University Of California, San Diego

NIH Research Projects · FY 2026 · 2026-05

SUMMARY Metabolic adaptation is recognized as a critical step for regulating macrophage function during inflammation onset and resolution. Metabolic dysfunction in macrophages leads to devastating outcomes including persistent infections, and chronic inflammatory and autoimmune disorders. While significant progress has been made in understanding how metabolism drives macrophage activation, and evidence show that targeting metabolic routes reappoints uncontrolled inflammation, the understanding of how mitochondrial proteins and mtDNA replication participate in bioenergetic and metabolic adaptation in activated macrophages remains incomplete. In this project, we are establishing a new role for CMPK2, a mitochondrial cytidine/uridine monophosphate kinase involved in mtDNA synthesis and the anti-viral nucleotide analog ddhCTP, in metabolic and bioenergetic adaptation during macrophage activation. Our compelling preliminary data support the overarching premise that the strong induction of CMPK2 by danger signals upholds a proinflammatory phenotype by enabling bioenergetic and metabolic adaptation. We hypothesize that CMPK2-dependent mtDNA synthesis sustains ATP production through both OxPhos and glucose oxidation, aiding metabolic adaptation and accumulating glycolysis and TCA cycle metabolites key for the inflammatory response (lactate, succinate, itaconate). CMPK2-driven mtDNA synthesis maintains mitochondrial dynamics and fuel flexibility that support residual OxPhos and ATP output (Aim 1). This process preserves NADH and NAD+ balances needed to support glycolysis. Hence, CMPK2 ablation, which further reduces NAD+, inhibits glycolysis and diverts glucose towards the PPP pathway producing NADPH required to catabolize arginine into nitric oxide, which may further restrain glycolysis through S- nitrosylation of GAPDH (and/or other metabolic enzymes) (Aim 2). We will use myeloid-specific CMPK2 knockout mice, primary mouse and human macrophages, genetic (dPCR, RNAseq), bioenergetic (Seahorse Bioanalyzer), and metabolic (GC/MS, stable isotope tracing, 1D 1H-NMR), and imaging (live cell and lattice sheet microscopy (LLSM) and MitoTNT) tools to study mitochondrial and metabolic adaptation during the induction and resolution of the inflammatory response in vitro and in vivo. Together, these studies will broaden our understanding of the contribution of CMPK2 induction and mtDNA synthesis to metabolic adaptation in macrophages and other cells with enhanced CMPK2 expression. We are optimistic that these findings will contribute to the development of innovative strategies to regulate innate response control, laying the foundation for future immunometabolic therapies. The discoveries generated in this project will have broad implications for human conditions linked to inflammation driven by macrophages and other immune cells.

NIH Research Projects · FY 2026 · 2026-05

1 Project Summary 2 3 Understanding the spatial and temporal organization of intracellular proteins is critical for advancing 4 biomedical research, particularly in disease diagnostics, personalized medicine, and drug discovery. 5 My research program focuses on detecting and quantitatively characterizing spatial patterns across 6 biological scales, from intracellular to tissue-level organization, to uncover the mechanisms driving 7 these patterns and their roles in both physiological function and disease. We focus on developing 8 computational tools to infer cell types and states from hidden symmetries and intracellular 9 organization. While omics approaches like transcriptomics and proteomics advance molecular 10 characterization, they fail to capture the temporal dynamics of cell state transitions. Additionally, 11 cellular functions are often directly linked to the spatiotemporal organization of intracellular proteins, 12 an aspect not addressed by molecular -omics techniques. To bridge this gap, we propose the 13 "Intracellular Protein Organization Landscape" (iPOL), a quantitative framework that defines 14 and characterizes cell types and states based on their spatial protein organization, rather than 15 molecular composition. iPOL integrates high-resolution imaging, feature extraction, and manifold 16 learning to map cell types in a new "protein organization morphological space." Our research aims to 17 answer three key questions: (1) Can iPOL quantitatively characterize cell state transitions during 18 processes like epithelial-to-mesenchymal transition (EMT)? (2) Does intracellular organization reveal 19 hidden aspects of cell type differentiation? (3) Do intracellular asymmetries encode positional 20 information during development? To address the first question, we will construct the iPOL for EMT in 21 development, wound healing, and cancer metastasis to quantitatively characterize, compare and 22 discover mechanistic differences between the cell state transitions in different biological contexts. To 23 address the next two questions, we will use early development in sea urchin as a model system to 24 interrogate how iPOL can reveal new cell states and spatiotemporal dynamics in their native contexts. 25 The conceptual innovation of this work is the development of iPOL as a novel framework to define 26 cell states and types based on cellular phenotype rather than molecular composition. The technical 27 innovation lies in leveraging higher-order morphological, topological, and symmetry-based metrics 28 to capture complex intracellular structures that more directly reflect cellular function. By integrating 29 spatial and temporal protein localization patterns with molecular data, iPOL offers a transformative 30 perspective on cellular function and behavior, with broad implications for understanding diseased 31 cellular states and advancing medical diagnostics through high-resolution imaging techniques.

NIH Research Projects · FY 2026 · 2026-05

Project Summary Aging leads to a variety of changes at the subcellular level, including structural and functional alterations to the nuclear envelope and conversely, genetic defects affecting the nuclear envelope trigger premature aging. Autophagy becomes critical during aging to recycle unneeded or damaged cellular components and to lower the biosynthetic capacity to conform to reduced cellular demands. The nucleus is central in this regard as it represents the site of DNA replication, RNA transcription, ribosome assembly and lipid synthesis. We will focus on the molecular mechanism of nucleophagy: the autophagic degradation of regions of the nuclear envelope. Impaired nucleophagy, like impaired autophagy, leads to premature cell death during chronological aging. Using a systematic, unbiased, genetic screen we have found that deletion of a gene encoding a constituent of the nuclear envelope causes a tight block in the autophagic degradation of an outer nuclear membrane protein, Hmg1. We will test the role of this novel component on a variety of autophagic pathways to define the range and specificity of its function. Autophagic degradation of Hmg1 relies on the selective autophagy receptor, Atg39. Preliminary data suggests that the deletion mutant blocks delivery of Atg39 to the vacuole in response to nutrient limitation. The Atg39 delivery pathway has been defined at a morphological level and several biochemical and visual landmarks on this pathway have been reported. To identify the site of action of this novel component on the Atg39 pathway we will test the deletion mutant for its effect on the ultrastructure of the nuclear envelope at sites of Atg39 foci during nucleophagy and on key landmarks along the pathway. We will probe for interactions with Atg39 using a coprecipitation protocol and will test the effects of the deletion mutant on chronological aging using two independent assays.

