Stanford University

NSF Awards · FY 2026 · 2026-05

This project focuses on developing the next generation of network scanning tools and methodologies for more efficiently finding all Internet devices and software, safely uncovering vulnerabilities and misconfigurations in them, and identifying device owners so that they can be notified before they are attacked. This project will introduce fundamentally new methodologies in three areas. First, drawing on advances in artificial intelligence and software fuzzing, the project will build new techniques for finding network scan probes that safely identify hardware and software manufacturers, products, and fine-grained versions. The project will build agentic approaches to scalably uncover human misconfigurations that could not otherwise be programmatically identified. Second, new methods to uncover relationships between Internet entities and to extract device owners will be developed. Third, building on the context and relationships derived about Internet assets, new predictive methods for finding Internet services as they come online will be developed. This project will provide new techniques for networking and security researchers to better understand the Internet, for U.S. organizations to more quickly protect themselves against attacks. The project will develop new curriculum to prepare computer science students to work in cybersecurity by providing them hands-on opportunities to understand Internet-security in practice as well as provide research opportunities to both undergraduate and graduate students. Publications, open source software, and other research outputs will be made publicly accessible at http://esrg.stanford.edu/. 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 · 2026-05

Recent studies have revealed the existence of distinct, non-membranous Ca2+ signaling compartments within the myocyte, which independently control gene expression involved in pathological cardiac remodeling. However, the precise mechanisms underlying such compartmentation remain poorly understood. Elucidation of the mechanisms conferring compartmentalized Ca2+ signaling in remodeling will inform the development of targeted therapies for heart failure, including non-ischemic Dilated Cardiomyopathy (DCM). We have defined a Ca2+ compartment organized by the scaffold protein A-Kinase Anchoring Protein 6β (AKAP6β, mAKAPβ) at the myocyte outer nuclear membrane (ONM), where AKAP6β is required for the induction of pathological gene transcription and myocyte hypertrophy by the Ca2+/calmodulin-dependent phosphatase calcineurin (CaN). In this application we present new preliminary data that phospholamban (PLN) interacts with AKAP6β and regulates Ca2+ efflux from the AKAP6β compartment into the lumen of the nuclear envelope. In addition, a pathogenic mutation in PLN (p.R14del) increases perinuclear CaN signaling in patient-specific induced pluripotent stem cell (iPSC)-derived cardiomyocytes (iCMs). These findings suggest a novel, non-canonical role for PLN in perinuclear Ca2+ homeostasis that regulates gene transcription. We propose the central hypothesis PLN is a critical regulator of perinuclear Ca2+ signaling responsible for pathological gene expression, such that targeting of PLN within this compartment comprises a new therapeutic strategy for DCM. Specific Aim 1: Defining the role of PLN in regulating AKAP6β Ca2+ signaling and myocyte hypertrophy. Preliminary data suggest that AKAP6β-bound PLN at the ONM plays a critical role in regulating Ca2+ efflux from a nanometer-scale perinuclear Ca2+ compartment. Using live cell imaging and biochemical and cytochemical assays in primary rat ventricular myocytes and human iCMs, we will elucidate how ONM-localized PLN modulates AKAP6β-associated Ca2+ signaling. Specific Aim 2: Targeting of Perinuclear PLN in Dilated Cardiomyopathy. To test the hypothesis that dysregulation of local Ca2+ efflux from the AKAP6β compartment contributes to DCM pathogenesis, we will use adeno-associated virus (AAV) vectors to confer gain- and loss-of perinuclear PLN function in wildtype and DCM mice. Specific Aim 3: Therapeutic targeting of perinuclear Ca2+ signaling in PLN R14del Cardiomyopathy. We hypothesize that increased AKAP6β-associated Ca2+ signaling contributes to PLN R14del DCM. We will use patient-specific iCM monolayers and engineered heart tissues to study transcriptional and contractile defects associated with PLN R14del DCM and test whether altered AKAP6β signaling will be beneficial in this disease. Together, these aims will define the function of ONM PLN in controlling Ca2+ efflux from the AKAP6β perinuclear compartment. As AKAP6β signalosomes regulate gene expression promoting pathological remodeling, these studies will establish a new paradigm for treating heart failure, including PLN DCM, based upon the targeting of AKAP6β-PLN complexes.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY/ABSTRACT This proposal seeks to fund and support trainees and junior faculty to attend the “Emerging Innovators in Ophthalmology Workshop” which will occur July 2026 at Stanford University with plans to make this a regular annual offering. Continued innovation in treatment, diagnosis and prevention of ophthalmic disease is critical for improving patient outcomes and reducing gaps in population health. Increasingly we recognize that innovation requires specific training and mentorship which is not broadly available. A specialized approach to evaluating clinical problems and creatively identify solutions has become codified and widely recognized around the world as the “Biodesign” approach upon which both the Stanford Byers Center for Biodesign Fellowship and, subsequently, the Stanford Byers Family Ophthalmic Innovation Fellowship Program are based. The “Emerging Innovators in Ophthalmology Workshop” will be an all-day course convened on Stanford campus to provide the framework of this approach and resources which attendees can use to further engage in the Biodesign process. Recognizing the importance of mentorship, senior faculty who both teach and engage in innovation will be present throughout the course and small group workshops to develop connections with the attendees. Additionally, each attendee will be connected with a formal innovation mentor based on their interest at the conclusion of the workshop with the expectation of regular meetings in the following year. Our objectives for the course are: (1) to teach the core principles of the Biodesign approach with a focus on Ophthalmic Innovation to ophthalmology residents, post-doctoral scholars, and junior faculty in hopes for encouraging innovation and (2) to provide and develop long term mentorship for clinical and scientific trainees as well as junior faculty in support of ongoing innovative work.

