Stanford University

NIH Research Projects · FY 2026 · 2026-04

PROJECT ABSTRACT Family members (FMs; biological, extended, or chosen family) impacted by SUD experience chronic stress that places them at high risk for mental and physical health consequences. These consequences are exacerbated by the stigma, guilt, shame and self-blame that often occur in families with an individual using substances. As a result, FMs impacted by SUD often experience social isolation and are unsure how to best support their loved one in recovery. While these FMs are motivated to support their loved one in the treatment navigation process, they seldom seek support for themselves. Programs like Community Reinforcement and Family Training (CRAFT) provide support to FMs and equip them with tools to improve their own lives while supporting their loved one. While CRAFT is well-established in community settings for increasing their loved one’s SUD treatment initiation, less is known about the applicability of CRAFT in clinical SUD settings. Thus, it remains unclear whether CRAFT can enhance patient treatment retention in these settings and whether FMs who might not otherwise seek care would participate. To advance the science of engaging and supporting families impacted by SUD, we will take a multiphase approach and: (1) conduct an iterative, online process with FMs and clinic staff to identify potential family engagement strategies that community health clinics (CHCs) can deliver that may be effective, feasible, acceptable, and appropriate (R61 Aim 1; N=100), (2) test those strategies using a fractional factorial trial (R61 Aim 2; N=100), (3) combine the most effective strategy with CRAFT and conduct an RCT to test this optimized intervention versus usual care for patient and FM dyads recruited from CHCs that provide SUD treatment (R33 Aim 3; N=200 dyads). Finally, we will conduct interviews with FMs, clinic staff, and financing experts to assess factors influencing future implementation and dissemination of FM interventions in clinical SUD settings (Aim 4; N=30-35). By prioritizing strategies to engage FMs, we aim to enhance both the effectiveness and adoption of family-focused interventions, while also advancing research on how to best optimize the involvement of this often-overlooked group.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY/ABSTRACT The goal of my proposal is to gain technical and professional skills that position me to become an independent investigator at a leading academic institution where I will develop a research program elucidating the molecular mechanisms driving benign prostatic hyperplasia (BPH), a condition affecting a significant portion of men and imposing an economic burden of over $4 billion annually. Through this project, I will determine the effects of bone morphogenetic protein 5 (BMP5) activation and inhibition on BPH growth as well as identify BMP5- mediated cell changes via spatial RNA sequencing, patient-derived xenografts (PDXs), and spheroid models. My training is focused on three key areas: 1). Gain hands-on training in spatial transcriptomic technology including sample preparation and data processing to identify BMP5-mediated changes using BPH PDXs 2). Develop an in vitro spheroid model to test growth factors alone or in combination with BMP5 that modulate BPH growth for therapeutic targeting. 3). Further characterizing the PDX model I developed for pre-clinical testing of BMP inhibitors. Benign urology research provides an ideal environment for interdisciplinary research and career development, supported by an advisory team specializing in spatial RNA sequencing, 3D-culture models, and BPH pathology, along with Stanford resources such as courses in translational genomics, departmental grand rounds/seminars, benign urology conferences, clinical training, and AUA courses. My hypothesis is that BMP5 promotes epithelial proliferation and survival, contributing to BPH progression, and that BMP5 inhibition will suppress these processes, offering a targeted therapeutic approach. I will test this hypothesis through three specific aims: 1. Determine the effects of BMP5 inhibition and exogenous BMP5 treatment on BPH PDX growth and survival; 2. Elucidate the molecular mechanisms underlying BMP5- mediated prostate epithelial growth and survival; 3: Identify additional growth factors alone or in combination with BMP5 that modulate BPH growth and survival for therapeutic targeting. To strengthen the clinical relevance of our findings, we will validate BMP5-related changes observed in pre-clinical models using human tissue microarrays (TMAs). This validation strategy fortifies the translational potential of BMP5 inhibitors and provides strong rationale for the clinical testing of potent and selective BMP5 inhibitors in BPH patients. This proposal will support my own unique research direction that will be independent of my mentors (e.g. focus on growth factor combinations and pre-clinical testing of inhibitors in vivo and in vitro) and integrate my prior training in molecular biology and engineering as well as expand my capabilities in prostate physiology, molecular profiling, and 3D cellular models. By targeting BMP5, this research addresses limitations of current nonspecific treatments and establishes a robust platform for advancing therapeutic strategies and understanding BPH pathogenesis. This study will not only generate real-world impact in patient care but also broaden the understanding of BPH biology and provide rich resources for the BPH research community.

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.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY The small intestine (SI) is a critical site of host-microbe interactions and nutrient absorption, yet it remains severely understudied due to the difficulty of non-invasively sampling its microbiome and environment. Most microbiome studies rely on fecal samples, which primarily reflect the large intestine and fail to capture the distinct microbial ecology of the SI. This knowledge gap limits our understanding of how environmental factors shape microbial composition and function in this essential gut region. Given the SI’s unique chemical landscape—characterized by microaerobic oxygen (O2) levels and high bile acid (BA) concentrations— microbes residing in this niche must adapt to these selective pressures, which likely influence their ability to colonize the SI and contribute to gastrointestinal health and disease. This proposal aims to elucidate how O2 and BAs drive microbial adaptation and interactions within the SI microbiome. We hypothesize that SI-enriched microbes exhibit greater tolerance to O2 and BAs than stool- enriched microbes and that BA metabolism plays a central role in shaping gut ecology by enriching for species capable of processing these antimicrobial compounds. To disentangle the relative contributions of these factors, it is important to isolate and quantify the effects on individual microbes. To do so, we will leverage a novel non-invasive sampling device that enables direct collection of viable SI microbes and metabolites, along with high-throughput culturomics, metagenomics, and metabolomics approaches. Using our established workflows and unique expertise, we will generate diverse isolate libraries and construct in vitro microbial communities that maintain the majority of microbial abundances found in the SI in vivo. We will evaluate the sensitivity of these isolates and communities to a broad range of O2 and BA conditions and determine whether these sensitivities predict the capacity to resist colonization by SI pathogens. These experimental systems will allow us to probe microbial dynamics at scales inaccessible through animal studies and reveal fundamental principles underlying microbial regional preferences in hosts. In Aim 1, we will systematically quantify the effects of O2 and BA concentrations on the growth and metabolism of SI and stool-derived isolates to establish how these factors drive microbial localization within the gut. In Aim 2, we will investigate the emergent effects of BA metabolism and O2 tolerance in microbial communities. Using in vitro community models, we will probe how these environmental factors modulate microbiome structure and function, particularly in the context of colonization resistance against pathogens linked to diseases such as irritable bowel syndrome (IBS) and small intestinal bacterial overgrowth (SIBO). This work will bridge long- standing gaps in microbiome science by providing novel insights into SI microbial ecology and a mechanistic framework for designing microbiome-based interventions, including personalized probiotics and targeted therapies for SI-associated diseases.