NIH Research Projects · FY 2026 · 2026-05

The overall goal of this K24 application is to provide protected time to enhance my capabilities and mentor the next generation of researchers in patient-oriented research (POR) on the intersection of substance use and HIV. Clinical research examining the combined effects of substance use and HIV is of significant public health concern. People with HIV (PWH) on antiretroviral therapy (ART) continue to experience persistent immune activation and inflammation that increases risk of central nervous system (CNS) dysfunction. Substance use is highly prevalent in PWH and linked to behaviors that increase risk for HIV transmission and may worsen HIV disease and clinical (e.g., neurobehavioral) outcomes. Methamphetamine (METH) and cannabis are two widely used substances by PWH with potentially opposing effects on the CNS. Estimates of their co-use reach up to 50%, though few clinical studies have investigated their interaction on CNS or health outcomes, and even fewer have investigated the underlying biological mechanisms. To address these gaps, the proposed K24 will support trainee integration into active NIH-funded studies of individuals with and without HIV and/or substance use. Under structured mentoring and Individual Development Plans, trainees will gain investigator-level training in study design and implementation, recruitment and informed consent, clinical and neurobehavioral assessment and interpretation, data and biospecimen quality assurance, multimodal data integration and analyses, professional development, and research dissemination. K24 research projects will leverage data collected from active, ongoing studies and retrospective assessments, which collect comprehensive neuromedical, laboratory, psychiatric, neurocognitive, and everyday functioning outcomes, to identify and characterize clinical-biological profiles of CNS dysfunction in HIV and substance use disorders. Mentees will benefit from the rich training environment of the HIV Neurobehavioral Research Program and the Center for Medicinal Cannabis Research (HNRP-CMCR), with access to infrastructure and a wealth of data and specimens collected by active and completed HIV and substance use focused NIDA-funded research projects. In addition to one-on-one structured training, mentees will also have opportunities through UCSD-wide seminars and UCSD’s NIDA-funded T32 Training in Research on Addictions and NeuroAIDS (for which I serve as MPI). My active studies are well suited to support POR research aimed at identifying clinical-biological profiles of CNS outcomes in HIV, METH, and cannabis with high potential for clinical translation. Research projects proposed in this K24 are designed to address critical gaps in the field that are high priorities for NIDA and OAR and to serve as platforms for mentored training. Trainees will be recruited and matched to these projects according to their career goals, prior experience, and commitment to POR. Through structured one-on-one, investigator-level training, this K24 will enable mentees to build the skills needed to establish independent clinical research programs while contributing to advances in this high-priority field.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY/ABSTRACT Cannabis use among parents has increased rapidly in the past 10 years. In 2023, 7.8% of parents in the U.S. used cannabis on the majority of days, 4.9% used cannabis every day, and 5.7% met criteria for Cannabis Use Disorder (CUD). Cannabis use has acute effects on neurocognition, mood, and behavior that would plausibly affect the parenting of young children. However, research on substance use and parenting has focused largely use of alcohol and hard drugs, not cannabis. This project will use an ecological, within-person design to study the acute effects of cannabis on parenting. We will recruit 190 parents who routinely use cannabis (≥4 days per week) and have a child ages 3-6 years old. We focus on parents of young children because parenting a younger child is more demanding, and thus more likely to be affected by acute use. First, the parent will complete a baseline visit to gather data about how they approach cannabis use around their child and characterize the sample. Second, the parent will complete a 21-day ecological momentary assessment (EMA) protocol designed to repeatedly measure parenting behavior when using vs. not using cannabis (5 surveys per day). Within the 21-day EMA period, the parent will also complete a videotaped, in-home, ecologically valid parent-child interaction task on 2 different days, once shortly after using cannabis and once when not having used. Masked coders will use a validated scoring system to measure behavioral and emotional aspects of parenting linked to healthy child adjustment. Ratings of subjective intoxication and measures of products’ putative THC/CBD content will be collected throughout the study to characterize dose-response. Aim 1: Describe how parents who routinely use cannabis approach cannabis use with children Aim 2: Determine the acute effects of cannabis use on parenting behavior Aim 3: Test potential moderators of the acute effects of cannabis use on parenting The team has expertise in cannabis, parenting, & child mental health and experience leading both intensive EMA studies of cannabis use and in-home assessments of parent-child interactions. This project will yield rigorous evidence on the acute effects of cannabis use on parenting. This evidence will be useful for parents, clinicians, and the public health conversation around cannabis.

