Stanford University

NSF Awards · FY 2025 · 2025-02

This project focuses primarily on three different problems in number theory, combinatorics, and ergodic theory. This includes work in additive combinatorics concerning generalizations of Szemerédi's theorem on arithmetic progressions (sequences of numbers that are all equally spaced, like 4, 6, 8, and 10), which, informally, says that any sufficiently large collection of whole numbers contains a long arithmetic progression. It is a central problem in additive combinatorics to determine how large "sufficiently large" is. The investigator will study versions of this question involving more complicated patterns than arithmetic progressions, and then use the results and techniques developed to make progress on a related problem in ergodic theory. The investigator will also study the size and structure of integer distance sets, which are sets of points whose pairwise distances are all whole numbers. This award will support undergraduate summer research on representation theory and additive combinatorics, and also support the training of graduate students. More specifically, the investigator will build on her previous work on quantitative bounds for subsets of the integers lacking polynomial progressions of distinct degrees and for subsets of vector spaces over finite fields lacking a certain four-point configuration to tackle more general polynomial, multidimensional, and multidimensional polynomial configurations. The results for multidimensional polynomial configurations of distinct degree will then be used to make progress on the Furstenberg--Bergelson--Leibman conjecture in ergodic theory, which concerns the pointwise almost everywhere convergence of certain nonconventional ergodic averages. She will also investigate the size and structure of integer distance sets, in both the Euclidean plane and in higher dimensions, by encoding them as subsets of rational points on certain families of varieties and then studying these varieties. With her undergraduate students, the investigator will study the distribution of entries in the character tables of symmetric groups and some algorithmic problems in higher-order Fourier analysis. 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 2026 · 2025-01

ABSTRACT This project will develop novel multimodal artificial intelligence (AI) platforms to predict clinical outcomes for patients treated with chimeric antigen receptor (CAR) T cell therapies and nominate molecular engineering strategies to enhance therapeutic potency and safety. We will build two complementary AI systems: (i) tcellGPT, which integrates single-cell multi-omic, perturbation, and clinical datasets to predict patient response and toxicity based on the molecular profile of infused CAR T cells, and (ii) tnicheAI, which maps the spatial organization and functional state of the tumor microenvironment in multi-modal histopathology images and integrates clinical data to identify suppressive niches that must be overcome by next-generation CAR T cell designs. These models will be fused into tcellAI to holistically predict patient outcomes by combining infusion product profiles, tumor characteristics, and clinical covariates. Key outcomes will include predictive tools to personalize CAR T cell therapies, accelerate preclinical development of novel cell engineering strategies, and elucidate biological mechanisms underlying treatment efficacy and toxicity. Clinical team and bioethicists will be engaged throughout to proactively address fairness, privacy, transparency, and accountability considerations in the AI development lifecycle. The work will be conducted by a diverse team spanning immuno-oncology, machine learning, clinical care, and bioethics to thoughtfully curate datasets, tailor architectures, and validate predictive insights in alignment with stakeholder needs. Ultimately, by enabling more effective, personalized, and equitable cell therapies, this ethically-grounded multimodal AI approach will bring curative treatments to more patients.

NIH Research Projects · FY 2026 · 2025-01

PROJECT SUMMARY Learning to read depends on a confluence of foundational skills. Some skills, such as phonological awareness, are known to be critical. However, the role of other factors – such as differences in visual processing and executive functions (EFs) – are still debated . The overarching goal of this proposal is to characterize consistency and heterogeneity in mechanisms associated with word reading difficulties (i.e., developmental dyslexia) using a deep phenotyping approach. Here we take an innovative approach involving a) development of new, open-source technology and b) large-scale data collection in a diverse sample spanning over 100 schools across 16 states to answer three significant questions regarding the mechanisms of word reading difficulties such as dyslexia: Do individual differences in visual processing and executive functions (EFs) explain additional variance in reading abilities above and beyond phonological awareness? Within the domains of visual processing and EF, does one factor or multiple independent factors contribute to differences in reading ability? Are measures of visual processing and EF useful additions to conventional dyslexia screening in kindergarten and first grade? These questions represent long-standing scientific challenges with significant implications for dyslexia screening and intervention. We address these significant questions through an innovative methodology: ● Open-source assessment platform: We have developed and validated an online platform for reading assessment - the Rapid Online Assessment of Reading (ROAR) - that allows us to collect reliable and valid measures of reading ability, phonological processing, rapid automatized naming, visual processing, and executive functions at scale. Our team has a long history of developing open-source software to support rigorous, robust, and reproducible science and will openly distribute the tools developed here to support clinical research and practice. ● Research Practice Partnerships: Through partnerships with a) schools serving children with learning disabilities, b) charter schools, and c) public schools, we will collect the first large-scale, longitudinal dataset with detailed measures of visual processing and EFs alongside measures of reading ability in a large and diverse sample of children with dyslexia and typical readers. Significance and innovation: Deep phenotyping is the foundation of precision medicine, but has seen little attention in reading and dyslexia research. This proposal will resolve long-lasting controversies regarding dyslexia phenotypes and create the next generation of open-source tools to revolutionize phenotyping of developmental disorders. Ultimately, this proposal will inspire future work linking phenotypes to interventions and catalyze new approaches in clinical practice.

NIH Research Projects · FY 2026 · 2025-01

PROJECT SUMMARY Hypercholesterolemia is a major public health crisis, underscored by the fact that cardiovascular disease is the leading cause of death globally. The standard treatment for hypercholesterolemia is statins, but more recently effective biologics have emerged, including antibodies targeting proprotein convertase subtilisin/kexin type 9 (PCSK9). Inhibition of PCSK9 results in greater liver low density lipoprotein receptor (LDLR) expression and lower cholesterol levels in the bloodstream, making it an effective treatment for hypercholesterolemia. While anti-PSCK9 antibodies are very effective, they require repeated dosing for a patient’s lifetime to maintain efficacy – highlighting the need for of a singular, lifelong therapeutic solution for hypercholesterolemia. Our group has pioneered use of precision CRISPR/Cas9 genome-editing of hematopoietic stem and progenitor cells (HSPCs) to not only correct underlying genetic defects, but to engineer cells with new biologic function. In this proposal, I will use this technology to test my hypothesis that engineering HSPCs to produce B cells that secrete anti-PCSK9 antibodies upon engraftment would be an effective and durable treatment for hypercholesterolemia. I will accomplish this by targeting an engineered antibody transgene delivered by a recombinant adeno-associated virus 6 (AAV6) vector into a genomic safe-harbor site to minimally disrupt normal B cell function and allow for antibody expression from a synthetic B cell promoter. I have demonstrated feasibility of this gene-targeted antibody (GT-Ab) strategy through efficient targeted integration of antibody cassettes in human HSPCs and subsequent engraftment and multi-lineage reconstitution in immunodeficient mice. In addition, I have shown that B cells engineered with GT-Abs secrete functional antibodies in vitro. In order to further evaluate the effects and therapeutic potential of engineering GT-Ab HSPCs, I propose to (i) characterize the effect of GT-Ab engineering of HSPCs on B cell development (ii) study GT-Ab B cell expression and reconstitution in vivo by engraftment of human GT-Ab HSPCs, and (iii) evaluate therapeutic efficacy of GT-Ab HSPCs in a disease model of hypercholesterolemia. Overall, the completion of this proposal will provide important safety and efficacy data for engineering a hematopoietic system capable of generating antibody-secreting B cells to inhibit PCSK9 for the lifelong treatment of hypercholesterolemia. This fellowship will take place at Stanford University School of Medicine in the Institute of Stem Cell Biology and Regenerative Medicine, providing robust scientific and training infrastructure for the proposed work. Dr. Matthew Porteus is the ideal sponsor for this project due to his expertise in genome-engineering HSPCs and translating therapies to the clinic as well as his extensive track record of mentoring independent investigators. I will also be supported by an advisory team with the diverse expertise necessary to carry out this proposal, comprised of Drs. Peter Kim (antibody engineering), Hiromitsu Nakauchi (hematopoietic stem cell transplant), Kara Davis (B cell development, single-cell immune profiling), and Joshua Knowles (hypercholesterolemia).