NSF Awards · FY 2026 · 2026-05

Nontechnical Description: Ultraviolet (UV) light is a crucial wavelength range for a wide range of technological applications, with important uses in sterilization, sensing, manufacturing, and many others. Relative to traditionally used UV lamps, UV light emitting diodes (LEDs) offer longer lifespan, eliminate the use of mercury, and can have significantly higher power efficiencies. Despite this promise, however, commercially available UV LEDs require a complex fabrication process at high temperatures, significantly increasing manufacturing costs. Further, their efficiency drops off significantly with shorter wavelengths. This combination of high costs, complex fabrication, and low efficiencies at short wavelengths highlights the need to explore material systems capable of remedying those shortcomings. LEDs based on perovskite materials have emerged as promising candidates for next-generation lighting technologies, yet efficiencies from high-energy-emitting materials have remained quite low. This challenge raises our fundamental research question: can the simple, scalable fabrication and high performance of perovskite LEDs be translated into the UV? Doing so would have tremendous impacts on light-emitting technology. We propose to investigate a wide range of perovskite material compositions, guided by theoretical modeling. By relating the underlying material properties to their emissive performance, we will establish design rules for UV material fabrication. We will design electrical contacts to enable charge injection into these materials, controlling the materials within the LED to ensure effective performance. Finally, we will understand the stability of these materials to ensure long-lasting performance towards real impact in a wide range of exciting fields, evidenced with real-world tests. We will build a successful world-class scientific workforce at all career levels through the creation of teaching, mentoring, and outreach programs. The PI will develop a brand-new education series to provide students with hands-on experience at the intersection of photonics, materials, and applications, and will host a local teacher each summer for a hands-on research experience, building connections with the local community and utilizing those teachers as conduits to create long-term engagement programs and partners. Finally, long-term recruitment and culture-building efforts will foster the continued community of the PI’s research group, leading to a more successful and supportive research environment. Technical Description: Ultraviolet light from wide-bandgap (WBG) semiconductor devices is a crucial wavelength range for our society, with important applications ranging from advanced manufacturing to sterilization and purification. Yet modern UV LEDs are complex and expensive to fabricate, and do not have sufficient efficiency far into the UV. We will examine new classes of perovskite and double perovskite materials for their UV-emissive properties, with emissive targets set by improvements on state-of-the-art materials and competitiveness with traditional WBG emitters. Utilizing a model-guided, combinatorial fabrication approach, we will understand the underlying chemistry, materials science, and device physics to enable robust UV emission with simple fabrication. We will identify the key role of charge transport layers to elucidate their role in emissive performance and stability. Finally, we will investigate the roles that material composition, device design, and external conditions have on stability to identify and eliminate the degradation mechanisms limiting devices, and measure the resulting materials for their efficacy in real-world conditions. By bringing new materials, fabrication techniques, and device structures into the fold, this work holds the potential to open new avenues for WBG materials and devices. These learnings will be directly applicable not only to the UV LED field, but to LEDs, lasers, photovoltaics, and broader fields of WBG devices such as power electronics and energy, providing a platform of both fundamental science and technological application to support wide-ranging research throughout the PI's career. 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 2026 · 2026-05

This project seeks to understand how marine animal body size, and thus biodiversity, have been shaped by environmental change over Earth’s history. By assembling the most comprehensive database of fossil body size measurements spanning the last 575 million years, the project will test whether the appearance of new marine animals follows predictable patterns linked to environmental factors. While most paleontological work has examined why animal taxa disappear, this study focuses on how new taxa originate, filling a fundamental gap in understanding of biodiversity generation. The findings will improve forecasts of how today’s rapidly shifting environments may affect species emergence and ecosystem resilience, issues that intersect national interests in food security, coastal economies, and biodiversity. The project will (1) build on a standardized database of marine animal body size measurements, incorporating previously unpublished Ediacaran body-size data; (2) test whether size bias of origination differs among major taxonomic groups, varies through geologic time, and changes consistently under distinct environmental regimes; and (3) evaluate the influence of sampling completeness on observed selectivity patterns. Body size is the chosen metric because it is easy to measure and correlates with key animal traits such as metabolic rate and generation time. Statistical models will be applied to assess correlations between body size trends and proxies for marine anoxia, temperature, and other environmental variables. The resulting analyses will quantify origination selectivity, a dimension that has been largely undocumented, and will generate open-access data for the broader scientific community. The anticipated outcomes include improved predictive tools for assessing how future environmental change may shape biodiversity, and training the STEM workforce. 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 · 2026-05

PROJECT SUMMARY An estimated 10-25% of human embryos contain incorrect chromosome numbers (aneuploidy), the leading cause of pregnancy loss and birth defects. Most critically, 25% of human oocytes are aneuploid, with this rate dramatically increasing after age 35, contributing to age-related fertility decline. The disproportionately high error rates in female versus male meiosis highlight fundamental gaps in understanding oocyte chromosome segregation. A critical knowledge gap exists in how oocytes assemble functional spindles without centrosomes—termed acentrosomal meiosis. While centrosomes organize microtubules in sperm meiosis, oocytes employ poorly understood alternative mechanisms. Additionally, although microtubules comprise diverse tubulin isotypes, their mechanistic significance in oocyte meiosis remains unexplored. Recent discoveries linking oocyte-specific tubulin TUBB8 mutations to human infertility disorders underscore the importance of understanding isotype-specific contributions to chromosome segregation. My goal is to elucidate the genetic and molecular mechanisms critical for acentrosomal meiosis and how tubulin isotype composition impacts chromosome segregation fidelity. My preliminary data using C. elegans β-tubulin isotypes TBB-1 and TBB-2 reveal these isotypes differentially affect spindle length, structural integrity of metaphase arrested spindles, microtubule motor sensitivity, and anaphase segregation velocity. I have remodeled existing tools, including a strain co- expressing endogenously tagged subunit of microtubule severing enzyme katanin (GFP::MEI-1) and mCherry::H2B, and single-β-tubulin substitution strains that also express GFP-tagged α-tubulin (GFP::TBA-2), providing unprecedented opportunities to dissect acentrosomal spindle assembly. I hypothesize that acentrosomal spindle assembly requires coordinated interactions between microtubule-interacting proteins and that such interactions are regulated by tubulin isotype composition. Using quantitative proteomics, forward genetic screens, in vitro biochemical analysis and high- resolution microscopy: Aim 1 investigates the molecular basis of differential β-tubulin isotype contributions through isotype-specific proteomics and biochemical characterization; Aim 2 identifies katanin-mediated mechanisms essential for acentrosomal spindle assembly using proximity labeling and genetic screening. This research aligns with my career objectives to become an independent investigator studying microtubule-dependent chromosome inheritance. The K99 phase will provide essential training in proteomics, biochemical reconstitution, and genetic screening—techniques underutilized in oocyte research. My mentoring team, led by Dr. Anne Villeneuve at Stanford, combines expertise in such essential techniques positioning me to master approaches that differentiate my research program. This project will establish the first comprehensive analysis of tubulin isotype-specific roles in any system and develop mechanisms enabling accurate chromosome segregation without centrosomes. The innovative methodological approaches will provide robust foundations for R01 applications, ultimately advancing diagnosis for reproductive health challenges affecting millions of families worldwide.

NIH Research Projects · FY 2026 · 2026-05

Despite tremendous advances in cancer detection, diagnosis and treatment, many gaps remain, and cancer continues to be a chronic disease and the second leading cause of death in the US. To further advance the health and longevity of all Americans, it is of paramount importance to train the next generation of biomedical scientists by providing the high-quality research experiences and mentorship. Studies suggest that undergraduate research experiences can support trainee career development to pursue research careers.  The goal of this new R25 program, Stanford’s Cancer Research Education Program (SCREP) is to provide necessary research experiences to undergraduate trainees enabling them to persist in STEM fields by cultivating a scientific identity by building their confidence in their ability to succeed in cancer research setting.  SCREP will provide undergraduate trainees with the opportunity to actively engage in cancer relevant research within the stellar scientific and educational environment at Stanford University and the mentors from the Stanford Cancer Institute (SCI). The SCREP is a fully funded 10-week summer cancer research program, during which undergraduate trainees will work in cancer laboratories of the SCI and receive training in a wide range of cancer research concepts and techniques combined with curated programming that includes career and research seminars, skill building workshops and social events to complement the research components of the program. Trainees will be provided with a multi-layered supportive ecosystem where Mentors, Program Administrator and a Peer Mentor will provide individualized support. Another layer of support will be provided through leveraging existing Stanford University Resources and career enhancement partnership programs to ensure trainees continue their profession growth. This supportive ecosystem that SCREP provides is intended to help undergraduates trainees cultivate a scientific identity by building their confidence in their ability to succeed in cancer research setting. Together, SCREP will create research and career development opportunities for all undergraduates to explore, experience and pursue cancer research and careers in medicine. SCREP’s impact and effectiveness will be measured longitudinally by tracking trainees’ persistence in STEM, level of confidence in their abilities, and educational and career trajectories post program. The program ultimately supports the National Cancer Plan to develop future biomedical scientists in cancer research and clinical care workforce.