NSF Awards · FY 2026 · 2026-04

This award funds the research activities of Professor Ken Van Tilburg at New York University. The current set of physical laws --- as encapsulated within the Standard Models of Particle Physics and Cosmology --- provide an exquisitely accurate and precise description of all known phenomena in nature. However, several puzzles still remain. The most tangible shortcoming is that the microscopic nature of dark matter, a mostly inert component comprising most of the matter density of the Galaxy and the Universe, is unknown, despite the troves of evidence for its existence through its gravitational influence. In his research, Professor Van Tilburg aims to develop observational probes of dark-matter structures smaller than ever detected before, using methods based on the gravitational deflection of starlight caused by small and otherwise invisible clumps of dark matter. Using X-ray satellites and terrestrial dark matter experiments, he will also aim to detect weakly-interacting low-mass particles, a motivated class of dark-matter candidates which are produced in the cores of stars. Research in this area advances the national interest by seeking to answer one of the most fundamental questions in physics, namely that of understanding what particle(s) comprise the dark matter. Professor Van Tilburg will also involve graduate students and a postdoc in his research, thereby training the next generation of junior scientists in this burgeoning new field at the intersection of particle physics and astrophysics. He will also visit local high schools to give public lectures about particle physics and cosmology and to educate students from underrepresented groups about pursuing scientific career paths. In a first research avenue, Professor Van Tilburg and his group will conduct a suite of analyses of time-domain, astrometric, weak gravitational lensing on public astronomical data sets, to search for entirely non-luminous dark matter structures lighter than 100 million solar masses. In particular, he aims to develop a data analysis pipeline to search for transient astrometric deflections in Gaia time-series data from ultra-compact dark-matter structures as well as from astrophysical compact remnants and black holes. He also seeks to analyze the correlated shifts in celestial proper motions and accelerations of background sources induced via gravitational lensing by more extended dark-matter structures. A (non-)detection of such small-scale structures would provide crucial new constraints on the microphysics of dark matter, as well as the primordial seeds of structure formation on small scales. In a second research avenue, Professor Van Tilburg will study a recently introduced phenomenon, dubbed "stellar basins", wherein weakly-coupled particles can be emitted from the entire stellar volume onto bound orbits whose density accumulates over time. This effect is generic for any particle type and important if the particle has a rest-mass energy not too far removed from the temperature in the stellar interior. Van Tilburg conjectures that phenomena associated with stellar basins --- direct detection in the laboratory and indirect detection in telescope observations --- will form the leading probes of any particle in the mass range from a few eV to hundreds of keV. The objective of this research avenue is to work out this phenomenology in detail: calculating all production mechanisms, performing computations for the observable signals, analyzing publicly available data, and interpreting the results in terms of the parameter space of the models. 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 Barrier epithelia face continual damage from environmental insults, and successful injury repair is crucial for organismal health. A prime case study is the one-cell-thick intestinal epithelium, which forms a leakproof bar- rier between the gut lumen and the body cavity. To replace damaged cells, the intestine mobilizes stem cells to divide rapidly; to restore intestinal form and function, these new daughter cells must also differentiate rapidly. Indeed, injury-born intestinal cells acquire their mature identity twice as fast as their normal counterparts. Using the Drosophila adult intestine, we recently discovered this injury-accelerated differentiation arises through disruption of Notch-Delta lateral inhibition circuitry that normally specifies stem versus terminal fate. During injury, many newly born cells exhibit >10x faster Notch signaling speed, which propels faster intestinal differentiation to restore the breached epithelial barrier. Yet this strategy comes with risks for long-term tissue health: For stem cells, loss of Notch-Delta feedback during injury skews daughter fates toward dead-end, ter- minal:terminal outcomes, which depletes the organ’s stem cells and culminates in stem cell exhaustion. For terminal progeny, accelerated differentiation yields provisional ‘stopgap’ cells—mature cells with digestive and barrier-forming functions but altered morphology and a supercompetitor-like transcriptomic profile. Here, we will investigate how the organ copes with these two tradeoffs. We combine physiological injury of the fly gut with in vivo live imaging and cutting-edge cell lineage tracing to elucidate how these ‘side effects’ of accelerated differentiation are managed at the organ-scale for post-injury tissue homeostasis. The fly gut com- bines conserved intestinal cell lineages, fate signals, and digestive physiology with supreme experimental trac- tability: A single Notch receptor and Delta ligand, an unparalleled wealth of genetic tools, and long-term in vivo live imaging—pioneered by our lab—provide the technical bases for deep mechanistic investigation. Leveraging these strengths, in Aim 1 we will define how some, ‘escaper’ stem cells persist after injury, de- spite disrupted Notch-Delta feedback that should force all cells to differentiate. We will test if escaper stem cells inherit an intracellular Notch inhibitor, autonomously override how Notch and Delta interact, or lose con- tact with their signaling partners via injury-induced epithelial fluidization. In Aim 2, we will ascertain the time- evolution and function of stopgap cells during and after injury. We will determine their ultimate fates in the tis- sue during recovery, e.g., they may evolve into normal cells, arrest in an abnormal state, or simply be shed. We will parse these scenarios using longitudinal live imaging, whole-population analyses, and single-cell tran- scriptomics. Finally, we will examine how stopgap cells shape the tissue post-injury by ‘purging’ unfit, toxin- exposed cells during injury or by exerting selective pressure on new cells during post-injury recovery. By probing these lineage tradeoffs of accelerated cell differentiation during injury, our work will suggest new strategies to promote intestinal regeneration and combat chronic intestinal disease.