NSF Awards · FY 2025 · 2025-01

Quantum computing will enable new computational and cryptographic capabilities which can exponentially surpass today’s computers. At the same time, quantum computers will be incapable of solving certain problems efficiently. The goal of this project is to advance quantum security by constructing new forms of cryptography based on quantum mechanics, which show it is possible to hide information in the physical properties of quantum systems. This will demonstrate the limitations quantum computers will face in learning physical properties of quantum systems. It may also enable new ways of hiding information in a way which is secure even against an adversary with a quantum computer. This project includes an integrated education and outreach program to build a robust pipeline of talent to push the field of quantum computing forward. The goal of this project is to construct quantum variants of pseudorandomness which are quantum analogues of pseudorandom generators. Instead of generating numbers which are indistinguishable from random, the goal is to instead construct quantum states which hide some of their quantum mechanical properties, such as their entanglement. This project aims to construct four new forms of quantum pseudorandomness tailored to different applications. These constructions will be designed to 1) show that it is cryptographically hard to deduce the entanglement of quantum systems which arise as ground states of local Hamiltonians, 2) create new post-quantum cryptographic primitives from learning properties of quantum states, 3) create new ways of testing if quantum devices are functioning properly, and 4) tackle core questions in quantum complexity theory, such as the complexity of implementing unitary transformations of quantum systems. 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 2026 · 2025-01

PROJECT SUMMARY The cardiovascular system is one of the earliest systems to develop and is critical for the survival of nearly all tissues and is comprised of four vessel types: arteries, veins, lymphatic vessels, and capillaries. Although they are all lined internally with a single-cell layer of endothelial cells (ECs), these ECs have cell identities specific to their vessel. Little is known about how the endothelial cell subtypes specialize, including veins. Disruptions in vein EC specialization and function can lead and/or contribute to conditions including arteriovenous malformations, cancers, or metabolic diseases. Previous research in mouse and zebrafish models revealed that a transcription factor, COUP-TFII, is required for vein EC identity specification. COUP-TFII is considered an orphan receptor since a physiological ligand has not been identified and is considered a key marker for venous identity. However, it remains unclear whether it is required for human vein development and critical aspects of its mechanisms of action are unknown. This is due to the lack of human culture systems for vein EC development and the difficulty of obtaining enough vascular cells for biochemical experiments from model organism blood vessels. Recently, our collaborators in the labs of Drs. Lay Teng Ang and Kyle Loh have established a stem cell differentiation protocol for vein and artery ECs from human pluripotent cells. The protocol results in the efficient (>85%) generation of highly pure vein ECs and recapitulates the steps of early embryonic cell differentiation. Leveraging this protocol, I aim to study COUP-TFII during human vein development. In Aim 1, I will establish if COUP-TFII is required for human vein EC specification, and if so, what protein domains of COUP-TFII are required. I will use and generate COUP-TFII loss-of-function CRISPR-modified human embryonic stem cell (hESC) lines to determine if markers of venous identity are disrupted in their gene and protein expression. I have already found that vein ECs generated from a COUP-TFII knockout hESC line has differential gene expression when compared to wildtype and that this is recapitulated in the COUP-TFII ligand binding domain truncation, suggesting that ligand binding plays an important role in vein EC development. In Aim 2, I will investigate if COUP-TFII regulated genes are required for venous EC specification, and what, if any, protein binding partners COUP-TFII is interacting with during human vein EC development. To do this, I will use COUP-TFII hESC lines that are tagged with FLAG, BioID and TurboID to perform immunoprecipitation and mass spectrometry experiments. Lastly, I will identify COUP-TFII ligands in Aim 3 through proximity labeling and mass spectrometry. Together, these aims will provide insight into the molecular dynamics of COUP-TFII in human vein EC development and allow me to gain technical and intellectual skills in experimental design and prepare for competitive postdoctoral positions.

NIH Research Projects · FY 2026 · 2025-01

PROJECT SUMMARY/ABSTRACT Sensorineural hearing loss (SNHL), the most common sensory deficit worldwide, is caused by damage to the fragile mechanosensory and neural structures of the human cochlea. The vast majority of SNHL remains irreversible, in part because the current clinical tools for otologic diagnosis, surgery, and therapy cannot visualize or provide functional information about the micron-sized cochlear cells and nerve fibers deeply embedded in a patient’s dense temporal bone. Thus, there is an urgent unmet need for an imaging tool that can determine the status of cochlear sensorineural cells to identify the underlying pathobiological defect, and ultimately determine the receptiveness of these cells to emerging SNHL treatments such as gene or cell therapy. To address this crucial challenge, we propose to significantly advance our existing intracochlear catheter that images sensorineural cellular structure with a high-resolution, cross-sectional imaging technology termed Micro-OCT (µOCT). Our proposed multimodality µOCT (MM-µOCT) technology will obtain improved images of cellular microstructure and simultaneously acquired and co-localized images of metabolic activity through 1) dynamic µOCT (DµOCT) imaging of intracellular motion and 2) metabolic autofluorescence imaging (AFI) of NADH/FAD. In Aim 1, we will develop and validate MM-µOCT technologies (both DµOCT and AFI) on the benchtop using mouse cochlear explants and whole excised mouse cochleae. Explants will be exposed to agents that simulate oxidative stress or hypoxia occurring during noise-exposure, while whole cochleae from noise- or gentamicin- exposed mice will be imaged in situ. In Aim 2, we will develop a flexible MM-µOCT endomicroscopic probe for imaging the sensorineural cells of the human inner ear, which will be tested in non-human primates following unilateral noise exposure. In parallel in Aim 2, we will develop clinical grade MM-µOCT system and probe using a medical device design control process and will apply for an FDA IDE for conducting a first-in-human study with this technology after the grant is over. Through this robust clinical translation strategy, we will create a minimally invasive tool for determining the microanatomic/metabolic states of critical cells implicated in human SNHL. This new capability will allow hearing loss treatments to be individualized and optimized, improving therapeutic success rates and restoring hearing in many more patients than is currently possible today.