NSF Awards · FY 2026 · 2026-05

Correct compilation is essential to scientific computing, as it provides the bridge from high-level algorithms in source code to computing machinery. LLVM is a critical backbone in this process, powering compilers and infrastructure for languages including Julia, Python, and Fortran. However, the engineering of LLVM has focused on improving general-purpose code, with relatively little attention given to the particular needs of scientific computing. The central question of this project is: Can compiler infrastructure be redesigned so that scientists can express and statically enforce the complex physical and mathematical constraints that define their work? For example, scientists interested in proving positivity for an advection-diffusion-reaction system should be able to do so statically, though the use of tools that lower the burden of proof. The project's novelties are methods to incrementally synthesize domain-specific and program-specific static analyses. The project's impacts are to integrate correct static analyses into a widely-used compiler, thereby enhancing the work of a broad community of scientists. Ultimately, the goal of this research is a compiler development process in which scientists specify what they want and tools generate the how automatically. This research consists of three technical thrusts toward a new, synthesis-based foundation for compiler construction: (1) synthesizing analyses one transformer at a time, through stochastic search and SMT-based verification; (2) creating semantic MLIR dialects for scientific computing domains, namely floating-point numbers and tensors; and (3) developing project-specific techniques to strengthen correctness claims. A key idea is to model traditionally-manual compiler components as compositions of semantic program transformers: small programs that summarize how instructions behave or how they can be replaced without changing observable behavior. These transformers are learned from examples, specifications, or profiling data, using a combination of symbolic reasoning and abstract interpretation. 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 ABSTRACT The work proposed here aims to advance our understanding of how cells ensure accurate inheritance of the replicated genome during cell division and to investigate newly discovered functions of the chromosome segregation machinery in embryonic development. A critical goal during cell division is to prevent errors in chromosome segregation, which can contribute to tumorigenesis, drive therapeutic resistance in cancers, and cause birth defects. Chromosomes are segregated to daughter cells by a microtubule-based spindle. The focus of our work is on kinetochores—specialized protein machines that assemble on mitotic chromosomes to create dynamic connections with spindle microtubules and facilitate chromosome segregation. The movement of chromosomes on the spindle requires the microtubule-bound kinetochores to transition between polymerization- coupled and depolymerization-coupled states. In prior work, we characterized the hierarchical assembly of kinetochores and how they utilize dynamic couplers that harness the free energy associated with microtubule dynamics, along with localized microtubule motor proteins, to orient and move chromosomes. This application builds on these prior studies, focusing on three key areas. In Area 1, we address a key knowledge gap: understanding how spindle structures, like centrosomes and pole-adjacent microtubules, communicate with kinetochores to help them sense their position on the spindle and regulate their state (polymerization-coupled or depolymerization-coupled) to control chromosome movement. Specifically, we will focus on how the spindle pole-localized kinase Aurora A functions with its activator TPXL1 (a homolog of human TPX2) to control kinetochore-microtubule attachments and allow them to exit a depolymerization-coupled state that would otherwise reel the spindle poles into the chromosomes, causing spindle collapse and segregation errors. In Area 2, we will use an in vivo approach we developed that isolates the three main interfaces between mitotic chromosomes and spindle microtubules to investigate the chromosome-spindle microtubule attachment machinery and its regulation. In the final area, we will pursue an intriguing observation that specific kinetochore machinery is important for embryo elongation, the process that transforms a “ball of cells” into an elongated shape during embryogenesis. We will build on our recent finding that the kinetochore protein BUB1 is essential in the post-mitotic embryonic epidermis to allow embryo elongation, by taking advantage of our ability to manipulate function in specific embryonic tissues to elucidate the underlying mechanism. All three areas will be pursued in parallel, are built on strong foundations, and will address major open questions while promoting the career development of a diverse group of trainees.

NIH Research Projects · FY 2026 · 2026-05

Host inflammation drives adaptive evolution in gut bacteria Summary Inflammatory bowel disease (IBD) has long been associated with compositional and metabolic changes in the gut microbiota, yet extensive research efforts have failed to identify a single pathogenic microorganism as the causative agent. Here, I hypothesize that gut inflammation facilitates adaptations in commensal bacteria that further exacerbates disease in IBD. Exposure to gut inflammation exposes bacterial strains to reactive oxygen species (ROS), creating a hostile environment that drives microbial adaptation. I will use the human commensal Bacteroides fragilis as a model system, as this gut-resident bacteria is known to promote anti-inflammatory responses during steady-state. Although traditionally considered a strict anaerobe, B. fragilis has a unique ability to tolerate and even utilize nanomolar concentrations of oxygen. In addition, it can acquire metabolic adaptations due to the strong selective pressures of oxidative stress which enable its persistence in the intestine despite the extreme inflammatory environment. Whether these subsequent changes alter its metabolic output and host interactions remains unexplored. Thus, there is a critical need to understand how the inflamed gut environment shapes commensal bacteria metabolism. We hypothesize that gut inflammation induces specific adaptive responses in B. fragilis, altering its immunomodulatory functions and metabolic output to worsen IBD symptoms. The goal of this proposal is to elucidate how gut inflammation drives adaptations in B. fragilis, and whether these adaptations contribute to disease progression in IBD. To achieve this goal, I will evolve B. fragilis strains using in vitro and in vivo models of inflammation, characterize the transcriptional and metabolic responses of B. fragilis to inflammatory conditions, and assess the functional changes in evolved B. fragilis strains and their subsequent impact on gut inflammation. The findings of this study will significantly advance our understanding of microbial dynamics in IBD, with broad implications for microbiology, immunology, and the development of therapeutic strategies targeting the gut microbiota.

NSF Awards · FY 2026 · 2026-05

This award will support the conference "When Analysis Meets Geometry", to be held in Santa Cruz, California, from May 18 - 21, 2026. The conference will feature approximately 20 invited lectures by leading international experts in analysis and differential geometry. Its primary goal is to bring together researchers of international stature to present recent advances at the forefront of these closely connected fields. The meeting will also provide valuable opportunities for early-career researchers to present their work and to engage in meaningful interactions with senior mathematicians. The conference focuses on cutting-edge developments at the intersection of geometry and analysis, highlighting recent breakthroughs across several key themes. In recent years, there have been tremendous breakthroughs and groundbreaking results in various directions, including geometry of Einstein metrics, geometric flows, fully nonlinear PDEs in differential geometry, geometric scattering theory and applications, and other areas. By fostering dialogue across these areas, the conference aims to stimulate new collaborations and generate innovative research directions. In addition to disseminating significant mathematical advances, the event places strong emphasis on professional development and research training for graduate students, postdoctoral scholars, and junior faculty. Here is the website link to the conference: https://sites.google.com/view/capitola2026/home 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 Selective autophagy pathways use cargo receptors to degrade organelles, organelle subdomains, and misfolded proteins that fail to be degraded by the proteosome. Endoplasmic reticulum (ER) autophagy (also called ER-phagy) is a selective autophagy pathway that acts in ER quality control. ER-phagy cargo receptors connect an ER domain to the autophagosome biogenesis machinery via their ability to bind Atg8 family members (LC3 or GABARAP in mammals). The studies in this proposal are aimed at addressing two important unanswered questions in the field. First, we will ask how the conserved yeast ER-phagy cargo receptor, Atg40, fragments domains of the ER that it targets for degradation. Second, we will ask how Atg40 loads ER domains into autophagosomes, sealed double-membrane structures that are delivered to vacuoles (yeast) or lysosomes (mammals) for degradation. We have found that a non-canonical form of the yeast COPII coat subcomplex, Sec23-Lst1, works with Atg40 to package ER domains into autophagosomes during ER-phagy. The COPII coat is a multi-subunit coat complex that is known for its role in sorting ER proteins into transport carriers that traffic on the secretory pathway. We identified a novel role for Sec23-Lst1 in ER-phagy that is independent of its role in secretion. While the reticulon homology domain of Atg40 has been implicated in ER fission, it is unclear if Atg40 requires Sec23-Lst1 to fragment ER domains. An in vitro approach is needed to unambiguously answer this question. We have found that a variation of the COPII coat in vitro vesicle budding assay can be used to assess the requirements for Atg40-mediated ER fission. The COPII coat is formed by the sequential interactions of the Sar1 GTPase and cytoplasmic coat subcomplexes. We will use this in vitro assay to address if Atg40, Sec23- Lst1 and Atg8 are all needed for fission. Additionally, we will determine if purified Sar1, and other purified cytoplasmic COPII subcomplexes are also required. A long-term goal of these studies is to develop a similar in vitro ER fragmentation assay with mammalian COPII coat subcomplexes. To address how Atg40 sequesters membrane domains into autophagosomes, we will take advantage of an unusual phenotype we observed in lipid droplet (LD) deficient cells. Lipid droplets are ER-derived organelles that contain a neutral lipid core, triacylglycerides (TAG) and sterol esters (SE), surrounded by a phospholipid monolayer. When yeast cells are devoid of LD, resident ER membrane proteins fail to be delivered to the vacuole via ER-phagy. This defect appears to be due to the inability of the cargo receptor, Atg40, to sequester ER domains into autophagosomes. We will perform biochemical, genetic and localization studies to ask how LD are needed to couple Atg40 to its cargo. A long-term goal of these studies will be to address the role of LD in mammalian ER-phagy. These studies will be relevant to variety of metabolic disorders in humans, including diabetes and obesity.