NIH Research Projects · FY 2026 · 2026-04

Project Summary/Abstract Cardiomyopathy is known to affect the myocardium and is associated with either mechanical and/or electrical dysfunction that can lead to ventricular hypertrophy or dilatation. These cardiomyopathies can affect people of all ages and can be either inherited or acquired, where inherited cardiomyopathies are due to mutations that alter the genes that control cardiac function and acquired due to associated co-morbidities such as diabetes or exposure to chemotherapeutic agents. Endothelial (EC) dysfunction has been shown to play an important role in the development and progression of cardiomyopathy, however the molecular mechanisms by which it imparts cardiac (CM) dysfunction remains elusive. The long-term goal of this proposal is to study and understand the pathogenesis of cardiac dysfunction via the lens of the endothelium. The endothelium is a critical component of the cardiovascular system that forms a protective barrier for CMs and releases paracrine factors to maintain CM health and function. Despite impressive progress, little attention has been given to the potential importance of cell-to-cell signaling between ECs and CMs. This knowledge gap impedes our comprehensive understanding of organ dysfunction at a multi- cellular level. With the knowledge that dysfunctional ECs can have a negative impact on CM function, we need a better understanding of the integral role of ECs in the development of myocardial injury. By utilizing a multidisciplinary approach that integrates human iPSCs, bioengineering tools, single-cell ‘omics’, and animal models of cardiomyopathy, we intend to decipher the EC-CM crosstalk. This research program focuses on two major forms of cardiomyopathy, inherited due to mutations, or acquired following exposure to chemotherapy. The proposal aims to provide important insights and map the role of endothelial cells in the development of cardiac dysfunction and define the mechanisms by which they cause cardiomyopathy. Accordingly, the data, methods and animal models generated from this R35 initiative can be useful for all HLBS investigators interested in targeting the endothelium to improve cardiac function.

NIH Research Projects · FY 2026 · 2026-04

Project Summary This project addresses the pressing and widespread challenges posed by Alzheimer's disease and related dementias (ADRD), particularly the frequently co-occurring neuropsychiatric symptoms (NPS). ADRD are prevalent, debilitating conditions that severely impair daily functioning and place a significant burden on patients, families and society. NPS affect nearly 80% of individuals with dementia, with symptoms such as apathy and disinhibition closely linked to deficits in the motivation and cognitive control systems. Neuroimaging studies have identified structural, functional and metabolic abnormalities in these systems among old adults exhibiting apathy and/or disinhibition. However, a mechanistic understanding of how dysfunction in motivation and cognitive control systems contribute to these symptoms remains lacking. Recent cognitive neuroscience models highlight the critical roles of neural dynamics in supporting motivation and cognitive control functions. Our recent findings indicate that both healthy and pathological aging significantly impact on brain circuit dynamics, influencing cognitive functioning in older adults. However, little is known about how AD pathology affects brain circuit dynamics and how aberrant neural dynamics in the motivation and cognitive control systems contribute to apathy and disinhibition. This proposal seeks to fill these critical gaps by investigating the intricate relationships between AD pathology, brain circuit dynamics in the motivation and cognitive control systems, and NPS in individuals with ADRD. Grounded in the Research Domain Criteria (RDoC) framework, our study focuses on cognitive and positive valence systems, which are highly relevant to apathy and disinhibition. We will leverage a novel computational model developed in our lab to identify latent brain states and characterize their temporal and spatial properties, including state-specific posterior probability, mean lifetime, and functional connectivity within the motivation and cognitive control systems. By integrating fMRI and PET data from the same participants, we will examine how accumulation of Aβ and tau proteins disrupts brain circuit dynamics in these systems and its downstream effects on daily functioning. Furthermore, we will develop statistical models to predict apathy and disinhibition in ADRD. To ensure reproducibility and generalizability, we will conduct reproducibility analyses to validate our findings using two independent large- scale neuroimaging datasets of ADRD. The proposed research has far-reaching implications. It will shed light on the neurobiological mechanisms underlying NPS manifested in ADRD, particularly disinhibition and apathy. Ultimately, this study will pave the way for the development of more effective diagnosis and intervention strategies for the NPS, thus significantly advancing both the healthcare system and the field of research dedicated to ADRD. Essentially, the integrative cognitive, neuroscience and computational framework developed in this study can be broadly applied to investigate numerous other psychiatric and neurological disorders that share similar cognitive deficits.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY A major advance for treating depression, the leading cause of disability worldwide, has been the non- pharmacological development of repetitive transcranial magnetic stimulation (rTMS). While rTMS is effective for some, only about half of patients demonstrate a sustained clinical response. This is partly due to stimulation parameters not being fully optimized. While recent research has focused on personalizing where to stimulate, a critical gap remains in optimizing how to stimulate for each patient. This study aims to improve rTMS treatment for depression by using prefrontal electrophysiological biomarkers to personalize stimulation. We seek to enhance target engagement and better understand how brain changes relate to clinical response. Our method centers on early local TMS-evoked potentials (EL-TEPs), which provide reliable measurements of prefrontal excitability at the individual level. Prefrontal EL-TEPs are altered in depression, correlate with treatment outcomes, and respond to neuroplastic interventions like intermittent theta-burst stimulation (iTBS). Our team has pioneered a novel method to optimize EL-TEP acquisition, significantly improving signal quality and reliability. We hypothesize that personalizing iTBS pulse count and intensity to maximize EL-TEP suppression will optimize neural effects and improve clinical outcomes. We propose a R61/R33 study to develop and validate a personalized iTBS protocol. The R61 phase will demonstrate target engagement based on prefrontal excitability changes in 80 patients with treatment-resistant depression (TRD). We will characterize how iTBS parameters affect EL-TEPs in an abbreviated protocol, focusing on acute neurophysiological effects. The R33 phase will confirm target engagement and relate brain changes to clinical response in 106 new patients with TRD, comparing EL-TEP-guided personalized iTBS treatment to non-personalized iTBS treatment. This phase will involve a randomized, triple-blind design with comprehensive neurophysiological, clinical, cognitive, and functional assessments at multiple timepoints. This research is innovative as it uses prefrontal electrophysiology to deliver personalized iTBS treatment. The significance lies in its potential to select treatment parameters based on brain changes. Impact: This project aims to improve iTBS treatment through neurophysiology-guided personalization. By demonstrating target engagement and relating brain changes to clinical outcomes of personalized iTBS treatment, we seek to advance our understanding of the neural mechanisms of depression. If successful, this research could lead to more effective and efficient personalized treatments for depression.

NIH Research Projects · FY 2026 · 2026-03

Project Summary/Abstract Cardiac disease remains the leading cause of mortality, yet existing models fail to capture the complexity necessary for effective therapeutic development. COIN (Cardiac Organoids in Niches) integrates in silico, in chemico, and in vitro methodologies to engineer patient-specific cardiac niches, enhancing disease fidelity and therapeutic screening. By leveraging AI-driven modeling, biomaterials engineering, and multi-omics analysis, COIN establishes a scalable, reproducible NAMs platform for disease modeling and drug discovery. COIN’s AI- powered niche design tailors cardiac microenvironments to genetic, sex, and age profiles, improving disease relevance and therapeutic predictability. Innovations in biomaterials engineering refine extracellular matrix (ECM) properties to replicate human cardiac physiology, while organoid villages enhance translational accuracy. Multi- scale validation ensures COIN models faithfully reproduce patient-specific disease phenotypes, supporting regulatory qualification and preclinical safety assessment. COIN collaborates with the VQN to establish regulatory validation benchmarks and with the NDHCC to facilitate FAIR-compliant multi-omics data-sharing. Supported by the nation’s largest academic iPSC biobank and the Stanford Center for Genomics and Personalized Medicine, COIN unites leading experts in bioinformatics, AI, biomaterials, and organoid engineering to develop standardized, regulatory-ready NAMs models. Comprehensive technical characterization ensures functional validation, disease fidelity, and industry readiness. Training and outreach initiatives drive interdisciplinary collaboration and workforce development, fostering broad industry adoption. By integrating multi-scale modeling, high-throughput biomaterials engineering, and AI-driven analytics, COIN reduces reliance on animal models, advances precision drug discovery, and establishes a gold-standard NAMs platform for cardiac medicine.