NIH Research Projects · FY 2026 · 2025-01

PROJECT SUMMARY In optic glioma, including that associated with Neurofibromatosis type-1 (NF1), retinal ganglion cells (RGCs) sustain axon injury, and patients often lose vision in early life. Damage to RGC axons in the optic nerve, whether compressive, traumatic, ischemic, or degenerative, results in an irreversible loss of vision due to the inability of RGCs to remain viable and regenerate their axons. NF1 occurs in every 1 in 3000 children. Glioma formation in the optic nerve often results in the loss of visual acuity in young children, and the only available treatment is chemotherapy, which has less than 30% success rate. Therefore, strategies that can provide RGC protection prior to injury and therapies that can replace lost cells are needed. One potential treatment showing high promise is cell transplantation therapy. However, most of this data was developed in acute trauma models of optic nerve crush, which may or may not translate to the axon damage and retinal and optic nerve environment in NF1 optic glioma. Furthermore, it is unclear if transplanted cells could harm the remaining circuitry in the retina. In the first part of this proposal, the candidate will evaluate the functional impact of RGC loss during the progression of NF1. They will also evaluate donor RGC transplantation’s impact on the remaining intact retinal circuitry. For the second part of this proposal, they will examine if transplanted RGCs can be encouraged to form functional connections within the retina when their activity is synchronized with the host retina. The candidate’s career goal is to obtain a tenured faculty position in neurosciences studying neural regeneration in models of optic neuropathy. They aim to develop an independent research group to address how newly transplanted RGCs can integrate successfully into the visual circuit pathway. The candidate has previous experience in retinal circuitry, behavioral assessment, and functional imaging in explanted tissue. In this proposal, they aim to 1) acquire the technical knowledge and skillset necessary to examine cell replacement therapy in an animal model of NF1, 2) learn the techniques to evaluate functional visual outcomes over time in vivo, 3) develop as a manager and leader to prepare for an independent faculty position. During the mentored phase of this award, the candidate will prioritize undertaking activities to increase understanding of glioma formation and vision loss in NF1, to do productive and meaningful science, and consequently to transition evaluating visual outcomes in vivo and correlating those with morphological changes. The PI will work with mentors Dr. Jeffrey Goldberg and Dr. David Gutmann and members of a Stanford faculty advisory team. The proposed research and training plans will occur in Dr. Jeffrey Goldberg’s laboratory, the Blumenkranz Smead Professor and Chair of the Byers Eye Institute Department of Ophthalmology at Stanford University. The outstanding vision science group at Stanford is embedded within the world-class neuroscience and broader life sciences community at Stanford as a whole, with the benefits of a close-knit and focused department and the resources of the wider university.

NIH Research Projects · FY 2026 · 2025-01

PROJECT SUMMARY Cancer immunotherapy has been one of the great recent breakthroughs in cancer treatment options. Antibodies that antagonize immune-inhibitory receptors, a therapy type known as immune checkpoint blockade (ICB), show great promise and further improvements in response rates and durability are likely with additional research. The potency of this cancer therapy demonstrates its incredible potential, and yet for most cancer patients these amazing benefits are currently unattainable. One current challenge in checkpoint blockade therapies is understanding the highly variable responses across patient cohorts. The gut microbiome, a major source of interindividual biological variability, is known to impact systemic immune status and specific features of microbiome composition have been linked to ICB in multiple human studies. Tests of causality in animal models of ICB have confirmed that addition of certain bacterial species to the gut microbiome induces improved tumor control. However, inconsistencies of implicated microbial species between studies and the lack of insight into molecular mechanisms that underlie the microbiome’s impact on response leave a large gap in understanding. The central hypothesis of this proposal is that discrepancies in findings between studies that focus on compositional associations are explained by a shared functional basis within phylogenetically distinct taxa. Since functions encoded by the gut microbiome are the mediators of interactions with the host, and are often shared between unrelated bacteria, a function-focused approach to study the microbiome’s effect on ICB is needed. This proposal addresses field-wide challenges in pursuing microbiome function by leveraging a broad array of tools that have been developed for the purposes of investigating microbiome functions and understanding mechanistically how they impact host biology. The goal is to identify bacterially encoded functions that enhance response to ICB. Aim 1.1 proposes metagenomic data aggregation and analysis across immunotherapy studies to identify genes associated with ICB response; the cutting-edge data analysis pipeline applied to all available data addresses previous limitations like study specific analysis choices and small cohort sizes. In Aim 1.2, isogenic pairs of bacteria that do or do not express the genes of interest will be genetically engineered; function and phenotypic differences will be characterized in culture. Aim 2 will test the impact of candidate genes/functions by colonizing a mouse model of cancer with one of each pair of isogenic bacteria and comparing ICB-mediated tumor control. In cases where microbial genes/functions enhance ICB mediated tumor control, microbiome focused metabolomics and immunological characterization of gut, tumor, and other immune compartments will provide insight into immune mediators of the effect. Definitive identification of microbiome encoded functions and mechanistic connections that determine gut microbial impact on ICB will inform individualized therapeutic suitability and enable the development of therapies that augment ICB.

NIH Research Projects · FY 2026 · 2025-01

ABSTRACT Clinician-scientists in ophthalmology play a critical role in bridging basic and translational sciences to advance and develop effective treatments for blinding diseases. There is a critical need to recruit and retain research- focused clinicians in vision sciences. The overall objective of this program is to continue and enhance a robust clinician-scientist training program in ophthalmology to prepare future leaders in vision science. Stanford University has developed a unique program, the Stanford Ophthalmology Advanced Research Program (SOAR), which provides a blueprint for recruiting and mentoring future clinician-scientists. The proposal responds to the RFA, NOT-EY-23-008, which addresses the critical need for training and retaining research- focused clinicians. The program aims to educate and train the next generation of clinician-scientists in ophthalmology, aligning with the goals of the Stimulating Access to Research in Residency (StARR) program. This vision science initiative aims to provide targeted support to surgical residents engaged in research focused on disorders and diseases related to the visual system. The program leverages the research infrastructure and expertise available within Ophthalmology and across the Stanford communities to enhance the research capabilities of residency training programs strong in clinical practice but limited in research experience. Additionally, it offers crucial support to talented graduates of the StARR program, facilitating a seamless transition from resident investigator to independent career scientist. This multifaceted approach will provide a robust mentorship network for vision-related diseases at Stanford. The initiative is committed to a concerted effort to recruit a broad range of trainees into vision science research. In this structured program for clinician-investigators, Aim 1) is to establish a comprehensive strategy for the recruitment and retention of resident investigators, drawing from a different educational backgrounds, with the specific intention of fostering their development into future academic leaders in the field of vision research; Aim 2) is to provide systematic training and rigorous preparation of resident investigators to equip them with the requisite knowledge, skills, and competencies for achieving autonomy and excellence in their research careers, ensuring they are well-prepared for the demands of independent research; Aim 3) is to establish a rigorous evaluation process designed to assess the overall efficacy and achievements of the Stanford SOAR Program. This program encompasses diverse metrics and performance indicators, aiming to achieve its overarching goals and its impact on academic ophthalmology and vision diseases research. Successful funding of this program will address the pressing need for an increased number of vision physician-scientists specializing in ophthalmology and for advancements in imaging, biology, and clinical studies aimed at providing transformative care for patients.