NSF Awards · FY 2026 · 2026-05

With support from the Chemical Structure and Dynamics (CSD) and Chemical Measurement and Imaging (CMI) programs, Professor Shaowei Li of the University of California-San Diego is investigating how the local surface structure and nanoscale environment control the chemical reactivity of individual molecules. Chemical reactions on surfaces underpin technologies ranging from catalysis to semiconductor manufacturing, yet most experiments measure billions of molecules at once, masking the unique behavior of any single one. At the smallest scales, tiny variations in the arrangement of surface atoms, local electric fields, or nearby molecules can dramatically change how chemical bonds vibrate and break. Watching specific chemical bonds is exceptionally challenging because it requires imaging atoms within a molecule while simultaneously detecting their vibrational motion. Professor Li and his students will combine a scanning tunneling microscopy (STM) with vibrational spectroscopy to observe and manipulate the motion of atoms in single molecules with sub-molecular precision. Their discoveries could advance our fundamental understanding of surface chemistry and enable new strategies for controlling chemical reactions at the atomic scale. The project will also contribute to the development of a STEM workforce by providing interdisciplinary training in nanoscience and quantum measurement. The project will employ STM-based vibrational spectroscopy to characterize bond-resolved vibrational fingerprints of individual molecules adsorbed on well-defined surfaces. By systematically tuning molecule–substrate interactions, tip-induced electric fields, coordination geometry, and charge transfer, the team will quantify how local potentials reshape vibrational energy landscapes and reaction coordinates. The research further explores strong coupling between molecular vibrations and other quantum degrees of freedom, including intermolecular vibrational coupling and vibrational polariton formation within the confined optical cavity of the STM junction. These studies aim to create hybrid eigenstates that selectively enhance or suppress specific reaction pathways, providing a platform for bond-selective control of surface reactions. Together, these efforts integrate high-resolution spectroscopy, atomic-scale manipulation, and quantum-state engineering to establish a predictive framework for understanding and controlling chemical dynamics in nanoscale environments. 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

ABSTRACT Solid organ transplantation has transformed care for patients with end-stage organ failure, dramatically improving survival and quality of life. In 2024, over 48,000 transplants were performed in the United States. Despite advances in immunosuppressive regimens, allograft rejection remains a major barrier to long-term graft survival, with 25–50% of recipients experiencing rejection. While effective at reducing early rejection, current immunosuppressive therapies carry significant long-term toxicities and have not meaningfully extended graft survival. This has driven the search for safer alternatives to promote immune tolerance. Adoptive transfer of regulatory T cells (Tregs) offers a promising immunomodulatory strategy to promote graft tolerance while minimizing systemic toxicity. However, without tools to monitor Treg trafficking and functionality, it is challenging to assess treatment efficacy or optimize therapeutic strategies. Magnetic resonance imaging (MRI) is ideally suited for this purpose—it is widely available, radiation-free, and capable of high-resolution imaging of labeled cells. Conventional MRI-based cell tracking relies on exogenous contrast agents such as iron oxide or fluorine compounds, which require labor-intensive labeling protocols often involving non-FDA-approved transfection agents that may impair cell viability or function. These challenges limit clinical scalability and regulatory approval. We propose a fundamentally different approach: the magnetic microbeads used in the process of Treg purification from blood leukapheresis will directly label the target cells, producing proton (1H) MRI contrast. Our goal is to develop magnetic resonance imaging methods to capture tolerogenic cell therapy fate in preclinical and ex vivo human transplant models. We propose the following aims: AIM 1 will capture longitudinal Treg activity in a murine transplant model. We will isolate and label mouse Tregs with CD25/CD4 beads, evaluate phenotype and cytokine expression, and infuse them into matched and mismatched skin and heart graft models to confirm preferential homing of injected Tregs in matched skin transplants via MRI followed by histopathology correlation. AIM 2 will evaluate immunomodulatory cell trafficking and imaging feasibility in a clinically relevant ex vivo human organ model. We will infuse microbead-labeled Tregs into discarded donor organs maintained on normothermic perfusion pumps. This platform will enable us to investigate critical questions about Treg and other immunomodulatory cell behavior post-infusion, including their distribution patterns, retention over time, and interaction with vascular and tissue compartments. This work will enable real-time monitoring of therapeutic cell fate, improve patient-specific immunosuppression strategies, and accelerate safe translation of Treg-based therapies for transplantation, autoimmunity, and beyond.