NIH Research Projects · FY 2026 · 2026-03

Summary The transformative advancements in cell and gene therapy have significantly enhanced our understanding and treatment of congenital diseases and regenerative medicine. As we approach the 10th annual Center for Definitive and Curative Medicine (CDCM) symposium, scheduled for March 30-31, 2026, at Stanford University's Li Ka Shing Learning and Knowledge Center, we seek financial support to facilitate this pivotal event. This symposium will serve as a platform for scientific discourse on the latest discoveries and developments in the field, inviting participation from experts and trainees across academia, non-profits, government, and industry. The two-day event will focus on the theme “Past, Present, and Future of Cell and Gene Therapy,” addressing critical challenges in translating laboratory discoveries into clinical applications. Day 1 will feature a Clinical Trial Bootcamp, workshops on relevant topics, a poster session for early- stage investigators, and an evening networking event. Day 2 will showcase luminary speakers discussing breakthroughs in lentiviral and AAV gene therapy, CAR-T, gene editing, regenerative medicine, and hematopoietic stem cell transplantation. Specific aims of the symposium include: (1) elucidating the bench-to-bedside journey through real-world case studies presented by the Stanford CIRM-funded Alpha Clinic; (2) providing a platform for graduate students and early-career researchers to present their findings; (3) facilitating workshops that address community engagement in clinical trials, the role of Artificial Intelligence in healthcare, and career opportunities in health sciences; and (4) fostering collaboration through platform sessions that expose participants to emerging research areas. This symposium has been a cornerstone of the Cell and Gene Therapy Community for the past nine years, celebrating past achievements while catalyzing future innovations. The 2026 meeting promises to be a significant milestone, driving forward the dialogue and collaboration necessary to tackle the complexities of cell and gene therapy and improve patient outcomes.

NIH Research Projects · FY 2026 · 2026-03

Project Summary/ Abstract. Generally, the accepted goal of cancer treatments is the eradication of cancer cells, which in itself will lead to cure. While this has been an effective strategy in some restricted instances, most adult solid cancers remain very difficult to cure and some, like the very malignant glioblastoma, remain exceedingly resistant to this approach despite years of dedicated research. We have been exploring strategies using a different framework of cancer development in which tumors arise as a maladaptive wound response that predicts that cure will not be possible without also focusing on normal tissue healing processes, i.e., tumor cell eradication is not enough. We have identified a prototypical agent, BPM31510, that possesses many of the features that fulfill the necessary requirements for inhibiting cancer while sparing noncancer tissue. This drug, which is composed of CoQ10 incorporated into a lipid nanoemulsion, enables delivery of supraphysiological doses of the highly hydrophobic CoQ10, orders of magnitude greater than are possible with CoQ10 alone. Based on data that is described within, we have demonstrated in vitro that this compound has marked differential effects on glioma cells relative to non-tumor cells and that we can reliably eradicate cancer cells without impeding normal cell growth; we’ve also identified that this effect is exquisitely dose dependent. Our in vivo studies also indicate that we can cure orthotopic glioma implants when this drug is used as a single agent at the correct dose. Our findings could therefore represent a transformative approach to cancer—not only for glioblastoma, but since it is genetically “agnostic”, to other cancers as well. However, a major hurdle in moving towards clinical translation is the lack of an appropriate real time measurement of response, i.e., tumors often grow before they respond, complicating assessment using standard anatomic criteria such as RANO or RECIST. Interestingly, major changes can be identified using noninvasive MR techniques such as proton MRS and deuterium metabolic imaging (DMI) even when MR imaging shows tumor growth, offering an alternative way to measure treatment efficacy. This highly technical proposal, which arises through a longstanding collaboration between a clinical neurooncologist and MRI/MRS engineering group, will offer a roadmap for optimizing three non-invasive imaging techniques, one in general use (proton MRS), one being explored for its clinical utilization (DMI) and one still in experimental development (PROXYL based redox imaging) as measurement tools for this treatment strategy. With their successful completion, our results will be immediately translatable to the clinic and could serve to assess any therapies that use this novel anticancer strategy.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY/ABSTRACT We form attachments at many levels of social interactions, including with spouses, family members, friends, and other members of the community. The neurobiological mechanisms that control the formation and maintenance of social attachment remain poorly understood. This is in part because traditional genetic model systems such as mice, fish, flies, and worms do not exhibit social attachment as adults, precluding the use of powerful molecular genetic approaches to dissect mechanisms underlying this behavior. Prairie voles are small rodents that form an enduring social bond (referred to as pair bonds) between adults, and they also display other related affiliative behaviors. Pharmacologic studies in prairie voles have implicated vasopressin and oxytocin signaling through their receptors OXTR and AVPR1A in the control of social attachment, providing a potential entry-point into the neural circuits that govern this behavior. However, in our published and unpublished work, we find that neither OXTR nor AVPR1A are genetically required for pair bonding. To realize our goal to understand how the brain encodes pair bonding, we propose a genetic approach that is independent of OXTR or AVPR1A to gain a new entry-point into the neural circuits underlying this behavior. In brief, we will use the FosTRAP approach first developed in mice to achieve our goal. This approach relies on using FOS to genetically tag neurons that are activated during a specific behavior, and in mice, this has revolutionized identification and functional characterization of neural circuits underlying diverse behaviors and physiology in health and disease. For the current project, we will generate genetically modified voles that have a small molecule-inducible Cre recombinase inserted into the prairie vole Fos locus and a Cre-dependent fluorescent reporter inserted into the prairie vole Rosa locus (Specific Aim 1); in Specific Aim 2, we will validate the use of these knock-in vole strains and identify neuronal populations that are activated during pair bonding. As with the FosTRAP strategy in mice, voles bearing the modified Fos and Rosa genes will enable genetic tagging of neurons activated during a specific behavior, pair bonding in our case for this project. Taken together, our studies will enable identification and functional studies of neural pathways that govern social attachment behavior in prairie voles. Health relatedness: Social attachments are thought to be critical for our mental health and personal and professional success. Failure to form or maintain social attachments is often an early indicator of a serious mental illness such as autism spectrum disorder, depression, and schizophrenia. Our proposal seeks to develop genetic means to access the neural circuits underlying social attachment in prairie voles, which have long been considered the premier mammalian model for these complex social interactions. Our projection may therefore provide a useful model system to study social behaviors relevant to human health and mental illnesses.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY: Harnessing the human myeloid system to improve surgical recovery Annually, 30 million patients undergo major surgery in the US, with 20-30% experiencing delayed surgical recovery. However, existing tools for predicting surgical recovery perform poorly. An effective immune response to surgical trauma is necessary for most biological processes driving surgical recovery, including infection control, functional recovery, and pain resolution. As such, in-depth analysis of local (i.e., at the surgical site) and peripheral immune mechanisms in patients undergoing surgery is an essential step for identifying accurate predictive biomarkers of surgical recovery and novel therapeutic targets. The human myeloid system (hMS), including monocytes, macrophages, neutrophils, and their subsets, plays a pivotal role in initiating and coordinating the immune response to surgical trauma. Initially focused on the peripheral hMS, our research uses high-dimensional immune monitoring technologies to identify modifiable mechanisms that predict a patient’s recovery. Over the past five years, we have: 1) developed single-cell mass cytometry assays for the functional and epigenetic monitoring of patients’ immune response to surgery and of pharmacological interventions (Nat. Commun., 2020; Ann. Surg, 2023); 2) characterized an hMS cellular program predicting surgical site infections (SSIs, Ann. Surg., 2022); 3) developed a machine learning framework for predictive modeling and selection of reliable biomarkers of surgical outcomes (Nat. Biotech., 2024). This MIRA program builds on our recent studies highlighting the role of the peripheral hMS in the pathogenesis of SSIs after GI surgery. We will first investigate the contribution of the local hMS to the pathophysiology of SSIs and determine the relationship between the local immune microenvironment and the peripheral hMS responses to surgery. Second, we will take an integrative approach to build and validate a predictive model of SSIs combining the single-cell assessment of immune signaling and epigenetic states in patient blood and tissue samples collected before and during surgery. Third, we will implement a drug repurposing strategy to identify novel immune-modulatory properties of FDA-approved drugs that can be leveraged in clinical trials to prevent SSIs. We will employ innovative, multidisciplinary approaches: 1) imaging mass cytometry for the 50-plex analysis of local hMS spatial and functional cellular organization in surgical tissue; 2) sparse machine learning methods for integrative analysis of mass cytometry, plasma proteomic and clinical data; 3) high-throughput mass tag barcoding immunoassay for selection of promising drug candidate targeting selective hMS responses. With a focus on the hMS and key clinical determinants of surgical recovery (infection), our MIRA research will identify reliable biomarkers and selective drug candidates for future testing in biomarker-guided clinical trials. Our work will also yield an extensive single-cell data repository, that can be shared with the scientific community and expanded to include other immunological dimensions (adaptive system), omic modalities (microbiome, metabolome, and transcriptome) and trauma-related outcomes (sepsis, organ damage, and cognitive decline).