NSF Awards · FY 2025 · 2025-01

The mammalian cell membrane is covered with a protective “shield” of proteins and sugars that enables cells to interact with their local environment. Important cell functions mediated by the cell membrane, like the delivery of growth factors and antibodies to cell surface receptors, requires these soluble species to penetrate through and interact within this thick shield that covers and protects the cell surface. The goal of this project is to develop a fundamental understanding of the physical organization of the proteins and sugars that make up the shield, and to identify the mechanisms of molecular transport and binding on the cell membrane. This will be achieved by studying the binding of one particular soluble species, a monoclonal antibody, on both live cells and on engineered synthetic surfaces. In addition to advancing a basic biophysical understanding of the cell membrane, this project may have significant broader impacts in biopharmaceutical drug discovery of antibody therapeutics that target diseased cell surfaces. The investigator’s research group will broaden STEM participation by integrating the proposed research with a two-part outreach program. First, the group will engage underrepresented groups with academic research, targeting junior transfer students to ease their transition to a four-year university and broaden their professional development. Second, the PI will teach effective science communication skills to students, which is an important skill that is largely missing in the traditional STEM curriculum. The objective of this project is to determine how the molecular organization of the cell surface glycocalyx modulates the biophysical interactions of proteins, polysaccharides, and macromolecules on the cell membrane. The project will combine coarse-grained molecular dynamics simulations, in-vitro reconstitution of engineered cell surfaces, and live cell experiments to provide a spatial and temporal description of the molecular-to-mesoscale surface interactions that govern plasma membrane organization. By quantifying the transport and binding of monoclonal antibodies to engineered antigen receptors with various chemical and physical properties, the project will determine the cooperative dynamics of multibody surface protein interactions. The project seeks to advance a quantitative framework to isolate the effects of protein glycosylation, density, charge, stiffness, and other biophysical properties on live plasma membranes. This project will determine surface protein interactions that cannot be obtained from studying purified proteins in isolation. Through the development of new tools and concepts, this project will advance the fundamental understanding of the cell membrane dynamics that govern a variety of surface-mediated cellular processes. 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 2026 · 2025-01

Glaucoma is the leading cause of irreversible blindness, affecting over 60 million people worldwide. Glaucoma patients vary widely in their presentation, with some retaining long-term disease stability, and others progressing quickly to vision loss. Recent advances in artificial intelligence (AI) for glaucoma have enabled integration of the rich and complex EHR data into algorithms that predict which patients will have progressive glaucoma, potentially enabling personalized treatments plans that prevent vision loss and reduce the overall burden of glaucoma care. In the rapidly evolving landscape of healthcare artificial intelligence (AI), there is a pressing need to prevent issues that may inadvertently worsen healthcare outcomes, if AI algorithms do not work well across different phenotypes of patients. For example, when the population used to train AI algorithms is dissimilar to populations where AI algorithms will be deployed, the generalizability of the AI algorithms across those populations is key to their effectiveness. There is an unexplored frontier in investigating generalizability in ophthalmology AI algorithms, largely due to the scarcity of large-scale multicenter ophthalmology datasets. The newly established multicenter Sight Outcomes Research Collaborative (SOURCE) registry, comprising data from 23 centers across the U.S., offers an unprecedented opportunity to assess AI algorithms in real-world scenarios and across different populations. The overall goal of this project is to develop generalizable prediction algorithms for glaucoma progression using multicenter scale EHR data. Aim 1 will compare established algorithm training methods aimed at standardizing performance between groups to investigate the tradeoff between overall algorithm performance and performance across subgroups, measured by equalized odds. Aim 2 will leverage the multicenter nature of SOURCE to train and test glaucoma prediction models across sites with highly varied population characteristics, investigating the impact of site and population differences on algorithm performance. Aim 3 will evaluate the use of novel group distributionally robust optimization methods to enhance generalizability in glaucoma prediction algorithms. Throughout this innovative project, we will use state-of-the-art AI methods for training generalizable algorithms to develop our glaucoma prediction algorithms in a large new multi-center ophthalmology EHR registry. Completion of these aims will mark the first systematic studies of generalizability for electronic health record prediction models in ophthalmology. The insights gained will not only optimize generalizability and performance in glaucoma AI but also extend to broader applications across many medical disciplines. By unveiling the intricacies of how AI algorithms perform when trained and tested in a variety of populations, this research is poised to significantly improve health outcomes for ophthalmology patients and serve as a guiding beacon for responsible AI implementation in healthcare.

NIH Research Projects · FY 2026 · 2025-01

ABSTRACT T2D and prediabetes are defined by measures of glucose elevation, but the underlying physiology is complex and differs between individuals: this heterogeneity is likely to drive differences in the course of diabetes, including development of comorbidities and response to treatment. Thus, while recent advances have led to greater individualization of diabetes treatment, current approaches, based on clinical traits such as cardiovascular (CVD) or kidney disease or desire for weight loss, do not truly represent precision medicine, which entails identifying the most appropriate therapy for a given patient based on biology. Furthermore, while there is a general consensus that subtyping T2D would be beneficial and enable targeted treatment approaches, current clustering methods have included only a few clinical and laboratory biomarkers that lack stability or presence of complications identified in the medical record. We have shown that individuals with prediabetes and early T2D can be subclassified according to defects in one of four major physiologic processes that are present in relatively equal distribution, including insulin resistance (IR), β-cell function, incretin effect, and hepatic IR, as quantified by gold-standard physiologic tests. The study goal is thus to advance precision diabetes medicine via the following AIMS: 1) define subphenotypes according to underlying metabolic physiology in the prediabetic/early diabetic state, 2) evaluate heterogeneity of responses to three established interventions according to metabolic subphenotype, 3) use integrated multi-omics to identify a molecular signature for each physiologic subtype and assess both baseline predictors of response and pathways that change differentially with treatment according to metabolic phenotype. To accomplish these aims, we plan to enroll 200 individuals with HbA1c 5.7 to 7.0% and perform gold-standard metabolic tests at baseline for muscle IR, hepatic IR, β-cell defect, and incretin defect. Relative deviance from cohort means will be used to classify individuals according to their dominant or co-dominant metabolic phenotype. To determine whether clinical response to treatment varies by metabolic subphenotype, individuals will then undergo three sequential treatments of 4-mos duration (andom order with 3-mo washouts): Mediterranean diet, metformin, and liraglutide. The primary endpoint is Δ HbA1c. Secondary endpoints include CGM glycemic measures, CVD risk markers, and regional fat distribution. With completion of 150 participants (37 per subphenotype), the study has 80% power, α=0.05, to detect a difference in Δ HbA1c of 0.17% in at least one treatment arm for a given subphenotype, or in at least one subphenotype for a given treatment. OMICS: we will apply our novel multiomics approach with soft hierarchical clustering that enables us to sample thousands of biomolecules to define a signature for each metabolic subphenotype. We will then identify a targeted panel of omics/clinical data that correspond to gold-standard defined subphenotypes and develop a CLIA- certified test for clinical use. Lastly, we will use omics to determine whether baseline signatures predict treatment response and examine longitudinal changes to highlight differences in biological treatment responses according to metabolic phenotype. The proposed study, leveraging our unique expertise, skills, and resources, will enable us to advance the goal of subclassifying T2D according to underlying physiology, and determine if a precision approach is effective.