NIH Research Projects · FY 2026 · 2026-05

Abstract The development of prime editing has allowed for genome manipulation with user-defined insertions, deletions, or single-nucleotide conversions, without installing harmful double-stranded breaks in the genome.5 This has revolutionized the genomic medicine field, with companies like Prime Medicine, Inc. now using prime editing in human clinical trials. Despite its versatility, prime editing often results in lower editing efficiencies for larger edits, and the nuances of how insertion and deletion edits are installed by prime editors are not well understood. 5,6,7,8 Past genomic mechanistic studies of prime editing have identified DNA mismatch repair (MMR) as a negative regulator of point mutation introduction9; however, MMR does not process loops or bulges larger than 16 nucleotides, which would be utilized to install large insertions and deletions by prime editing.10,11,12 Therefore, the mechanism(s) by which the cell processes prime edits larger than 16-nt is unexplored. While traditional prime editing often becomes hindered by longer edits, “paired” prime editing techniques can facilitate larger genome modifications by replacing a sequence between two nick sites. 8,13 More thorough understanding of the DNA repair pathways will improve both traditional and paired prime editing. Aim 1 of this proposed project will develop a “dead” fluorescent reporter that is corrected by a large genomic modification by either traditional or paired prime editing. The reporter will be utilized in Aim 2, in which a high-throughput Cas12 knockout screen will be used to identify the repair pathways involved in processing large edits by traditional and paired prime editing. DNA damage repair genes will be knocked out, and K562 cell lines constitutively expressing the developed reporter and prime editor system will be separated by editing efficiency via fluorescent activated cell sorting (FACS), high-throughput sequencing (HTS), and large-scale bioinformatics data processing. In Aim 3, the results from the genomic screen will be validated through testing at multiple endogenous sites and in various cell types to ensure reproducibility and rigor in identifying hit genes. With an increased understanding of traditional and paired prime editing, the resulting gene hits will be incorporated into novel prime editor systems to increase editing efficiency for longer edits, which can fill gaps on treating all genetic disease. Additional knowledge of what repair pathways process large edits will also add to the DNA damage repair field, enriching understanding on structure and biology of genomes. Ultimately, the proposed training plan is set to advance the PI’s technical foundation of genomic, high-throughput screening methods, as well as provide steps to develop professional skills, leadership, and scientific independence for a future in academic research. It will be supported by the sponsor Dr. Alexis Komor and UCSD’s Chemistry and Biochemistry department, in consortium with the many UCSD and Sanford core research facilities that will provide the necessary FACS, HTS, and supercomputing instruments.

NIH Research Projects · FY 2026 · 2026-04

Chronic phantom limb pain (cPLP) is a debilitating chronic pain disorder that is experienced by up to 64% of the 356 million people with amputations worldwide. The prevalence of cPLP is rapidly rising due to the increased incidence of severe diabetes mellitus and vascular diseases. The primary symptom of cPLP is pain, which, in the majority of cases, is severe, treatment resistant and consequently signifies the importance of developing fast acting cPLP treatments. Chronic pain severity and corresponding comorbidities are driven by amplified sensory, self-referential, and negative affective interactions that intensify the transition of acute to chronic pain. Thus, pain therapies that reliably target nociceptive specific and affective mechanisms may produce durable improvements in pain symptomology and well-being. The recent “psychedelic renaissance” has generated wide-reaching interest into the potential efficacy of psilocybin as a pain therapeutic. Psilocybin (4-phosphoryloxy-N, N-dimethyltryptamine), a hallucinogenic drug that modifies self-referential processes, has shown promise at reducing cPLP. Mechanistic appreciation of if and how psilocybin modifies pain is needed. The default mode network (DMN), a midline cortical neural network supporting egocentric and affective pain appraisals, has been revealed as a neural target for chronic pain and psilocybin. Yet, the analgesic effects and supporting brain mechanisms through which psilocybin can modulate chronic pain are unknown. The proposed research activities will significantly expand our understanding of the impact of psilocybin on chronic pain and the corresponding neural mechanisms. In a recently completed pilot clinical trial, 25mg of psilocybin (n = 5) was found to be a safe and feasible treatment for cPLP as compared to niacin (100mg; n = 4). Importantly, four weeks after dosing, psilocybin was associated with reductions in weekly cPLP (- 43%). In contrast, the niacin group exhibited no change in cPLP four weeks after dosing as compared to baseline. Weaker resting state functional connectivity (rsFC) between the DMN and thalamus predicted greater psilocybin-based cPLP relief 4 weeks after dosing. The proposed R01 application will expand on our pilot study and aims to identify the neural processes supporting the effects of psilocybin on cPLP. In the proposed mechanistic clinical trial, 60 patients with lower limb amputations and cPLP will be recruited and randomized to receive double blind administration of 25mg psilocybin (n=30) or 50mg niacin (n=30) after completing baseline assessments. “Past week” cPLP will be assessed at baseline and 1 day, 2-, 4- and 12-weeks post-dosing. Functional MRI will be acquired at baseline, and 1 day and 4 weeks post-dose. We hypothesize that psilocybin induced cPLP relief will be associated with weaker DMN–thalamic rsFC four weeks after dosing when compared to baseline. Exploratory analyses will also test if psilocybin elicits greater cPLP relief when compared to niacin. The knowledge gained from the proposed work will provide novel mechanistic understanding of psilocybin-induced cPLP relief.

NIH Research Projects · FY 2026 · 2026-04

ABSTRACT The development of the cerebral cortex is one of the most intricate processes in neurobiology. Disruptions to this complex and highly regulated process are central to neurodevelopmental disorders (NDDs), which collectively impact an estimated 317 million individuals globally. Adenosine-to-inosine (A-to-I) RNA editing, catalyzed by the ADAR (adenosine deaminase acting on RNA) family, has emerged as a potent regulator of post-transcriptional gene regulation in the brain. A-to-I editing is highly dynamic in the developing human brain and has been implicated in a range of NDDs, including autism, schizophrenia, and epilepsy. A growing body of evidence suggests editing may contribute to neuronal maturation, synaptic regulation, and the diversification of the brain transcriptome. Yet, a single-cell resolution map of A-to-I editing and direct evidence of essential ADAR function during human corticogenesis have never been achieved. This proposal presents a comprehensive and mechanistically focused investigation into how editing shapes transcriptional and translational landscapes during human cortical development. It represents the most comprehensive and detailed investigation of A-to-I RNA editing in the developing human brain to date (Aim 1). I propose to map the RNA editome at unprecedented scale: across over 2.3 million cells from both fetal brain tissue from 26 individual donors and human cortical organoids. This work will reveal cell type- and lineage-specific editing programs and evaluate the fidelity of organoids in modeling A-to-I editing dynamics. This work will be achieved without cell sorting or complex tissue pre-processing prior to sequencing with MARINE, a first-in-class computational tool for detecting editing that preserves single-cell resolution. Additionally, this proposal is the first systematic dissection of ADAR enzyme function in a complex human model of corticogenesis (Aim 2). To systematically evaluate the importance of the ADARs in corticogenesis, each ADAR is repressed in several cell lines engineered for CRISPR interference and ribosome-based translational profiling (Ribo-STAMP). ADAR-repressed cortical organoids are evaluated with several modalities to understand how ADAR shapes cell fate specification, lineage progression, and mRNA translation. The use of Ribo-STAMP provides the first transcriptome-wide readout of ADAR-dependent translation in the developing human cortex, revealing regulatory layers inaccessible by transcriptional profiling alone. By uniting high-resolution transcriptomic, translational, and morphological profiling in tractable human models, this study establishes a systems-level framework for decoding post-transcriptional regulation in the developing brain and lays critical groundwork for therapeutic advances in NDDs.