NIH Research Projects · FY 2026 · 2026-05

The embryonic, fetal, and neonatal periods are critical for lifelong health. During early human development, the coalescence of genomics and other endogenous factors with exposure to maternal and environmental influences plays a vital role in shaping infant health and lifelong disease risk. These most plastic phases of intrauterine and early extrauterine periods are also defined by dramatic changes in human physiology, when the fetus transitions through embryonic and neonatal states. Not surprisingly, therefore, common syndromes that occur during these vulnerable developmental phases have a major impact on health across the lifespan, and thus, on the future of humanity. Major gestational syndromes currently affect more than one in every ten pregnancies nationwide, with an even greater frequency in the developing world, with extraordinary consequences to the physical and emotional health of an individual, as well as to healthcare and economy. Despite its impact on health, inquiries into antenatal, perinatal, neonatal, and infancy phases early human development have not received adequate attention by researchers. We have been particularly concerned about the lack of trainees who are proficient in understanding the transition from intrauterine to early extrauterine life. We are also motivated by the shortage of well-trained researchers who can embrace cutting edge artificial intelligence and other data science tools and harness their power in deep investigation into the transitions that take place during early human developments, and the translation of that knowledge to human health for individuals, families, and all human communities. Therefore, our proposed T32 training program, termed “Advanced Stanford Center for Early HumaN Development” (ASCEHND) will equip two graduate and three postdoctoral scholars with a 2-3 year investigative training in the biology of early human development, from early pregnancy to the neonatal period. We will instruct scholars in the biology, data-science, biomedical and epidemiological aspects of embryonic development, fetoplacental growth, parturition, and early infancy, and the diseases that affect humans during these developmental epochs. The knowledge and experience gained through our well defined and rigorous program will amalgamate multiple research trajectories with AI tools and technologies to form a pipeline for experts in the biology of early human development. Using hands-on research training, courses and classwork, seminars and group sessions, trainees of various scientific perspectives will be trained to face tomorrow’s challenges in the field. Supplemental instruction in cell biology, molecular biology, genomics, statistics, ethics, and similar high priority areas will serve to bring all trainees to a very high level of data science-driven investigative sophistication. The intellectual environment at Stanford emphasizes imaginative thinking, cross-fertilization and collaboration that bridges basic sciences and clinical medicine and will serve to propel our T32 scholars through a uniquely stimulating and enriching experience.

NIH Research Projects · FY 2026 · 2026-05

Malaria due to Plasmodium Falciparum (Pf) remains a highly lethal disease, resulting in 610,000 deaths annually. In the US, there are ~2000 malaria cases and 5-10 deaths each year, nearly all contracted in Africa, and malaria poses a significant and growing risk to US international travelers and military personnel in endemic deployments. Notably, competent Anopheles mosquito vectors persist across the United States, raising the specter of domestic malaria re-emergence. Optimizing malaria prevention is therefore a pressing US public health priority. An affordable malaria vaccine, R21, is now being deployed in Uganda and other African countries for infants beginning at 5-6 months of age. However, in perennial, high transmission settings, the burden of malaria can be high prior to the age at which R21-elicited protection is expected to begin, and vaccine efficacy and durability are expected to be sub-optimal. In these settings, additional interventions will be needed to best prevent malaria. A promising approach to enhance protection is to administer vaccine along with antimalarial chemoprevention, although optimal regimens and dosing schedules for perennial malaria transmission settings (PMC) are undefined. Two regimens are promising: PMC with SPAQ (currently used for seasonal malaria chemoprevention), or DP (which we have found to be safe and highly effective when used as monthly chemoprevention in infants). However, their efficacy when given at expanded programme on immunization (EPI) visits remains unevaluated. We will test the hypothesis that R21 combined with either PMC-DP or PMC-SPAQ will offer better protection against malaria compared with R21 alone, that PMC-DP will be more efficacious and better tolerated than PMC-SPAQ, and that both PMC arms will enhance R21 immunogenicity and durability without significantly impacting parasite drug resistance. We will test these hypotheses in Busia District, Uganda, an area with high, perennial malaria transmission. As Pf malaria is not endemic in the United States, it is not possible to conduct this trial domestically, and since the overwhelming burden of Pf cases are in sub-Saharan Africa, conducting this trial there allows us to accrue sufficient endpoints far more rapidly than would ever be feasible domestically. Busia District, Uganda—where our team has established regulatory approvals, community trust, and health infrastructure over 15+ years—is uniquely positioned as R21 is now deployed as Uganda’s standard of care for infants. We will randomize 1290 infants to receive 8 doses of PMC-DP, PMC-SPAQ, or placebo between 10 weeks and 18 months of age, given at the time of EPI visits. All subjects will receive R21 at 6, 7, 8, and 18 months of age, the standard of care in Uganda. Children will be followed to 5 years of age to determine the long-term effects of these interventions. This first-of-its-kind trial will thus have direct policy implications. Knowledge gained will inform travel guidelines and chemoprevention strategies, as well as our understanding of malarial immunity and drug resistance. Control of malaria in Africa also advances US economic interests, international stability, and national security.

NIH Research Projects · FY 2026 · 2026-05

Psychotic disorders are a leading contributor to the global disease burden, causing high levels of disability and increased mortality. To improve outcomes, it is essential to identify and treat patients in the early stages of psychotic disorders, especially before overt symptoms appear. Yet, despite decades of research, we are unable to accurately identify early on individuals who will progress to develop a psychotic disorder, even those who are clinically high risk for psychosis, due in part to small sample sizes and extant approaches that do not capture the multifactorial etiology of psychotic disorders. There is therefore an urgent need to substantially improve prognostic precision. Critically, accurate and robust prognostic markers are needed to understand the origins and progression of psychosis and to identify precise neurobiological targets for early treatment. Newly available large-scale multimodal data—clinical, cognitive, and neurobiological—as well as exciting recent advances in artificial intelligence models and methods that overcome limitations of extant approaches offer an unprecedented opportunity for developing accurate and robust prognostic markers for psychosis. The overarching goal of our proposal is to identify accurate and robust multimodal prognostic markers for psychosis using a novel data-driven AI-based computational framework. Building on our highly encouraging preliminary results, we will use an innovative approach combining our recent work on AI models and explainable AI methods as well as integrative theoretical models of psychosis with a wealth of newly available large-scale multimodal data from multiple consortia. The specific objectives of our proposed work are threefold. In Aim 1, we will identify prognostic markers using clinical, cognitive, and neurobiological data to predict future psychosis transition, particularly in youths at clinical high risk. In Aim 2, we will evaluate the generalizability and the temporal (longitudinal) stability of the identified prognostic markers. In Aim 3, we will determine whether the identified prognostic markers predictive of future psychosis transition in youths at clinical high risk are a characteristic trait of psychosis. Through the successful completion of the work described here, our multidisciplinary team is uniquely positioned to transform our understanding of the mechanisms associated with the risk for and development of psychotic disorders, as well as identify neurobiological targets. Ultimately, these advances will lead to the development of individualized prognostic tools and early targeted treatments for psychosis and, more broadly, advance precision psychiatry.