NIH Research Projects · FY 2026 · 2026-03

ABSTRACT Bacteriophages are integral components of the human microbiome, shaping microbial diversity and influencing host health, yet our understanding of phage-host dynamics remains limited, particularly for integrated phages. Recent discoveries reveal that lysogenic phages dominate the human gut microbiome over lytic phages, but current methods using short-read sequencing fail to capture phage integration sites and host attribution. This project will elucidate integrated phage-host dynamics in the human microbiome using innovative long-read sequencing approaches. The central hypothesis of this proposal is that integrated phages play critical roles in microbial community dynamics that can be detected, experimentally tested, and modeled to advance our understanding of microbiome function. Our preliminary data demonstrates that long-read sequencing dramatically improves phage genome assembly, host attribution, and integration site identification. Specifically, we have shown that geNomad most accurately detects phage boundaries when compared to ‘gold standard’ structural variation evidence of phage boundaries from Sniffles (DNA structural variant detector). We have also successfully propagated non-plaque-forming phages using stool-based cultures and discovered that p- crAssphage (Carjivirus communis) adopts a phage-plasmid lifestyle, challenging traditional models. Additionally, we have developed a quantitative modeling framework that revealed surprisingly low rates of phage induction in the microbiome. Building upon these findings, we will: (Aim 1) develop a computational framework to identify integrated prophages, their hosts, and integration sites from long-read metagenomic data, including a nextflow pipeline for assembly and annotation; (Aim 2) establish a stool-based culturomics platform to isolate non-plaque- forming phages and identify their bacterial hosts using meta-Hi-C sequencing and qPCR-based growth dynamics analysis; and (Aim 3) create computational models for viral-host population dynamics to test longstanding hypotheses about virus-host interactions in the human gut, extending our modeling to account for within-host spatial structure. Our multidisciplinary team brings together expertise in microbiome science, genomics and clinical applications (Bhatt), quantitative modeling and microbial biophysics (Huang), and evolutionary dynamics and microbial ecology (Good). We have collaborated successfully for several years and are supported by robust computational resources and experimental facilities. This project offers technological innovations through novel long-read sequencing pipelines and conceptual advances in understanding lysogenic phage ecology and lifestyle diversity. Successful completion will yield a suite of computational and experimental methods to identify integrated phages, their hosts, and viral-host interactions within the human microbiome, significantly enhancing our understanding of how phages impact human health and potentially informing future phage-based therapeutic strategies for microbiome modulation.

NIH Research Projects · FY 2026 · 2026-03

ABSTRACT: Bariatric surgery provides substantial health benefits, including diabetes remission, but up to 38% of cases are complicated by symptomatic and disabling postprandial hypoglycemia which occurs multiple times per day, with glucose concentrations low enough to cause seizures, loss of consciousness, disability, and death. While the physiologic mechanisms are not fully elucidated, altered nutrient transit, with overstimulation of GLP1-secreting cells in the distal ileum and hindgut, has been implicated. The reason why some but not other individuals develop postbariatric hypoglycemia (PBH) is unknown. We recently showed that individuals with PBH, as compared to unaffected surgical controls, have significantly faster gastric emptying, which is congruent with the altered nutrient transit hypothesis and importantly, points to a new target for treatment. In the current proposal, we will test three potential treatments that in nonsurgical patients are known to slow gastric emptying. Two of these are supported by preliminary data within the PBH population and one by data in the nonsurgical population. There is a dire need for rigorous studies in the PBH population as physiology and metabolism are unique and observed treatment-related effects in nonsurgical populations may not translate. The planned studies will directly highlight potential dietary, medical, and surgical interventions to treat hypoglycemia in PBH patients. The proposed interventions are already readily clinically available and thus could be adapted for the use in PBH immediately. AIM1. Test the hypothesis that in PBH patients with RYGB and/or VSG, adding fat prior to a standardized meal will slow gastric emptying and raise glucose nadir during standardized MMTT AIM2. Test the hypothesis that in PBH patients with RYGB and/or VSG, use of the GLP1 agonist semaglutide will slow gastric emptying and raise glucose nadir during standardized MMTT AIM3. Test the hypothesis that in PBH patients with RYGB and/or VSG, the surgical procedure transoral gastric outlet reduction (TORe) will slow gastric emptying and raise glucose nadir during standardized MMTT.

