-year mortality (secondary) at the patient-level. We will also evaluate the observed versus expected mortality at the ED-level to facilitate the positive deviance analysis.

NIH Research Projects · FY 2025 · 2025-12

Project Summary/Abstract Cadherin mediated cell-cell contact formation is essential for tissue integrity and organization. It has been proposed that the dynamic reorganization of cadherins and the actomyosin cortex is critical for the opening of cell-cell contacts. Although disruptions in adherens junctional complex can lead to diseases such as tumor metastasis and developmental disorders, the mechanisms by which cadherins regulate the mechanical properties of the actomyosin cortex are not fully understood. Active gel theory suggests that uneven mechanical stress within the actomyosin network drives flow, which facilitates the opening of intercellular junctions by depleting the F-actin and reducing interfacial tension. E-cadherin clusters are thought to modulate mechanical stress within the cortex through two primary pathways: (1) local inhibition of myosin contractility via depletion of Rho GTPases, and (2) direct mechanical coupling with actin. The current model primarily focuses on the first pathway, where E-cadherin-mediated downregulation of RhoA-GTP inhibits myosin-II activity at the contact center, initiating centrifugal F-actin flows. However, this model does not fully explain how E-cadherin clusters and actin co-localize at the contact rim once a steady state is reached. Therefore, we aim to investigate how the alternative pathway, involving direct interaction between E-cadherin and actin, modulates actomyosin symmetry breaking and leads to the dynamic reorganization of the cortical actomyosin network. Previous studies have identified key mechanical properties of the adherens junctional complex and the actomyosin network, showing that junctional adaptor proteins such as α-catenin and vinculin form directionally asymmetric catch bonds with F-actin. These asymmetric interactions suggest that E-cadherin clusters may promote the formation of anisotropic F-actin polar asters, with (+)-barbed ends oriented toward the center. Since myosin motors generate contractile forces between antiparallel actin filaments, the arms of these asters can be stabilized by catch bonds when they coupled to the opposite arm of another aster. Therefore, I propose that chain of E-cadherin clusters, linked by arms from actin asters, form the basic architecture of the interfacial actomyosin network. This ring- shaped structure can then expand due to the outward mechanical stress superimposed by local anisotropy and concentration gradients within the actomyosin network. In this proposal, I will test the following hypotheses to explore this working model. First, I will examine the mechanical coupling between E-cadherin clusters in close proximity using a patterned supported lipid bilayer model. Next, I will Investigate the arrangement-dependent mechanical coupling between E-cadherin clusters by addressing quantification of attractive force and position- dependent lifetime of E-cadherin clusters. Finally, I will develop a biophysical model, grounded on active polar gel model, to understand the role of mechanical coupling in interface opening. By addressing these hypotheses, this research will enhance our understanding of how E-cadherin clusters and actomyosin networks interact to regulate the formation of cell-cell contacts.

NIH Research Projects · FY 2026 · 2025-12

ABSTRACT FROM PARENT GRANT Colorectal cancer (CRC) is the 2nd leading cause of cancer death in the United States. The American Cancer Society (ACS) recommends normal body mass index (BMI), regular physical activity, and a healthy diet for cancer survivors. In 2018, we estimated that 38% of deaths within 5 years of diagnosis could be prevented in stage III colon cancer if all patients followed the ACS guidelines. Yet, <10% of CRC patients closely follow these lifestyle guidelines. Investigators have yet to optimize a lifestyle intervention, capitalizing on effective scalable components, to improve lifestyle behaviors in CRC survivors. Critical research gaps include: 1) whether specific intervention components (e.g., text messaging, etc.) are effective, overall or in sub-groups (men vs. women, etc.); 2) insufficient focus on improving diet; and 3) few studies with remote interventions have measured biological outcomes. To address these gaps, we propose to use the multiphase optimization strategy (MOST) framework to identify effective intervention components to increase the ACS guideline score (a standardized measure of physical activity, diet, and body size) among CRC survivors. The MOST framework is an engineering-based approach to efficiently optimize behavioral interventions while managing limited resources. Our team at the University of California, San Francisco; Dana-Farber Cancer Institute; and Northwestern University have strong expertise conducting lifestyle interventions in cancer survivors, including using MOST. Building on this experience, we propose a 12-month (mo.) randomized factorial experiment among 400 CRC survivors to determine the effect of 4 candidate intervention components [text messaging, digital health tool kit (physical activity tracker, apps), health coaching, buddy training (e.g., friend, family)] on change in the ACS guideline score from 0 to 12 mo. Changes in the ACS score (our primary outcome) have high potential to impact CRC survival, and it is modifiable and measurable remotely. Our Specific Aims are to: Aim 1) Identify which of 4 candidate intervention components increase the ACS guideline score at 12 mo. among CRC survivors. We will determine the individual and interaction effects of each component. Secondarily, we aim to: Aim 2) Examine mediators and moderators of the intervention components’ effects on change in the ACS guideline score from 0 to 12 mo. We will examine social cognitive theory constructs as primary target mediators and sociodemographic, clinical, and psychological/behavioral factors as potential moderators. This aim will help us understand how and for whom the intervention components affect lifestyle behaviors. Aim 3) Examine the ACS guideline score in relation to levels of fasting insulin, glucose, HOMA-IR and inflammatory markers at enrollment and 12 mo. The data from all three aims of this proposal will guide our next step to conduct a definitive randomized controlled trial to evaluate the effect of the optimized intervention versus standard care on risk of CRC recurrence. Overall, this proposal is a critical step toward developing an effective and scalable lifestyle intervention to reduce CRC mortality with potential for high public health impact.