NIH Research Projects · FY 2026 · 2026-05

Cellular membranes serve as dynamic platforms for cell communication and signaling. On each plasma and organelle membrane, lipid–protein and protein–protein interactions are spatiotemporally organized to regulate key biological processes, such as receptor activation and oncogenic signaling. Despite their critical roles, these membrane-specific interactions remain challenging to study due to their transient and context-dependent nature. This proposal aims to develop a novel membrane-centric proximity labeling approach to systematically map lipid–protein and protein–protein networks in live cells. Proximity labeling is a powerful technology for mapping the protein interactome and spatial proteome in living systems. However, conventional tools, such as TurboID and APEX2, lack the spatiotemporal control required to target and capture the dynamic and heterogeneous membrane microenvironment. To address this limitation, I will engineer conditionally activated proximity labeling enzymes that sense their membrane microenvironment and directly couple it to their activity. The first phase (K99) will focus on developing Antigen-Controlled TurboID (ACTurbo), a proximity labeling enzyme activated upon binding to protein of interest, and applying it to dissect compartment-specific μ-opioid receptor signaling pathways in neurons. The second phase (R00) will develop Lipid-Activated Biotin Ligases (LABL) to enable phosphoinositide-centric mapping of oncogenic lipid signaling. This work will establish an innovative and versatile framework for studying lipid–protein and protein–protein interactions in their physiological context, addressing fundamental gaps in membrane biology. By systematically mapping lipid–protein networks on live membranes, this project will provide insights into how membrane dynamics regulate cellular signaling in both normal and degenerative conditions, with potential implications for therapeutic interventions. To achieve this goal, I will integrate my expertise in lipid biology, membrane biology, chemical biology, and protein engineering, bolstered by guidance from my primary mentor, Dr. Alice Ting. To facilitate my proposed research and training, I have assembled a team of leading experts, including Dr. David Baker (computational protein design), Dr. Ilme Schlichting (structural biology), Dr. Ivan Soltesz (neuroscience), and Dr. Ruth Huttenhain (GPCR proteomics). Upon completing this proposal, I will be fully equipped to establish my independent research program focused on developing molecular tools to decipher and manipulate the complex and dynamic networks of membranes, proteins, and lipids.

NIH Research Projects · FY 2026 · 2026-04

ABSTRACT Gastric precursors are precancerous, intermediary states between normal tissue and gastric cancer (GC). Precursors originate through a carcinogenic cascade (Correa’s cascade) from a source of chronic inflammatory insult such as infection by Helicobacter pylori (Hp). While prevalent lesions (5-10% of all endoscopies performed), the management of precursors has proven controversial in the United States. There exist 1) sparse data on the natural history of precursor progression to GC derived from multiethnic populations, 2) no validated clinical risk stratification algorithms, and 3) no clinical trial data that endoscopic screening of precursors provides mortality benefit. There exists an absence of centralized pathology registries to create cohorts of substantive power, as well as difficulties in linkage between pathology databases and cancer registries of sufficient geographic coverage. In this project, we will perform a multi-institutional linkage of electronic health records (EHR; including clinical notes, pathology databases, and endoscopic records) from 1) a large academic healthcare system (Stanford Health Care), 2) an integrated healthcare network serving Northern California (Sutter Health, comprising eight hospitals, >200 clinics), and a comprehensive state-level tumor registry with legally-mandated reporting (California Cancer Registry, CCR). Our central hypothesis is that a unique and large cohort of gastric precursors (Gastroshare) with detailed EHR phenotyping can be created, comprehensively linked to cancer occurrence, and utilized to answer key questions in progression, screening, and outcomes. In Aim 1, we will determine if a hybrid modeling approach consisting of both structured data extraction and natural language processing methods, including generative large language model-based methods, can enhance characterization and reduce missingness in this integrated database. In Aim 2, we will leverage high-dimensional competing-risk EHR data to develop dynamic risk prediction models for GC, employing a temporal landmark framework. This method will be applied to predict dynamic GC risk by capturing evolving EHR data measured after precursor diagnosis, such as Hp eradication, medication use, and smoking behavioral changes. In Aim 3, we will evaluate the feasibility and utility of a novel causal inference method which explicitly emulates a hypothetical randomized surveillance trial. Using this emulation framework, we will evaluate the effect of endoscopic surveillance of precursors on GC mortality. Successful completion of this proposal will provide key clinical data on the natural history of precursors, assess clinical risk stratification tools, and evaluate the efficacy of secondary prevention strategies in this enhanced-risk population.