NIH Research Projects · FY 2026 · 2026-03

Project Summary/Abstract Our research project aims to develop next-generation proximity labeling (PL) enzymes, specifically FlexID and LaccID, to enhance our understanding of molecular interactions and spatial compartmentation within living cells. These principles are foundational to cellular biology; however, current methodologies for mapping cellular interactomes and organelle proteomes, such as microscopy and biochemical fractionation, often lack accuracy and comprehensiveness. Proximity labeling has emerged as a powerful alternative, yet existing methods like APEX and TurboID face significant limitations in specificity, sensitivity, and practicality in vivo. Our proposal seeks to address these challenges. In Aim 1, we will optimize FlexID, an innovative PL enzyme capable of utilizing diverse non-biotin substrates for rapid, non-toxic labeling. This enzyme will be engineered for fast labeling times (within one minute) while maintaining high spatial specificity across various subcellular compartments. Rigorous characterization and improvement of FlexID1 will be conducted through computational design and directed evolution, with the goal of establishing FlexID2 as a versatile tool for spatial proteomics in cell biology, neuroscience, and immunology. In Aim 2, we will engineer LaccID, designed specifically to label surface proteins and reduce background labeling from intracellular pools. By enhancing LaccID’s speed and in vivo functionality, we will develop LaccID2 for mapping specific cell-type surface proteomes in various contexts. This aim will involve exploring alternative laccase templates and utilizing directed evolution under physiologically relevant conditions. The third aim is to conduct a quantitative comparison and benchmarking of PL enzymes, including FlexID, LaccID, APEX, and TurboID. We will systematically evaluate metrics such as sensitivity, specificity, and labeling radius through quantitative mass spectrometry-based proteomics across different cell models. This comprehensive analysis will produce guidelines that assist the scientific community in selecting the most effective PL methodologies for their specific research needs. Overall, this research has the potential to significantly advance the tools available for probing protein dynamics and molecular interactions in living cells. By addressing the limitations of existing PL methodologies, our work aims to facilitate transformative insights into cellular processes, enhancing the understanding of disease mechanisms and aiding therapeutic development. The successful implementation of these innovative PL enzymes will lead to exciting new applications across cell biology, neuroscience, and immunology, catalyzing further advancements in biotechnological and biomedical research.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY This project aims to uncover the molecular mechanisms that regulate membrane protein complex assembly at the human endoplasmic reticulum (ER) membrane. While significant progress has been made in understanding membrane protein insertion and folding, little is known about how thousands of membrane proteins find their correct binding partners to assemble into functional complexes of defined stoichiometry. Based on our preliminary data and published work, we hypothesize that assembly is highly regulated, and we plan to uncover the physiological roles of the underlying regulatory mechanisms using the large family of oligomeric voltage- gated ion channels (VGICs) as model complexes. VGICs fulfill many essential functions and for example mediate excitation-contraction coupling in heart and muscle cells, and trigger hormone and neurotransmitter release in secretory and neuronal cells. Mutations that impair VGIC biogenesis or function cause severe cardiological, neuropsychiatric, and neurodevelopmental diseases, emphasizing a critical need to better understand the assembly and quality control pathways that control their cellular levels. Our approach combines genetics, cell biology, and structural biology to determine the physiological role and mechanism of action of two poorly characterized VGIC assembly factors and to identify and characterize novel VGIC assembly factors. We will begin by advancing our understanding of voltage-gated calcium channel assembly by dissecting a potential novel chaperone function of the ER membrane protein complex (EMC). Using fluorescent calcium channel reporter cell lines and function-separating mutations, we have shown that EMC’s novel assembly function is required for calcium channel assembly in human cells. By reconstituting early calcium channel assembly events using an in vitro translation and ER insertion system, we will analyze how the EMC protects nascent channels from promiscuous interactions, aggregation and premature degradation to facilitate assembly. Additionally, we have developed selective nanobody inhibitors to investigate the physiological relevance of EMC’s novel assembly factor function in human iPSC-derived cardiomyocytes. These selective tools and assays now enable us to explore EMC’s assembly client spectrum using mass spectrometry. In parallel, we will investigate the assembly and quality control of other VGICs, such as potassium channels, using genome-wide genetic screens and characterize candidate factors using our established pipeline. This research will yield critical insights into the regulatory processes governing membrane protein assembly and identify potential therapeutic targets for VGIC- related diseases.

NIH Research Projects · FY 2026 · 2026-03

Project Summary/Abstract Prosody is a salient feature of speech that helps listeners anticipate when the most informative parts of a message will occur, facilitating comprehension. Prosodic impairments are linked to language deficits across disorders, yet prosody is largely absent from neural models of language processing. This proposal addresses this gap by investigating how neural tracking of prosody allows listeners to anticipate the expected informativity of upcoming words, engaging cortico-subcortical mechanisms to support linguistic processing and memory encoding. We overcome limitations of prior behavioral and scalp EEG work based on artificial paradigms, by leveraging intracranial EEG (iEEG) and machine learning (ML) to measure the contribution of subcortical structures to naturalistic comprehension. The mentored phase will involve intensive analyses of iEEG data from neurosurgical patients listening to naturalistic stories. Aim 1 tests whether prosodic tracking enhances the encoding of phonetic, semantic and syntactic features throughout the temporal lobe. Aim 2 investigates whether prosodic tracking supports memory encoding by modulating hippocampal theta (2.5–5 Hz). During the independent phase, I will combine naturalistic and factorial designs to orthogonalize prosodic cues and actual informativity (semantic surprisal). Aim 3 will dissociate how the brain tracks prosody to prepare for greater information load, from how it predicts and responds to the content of that information. The proposed work will advance neurolinguistic models by identifying the understudied key role of prosody as a cue to expected informativity. It will also contribute to ongoing debates on whether the hippocampus supports language processing, and how this interacts with its established role in memory encoding. I will achieve my long-term goal of launching an independent research career in speech neuroscience through critical new training during the mentored phase, addressing two key gaps. First, I need to move beyond controlled psycholinguistic paradigms by mastering the use of ML methods to study the processing of naturalistic speech. Second, I need to develop a deeper understanding of systems neuroscience, acquiring new theoretical background and methodological skills for the analysis of high-resolution imaging methods such as iEEG. This project integrates ML tools and iEEG with my prior background in psycholinguistics and scalp EEG, advancing a highly innovative approach that takes advantage of the benefits of multiple methods. I will receive exceptional training by working with Dr. Gwilliams, a pioneer in the application of ML for speech neuroscience, and Dr. Parvizi, a leader in use of iEEG. Stanford is an ideal training environment, as a hub for collaborative research between neuroscientists and clinician-scientists across the country. Joining this collaborative network will ensure I will continue to have access to iEEG or other high-resolution methods at the R00 institution. In sum, this proposal offers a novel neurocognitive framework for how prosody guides processing of the most informative parts of speech, laying the groundwork for understanding how disruptions in this system contribute to communication disorders.