NIH Research Projects · FY 2026 · 2026-04

This application is focused on the study of bioengineered plant virus-based adjuvant and vaccine technology. We discovered that some plant viruses serve as potent adjuvants in the context of infectious disease and cancer vaccines/immunotherapy. Cowpea mosaic virus (CPMV) was identified as a uniquely potent adjuvant with distinct mechanism of immunomodulation compared to small molecule agonists, other plant viruses, or oncolytic viruses. Recently we discovered that systemic CPMV administration prior to tumor challenge protects mice from onset of tumor growth. Data indicate that the innate immune stimulation by CPMV is durable and lasts for weeks after CPMV exposure when innate cells would have returned to a homeostasis state – therefore data are consistent with induction of trained immunity. Single cell sequencing analysis of human PBMCs after CPMV adjuvant exposure indicates stimulation of interferon signaling pathways along with metabolic changes, and epigenetic rewiring – also consistent with a mechanism involving trained immunity. Together our data suggest that CPMV could act as an inducer of trained immunity – to date there are no reports on the study of plant viruses in trained immunity. Proposed studies will help elucidate the foundational principles that make CPMV a uniquely potent immunomodulator. We will fulfil the following specific aims: (1) We will establish the mechanism of CPMV as a training agent in vitro using immune cells followed by LPS challenge; longitudinal studies will be carried out and analysis will include measure of pro- inflammatory cytokine as well as CHiP and ATAC sequencing to confirm epigenetic rewiring and metabolic cell changes. Structure-function studies of bioengineered viruses will provide foundational insights into differential potency. (2) We will establish the mechanism of CPMV as a training agent using the B16F10 tumor model using WT and Rag 1 vs CCR2 knockout (KO) mice to delineate the role of adaptative vs. innate immune cells (β-glucan will serve as benchmark). Hematopoietic stem cells (HSCs) and multipotent progenitors (MPPs) will be analyzed by single cell sequencing, CHiP and ATAC sequencing to delineate the mechanism of action. Studies will be paralleled with safety and biodistribution studies. (3) We will test the ability of the CPMV training agent to facilitate protection from influenza virus challenge; protection from influenza virus infection and pathology from CPMV will be benchmarked against FLUMIST and β-glucan. These studies could lay the foundation for continued and deeper studies of CPMV as an adjuvant technology towards the development of more broadly protective and efficacious vaccine formulations and immunoprevention strategies.

NIH Research Projects · FY 2026 · 2026-04

Project Summary. Polyketide natural products have provided critical therapeutics, and they will remain an important component of new drug discovery and manufacturing. This program aims to develop new technologies to enable the high resolution cryo-EM structural elucidation of Type I polyketide synthases (PKSs) isolated directly from natural producer organisms. To date these megasynthase proteins have proven challenging for structural biology studies due to significant technical challenges, including extremely large molecular weights, difficult heterologous expression and highly dynamic structural features. As such, very few structures have been reported, and most are at low resolution and do not represent full synthases. We have recently developed tools for dual site-selective crosslinking of PKSs that enforces dynamic constraint and has led to the collection of high- resolution cryo-EM structures in single-modular Type I PKSs. Here we propose the development of two key tools. The first will convert native holo-PKSs to their cognate apo- forms to enable crosslinking within native PKSs. The second is the development protein isolation methodologies for very large megasynthases (500 kDa to 2 MDa) from within native producer proteomes, such that the resulting isolated forms can be structurally elucidated by cryo-EM. The amphotericin synthase pathway from producer bacterium Streptomyces nodosus will serve as a model system for high-resolution structural analysis. Together these tools will offer a fundamental step-change in access to molecular detail of PKS megasynthase structure.

NSF Awards · FY 2026 · 2026-04

Quantum computing is a promising new paradigm for computation that could radically change our understanding of scientific phenomena in fields from medicine to chemistry. An implicit assumption in this claim is that quantum computers are more powerful than the (classical) computers that we have today. Somewhat surprisingly, however, mathematically proving the superiority of quantum computers is a longstanding and challenging question. The quest to prove this "quantum advantage" is not only important from a scientific perspective, but also from an economic one, since building and maintaining quantum computers is both difficult and expensive. This project lays out an ambitious program to methodically strengthen the theoretical foundations of quantum advantage. Namely, the project will develop new techniques to give irrefutable mathematical evidence that there are certain tasks that admit highly parallel quantum algorithms that cannot be parallelized with classical computers. In addition, the project describes a variety of educational initiatives that expand access to quantum computing both at the university level and for researchers outside of academia seeking to understand the theoretical underpinnings of this research program. The project addresses the following theoretical challenges: First, barriers in complexity theory have traditionally prevented claims of unconditional quantum advantage against arbitrary polynomial-time classical computation. Those barriers have not yet been reached in the low-depth setting, but to make progress, new lower bound techniques for models of low-depth classical circuits are required. Second, noise has always been a preeminent concern when scaling quantum experiments, preventing asymptotic quantum advantage in popular experiments such as random circuit sampling. In contrast, random constant-depth quantum circuits may still enjoy an asymptotic quantum advantage against constant-depth classical circuits in the presence of noise. This necessitates a more thorough understanding of the robustness of entanglement at these low depths. Finally, proofs of quantum advantage are often predicated on the structure of the underlying circuit topology. This project will develop concrete characterizations of the topologies that are amenable to these techniques. 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 support the 31st Southern California Geometric Analysis Seminar (SCGAS) to take place at UC San Diego on April 4-5, 2026. The SCGAS is an annual two-day conference that rotates between the University of California - Irvine and the University of California - San Diego. It will feature 7 lectures by world leading experts in Geometric Analysis and its applications. A major goal of the meeting will be to promote interactions among members of the southern California mathematics community and, more broadly, the American mathematical community working in the field of Geometric Analysis and related areas. Geometric Analysis is a central area of modern mathematics, with far reaching connections to Analysis, Geometry, Topology and Physics. Using analysis as its main tool with differential geometry, topology, and algebraic geometry as foundations, geometric analysis has solved a multitude of problems in global geometry, topology, several complex variables and mathematical physics. Over the years the SCGAS has successfully contributed to the dissemination of these problems and to their discussion, by inviting the leading experts in the field and by stimulating interactions among the participants. As the success of the first thirty meetings have demonstrated, the SCGAS conference has now become an important and anticipated event for the southern California region and has also attracted a substantial number of participants from the rest of the country each year. The website of the 31st Southern California Geometric Analysis Seminar may be found at https://sites.google.com/ucsd.edu/lucaspolaor/xxxi-scgas?authuser=0 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