NIH Research Projects · FY 2026 · 2026-04

Pulmonary Hypertension (PH) is a fatal disease where abnormal cells termed “neointima” progressively occlude the pulmonary arteries leading to debilitating right heart failure. PH pathology is characterized by perivascular inflammation, including T cell rich Tertiary Lymphoid Follicles (TLFs). Although perivascular inflammation associates with worse outcomes, preclinical studies implicate T cells as having both pathogenic and protective roles in PH. A repertoire of helper (Th) and regulatory (TReg) T cells shape the immune response by sensing antigen via their T cell Receptors (TCRs) and clonally expanding in response. Current PH therapies do not target neointima or inflammation. Lung transplant remains the only curative therapy. There is a critical unmet need to understand how proliferating T cell lineages and their expressed ligands contribute to neointima development in PH. Here, a mouse model of PH has been developed where human-like perivascular inflammation, including TLFs form alongside occlusive neointimal lesions following chronic intranasal antigen administration. Preliminary data finds that neointima and TLF formation is both T cell and antigen dependent. Ablation of Tregs accelerates neointima formation and implicates a Th17 response. A single cell RNA sequencing “Interactome Map” between T and vascular cells identifies Lymphotoxin (Ltb) as a major T cell- vascular signal. Ltb expression is validated in human PH and Ltb blockade halts neointima and TLF formation in mice. Using bulk and single cell TCR sequencing, the development of neointima formation associates with the growth and suppression of T cell clones responding to antigens. The proposals central hypothesis is neointima development in PH is dependent on a repertoire of pathogenic Cd4+ Th cell clones and the pathogenicity of these clones is mediated by T cell expressed ligands, including Ltb. To test this, three Aims are proposed: (1) Determine the Th cell sub-lineages responsible for pulmonary vascular neointima formation, (2) Functionally test how the T cell specific ligand Ltb mediates neointima development, and (3) Define the neointima-associated T cell repertoire in mouse and human. The proposed training plan augments PI Dr. Adam Andruska’s experience in vascular biology with training in advanced spatial transcriptomic technologies, immunologic mouse models, T cell biology, immune reconstitution, mouse genetics, and single cell paired RNA and TCR sequencing. These studies and training will be guided by co-mentors Maya Kumar, PhD (Aims 1-3) and Mark Nicolls, MD (Aim 1, 2). Consulting will be Dr. Mark Krasnow (Aim 1, spatial transcriptomics), Dr. Ansuman Satpathy (Aim 3, TCR repertoire analysis), and Dr. Rubin Tuder (Aim 1, 3, pathology adjudication). These activities will leverage Stanford University’s research infrastructure and obtain de-identified explanted lung tissue through the Laboratory for Organ Recovery and Bioengineering led by. Dr. Brandon Guenthart. The proposed activities lay a framework for future high impact studies (1) preclinically validating precision immunotherapy in PH and (2) improving the basic understanding of lung vascular inflammation.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY Major depressive disorder (MDD) is a leading cause of disability, with substantial individual and societal costs. The heterogeneity of MDD and the lack of predictive tools for individualized treatment present significant challenges to effective care. This proposal aims to leverage recent advances in foundation models, a type of artificial intelligence (AI) that has demonstrated remarkable success in natural language processing, to develop a neuroimaging-based tool that can aid in prognostication, treatment stratification, and biotype discovery in MDD. Foundation models are pretrained on massive datasets, enabling them to learn generalizable features that can then be adapted to smaller, more specific datasets. This approach is ideally suited for psychiatric neuroimaging, where clinical datasets are scarce; however, non-clinical datasets like the Human Connectome Project and UK Biobank are extensive. I have developed a functional prototype by adapting a transformer architecture to analyze functional magnetic resonance imaging (fMRI) time-series data and training it on the UK Biobank. Preliminary data generated using this prototype indicate strong potential for this approach. Applying this innovative technique to psychiatry holds great promise for advancing the understanding and treatment of MDD. To achieve this, I propose three specific aims. Aim 1: Use pooled fMRI data from individuals with MDD to fine-tune the pretrained model to decode depression severity and uncover MDD biotypes; Aim 2: Use pooled fMRI scans from longitudinal treatment data to fine-tune the pretrained model to predict antidepressant response and identify neural circuits of treatment response; Aim 3: Prospectively evaluate the performance of MRI-based treatment prediction models in a pilot clinical trial. If successful, this work will yield a novel neurocomputational framework for personalized treatment stratification and significantly advance our understanding of MDD neurobiology and heterogeneity. Through this research, training, and expert mentorship, I will gain expertise in: 1) AI foundation models, including transformer architectures and interpretability techniques; 2) applying foundation models to neuroimaging to generate clinically actionable predictions and mechanistic insights; 3) clinical trial design and analysis of longitudinal data; and 4) professional skills for transitioning to independence. The training plan—which includes coursework, workshops, close mentorship, and hands-on research experience—builds on my existing expertise in neuroimaging, network neuroscience, and clinical psychiatry. Stanford University offers an exceptional environment with access to cutting-edge computational resources, neuroimaging facilities, and a vibrant community of AI experts and clinician-scientists. In sum, through the K23 award, the proposed research, training, mentorship, and pilot data will enable me to successfully compete for independent research funding and establish a high-impact patient-oriented research program in neurocomputational psychiatry at the intersection of AI, neuroimaging, and precision treatment.

NIH Research Projects · FY 2026 · 2026-04

SUMMARY The gut microbiome plays a key role in modulating host metabolism and immune responses. Industrialized populations, like U.S. residents, have gut communities with reduced microbial richness and missing key functions, particularly the degradation of microbiota-accessible carbohydrates (MACs, a component of dietary fiber) and the subsequent production of fermentation products, the short-chain fatty acids (SCFAs) acetate, propionate, and butyrate. These changes are linked to increased prevalence of a broad range of inflammatory diseases such as diabetes, metabolic syndrome, and autoimmune disorders. Our human dietary intervention study (NCT03275662) shows that reintroducing high dietary MAC levels in humans fails to restore SCFA production in most healthy adults, likely due to the scarcity of MAC-fermenting microbes in industrialized guts. A minority of participants with the highest microbiota richness did show decreased inflammatory markers and increased fecal butyrate during the intervention, termed “high-fiber responders”. We hypothesize that replenishing MAC-fermenting microbes in individuals with depleted microbiomes can increase SCFA production, reduce inflammatory markers, and improve host health. This project aims to target specific diseases with highly deteriorated gut microbiomes by repopulating the gut with bacteria that can ferment dietary MACs and deliver key metabolites to support human health and recovery. Aim 1 will characterize an existing repository of strains for MAC-degradation and perform additional isolations using a novel protocol for whole-food intact, low solubility fibers. SCFA profiles will be determined, along with functional assays to assess production of secondary bile acids and aryllactates. Aim 1 will result in a comprehensive repository of strains that can ferment various MACs into SCFAs and produce other key metabolites. Aim 2 will use an in vitro fermentation model to test microbial cocktails of 5-20 strains with a goal of optimizing production of SCFA and other metabolites. Augmentation of cocktails with strains possessing additional metabolic capabilities, such as hydrogen consumption or MAC- independent SCFA production pathways, will be explored to enhance SCFA output. Aim 2 will result in optimized candidate cocktails for further testing in mouse models. Aim 3 will evaluate the functionality of these cocktails in mouse models humanized with low richness gut microbiomes including those of people with metabolic syndrome. Mice will be fed a custom MAC-rich diets to promote cocktail engraftment. Impact on the microbiome will be assessed via metagenomic sequencing and SCFA and other metabolites measured. Host immune and metabolic responses will be profiled to understand the impact of enhanced SCFA production on inflammatory and metabolic status. This project leverages the expertise of PIs Sonnenburg and Martens including in the mechanisms connecting diet-microbiome interactions with host biology. Successful completion will provide foundational knowledge linking specific dietary MACs to microbiome function and yield trial-ready microbial cocktails aimed at restoring health-promoting functions in depleted microbiomes such as individuals with metabolic diseases.