NIH Research Projects · FY 2025 · 2025-11

PROJECT SUMMARY To retain new memories over long periods of time, the brain must be able to change in response to learning and then stabilize those changes to store long-term memories. However, the cellular mechanisms that enable long-term memory recall remain incompletely understood. Intriguingly, recent evidence suggests that myelin, the lipid-rich substance produced by glial cells known as oligodendrocytes, is critical for long- term memory recall. Myelin, previously thought to be static and stable after development, is critical for nervous system function; its primary role is to increase the conduction velocity of electrical signaling by neurons. In the adult brain, learning can induce the formation of new myelinating oligodendrocytes, known as oligodendrogenesis. The new myelin sheaths created by oligodendrogenesis are critical for the recall of long-term memories. However, how myelin is precisely modulated to regulate the neural activity underlying long- term memory storage remains an open question. To address this, I use an active avoidance paradigm in which mice learn to associate a light cue with a mild footshock and escape by shuttling to avoid footshock. The trial-based structure, the ability to compare correct and incorrect trials, and the greater diversity of behavioral readouts enable precise correlation between neural features and behavior. Furthermore, the specificity of these readouts can help uncover the precise circuits that are impacted by new myelin formation. Using the active avoidance, I will 1) identify which neurons become myelinated in the medial prefrontal cortex after avoidance learning using two-photon microscopy and 2) determine how oligodendrogenesis influences synchronization in the cortical-hippocampal-amygdala network during avoidance memory recall. Together, I will uncover how learning shapes myelination and how this myelin plasticity influences neural dynamics during long-term memory. These studies will shed light on underexplored, non-neuronal plasticity mechanisms that shape neural dynamics and have broad implications for our understanding of how the brain changes after learning. I will be conducting these experiments in Dr. Mazen Kheirbek’s laboratory, where all the techniques necessary for my project have been set up. The Kheirbek laboratory is located at the University of California, San Francisco, a world-renowned biomedical research facility. With the support of Dr. Kheirbek, co-sponsor Dr. Vikaas Sohal, and additional support from Dr. Jonah Chan, I am perfectly positioned to complete the described project. My postdoctoral work will enable me to achieve my ultimate career goal of running an independent academic laboratory studying how neuron-glia interactions influence neural circuit dynamics and behavior.