NIH Research Projects · FY 2026 · 2025-01

PROJECT SUMMARY Acute myeloid leukemia (AML) is an aggressive malignancy of the bone marrow affecting more than 20,000 adults annually in the United States. Even with aggressive chemotherapy and/or bone marrow transplantation, five-year overall survival is between 30-40%. Genomic studies have demonstrated that most cases of AML are associated with mutations in multiple genes, often occurring with a complex clonal architecture. Previous studies demonstrated that these mutations are serially acquired in clones of self-renewing hematopoietic stem cells (HSCs), identifying pre-leukemic HSCs (pHSCs) bearing pre-leukemic mutations. These pre-leukemic mutations are enriched in genes involved in regulation of the epigenome, and the pre-leukemic cells acquire additional mutations, often in genes involved in proliferation, leading to AML. Stratification of a cohort of AML patients into high or low pHSC groups demonstrated that the high group had much worse overall and relapse-free survival, indicating that the presence of pHSCs may be critical for clinical outcomes. A parallel line of genomic studies investigated the presence of these AML-associated mutations in the blood of individuals with no history of hematologic disease, a condition termed clonal hematopoiesis (CH). CH was found to be associated with an increased risk of development of myeloid malignancy. Further whole genome sequencing studies used single cell and computational methods to determine phylogenies of HSCs in individuals and to estimate time since initial mutation and clonal expansion rates. These studies led to the conclusion that these pre-leukemic/CH mutations can occur decades prior, even as far back as in utero, and that rates of clonal expansion can be predicted from a single time point assessment, adding further complexity to the study of pre-leukemia and CH. These studies provide novel and significant insights into the genetic events and cellular kinetics that occur in the development of de novo AML. However, they also raise a number of new detailed questions with significant implications for disease pathogenesis, prevention, and treatment. What is the duration of the pre-leukemic phase in individuals that eventually progress to AML? Does this duration have any impact of disease pathogenesis? The pre- leukemic HSCs give rise to a clone (clonal hematopoiesis) that produces cells of divergent phenotypes. What are the characteristics and features of the pre-leukemic clone that eventually becomes transformed into AML through the acquisition of additional mutations. As we noted in our prior studies, AML can develop in the background of varying sized pre-leukemic clones, which is associated with patient outcomes. How does the size or burden of the pre-leukemic clone impact the corresponding AML? Is this impact direct or indirect? This proposal aims to investigate key questions related to pre-leukemic HSC clonal evolution, kinetics, and cell non- autonomous effects based on the hypothesis that these features of the pre-leukemic phase and the pHSCs themselves are critical contributors to AML pathogenesis. Ultimately, we postulate the pHSCs represent a critical cellular target for the development of curative targeted therapies.

NIH Research Projects · FY 2026 · 2025-01

PROJECT SUMMARY Proteasome inhibitors (PIs) represent novel cancer therapeutics highly effective in treating hematologic malignancies and have remarkably improved cancer survival rates. However, the utilization of PIs, particularly carfilzomib (CFZ), is largely hampered by substantial cardiovascular toxicity, which occurs through poorly characterized mechanisms. In this proposal, we aim to leverage a humanized multiple myeloma (MM) mouse model, human induced pluripotent stem cells (iPSCs), CRISPR interference and activation (CRISPRi/a) screens, single-cell RNA sequencing (scRNA-seq), deep learning, and RNA splicing biology to elucidate the molecular signatures underlying CFZ-induced cardiovascular dysfunction. We will focus on investigating the role of pathogenic alternative splicing events (ASEs) in smooth muscle cells (SMCs) and endothelial cells (ECs) in both mice and iPSCs. Finally, we will employ antisense oligonucleotides (ASOs) targeting candidate pathogenic ASEs to evaluate their effectiveness in preventing or mitigating CFZ-induced cardiovascular toxicity. In Aim 1, we will confirm CFZ-induced cardiovascular dysfunction phenotypes (e.g., hypertension, microcirculation dysfunction, and cardiac hypertrophy) in an MM mouse model and collect vehicle- and CFZ-treated mouse aortas for scRNA- seq. We will then perform extensive alternative splicing analysis using two novel algorithms, SpliZ and SpliceAI, developed by our team. In Aim 2, we will differentiate pooled iPSC lines derived from healthy donors and CFZ- treated cancer patients with or without cardiovascular phenotypes (5M+5F/group) into iPSC-SMCs and iPSC- ECs and construct 3D-engineered vascular tissues (iPSC-EVTs). We will select species-conserved, CFZ- induced differentially expressed splicing factors predicted to be pathogenic to conduct CRISPRi/a screens in pooled iPSC-EVTs and identify causal genes downstream of candidate splicing factors. In Aim 3, we will employ minigene splicing assays to confirm putative pathogenic ASEs in identified causal genes and design specific ASOs to block their activity. Therapeutic efficacy of ASOs will be validated first in primary and iPSC-derived EVTs. Promising candidate ASOs will undergo further validation in MM mice to evaluate their rescue effects on CFZ-induced hypertension, thrombosis, arrhythmia, and cardiac dysfunction. We anticipate that the successful completion of these studies will provide new mechanistic insights into CFZ-induced cardiovascular dysfunction and facilitate the development of novel therapeutics, enabling cancer patients to safely receive life-saving PI- based therapies. Moreover, this proposal will contribute novel insights into the role of aberrant alternative splicing in vascular pathology beyond the scope of cardio-oncology.

NSF Awards · FY 2025 · 2025-01

Subduction zone volcanoes occur where one tectonic plate goes beneath another. Many millions of people live near subduction volcanoes. This means that understanding subduction volcanoes and the hazards they present is important. Magmatic activity at a volcano is usually studied using methods from geophysics. One such method is monitoring how volcanoes change shape (volcano deformation) over time. Geologists can also study igneous rocks, which form from magmas, to learn about volcanoes and magmas. Extrusive igneous rocks form from magmas that erupt from a volcano. Intrusive igneous rocks form from magmas that crystallize beneath the Earth's surface. For this project, the research team will study an ancient subduction zone volcano in Washington where they find both types of igneous rocks. They will reconstruct the record of volcanic eruptions and subvolcanic intrusive activity. To do this, they will study the geochemistry, geochronology, and petrology of the rocks. They will use these data to understand three things. First, they will determine when the magmas formed and if the erupted magmas and intrusive magmas existed at the same time. Second, they will determine how the composition of the magmas changed through time. Third, they will determine how deep the magmas were beneath the Earth's surface. The research team will also make videos about the motivation, importance, and results of their research. They will work with Professor Nick Zentner (at Central Washington University) to make these videos. The research team will also work with the Indiana School of the Deaf to produce new lab exercises for their high school science courses. The ancient volcano that will be studied lies just to the north of Mount St. Helens and includes the upper crustal Oligocene Spirit Lake Pluton and surrounding volcanic rocks. It represents a deeply eroded portion of the ancestral Cascade Arc and was the focus of detailed 1:24,000-scale geologic mapping by the USGS in the 1980s and 1990s. Existing geo- and thermochronology constrains the duration of pluton emplacement to <1.5 Myr and demonstrates that eruptions of the surrounding volcanic rocks pre-dated, were coeval with, and post-dated the pluton. Existing whole rock geochemical data show a compositional range from quartz diorite to granite in the pluton, and a range from basalt to high-silica rhyolite in the volcanics. This research aims to produce a detailed chronological and geochemical record of pluton construction and associated volcanism to better understand when the intrusive rocks were emplaced, if intrusive activity affected the rate and/or style of volcanic eruptions, and if any of the erupted magmas were derived from the pluton. This project will produce a detailed timeline of events using high-precision U-Pb zircon geochronology for 15 samples each from the pluton and the associated volcanic section. These data, along with geochemical and textural observations, will allow the team to answer questions such as: 1) Was there a long-lived magmatic mush within the now solidified plutonic complex? and 2) Did emplacement of the pluton lead to changes in eruption style, composition, or rate? Geobarometric data will allow the team to directly test whether any volcanic eruptions were sourced from the same depth as the currently exposed pluton. Taken together these geochronologic, geochemical, and geobarometric datasets will offer a holistic record of how the magmatic system evolved over the lifespan of a single arc volcano. 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 2026 · 2025-01