NIH Research Projects · FY 2026 · 2026-04

Project Summary Accidental exposure to ionizing radiation (IR) poses a significant risk for cardiovascular morbidity, a leading cause of mortality among irradiated populations. However, the mechanisms driving long-term cardiovascular risks remain poorly understood. IR disrupts immune homeostasis, exacerbating chronic inflammation and accelerating pathological remodeling. The current multi-PI U01 proposal seeks to address this knowledge gap by developing an innovative extracorporeal system composed of human stem cell derivatives to identify biomarkers and medical countermeasures (MCMs) for radiation-induced delayed cardiac remodeling (RidCR). In Milestone 1, we will establish a 3D cardiac-immune co-culture system using iPSC-derived cardiomyocytes, endothelial cells, fibroblasts, and macrophages to simulate the immune-competent 3D microenvironment. Optimized culture conditions will be validated in 3D engineered cardiac tissues (EHTs) for physiological and inflammatory responses. In Milestone 2, we will perform multi-omics analyses on irradiated EHTs and parallel animal models to identify molecular signatures of RidCR via multi-omics and functional assessments of tissue contractility. In Milestone 3, AI/ML will integrate the generated datasets to predict candidate MCMs, which will be validated in vitro and tested in vivo using a protracted irradiation mouse model. Comprehensive evaluations will assess the efficacy of the lead MCM in mitigating RidCR.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY/ABSTRACT MRI is limited by slow encoding. This has resulted in undesirably lengthy MR exams, and long scheduling time that hampers timely diagnosis. The slow encoding also limits the spatial and temporal resolutions of in vivo scanning, which limits our ability to extract key structural and physiological information in numerous clinical and neuroscientific applications. The main thread of technology development for faster imaging has been in array reception and constrained reconstructions, which has provided impressive speed gains. Nonetheless, significant further gain is highly desirable, with complementary research into advanced gradient coil design being actively pursued, via head-insert, non-linear arrays, and resonance designs. These developments have resulted in exciting speed gains, but their wide-spread usage is hampered by: i) expensive/specialized hardware that requires complex calibration, and ii) computationally intensive image reconstruction; limiting their impact. The goal of this proposal is to overcome these constrains by developing portable resonance gradient coils (RGC) that are low-cost and simple to calibrate, and to develop a real-time reconstruction algorithm for data acquired using such hardware. RGC operates at a single resonance frequency to create a sinusoidal gradient that can supplement the encoding provided by traditional gradient coils. The use of such high-frequency wave- like encoding (wave-RGC) during data readout have been shown to enable very high accelerations. Nonetheless, current wave-RGC efforts require calibrations through expensive field probes to capture spatiotemporal field non-idealities, and computationally intensive reconstruction. A key innovation in this proposal is to overcome these issues using i) a concept we termed ‘‘Implicit Representation of GRAPPA Kernels’, which we combined with ii) an observation that a family of GRAPPA kernels can be used to represent the spatiotemporal field of wave-RGC; an idea akin to ESPRIT for coil sensitivities. Ultlizing these ideas, a rapid GRAPPA-like calibration scan will be developed for use to train a Multilayer perceptron to implicitly represent a family of GRAPPA kernels, from which high-fidelity estimates of wave-RGC’s spatiotemporal field can be obtained. A k-space interpolating algorithm will then be developed to apply these GRAPPA-like kernels to transform highly-accelerated wave-RGC data to densely sampled cartesian data for real-time FFT-based SENSE reconstruction. To demonstrate the benefits of our rapid calibration and efficient reconstruction, they will be used to facilitate two-challenging new wave-RGC applications with high payoffs. First, wave-RGC will be deployed in SMS-EPI to enable 16x accelerated functional MRI and provide a dramatic step gain in the spatiotemporal resolution at which we can study brain function non-invasively. The second application is to create a flexible, form-fitting RGC suitable for rapid knee-imaging (and extremity). Such flexible design creates undesirable cross-subject field variations that our proposed rapid calibration can effectively calibrate, while allowing the RGC’s diameter to be small to dramatically reduces power requirement (scale as r5); enabling it to be driven using a low-cost amplifier.

NIH Research Projects · FY 2026 · 2026-04

ABSTRACT | NARRATIVE The thymus instructs T cell immunity and central tolerance, yet its therapeutic potential remains clinically untapped as the signals that drive thymic epithelial cell (TEC) differentiation remain incompletely understood. The thymic epithelium comprises a highly specialized set of cells that attract lymphoid progenitors, promote their proliferation and maturation into thymocytes, and facilitate the selection of a diverse, self-tolerant T cell receptor (TCR) repertoire. The role of the thymus in building immune identity begins before birth. The organ peaks in size in infancy and then structurally and functionally involutes over time. This process causes the decline in immune competence with age (immune senescence). The impact of this phenomenon was exposed during the COVID-19 pandemic when waning immunity left the elderly more vulnerable to adverse outcomes. Thymus insult also occurs in many patients through medications, radiation, infections and graft-versus-host disease. The most severe form of thymic compromise is congenital athymia, the inborn absence of the thymus due to genetic mutations. Genetic or acquired thymic injury leads to immunodeficiency, autoimmunity, inflammation and increased cancer risk. Regenerating thymic function, e.g., through human induced pluripotent stem cell (iPSC)-derived regenerative thymic tissues holds greatest therapeutic promise for these patients. We have used single-cell transcriptomics of human fetal anterior foregut-derived organs to uncover the signals that drive TEC differentiation. We have translated these insights into a novel differentiation platform for the derivation of TECs from iPSCs in vitro. When iPSC-derived TEC organoids are transplanted into athymic NSG nude (NSG-Foxn1-/-) mice engrafted with human hematopoietic stem cells, they function like the human thymus, giving rise to human ab-T cells with a diverse TCR repertoire, gd-T cells and regulatory T cells. In this application, we now seek to advance the translation of iPSC-derived TECs (iTECs) by testing their safety and efficacy as cell therapy for vulnerable patient populations in need of improved T cell immunity. In Aim 1, we will determine the capacity of iTECs to promote T cell reconstitution, functional antigen-specific T cell responses and the development of a broad TCR repertoire in vivo. In Aim 2, we will assess if T cells educated on iTEC are tolerant to “self” but respond to “non-self”. In addition, we will directly analyze the HLA-associated peptide repertoire presented on iTECs using immunopeptidomics. In Exploratory Aim 3, we will test if HLA-editing of iPSCs for iTECs derivation affects antigen-specific immune responses, TCR repertoire, and immunopeptidome in vivo. Advancing the translation of iPSC-derived TECs into a cell therapy is an entirely new strategy to leverage the therapeutic potential of T cells from inside the body and could begin a new chapter of immunotherapeutics.