ABSTRACT The origins of cancer lie in genetic mutations, but these mutations ultimately impact protein function, and most proteins in turn form intricate protein complexes and signaling networks to regulate cellular activity and phenotypes. Just as in-depth study of the landscape of driver genes and mutations has led to the development of targeted therapies, profiling protein interactions to identify those most critical for promoting oncogenic signaling in specific mutational contexts has the potential to reveal cancer cell vulnerabilities and mechanisms of drug resistance. In this regard, intrinsically disordered regions (IDRs) of several cancer drivers have emerged as central mediators of oncogenic signaling, protein-protein interactions (PPIs), post-translational modifications and drug resistance. However, systematic and at scale functional mapping and mechanistic dissection of IDRs is challenging. Towards this, we propose to utilize a panel of novel and complementary high throughput functional screening technologies developed by us that enable systematic protein perturbation at protein domain resolution and residue resolution, as well as a computational framework to convert these data to interpretable maps of oncogenic dependencies. Specifically, we will functionally map IDRs of all high confidence human and viral derived cancer drivers (~1000 proteins) across a panel of clinically relevant melanoma cancer cell lines (wild- type and mutant NRAS), and in the presence and absence of BRAF inhibitors. Integrating resulting large-scale IDR perturbation data with available protein interaction information and novel computational analyses, we will systematically interrogate underlying IDR driven oncogenic networks and their rewiring across the above cell states. Our hypothesis is that comprehensive domain and residue level perturbation screening of IDRs across all annotated cancer drivers will enable us to systematically uncover their mechanisms of action and reveal the most critical IDRs in drug sensitive and resistant contexts, thus informing more effective selection and development of cancer drugs.

NIH Research Projects · FY 2026 · 2026-04

To take advantage of recent and ongoing advances in intensive and large-scale computational methods and to preserve the scientific data created by publicly funded research projects, archives for sharing data must be created, as well as standards for specifying, identifying, and annotating deposited data. The value of an interest in such archives among researchers can be greatly increased by adding to them an active computational capability and framework of analysis and search tools that support further analysis as well as larger-scale meta-analysis and large-scale data mining. OpenNeuro.org, founded as a repository for functional magnetic resonance imaging (fMRI) data, is such an archive. We have built a web portal, NEMAR, to OpenNeuro data for human electrophysiology data (EEG and MEG) and for intracranial (iEEG) data recorded from clinical patients during planning for brain surgery or other therapies – we here refer to these as neuroelectromagnetic (NEM) data. NEMAR, maintained at the San Diego Supercomputer Center, acts as a portal to NEM data shared publicly via the OpenNeuro data archive. Upon receipt by OpenNeuro, NEM data are copied to NEMAR and made available for processing without charge on the ACCESS high-performance computing resources of the San Diego Supercomputer Center (SDSC) via the Neuroscience Gateway (NSG) project. NEMAR offers a search engine for NEM data whose results can be inspected in detail from a web browser, including visualizations of data from each subject plus a number of data activity measures and quality estimates. A forum for each dataset records visitors’ comments and lists papers citing the data. Next, we will build large, multimodal foundational deep neural network models allowing users to explore relationships between NEM signal brain dynamics, experience, and behavior.

NIH Research Projects · FY 2026 · 2026-04

Project Summary While response rates to Checkpoint Blockade Immunotherapy (CBI) in Head and Neck Squamous Cell Carcinoma (HNSCC) are generally low, approximately 3-5% of patients show durable complete responses (dCR) and remain disease-free for at least two years following treatment. The mechanisms underlying these exceptional responses are unknown and may hold great promise for the development and refinement of immunotherapies. Remarkably, our recent work has determined that B-cell anti-tumor activity is associated with complete responses to CBI in HNSCC. However, the mechanisms underlying this increase in B-cell-mediated antibody activity, and the pathways by which B cells contribute to tumor control are understudied. The primary long-term goal of this project is to better understand the role of B cells in complete responses to CBI in HNSCC and thus improve immunotherapeutic approaches and increase complete response rates. The overall objectives of this application are to (i) test novel agents to harness and enhance B-cell mediated anti-tumor immunity, (ii) dissect the mechanism of action of B-cell mediated tumor control; and iii) define the specificity and identity of B-cell antibody profiles from patients with dCRs in HNSCC. The central hypothesis is that adaptive B cell activity is critically involved in complete responses to CBI in HNSCC and will be tested with three specific aims. Specific Aim 1 will determine the effects of CBI on B-cell activation and whether combinations of specific B-cell activators enhance anti-tumor immune responses and tumor control. Specific Aim 2 will identify B cell subtypes that mediate anti-tumor immunity, and dissect the mechanism of action of B- cells in orthotopic models of HNSCC. Specific Aim 3 will define the specificity and identify novel B-cell antibody repertoires that drive durable complete responses in HNSCC patients. The research proposed in this application is innovative due to the focus on durable and complete responses to cancer immunotherapy and the exploration of the mechanisms underlying these exceptional responses associated with the critical yet understudied role of B cells. The research is significant because it will identify specific B-cell agonists that can be used to enhance tumor control with CBI or XRT, elucidate the mechanism of action of B-cells and critical B-cell subtypes; and establish whether B-cell mediated antibody responses drive exceptional completed responses in HNSCC patients. Ultimately, these findings can be directly translated to improve outcomes for HNSCC patients.