NSF Awards · FY 2025 · 2025-10

This project focuses on developing and expanding Workplace Navigation (WN) skills training for two-year college students in technical programs. This initiative equips students with essential skills to 1) identify workplace opportunities that align with their personal needs, goals, and priorities, 2) assess their work environment critically, and 3) overcome challenges that could hinder their success, such as by clarifying expectations and seeking constructive feedback. This initiative builds on insights from two-year college graduates who have identified WN skills as key to their career growth. By creating accessible, scalable training and resources for students and programs nationwide, this project supports students to confidently navigate technical workplaces, positioning them for success and contributing to a stronger, more adaptable national workforce. The goals of this project are to accelerate the integration of WN skills training across two-year college technical programs and explore the scalability of these modules beyond the biotechnology sector. In collaboration with the California Bioscience Workforce Development Hub and InnovATEBIO, a national center for biotechnology education, the project seeks to establish a national Workplace Navigation Hub to 1) provide WN modules for students, 2) support faculty nationwide in embedding these modules into their curricula, 3) examine the broader applicability of WN modules in technical fields beyond biotech, and 4) offer guidance to work-based learning programs on incorporating WN practice strategies. The scope includes not only developing training materials but also studying their effectiveness in improving student learning and success in technical careers, ultimately shaping a workforce equipped to meet the demands of advanced technology fields that drive the nation's economy. To maximize impact, the project plans to disseminate outcomes and materials widely through the Workplace Navigation Hub, InnovATEBIO, and social media channels, including LinkedIn biotech education groups. This project is funded by the Advanced Technological Education program that focuses on the education of technicians for the advanced-technology fields that drive the nation's economy. 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 Global Ophthalmology is an expanding field within ophthalmology that unifies the local and international community to advance research, clinical care, education, and policy to prevent blindness worldwide. The Global Ophthalmology Summit is the only United States (U.S.) based meeting that delivers in depth and focused content in research in global eye health and health equity. It brings together leaders to create community and foster collaboration amongst meeting participants which is an opportunity to captivate a young audience to lay the foundation for future collaborations, mentorship, and inspire a career in vision science. Key research topics addressed include global scale collaborative research consortia, disease-specific interventions, technology and innovation, sustainability, education, and advancing eye health systems in the U.S. and globally. The resources sought in this proposal aim to enhance the participation of young researchers within the field of global ophthalmology through the following aims. In aim 1 we want to provide an opportunity to strengthen the global eye research community by bringing local and international expertise together to focus on innovative solutions to prevent and treat blindness worldwide. In aim 2 our goal is to create collaboration through providing intentional meeting content amongst the diverse group of attendees. In aim 3 we want to support innovative vision research in global ophthalmology of trainees and early career investigators. The mission of the Global Ophthalmology Summit is in alignment with the National Eye Institute’s new strategic plan to drive innovative vision research, foster collaboration, build global research consortia, inspire and recruit a diverse workforce, and educate our community and policymakers on the pressing needs of vision research. The National Eye Institute’s cross cutting areas of research emphasis addressed in past and future Summits include genetic research, data science, individual quality of life, and public health and disparities research.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Dry eye disease (DED) is one of the most common chronic eye diseases. Traditional randomized clinical trials for DED are challenged with sample sizes too small to demonstrate effect, lack of diversity among participants, and insufficient correlation between objective markers and patient-reported symptoms. This proposal outlines a novel approach to studying evaporative loss DED through a decentralized clinical trial design. This non- interventional planning and feasibility proposal shifts the focus of DED study away from doctors’ offices and into participants’ home environments. Subjective evaporative loss DED symptoms are collected remotely, electronically, and sequentially. Self-collected ocular surface samples are collected in two ways: with a self- collected Schirmer strip and with a self-collected conjunctival swab. All study material is mailed to participants’ homes. Self-collected ocular surface samples are placed in study vials and return mailed to a central location, UCSF Proctor Foundation laboratory, for RNA-deep sequence exploratory analysis of the transcriptome as a biomarker for DED. To mimic repeat ocular surface collection after a future DED intervention, Schirmer strips and conjunctiva self-swabbing will be repeated after 4 weeks. This decentralized approach to DED study promotes patient engagement, recruitment, communication, and participant diversity and also seeks to identify new objective markers of DED efficacy that can be collected remotely. Specific aims of this R34 are (1) To develop a remote trial design allowing for decentralized recruitment and study of DED, (2) To prepare an operations manual and statistical analysis plan allowing for execution and scalability of a decentralized DED study design, and (3) To determine feasibility and utility of obtaining transcriptomic analysis from remotely collected Schirmer strips and conjunctiva self-swab collection. This planning grant leverages the power of decentralized trials to efficiently, economically, and objectively study one of the most encountered eye diseases, evaporative loss dry eye. Ultimately, this decentralized study platform will provide a foundation for future DED trials, facilitating the comparative re-evaluation of existing therapeutics and a standardized platform for assessing the efficacy of new dry eye treatments.