Innovations in precision medicine are rapidly changing scientific understandings of the causes of and potential treatments for a broad range of chronic health conditions. Alongside the potential benefits of precision medicine research (PMR) initiatives comes a range of perspectives on the role PMR and precision medicine should play in treating or curing chronic health conditions, especially early onset neurological disorders. However, little is known about the perspectives of individuals with early onset neurological disorders towards emerging PMR into conditions that have not historically been understood as genetic. Prospectively facilitating values alignment raises ethical challenges. Existing literature provides insufficient guidance on how to facilitate consensus among the perspectives of researchers, people with early onset neurological disorders, their caregivers, and clinicians. Using emerging PMR on cerebral palsy (PMR-CP) as a case study, the overall objective of this K01 is to prospectively align the values of precision medicine researchers and people with early onset neurological conditions in order to guide development of diagnostics and treatments that better serve the needs of those with these conditions. The proposal has three specific aims. AIM 1: Assess the values and priorities of key stakeholders in PMR-CP, using semi-structured interviews to characterize how they perceive potential benefits and harms of PMR-CP. Stakeholders will include PMR-CP researchers, adults with CP and primary caregivers of those with CP, and clinicians caring for CP patients. AIM 2: Using data from Aim 1, create and test briefing materials for guiding deliberation on PMR-CP. AIM 3: Using the data from Aim 1 and materials developed in Aim 2, facilitate deliberative sessions with members of the stakeholder groups interviewed to negotiate consensus on the ethical values that should motivate future PMR-CP, which can serve as a model for other neurological conditions with genetic etiologies. Dr. Mintz will achieve these aims by drawing on his current skills in special education, political theory, and clinical bioethics, as well as on additional training in human genetics and genomics and empirical deliberative methodologies. Dr. Mintz’s approach to the project will also be informed by his experience of cerebral palsy. His proposed training and research will take place at the Stanford Center for Biomedical Ethics. Dr. Mintz is already widely respected in bioethics for his scholarly accomplishments. Through the support of this award, Dr. Mintz will build upon his current expertise to become one of the few bioethicists who is trained in genetics and empirical approaches to deliberative methods. If successful, his research will refine a methodology for negotiating consensus among precision medicine researchers, members of the CP community, and clinicians, which can be used as a model for other conditions.

NIH Research Projects · FY 2025 · 2025-01

PROJECT SUMMARY/ABSTRACT Visual areas show heightened plasticity in the first year of life, making this time period a key window for identifying and intervening in the case of developmental atypicalities. Myelination is a likely mediator of experience- dependent plasticity in visual cortex, as it occurs rapidly in the first two years of life and can influence neuronal communication, learning, and memory. Yet, little is known about the contribution of myelination to the development of human visual circuits. To address these gaps in knowledge, the goal of this research is twofold: 1) Using innovative quantitative magnetic resonance imaging (qMRI), longitudinally measure the microstructural development of the human visual system during the first year of life, and (ii) Using advanced histological methods in pediatric and adult samples of visual cortex, determine the development of myelination in visual cortex and validate in vivo metrics of microstructural development. In three visual areas with distinct functional development (primary V1 in calcarine sulcus, place-selective cortex in collateral sulcus, and face-selective cortex in fusiform gyrus), I will (i) test the hypothesis that human visual areas with prolonged functional development (i.e. face-selective area) exhibit prolonged myelination and (ii) validate whether the development of myelin can be measured with specific qMRI metrics. First, I will use histology to map the development of myelin across visual cortex (Aim 1). Next, I will use qMRI to determine the in vivo longitudinal development of visual cortex microstructure (Aim 2). Finally, I will validate whether myelination can explain in vivo measures of cortical development using a combination of in vivo and ex vivo qMRI, quantitative mass spectrometry, and histology (Aim 3). Achieving these aims will resolve the contribution of myelin to the development of human visual cortex and validate which MR metrics can be used as potential diagnostic tools in atypical neurodevelopment. My sponsor, Dr. Kalanit Grill-Spector, is an expert in pediatric in vivo neuroimaging, and our collaborator, Dr. Mercedes Paredes, is an expert in pediatric ex vivo histology. Their combined expertise and strong mentorship will guarantee my training goals are met: developing a strong neurodevelopmental research question, completing the proposed research, and obtaining training crucial to furthering my future career goals. An F31 NRSA fellowship would enable me to cultivate my neurodevelopmental and human neuroimaging skillsets, progressing me towards my goal of becoming an academic principal investigator studying activity-dependent myelination in health and disease to develop interventions in cases of atypical myelination.

NSF Awards · FY 2025 · 2025-01

Nontechnical description The relentless growth of data-driven computing and artificial intelligence is pushing conventional microelectronics to their limits, necessitating new technologies that reduce power consumption and latency. This project explores a new family of atomically thin ferroelectric semiconductors—materials that maintain a reversible electric polarization—to advance high-performance logic devices, efficient memory architectures, and integrated nonlinear photonics. By developing robust synthesis techniques and controlling atomic-scale features within semiconductor materials and interfaces, the research aims to enhance next-generation electronic devices. A key aspect is understanding how ferroelectric polarization switches in these materials, measuring the speed of this switching process, and observing its impact on electronic properties. To inspire future engineers and address the growing needs of the semiconductor industry, the educational outreach component targets middle school students, igniting their curiosity about the quantum origins of everyday phenomena. This includes workshops for middle school teachers, providing them with lessons and supplies to demonstrate two-dimensional semiconductor physics in the classroom. The project also engages high school interns in building new software tools for open-source two-dimensional semiconductor metrology. Technical description The research focuses on rhombohedral transition metal dichalcogenides, such as tungsten disulfide and tungsten diselenide, which exhibit van der Waals ferroelectricity due to non-centrosymmetric interlayer stacking configurations. These materials have recently gained interest for their reported enhancements in carrier mobility, their high-speed, high-fatigue-resistance switching properties, and their efficient nonlinear optical frequency doubling. This project addresses the challenge of synthesizing these materials and understanding their ferroelectric and charge transport properties. The core scientific objectives include: (1) synthesizing molybdenum and tungsten-based rhombohedral transition metal dichalcogenides as large single crystals on standard semiconductor substrates with control over substitutional doping via chemical vapor deposition; (2) applying nanoscale microcopy and spectroscopy with high spatial and temporal resolution to study ferroelectric domain dynamics and to measure and optimize switching speeds; and (3) measuring electronic transport in devices to characterize how ferroelectric polarization affects charge transport through multilayer domain configurations and interactions with dopants. These studies aim to improve integration potential, switching speed, and charge transport in ferroelectric two-dimensional semiconductors, influencing the design of future memory and logic-in-memory devices. The research aligns with the goals of the Electronic and Photonic Materials program by advancing the understanding of materials with reduced dimensionality, exploring fundamental mechanisms at the atomic level, and potentially offering new paradigms in computing and communications. 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.

NSF Awards · FY 2025 · 2025-01

This award will support the conference “Structure and Polarization in the Interstellar Medium: A Conference in Honor of John Dickey.” This conference will be held on 18–21 February 2025. This conference will be run simultaneously at two sites – Stanford University and the Australian National University. This conference will bring together global experts to discuss the structure of the Milky Way, the interstellar medium (ISM), polarization, and Galactic magnetism. This award supports the participation of graduate students and postdoctoral fellows in this conference. This meeting will provide an opportunity for early career researchers to establish collaborations with experts in the field. Topics will include recent and ongoing work on the structure, magnetism, polarization, and chemistry of the Milky Way and nearby galaxies using radio observations of the interstellar medium. The conference will stimulate collaborative work in two creative ways. Simultaneous work sessions at each site will actively promote real-time collaboration and discovery. Cross-site collaborative work sessions (one hour per day) will synthesize ideas and share breakthroughs achieved during the independent collaborative work sessions at each site. 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.