NIH Research Projects · FY 2026 · 2026-04

Project Summary/Abstract Many cells are responsive to electrically conductive materials; however, to date electrical conductivity is mostly achieved through graphene or synthetic polymers. These materials have limited translational use due to a lack of biodegradability and rigid mechanical properties. To overcome these challenges, we propose the design of a recombinant engineered, conductive, injectable, and biodegradable hydrogel that has the potential to induce regeneration across a wide range of tissues. We have recently pioneered the synthesis of a fully recombinant gel that incorporates electrically-conductive protein nanowires (ePN), an engineered matrix-like protein, and the polysaccharide hyaluronic acid (HA). While the ePN provides conductivity, the engineered matrix-like protein and HA provide biochemical ligands that promote cell adhesion. The hydrogel material is crosslinked through dynamic covalent chemistry, allowing for tunable viscoelastic properties and injectability. The resulting gel supports three-dimensional cell culture and biodegrades in response to cell-secreted enzymes. As the spinal cord is an electrically conductive tissue, we will demonstrate the efficacy of our technology in a cell-based therapy for spinal cord injury (SCI). Less than 1% of SCI patients have full neurological recovery by the time of hospital discharge. We previously demonstrated with non-conductive hydrogels that intraspinal transplantation of neural progenitor cells (NPCs) can significantly improve function in a rodent SCI model, but only when they are sufficiently matured into a neuronal phenotype. We have also demonstrated that NPCs enhance their neuronal maturation in vitro when grown on conductive biomaterials that were rigid and non-biodegradable. Thus, we hypothesize that our new hydrogel will facilitate the intraspinal injection of NPCs and significantly promote their neuronal maturation, thus resulting in significant functional and histological improvements. In Aim 1, we identify the gel formulation that best promotes neuronal differentiation and maturation of human induced pluripotent stem cell-derived NPCs in vitro. Specifically, we will tune the bulk conductivity of the fabricated gels through altering the ePN concentration and amino acid sequence. Recombinant engineering of ePN allows for tunability of the electrical conductivity along a single protein wire. The cell morphology, gene expression, and protein expression of encapsulated NPCs in the gels without and with varying levels of conductivity will be quantified. In Aim 2, we will select the gel variant that provides the best in vitro results for assessment in a preclinical, rat model of cervical SCI. NPCs will be transplanted within the conductive, biodegradable gel and evaluated for functional behavior over 6 weeks. Histological outcomes include transplanted cell survival and neurite outgrowth. Controls include conductive gels without cells and non-conductive gels with cells. This study would represent the first use of conductive, biodegradable, recombinant nanowires in tissue engineering, which can have broad application in conductive tissues including brain, cardiac muscle, skeletal muscle, and skin.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY Numerous environmental agents (hereafter, genotoxins) induce DNA lesions or create other types of barriers that stall replication forks. This can lead to replication stress, and failure to alleviate this stress and restart stalled forks can cause genome instability. Elevated replication stress and the replication-associated mutations that result from genotoxin-induced fork stalling contribute to aging, inflammation, cancer, and numerous other chronic diseases in humans. This project aims to advance understanding of the cellular responses to replication stress. One crucial aspect of the replication stress response involves replication fork reversal, a process that remod- els both the nascent and parental DNA strands to form a four-way junction structure. Fork reversal is carried out by a family of ATP-dependent translocases. Why multiple enzymes with similar activities are involved in this process is not understood. We showed that one of these translocases, HLTF, prevents a remarkably DNA dam- age-tolerant mode of replication by promoting fork reversal and preventing alternative and potentially error-prone modes of DNA synthesis. The unanticipated resilience of the replication fork to various genotoxins in HLTF’s absence may drive mutagenesis and promote the survival of damaged cells. We will investigate the cellular responses to genotoxic and oxidative damage, focusing on the mechanism of replication fork reversal and the impact of loss of fork reversal on genome stability and cell fitness. By combining molecular, biochemical, genomic and proteomic approaches, as well as state-of-the-art single-molecule ap- proaches, we will address the following broad questions: What are the functions of fork reversal and how does it occur in response to environmentally relevant forms of genotoxic damage? What are the specific functions of a central regulator of fork reversal, HLTF, in the face of oxidative and genotoxic DNA damage? Does loss of HLTF and fork reversal increase mutation (rates) in the context of environmental stressors? Our strategy will initially focus in large part on HLTF, elucidating its unique roles. As the project evolves, we will phase in further studies on other remodelers so as to understand, over the long-term, the overall fork reversal process and the unique contributions of each protein to the replication stress response. The knowledge we gain from this research will ultimately facilitate the development of new strategies that i) alleviate the pathological states observed in the absence of the replication stress response, and ii) prevent cancer cells' ability to tolerate DNA damage and develop drug resistance.

NSF Awards · FY 2026 · 2026-04

Non-technical description: Quantum science and engineering research has made tremendous progress over the past two decades, moving from simple demonstrations of single quantum bits in various platforms to proof-of-concept demonstrations of quantum technologies, including quantum computers. These technologies are also of great national importance because of their promise to provide secure communication (quantum networks), better sensors for medicine and navigation (quantum sensors), and hardware much more powerful than today’s supercomputers for certain tasks (quantum computers and simulators). However, the discovery and development of suitable materials for such technologies has been one of the main bottlenecks in their scaling. We propose to develop an experimental setup for the study of new quantum materials. This will be a unique and interdisciplinary scientific tool that brings together multiple experimental techniques (cryogenics, optics, electronics) across science and engineering disciplines to achieve groundbreaking advances in quantum science and technology. This system will be used as a regional hub for quantum spectroscopy, and will provide training and mentorship for several generations of Ph.D. students, postdocs and undergraduates spanning multiple departments and institutions: Stanford Electrical Engineering, Materials Science, Applied Physics, and SLAC, as well San Jose State University and Santa Clara University. Technical description: We propose to develop a state-of-the-art experimental setup for the study of quantum materials including novel color center spin qubits and electro-optic materials, and the application of these material platforms toward scalable quantum technologies. The core of the instrument will be a state-of-the-art dilution refrigerator capable of achieving milli-kelvin base temperatures and with 3D vector magnetic fields of up to 1 Tesla. It will have a custom-made confocal microscope, coupled to tunable lasers and a high-resolution spectrometer, allowing for the study of quantum emitters over a broad range of frequencies. Advanced control electronics will enable sophisticated protocols, such as real-time feedforward and data-driven feedback, for exploring multi-qubit experiments with applications in quantum sensing, networking, and information processing. The unique proposed setup will ultimately enable the rapid discovery and comprehensive study of color center qubits and cryogenic electro-optic materials, which are essential building blocks for transducers and quantum interconnects, as well as the study of microwave and optical cavity QED systems. More broadly, this one-of-a-kind instrument will be set up as a shared facility, whose impact will extend beyond Stanford. The proximity to Silicon Valley will open the door for partnerships with industry, accelerating scaling, system integration, and real-world deployment. In addition, publications of the design of our instrument and detailed experimental protocols will accelerate the development of similar platforms in academic and national lab settings. 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 2026 · 2026-04

This award will partially cover travel expenses of invited speakers and student participants and organizing expenses related to the workshop entitled "The Center for Turbulence Research (CTR) Summer Program," to be held at Stanford University. The program is scheduled to be held at Stanford from June 26 to July 24, 2026. Participants will include faculty, graduate students, and a cadre of 10-20 postdocs that will assist visitors to promote successful outcomes in every research project. The 2024 program was the largest to date with 103 external participants from 15 countries, including participants from 60 institutions. The participants included experimentalists, theoreticians, and computational scientists. A competitive process will be used to select participants based on their research credentials, the merits of their research proposals and the relevance to areas of interest to CTR. Graduate students will be accepted to accompany their research advisors. One goal of the workshop will be to frame the challenges in turbulence modeling for the next few years. The findings of the program will be collected and published as a comprehensive technical report. The report is expected to consist of forty to fifty technical papers (about 500 pages) which will be delivered to NSF and to other sponsors of the program and disseminated worldwide at the end of the calendar year. The report, like the reports from the prior workshops, will be available at https://ctr.stanford.edu/summer-program. Many papers in the report will be eventually published in high quality technical journals. The bulk of the CTR Summer Programs will involve hands-on interrogation of numerical simulation databases for testing models and hypotheses proposed by the participants. Additional calculations to generate new databases may be performed during the summer. The participants will be divided into focus groups based on their proposed areas of research. Emphasis will be placed on proposals in advanced computing (e.g., mixed precision arithmetic and quantum computing), machine learning for uncertainty quantification and turbulence modeling. Other topics of interest will include, control, sensing, non-equilibrium flows, data compression, and model reduction. 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 · 2026-04