NSF Awards · FY 2026 · 2026-03

Reconstructing how land temperatures changed over geological time is critical for understanding Earth’s geologic past. So far, oceans have been the main source of ancient geological data, leaving the land’s history largely untold. This project will investigate a recently discovered, unique group of bacterial membrane lipids that are well preserved in the rock record and could function as molecular fossils that provide valuable information on past ecosystems. This work aims to improve understanding of Earth’s environmental history, train the future workforce, and contribute to fields such as microbiology, biogeochemistry, and cellular dynamics. Insights on how microorganisms adapt to changing environmental conditions could also have implications for biotechnology, bioengineering, and even the search for life on other planets. This project will explore the use of bacterial membrane lipids called branched glycerol monoalkyl glycerol tetraethers (brGMGTs) as geological proxies that can provide insight on past terrestrial environments. The study will (1) identify the bacteria that produce brGMGTs through heterologous gene expression, (2) develop a culture-based temperature calibration of brGMGT production, and (3) use computer simulations to determine the biophysical impacts of brGMGTs in membranes. These results will allow the development of a brGMGT paleothermometer that would be widely adopted as a robust terrestrial proxy. These advances could transform understanding of past terrestrial environments and open new research frontiers in microbial ecology, environmental chemistry, and microbial membrane dynamics. This award was made possible through the NSF/GEO-UKRI/NERC lead agency opportunity. 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 · 2026-03

PROJECT SUMMARY The human genome encodes over 2 million DNA regulatory elements called enhancers that control gene expression in specific cell types and states. Enhancers harbor tens of thousands of genetic variants that influence risk for common diseases and traits. Each of these enhancer variants could reveal insights into the molecular mechanisms of human diseases. Yet, we have lacked tools to systematically map which enhancers regulate which genes in each of the thousands of cell types in the human body. To address this challenge, we have recently applied CRISPR tools to experimentally test thousands of enhancers in parallel, developed simple computational models that can predict enhancer-gene regulatory interactions from chromatin state, and demonstrated that these predicted enhancer maps can link noncoding variants to novel target genes. These technologies suggest a new strategy to map enhancers across many cell types to connect noncoding variants to target genes. Here, we will extend these technologies to map and predict enhancer-gene regulatory interactions using single-cell multiomic input datasets, and thereby enable applications to many additional cell types and states. First, we will optimize, stress-test, and deploy a computational model to predict E-G regulatory interactions from single-cell datasets in complex tissues. Second, we will build a genome-wide map of enhancer regulation across 100s of human cell types, and explore variation across disease state, biological sex, and age. Third, we will apply these tools to functionally characterize genetic variants associated with cardiovascular diseases and traits, as an exemplary system to validate the utility of these maps in linking variants to functions. Together, this proposal will deliver (i) a predictive model to map E-G interactions across many cell types and states; (ii) a genome-wide resource of E-G regulatory interactions across human cell types; (iii) insights into how this regulatory wiring differs across cell types and key biological variables; and (iv) novel enhancers, genes, and cell types that affect risk for heart structure and function. These methods will enable future studies to study the impacts of variants and elements on genome function across a wide range of biological contexts and diseases.

NIH Research Projects · FY 2026 · 2026-03

Myosin molecular motors play important roles in many cellular processes, including migration, transport of intracellular contents, and contraction. A variety of heritable diseases owe their origins to defects in the myosin family of molecular motors. One of the most severe examples is inherited familial hypertrophic cardiomyopathy (HCM), which leads to hyper-contractility and impaired relaxation of the heart. Untreated, this hyper-contractility causes significant thickening (hypertrophy) of the walls of the left ventricle of the heart, which can lead to heart rhythm disorders, heart failure, and even sudden death. For most patients, therapeutic interventions for HCM are currently limited to symptomatic relief, which in severe cases requires invasive procedures such as heart muscle reduction surgery, defibrillator placement, or even heart transplantation. HCM results from mutations in various cardiac muscle proteins, with mutations in -cardiac myosin, the motor that drives ventricular contraction, and myosin binding protein C accounting for about 90% of these cases. HCM is not rare, affecting as many as 1 in 500 people. Studies using human -cardiac myosin have shown that HCM mutations induce variable changes in the basic biochemical and biomechanical parameters of the myosin motor such as force production and velocity of moving actin filaments. However, these variable changes do not adequately account for the cardiac hyper-contractility that is a clinical hallmark of HCM. Rather, it has recently been shown that HCM- causing mutations in the myosin motor domain disrupt intramolecular interactions that stabilize a folded-back, off state of myosin. This results in an increase in the number of heads functionally accessible to interact with actin, which in turn may lead to hyper-contractility. In this proposal, the effects of HCM-causing point mutations in different regions of human -cardiac myosin and myosin binding protein C will be explored to determine if disruption of the off-state is a common mechanism driving HCM. A small molecule direct cardiac myosin inhibitor was recently approved to treat a subset of HCM patients. It is thought to work, at least in part, by stabilizing the folded back, off-state. Whether HCM mutations that affect the stability of the folded back state alter the efficacy of the drug will be tested, as variable clinical responses to the drug have been reported. The effects of HCM mutations on the efficacy of two other drugs in clinical trials/development that inhibit myosin in different ways will be compared as well. Finally, a variety of approaches will be employed to determine the effects of both HCM mutations and small molecule myosin inhibitors on the high-resolution structure of the myosin motor domain and the structure of the folded-back state of myosin, including X-ray crystallography and cryo-electron microscopy. FRET probes will be placed on normal and mutant -cardiac myosin to observe the effects of HCM mutations on the transition between the on-and-off states in the presence and absence of the cardiac myosin inhibitors. These studies will provide important insights into the disease pathogenesis of HCM and the efficacy of small molecule myosin inhibitors in treating the underlying molecular pathology.