NSF Awards · FY 2025 · 2025-01

Ocean ecosystems are reliant on tiny, microscopic phytoplankton that form the base of the marine food web, yet vast regions of sunlit open ocean waters also have chronically low concentrations of dissolved nitrogen (N), a nutrient that limits photosynthesis and growth. These ecosystems are highly regenerative, meaning that the organisms are adapted to low concentrations of nitrogen and recycle it efficiently. While this nitrogen recycling sustains growth, addition from other sources (or “new” nitrogen) is important for fueling new growth and is ultimately linked to the ocean’s ability to remove carbon dioxide from the atmosphere and store it in the deep ocean. New nitrogen is introduced into the surface ocean through the movement of deep waters with high nitrogen concentrations to the surface or through the process of biological nitrogen fixation -- the microbial conversion of nitrogen gas into a biologically available form. Diatoms are one of the most important phytoplankton groups in modern oceans and form the base of the food web in the most productive ocean ecosystems. In the low nutrient open ocean they can sometimes form dense aggregates (or “mats”) that can descend into deeper waters to obtain the nitrogen needed for their growth using buoyancy regulation. The investigators recently observed and sampled mats of multiple Rhizosolenia diatom species in the North Pacific Subtropical Gyre (NPSG) and showed that their microbiome contained a diverse array of microbes capable of nitrogen fixation. This discovery calls into question where Rhizosolenia mats acquire nitrogen and suggests that they may obtain it from living in symbiosis with nitrogen-fixing microbes. Importantly, fragile Rhizosolenia mats are not well sampled using traditional oceanographic techniques, as such we know very little about these microbial ecosystems and their contribution to oceanic productivity. This project is characterizing Rhizosolenia mat ecosystems, determining whether they are growing on nitrogen from nitrogen-fixers, and assessing their contribution to the nitrogen cycle in the NPSG. The investigators are combining traditional microscopy techniques, as well as modern multi-omics, imaging, and stable isotope tracer techniques. They are using deployable optical instrumentation and satellite data to track the location of mats during a research cruise to the NPSG, and using blue-water diving to sample and incubate the fragile mats. This project is having an impact beyond advancing discovery by providing professional development opportunities for early career ocean researchers, including exposure to a broad array of transferable skills, from scientific diving to molecular techniques. The investigators are also developing a hands-on educational module about marine phytoplankton, symbioses, and ocean nutrient cycles to be featured at the Moss Landing Marine Labs Open House, a free public outreach event held annually each spring. Diazotrophy, the microbial fixation of dinitrogen gas into ammonia, supports a significant amount of primary production in the chronically nitrogen-limited oligotrophic ocean. However, the relative importance of different diazotrophs to primary production is not clear, and ongoing discoveries of novel diazotrophs highlight our incomplete understanding of marine nitrogen-fixers. Phytoplankton vertical migration is an additional source of new nitrogen to surface waters in oligotrophic systems, and multispecies, migrating Rhizosolenia aggregates (or “mats”) have been reported to contribute significantly to both primary production and carbon export fluxes due to their ability to transport deep nitrogen into surface waters. The investigators encountered Rhizosolenia mats on a research cruise in the North Pacific Subtropical Gyre (NPSG) in 2022, which led to the discovery that they contain a varied assemblage of diazotrophs, but not the heterocyst-forming Richelia known to form associations with some Rhizosolenia sp. These findings, along with a historical observation of dinitrogen gas fixation in Rhizosolenia mats, suggest that these mats may acquire some of their needed nitrogen from diazotrophy, and mat-associated dinitrogen gas fixation constitutes an unrecognized important source of nitrogen to the NPSG. This project is assessing the composition, activity, and symbiotic nature of Rhizosolenia mat communities, as well as determining their significance to the nitrogen inventory in the NPSG. The investigators are providing the first detailed characterization of mat-forming Rhizosolenia and their associated diazotroph communities by using a combination of traditional microscopy techniques (light microscopy, Scanning Electron Microscopy, Transmission Electron Microscop), molecular and ‘omics tools (metagenome-assembled genomes, Rhizosolenia barcoding using voucher isolate strains, fluorescence-based visualization, amplicon High Throughput Sequencing) and stable isotope-based approaches at both whole mat and sub-mat scales (using nanoscale secondary ion mass spectrometry). Demonstrating that Rhizosolenia mats obtain diazotroph-derived nitrogen would transform the current paradigm about the role of these mats in nitrogen and carbon biogeochemical cycles and identify a novel diazotroph niche that is missed with conventional sampling. This project is also opening avenues to explore fundamental questions of diatom evolution and characterization of diatom strategies for metabolic adaptation to low nutrient environments through the isolation of mat-forming diatoms and generation of metagenome-assembled genomes. Additionally, morphological and molecular characterization of these fragile and cryptic Rhizosolenia mats is significantly contributing to illuminating the unseen pelagic microbiome. 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 2026 · 2025-01

PROJECT SUMMARY/ABSTRACT Chimeric antigen receptor (CAR) T cells have emerged as breakthrough treatments for patients with hematologic malignancies, earning 12 approvals from the U.S. Food and Drug Administration (FDA) since 2017. Experimental CAR T cell therapies have also demonstrated complete remissions in solid tumors, and the FDA is projecting to grant 10-15 approvals per year by 2025, highlighting the potential of these ‘living therapies’. Despite this, current CAR T cell designs have not yet mediated sustained efficacy in solid tumors, and only 30-50% of B cell leukemia and lymphoma patients experience long-term disease control. To develop safe and potent next-generation CAR T cell therapies, it is critical to understand why existing CAR T cells succeed or fail in patients. As a scientist trained in both experimental and computational immuno-oncology, I have chosen to focus my career on using a systems biology approach to uncover the molecular mechanisms governing efficacy of engineered T cell immunotherapies. This proposal outlines a structured 2-year training plan and a comprehensive 5-year career development program to complete my training and launch an independent research career. My specific research goals are: (1) to define the most therapeutically relevant CAR T cell subsets in patients with large B cell lymphoma (LBCL), and (2) to overcome an immune suppression mechanism of resistance to CAR T cell therapy for LBCL. First, I will follow individual CAR T cell clones through time in patients treated for LBCL using matched single-cell sequencing of transcriptome, a panel of surface proteins, and endogenous T cell receptors (Aim 1). This approach, termed reverse fate mapping, will pinpoint T cell clones in the pre-manufacture apheresis and infusion products with sought-after properties, including abilities to expand, persist, and home to the tumor. In Aim 2, I will apply reverse fate mapping and methylation analyses to identify the origin of circulating CAR T regulatory (Treg) cells that I recently linked to limited CAR T cell efficacy in LBCL. In Aim 3, I will mechanistically dissect the interplay between Treg and non-Treg CAR T cells to design a potent ‘Treg-free’ CAR T cell therapy for clinical evaluation. My work will generate a comprehensive CAR T cell atlas and insights, leading to promising avenues for engineering the next-generation CAR T cell therapies. The results of my proposed research will positively impact public health, as they will gather sufficient preliminary data for testing a ‘Treg-free’ CD19-CAR T cell therapy for LBCL in a clinical trial and will deliver fundamental insights into CAR Treg biology that may generalize to other diseases, including solid tumors, where engineered T cell therapies have not manifested similarly potent effects as in LBCL. To build upon my skills, I have assembled a mentorship team, including my primary mentor, Dr. Crystal Mackall, a pioneer in CAR T cell immunotherapies; co-mentor, Dr. Sylvia Plevritis, a leader in cancer systems biology; and an advisory committee with extensive expertise relevant to all aspects of this proposal. The completion of this K99/R00 program will prepare me to compete for R01 funding and to launch an independent research career focused on improving immunotherapies for patient with cancer.