PROJECT SUMMARY/ABSTRACT Bacteriophages (phages) – viral predators of bacteria – are a promising solution to antimicrobial-resistant bacterial infections caused by ESKAPE pathogens, particularly for Pseudomonas aeruginosa airway infections in people with cystic fibrosis (CF), a genetic disease involving mutations in the CFTR protein. While phage therapy in CF can be successful, results are inconsistent. Unfortunately, we do not know how best to dose and deliver phages to sites of infection, reflecting underlying knowledge gaps in phage pharmacokinetics and pharmacodynamics (PK/PD) that frustrate drug development of phage therapies. While pharmacology is the cornerstone of modern drug development, phage PK/PD studies are rarely performed. This is because existing bioanalytical approaches are time-consuming, labor-intensive, and require large numbers of samples for statistical rigor. Moreover, we lack animal models of chronic bacterial infection that recapitulate the pathophysiology of CF and can support chronic lung infections. This has made it challenging to optimize phage therapy dosing regimens, delaying the development of phage therapy as a reliable adjunct or alternative to antibiotics in CF and other therapeutic settings. To address these challenges, we will establish the Center for Phage Pharmaceuticals (the "Phage Pharm"), a research collaboration devoted to developing cutting-edge tools and rigorous pharmacologic approaches to phage therapy development. Our center proposes two synergistic but independent projects: Project 1 pioneers approaches adapted from nuclear medicine, including positron emission tomography (PET) imaging of radioisotope-labeled phages and sophisticated analytical methods, to track lytic phage distribution and develop quantitative pharmacokinetic models. Project 2 will establish a novel preclinical model to study respiratory phage therapy PD. First, we will develop the CFTR-/- rat, which recapitulates many aspects of CF in humans including the development of chronic P. aeruginosa lung infections, as a robust, standardized preclinical model of phage therapy. Using this model, we will then optimize delivery of respiratory phage therapy. Finally, we will establish assays for evaluating the host response to phage therapy, including neutralizing antibodies. A set of core facilities will support these efforts with cutting-edge technologies and focused expertise. The Administrative Core (Core A) will ensure coordination between projects, cores, and CAPT-CEP centers. The Phage Production and Radiolabeling Core (Core B) will produce standardized radiolabeled phages. The Phage Pharmacology Core (Core C) will develop mathematical models to analyze PK and optimize dosing strategies. While this proposal focuses on P. aeruginosa and CF, the knowledge and approaches developed here will be broadly applicable to any phage-based therapeutics. Our vision is that the Phage Pharm will empower respiratory phage therapy, unlocking the therapeutic potential of phages in CF and other settings.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY Clostridioides difficile infection (CDI) poses a significant public health burden, with approximately half a million cases annually in the United States and recurrence rates of up to 25%. CDI is primarily driven by disruptions to the gut microbiome, often due to antibiotic treatment, which creates an environment conducive to C. difficile (Cd) colonization. Current microbiome-based therapeutic strategies, such as fecal microbiota transplants (FMTs), have shown promise in restoring colonization resistance; however, their safety, reproducibility, and regulatory challenges limit widespread clinical application. While defined microbial consortia represent a promising alternative, their efficacy remains suboptimal. We hypothesize that these failures stem at least in part from an over-reliance on high-abundance (HA) species and an incomplete understanding of how low- abundance (LA) species contribute to microbiome stability and pathogen resistance. This project seeks to systematically evaluate the role of LA species in microbiome assembly and in conferring colonization resistance using a combination of synthetic microbial communities, metabolomics, and gnotobiotic mouse models. We hypothesize that LA species play crucial metabolic and ecological roles, through direct competition with Cd and by reinforcing community resilience under antibiotic-induced perturbations. To test this hypothesis, we will employ a defined yet complex synthetic community, mhCom, that encompasses both HA and LA species and assembles reproducibly in vitro and in vivo. Leveraging high-resolution metabolomics, we will (i) characterize the metabolic niches and functional redundancies of LA species and (ii) determine their role in resistance to Cd colonization and microbiome recovery and Cd suppression following antibiotic-induced CDI. In Aim 1, we will map the metabolic functions of LA species within mhCom in vitro, identifying privileged metabolic niches and cross-feeding interactions that contribute to community stability. We will use untargeted metabolomics and species dropouts to establish whether LA species and/or Cd fill metabolic voids when HA species are lost. In Aim 2, we will use gnotobiotic mice to assess the impact of LA species on C. difficile colonization resistance, determining whether the inclusion of LA species enhances pathogen exclusion both before and after antibiotic-induced microbiome disruption. By addressing a critical knowledge gap in microbiome ecology, this study has the potential to redefine microbiome-based therapeutics, either by demonstrating that LA species are not merely passive members of the gut community but essential contributors to microbiome resilience or by affirming strategies focused on HA species. The outcomes of this research will inform the rational design of next-generation microbial therapeutics with enhanced robustness against CDI and will have direct impact for other microbiome-related diseases, providing a foundation for safer, more effective, and precision-targeted microbiome interventions.

NIH Research Projects · FY 2026 · 2026-04

Project Summary Systemic lupus erythematosus (SLE) is a complex autoimmune disease driven by the breakdown of B cell tolerance and the production of autoreactive antibodies. We recently identified the presence of autoreactive B cells in spleens from healthy individuals and observed a 20-fold increase in spleens derived from SLE patients. This proposal will investigate a critical gap in understanding how autoreactive B cells transition from a tolerogenic state to a pathogenic one through: (i) analysis of dysregulated transcriptional pathways in spheromer-sorted autoreactive B cells derived from SLE patients, (ii) investigation of human-specific TLR7 mutants in mediating autoreactive B cell activation using immune organoids, and (iii) characterization of proinflammatory monocytes triggered by bacterial peptidoglycans in SLE. We will test the hypothesis that autoreactive B cells in SLE have distinct transcriptomic profiles and increased somatic hypermutation frequencies compared to healthy donors. We further hypothesize that amplified TLR7 signaling due to gene mutations and proinflammatory monocytes activated by bacterial peptidoglycans are pathognomonic for distinct SLE disease subtypes and characteristics. Aim 1 will characterize the transcriptomic and B cell receptor (BCR) profiles of autoreactive B cells from lupus patients. Aim 2 will investigate the autoimmune response in immune organoids expressing the TLR7Y264H mutant. Aim 3 will examine the ability of proinflammatory monocytes from SLE and healthy monocytes primed by peptidoglycan to trigger autoreactive B cell activation. The success of the proposed studies will elucidate the mechanisms by which autoreactive B cells become pathogenic and cause SLE, fundamentally transforming our understanding of SLE and potentially leading to novel therapeutic strategies.