NIH Research Projects · FY 2026 · 2026-04

ABSTRACT The gut microbiome is a cornerstone of host health, shaping immune responses, metabolism, and resilience to disease. However, attempts to treat dysbiosis via fecal microbiota transplantation (FMT) are frequently limited by colonization resistance, where resident microbes inhibit new strains from being introduced. Current reliance on broad-spectrum antibiotics to mitigate this competition typically results in only transient engraftment and limited therapeutic efficacy. Furthermore, despite refinements in donor selection and administration, no models or pipelines exist to allow clinicians to accurately predict FMT outcomes or systematically introduce microbiota into the highly variable patient microbiomes. There is a critical gap in understanding how to identify which microbial communities and donor microbiomes can integrate robustly into individual recipients. This proposal addresses this gap by leveraging computational and experimental approaches to identify “orthogonal” donor communities that bypass metabolic niche competition. We hypothesize that donor consortia whose metabolic requirements differ when compared to the FMT recipient microbiota are more likely to stably engraft. In Aim 1, we will use metabolic models (MICOM) to extract metabolic features from microbial communities and train statistical classifiers that predict FMT engraftment outcomes between microbiomes in both murine and human cohorts. In Aim 2, we will develop a culturomics-based strategy to experimentally profile unused niches within recipient microbiomes and introduce donor-derived communities specific to those niches. We anticipate that these aims will yield a novel computational framework for donor-recipient matching as well as an experimental pipeline to identify niche-associated microbial communities that are capable of engrafting in target recipients. These precise and predictable microbial engraftment strategies will allow for personalized microbiome therapies and more durable non-pharmacological treatments for conditions linked to dysbiosis.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY/ABSTRACT Inflammatory bowel disease (IBD) affects up to 3.1 million adults in the U.S. Bile acids are recognized as key signaling molecules in microbe-immune communication and may therefore be new therapeutic targets for IBD. Microbes deconjugate bile acids with bile salt hydrolases (BSHs), which can produce a variety of bacterial bile acid amidates (BBAAs). However, whether the microbiome affects the immune system through BBAAs remains a gap in knowledge. To investigate this, there is a critical need for a research tool that allows us to overexpress specific BSHs in the gut microbiota to manipulate the BBAA pool. The innovation of this proposal is the use of engineered native bacteria, which allow the stable overexpression of single BSH enzymes in the lumen without disrupting the native microbiota. Preliminary data show that an engineered native bacteria expressing BSH is protective against colitis. The overall goal of this study is to determine how BSH has this effect. The candidate will colonize mice with BSH-expressing engineered native bacteria to test the central hypothesis that BSH protects against colitis through the production of specific BBAAs. In the next three years, the candidate will pursue this hypothesis with two specific aims. The first aim will determine if BBAA production is necessary for BSH to protect against colitis. The candidate will administer engineered native bacteria that produce different BSHs to mice in the dextran sodium sulfate colitis model and determine whether only BSHs that produce BBAAs reduce colitis severity. The second aim will determine if BBAAs are sufficient to recapitulate the effects of BSH. The candidate will administer synthesized BBAAs to mice in the dextran sodium sulfate colitis model and determine if BBAAs alone are protective against colitis. The expected outcome of this study is a mechanistic understanding of how BSH activity ameliorates colitis, and clarity as to whether the production of certain BBAAs mediates this effect. These findings will have a positive translational impact, since characterizing microbial metabolites that ameliorate colitis could provide new therapeutic targets for the development of IBD treatments. The candidate is an outstanding scientist with a clear goal of establishing herself as an independent researcher specializing in the host-microbiome interface in inflammatory disease. Her training objectives include: designing experiments with engineered native bacteria, conducting microbiome and metabolomics studies, gaining expertise in animal models of inflammatory bowel disease, acquiring the skills necessary for independent research, and expanding her professional network. To achieve these objectives, she has developed a comprehensive plan that integrates hands-on bench research, targeted coursework, seminars, participation in national meetings, and other career development activities. This plan will be carried out under the guidance of a mentorship committee led by Drs. Amir Zarrinpar and Pieter Dorrestein.

NIH Research Projects · FY 2026 · 2026-03

Current training models for bioengineering design often do not adequately prepare students for 21st-century challenges in the medical device industry, as they lack appropriate training in team-oriented science, critical thinking skills to identify medical problems, and immersion in clinical medicine, which is essential for addressing these problems. Responding to PAR-22-000, we at UC San Diego propose to re-envision our Bioengineering senior design curriculum through the implementation of the Clinical Undergraduate Research Experience and Skill-building (CURES) initiative. This program adopts a vertical integration model to: (1) expand clinical immersion and team-based medical device design modules within bioengineering coursework by incorporating a structured sequence of clinical modules and digital twin technology starting at the undergraduate level, (2) align clinical project conceptualization in BENG193: Clinical Bioengineering with senior design courses such as BENG187 and BENG188, ensuring clinical projects progress seamlessly into senior design teams co-mentored by clinical and bioengineering faculty, and (3) disseminate program materials and clinical digital twin systems through interdisciplinary campus events and broader regional and national networks to enable access across engineering departments. This vertically integrated, three-pronged approach will empower clinicians to mentor student teams in the didactic courses, whose enrollment we will double to accommodate half of all undergraduate students. Beyond coursework, the initiative will extend to include the majority of UC San Diego Bioengineering students in clinically focused senior design projects that incorporate real-world clinical problem-solving. The integration of innovative tools such as clinical digital twin technology, combined with models like progressive team-based training, will provide scalable and accessible approaches for delivering this education. We believe this initiative addresses critical gaps in bioengineering education by preparing students for the 21st-century workforce with hands-on clinical immersion, interdisciplinary collaboration, and structured mentoring. Moreover, this program will also address gaps for medical students who currently lack access to courses in medical device design, despite UC San Diego’s proximity to a leading biotechnology sector. Program success will be assessed by comparing cohorts with and without additional clinical immersion and team-based design coursework, as well as previous cohorts under the prior curriculum. With data on student interest, pilot successes, and measurable outcomes, we aim to achieve the following ambitious goals over five years: developing and integrating clinical immersion and digital twin technology into bioengineering courses, increasing clinical mentor involvement in senior design, and disseminating educational materials and program outcomes to create a scalable, sustainable impact.