NIH Research Projects · FY 2026 · 2024-12

Project Summary/Abstract: This is a proposal to consolidate our NINDS research projects into one larger R35 award, enabling us the time and flexibility to explore important biological questions relevant to human neurodegenerative diseases. My laboratory has used a combination of yeast and human genetics to define novel mechanisms of ALS, FTD, and Parkinson’s disease. These experiments have led to the discovery of ataxin 2 intermediate-length polyglutamine expansions as a major genetic risk factor for ALS. We found that reduction of ataxin 2 in mouse profoundly extends survival of TDP-43 transgenic mice (either by genetic knockout or using ASOs). These preclinical studies have led to the initiation of a clinical trial in human to test ataxin 2 ASOs in human ALS. We have pursued ataxin 2 as a therapeutic target in ALS and have identified additional regulators of ataxin 2 levels including a small molecule that can lower ataxin 2 levels in vitro and in vivo. Given the success of these genetic screens for finding regulators of ataxin 2 levels, I propose performing genomewide modifier screens in human cells using CRISPR/Cas9 for regulators of additional neurodegenerative disease proteins. We recently identified dozens of cryptic splicing events that occur in neurons harboring TDP-43 pathology, including one in the UNC13A gene, one of the strongest GWAS hits for FTD/ALS. Importantly, we found that the genetic variations in UNC13A that increase risk for disease increase cryptic exon inclusion in the face of TDP-43 pathology. We propose functional studies to elucidate the role of additional cryptic splicing targets in ALS pathogenesis. Finally, we have expanded efforts to include single-cell sequencing and have performed RNA- sequencing on adult mouse spinal cord, revealing remarkable heterogeneity and new markers of skeletal motor neuron subtypes. We propose studies to apply this technology to mouse models of ALS and to human spinal cord. Together, we present an ambitious research program aimed at defining novel mechanisms of human neurodegenerative diseases and then intensely working to translate those mechanisms to novel therapies to help treat these devastating conditions.

NIH Research Projects · FY 2026 · 2024-12

Abstract: Auditory and vestibular sensory cells use the hair bundle, a stair-cased array of actin-filled stereocilia, to translate hair bundle motion into an electrical signal. Mechanically gated (MET) ion channels are activated by force created by the pulling of a tip link that extends between stereocilia. Coordinated stimulation of tip links regulates multiple channel openings to generate a receptor current. Mammalian cochlear hair bundles unexpectedly were found to have weak interstereocilia connections which sensitize them to the stimulus mode. The cochlea machine is designed to stimulate hair bundles in a manner that maximizes their sensitivity and frequency selectivity, understanding how hair bundles are stimulated is critical to our understanding of cochlear mechanics. We seek to understand how the mechano-electrical and electromechanical feedback between the hair bundle, its environment and outer hair cell electromotility regulate sensitivity and selectivity of the cochlear output. A first step in unraveling these interactions is to understand and document how hair bundles move in situ and how this motion shapes the receptor current. This proposal bridges from the system level cochlear mechanics to how hair bundle motion shapes the receptor current. We are uniquely positioned to investigate these questions because we have developed the technology and created collaborations to image hair bundles (even stereocilia in inner hair cells), tectorial membrane (TM) and reticular lamina (RL), in situ and in vitro. We are coupling the high spatial resolution of imaging XY with optical coherence tomography which has high vibrational resolution in Z but poor spatial resolution and with low coherence interferometry that has better spatial resolution and excellent vibrational sensitivity. Together these tools provide a powerful platform in which to validate our in vitro preparation and to investigate cochlea vibrational patterns, providing the first measurements of mature hair bundle motion in situ. We will leverage this data to investigate MET receptor currents in vitro to directly assess hair bundle filtering properties. This proposal will address three important topics: How are hair bundles stimulated in situ (SA1)? Which hair bundle components most impact in situ motion (SA2)? How are receptor currents modified by natural hair bundle stimulation (SA3). Specific Aim 1 measures motion in situ from mice aged P10-15 and P24-35. These data, assisted by physics-based models of motion will determine the mode of hair bundle stimulation and how hair bundle motion relates to TM and RL motion. SA2 probes a set of genetically altered mice, to identify the hair bundle and TM components driving the hair bundle response. SA3 develops stimulus technology to mimic in situ stereocilia motion for IHC and OHC bundles in vitro to assess receptor current properties under physiological conditions using physiologically relevant modes of stimulation. These data provide insight into cochlear mechanics and into how hair bundles are specialized to best respond to their mode of stimulation. The hair bundle is the site of many genetic disorders and the target of noise and age-related hearing loss. This proposal provides foundational data needed for developing treatment strategies.

NIH Research Projects · FY 2026 · 2024-12

PROJECT SUMMARY A major challenge to treating chronic pain is patient-to-patient variability in the underlying pathophysiology, which can predominantly feature sensory dysfunction, or include higher-order dysfunction involving cognitive expectations, emotional processes, and/or sympathetic arousal. Thus, there is a need to develop therapies that can specifically modulate sensory and higher-order integrative aspects of pain processing such that they can be personalized to each patient’s pathophysiology. The goal of the proposed research is to set the stage for brain stimulation technology targeting insula that can target both bottom-up sensory processes, and top-down integrative processes that contribute to pain. Based prior findings, including preliminary evidence from our team, we hypothesize that electrical stimulation within the insula can alter pain thresholds by at least two distinct mechanisms: 1) by modulating sensory pain signals in posterior insula, and 2) by modulating higher-order, integrative pain signals in the anterior insula. We will test this hypothesis by leveraging rare opportunities to directly study human insula function in neurosurgical patients who have indwelling insular electrodes for evaluation of medically refractory epilepsy. We will combine direct intracranial electrical stimulation (iES) and quantitative sensory testing (QST), an established methods to test causal relations between local neural activity and pain processing. We will perform experiments to support the following Specific Aims: 1) To determine whether insula stimulation alters both pain and sensory thresholds in the posterior insula, but only pain thresholds in the anterior insula; 2) To determine whether thermal sensory-evoked neural activity can predict stimulation- related changes in pain and sensory thresholds. If we find that electrical stimulation of distinct insula subregions can influence distinct aspects of pain processing, it will show proof-of-concept that multi-site insula stimulation can simultaneously modulate sensory pain and higher-order, integrative aspects of pain processing. Otherwise, it will suggest that neuromodulation of sensory and higher-order pain processes will require combined targeting of insula and other brain regions (e.g., thalamus or cingulate). Thus, regardless of the outcome of these experiments, our results will inform future efforts to develop intracranial neuromodulation treatments for chronic pain that can be personalized to patient’s specific pathophysiology.