NIH Research Projects · FY 2026 · 2026-03

Project Summary/Abstract My long-term goal is to understand what determines the 3D folding of our genome in different cell types/states. In biology, it is well established that proteins must fold properly to function; so too must DNA fold properly to express the genes it carries. DNA folding is especially exciting because our genome (~6,000,000,000 base pairs) is much longer than even the largest protein (~30,000 amino acids). I previously solved the first 3D structure of the human genome in a single cell, and developed a series of single-cell sequencing technologies and algorithms to precisely measure genome-wide 3D structure and its associated modalities. While the field of protein folding has made substantial progress in the past decades, the principles of DNA folding has remained largely unknown beyond a handful of proteins. Because DNA folding controls gene expression and plays a critical role in both normal physiology and diseases, there is an urgent need for a comprehensive rulebook of DNA folding. A major bottleneck is that of technology: In contrast to the power and throughput of 3D genome measurement tools including mine, 3D genome perturbation has remained extremely laborious and mostly done one protein or DNA element at a time. This severe lack of perturbative tools and data has led to a poor understanding of the fundamental physical and chemical principles of DNA folding. To fill in this technology and knowledge gap, in the next five years, my research program will substantially expand the boundaries of current 3D genomics research by enabling systematic, large-scale genetic and chemical perturbation screens with single-cell whole-genome 3D structure and transcriptome as the phenotype, and learning from this rich, first-of-its-kind data the physical and chemical principles of genome-wide DNA organization through integrative analysis. For this goal, I will combine my high-precision single-cell 3D genome measurement technologies with recent advances in multiplex genetic and chemical screens—whose phenotype has so far been limited to either the transcriptome or a very low-dimensional representation of the 3D genome. My creative combination of concepts across disciplines will lead to three new technologies and algorithms that are uniquely capable of systematically identifying proteins, small molecules, and DNA sequence variants, respectively, that determine DNA folding. By developing these tools in cell cultures and applying them to the mouse brain in vivo, where I recently discovered life-long, cell type–specific 3D genome restructuring, my proposal will chart the rulebook of genome architecture: which protein/small molecule/DNA sequence variant folds the genome of which cell type in which way. My tools and data will have a broad impact on the fundamental biology of gene expression far beyond the cells and tissues studied here, by creating an “AlphaFold for DNA” that is widely applicable to many types of cells and thus to many areas of biomedicine such as cancer and immunology, paving the way for precision 3D genome medicine for developmental and degenerative disorders.

NIH Research Projects · FY 2026 · 2026-03

Project Summary Modern genome sequencing has shown that many species exchange genes with their close relatives through a process known as hybridization. As a result, the genomes of modern species are a mosaic of regions derived from past hybridization. Because of this, many species including our own must contend with the potentially negative consequences that can arise from mixing two divergent genomes. One of these negative consequences is the exposure of “hybrid incompatibilities” or genes that do not interact properly in hybrids. Uncovering the evolutionary forces that drive the formation of these hybrid incompatibilities is crucial to understanding how the genomes of modern species function. Although this is an important question, we have rarely been able to identify the genetic architecture of hybrid incompatibilities in vertebrates and lack the empirical data needed to understand what predisposes certain genes or genomic regions to negative interactions in hybrids. My postdoctoral research will investigate the evolution of a repeatedly evolved hybrid incompatibility in fish species where hybrid offspring from multiple crosses develop melanoma. I will combine classical genetic crosses, population genomics, and state-of-the-art functional genomic techniques to generate a comprehensive model of how hybrid incompatibilities evolve. In Aim 1, I will perform multiple genetic mapping crosses to identify genomic regions that drive hybrid melanoma. In Aim 2, I will characterize structural variation in the genome and its functional consequences on pigmentation genes involved in hybrid melanoma. Finally, in Aim 3, I will complement this work with a comparative genomic and transcriptomic approach to investigate how genes controlling pigmentation function within gene regulatory networks and become disrupted in hybrids with melanoma. Together, these approaches will give us unprecedented insights into how hybridization has shaped our genomes and the repeated origin of an evolutionarily and biomedically important phenotype. My primary goal under this NRSA F32 fellowship is to receive the scientific and professional training I need to establish my own independent research lab that unites molecular and computational biology with cutting-edge genomic approaches to establish models for how evolutionary processes shape genome content and function. As a postdoctoral fellow in the Schumer and Petrov labs at Stanford University, I will receive training in cutting-edge genomic techniques and analytical approaches. In addition to my scientific training, I will strengthen the professional skills needed to establish my future lab including grantsmanship, network building, and mentorship. In sum, with the training I will receive under this fellowship, I will be poised to lead a research program with great power to link molecular mechanisms to evolutionary outcomes and connect genotypes to phenotypes at the molecular and organismal level.

NIH Research Projects · FY 2026 · 2026-02

Project Summary Host-adapted Salmonella enterica strains cause systemic infections and can persist in granulomas within host tissues for extended periods. Often asymptomatic, persistently infected hosts act as crucial reservoirs, silently transmitting the pathogen to new hosts. From a bacterial perspective, maintaining a persistent state is vital for survival in natural settings. Despite this importance, the molecular mechanisms governing Salmonella persistence and host-to-host transmission remain elusive. A clearer understanding of these processes could pave the way for pharmacological eradication of the Salmonella carrier state. Our overarching goal is to unravel how Salmonella enterica serovar Typhimurium (STm) maintains persistence in mammalian tissues, aiming to identify host pathways for preventive and therapeutic innovations. This proposal’s objective is to uncover how STm achieves persistence in mammalian tissues, with the aim of identifying host pathways amenable to preventive and therapeutic strategies. Specifically, we will examine granuloma dynamics and STm survival mechanisms in mesenteric lymph nodes (MLN). The primary objective of this research is to comprehensively characterize dynamics of STm colonization of MLN and to elucidate eosinophil functions that impact pathogen persistence. This will be investigated by examining the interactions between eosinophils and STm, both in vitro and in vivo (Aim 1), and exploring immune-pathogen interactions within distinct MLNs through spatial transcriptomics and immune profiling (Aim 2). Additionally, we aim to characterize the immunoregulatory functions of eosinophils that influence STm persistence in MLNs (Aim 3). Through these efforts, we aim to reveal critical insights into the interplay between host immune pathways and persistent Salmonella infections, informing future strategies to combat chronic bacterial carriage.