University Of California At Davis

NIH Research Projects · FY 2026 · 2026-06

Project Summary Psoriasis is a chronic systemic inflammatory disease that affects approximately 100 million people globally. It arises from complex interactions between polygenic host susceptibilities and environmental factors like diet and the microbiome. While many genetic psoriasis susceptibility loci have been identified in Western populations, some of these have not been replicated in Asian populations, underscoring the need to study the effects of genetic variability on psoriasis. Importantly, several macrophage-associated genes have been found to have strong associations with psoriasis. Although the disease has traditionally been seen as T-cell-driven, recent evidence points to the significant role of macrophages, which respond to environmental factors and modulate T-cell activity, positioning them as key contributors to psoriasis pathology. Given their central but understudied role in the disease, macrophages represent a promising target for therapeutic intervention. My recent work has shown that diet significantly influences systemic immunity in humans, with considerable individual variability, suggesting that genetics and diet must be examined together to tailor dietary interventions for psoriasis. Additionally, I developed a murine model of psoriasis where microbial exposure induces a Th17-driven immune response, closely mimicking human disease, and revealing how microbial factors contribute to inflammation. To unravel how these factors - genetics, diet, and the microbiome - intersect and affect psoriasis disease onset and severity, I hypothesize that macrophage phenotypes, shaped by these variables, play a critical role in psoriasis. Specifically, I will: 1) investigate how genetic diversity, diet, and microbial exposure affect the transcriptional, epigenetic, and proteomic landscapes of macrophages, 2) clarify macrophage functions in psoriasiform inflammation, and 3) explore how dietary interventions can modulate macrophage responses to reduce inflammation. This project will leverage cutting-edge single-cell multi-omics technologies, including scRNA-seq, scATAC-seq, and single-cell proteomics, integrated with natural genetic variation and microbiome data. Given the scarcity of multi-omics approaches that incorporate genetic and microbiome information, I will also develop new network- and AI-based algorithms to integrate these data streams. Ultimately, this systems biology project will uncover common key transcription factor networks, genes, and pathways that govern macrophage responses to diet and microbiome signals during psoriasiform inflammation. It will further elucidate the magnitude of genetic-specific transcription factors, genes, and pathways and their influence on psoriasiform inflammation, as well as host response to diet and the microbiome. This work has the potential to identify novel therapeutic targets to modulate macrophage phenotypes, offering new avenues for treatment. Furthermore, the insights gained will form the basis for future nutritional intervention studies in humans and inform new therapeutic strategies for managing psoriasis symptoms.

NIH Research Projects · FY 2026 · 2026-06

PROJECT SUMMARY The mission of the UC Davis Clinical and Translational Science Center (CTSC) is to advance clinical and translational science (CTS) by coalescing the expertise within our premier, comprehensive university and core collaborators to improve human health. We have been the home for CTS researchers at UC Davis for nearly 20 years and have exceeded the essential characteristics of successful CTSA Hubs, both locally and nationally. For the proposed grant period, the UC Davis CTSC will integrate the broad knowledge and expertise of our public, land-grant, research-intensive academic institution and the geographic reach of our university to generate broad knowledge translation. Our CTSC will build transformative teams to uniquely tackle CTS barriers by coalescing the expansive expertise in six UC Davis schools and four colleges, our leading healthcare system at UC Davis Health, rural cooperative extension sites across the state, and community partners representing our broad catchment areas. The Specific Aims of our proposal are: Aim 1: Synergize our existing CTSC systems and infrastructure with new multi-sector leadership, empowered team and staff management, and team science- focused evaluation (A: Overview and B: Strategic Management); Aim 2: Proactively coordinate staff and trainee as well as core collaborators with our services, pilot awards, and data science approaches to support the day-to-day and future work of transformative CTS teams (C1: Workforce, C2: Engagement, D1: Resources, D2: CTS Pilots, D3: Data Science); Aim 3: Implement new projects and teams that address CTS gaps, in both community and clinical settings, and with a focus on dissemination of successful processes and findings back into our Center’s unified suite of assets and to the broader CTS field (E: CTS Research). To achieve these Aims, we strategically developed structures and activities to facilitate CTS within and across every Element of the application and have: 1) elevated all core collaborator audiences to the leadership board, including academic, healthcare system, rural cooperative extension partners, and community members representatives (B: Strategic Management); 2) rooted our training in transdisciplinary and team-centered knowledge creation and standardized our broad array of programs with foundational skill development (C1: Workforce); 3) re-focused our engagement activities on co-creation of scientific questions and long-term partnerships across the spectrum of research processes (C2: Engagement); 4) linked cross-cutting offerings and developed new communication strategies to ensure researchers gain access more efficiently and holistically across disciplines, while maintaining rigor, reproducibility, and high ethical standards (D1: Resources); 5) redesigned the CTSC pilot awards to support these alignments across research teams and collaborator audiences (D2: CTS Pilots); and 6) emphasized continuous iteration and improvement of core CTSC resources, innovation within implementation and data science methodologies, and upfront multi-sector collaborator engagement to speed up impact into real- world settings (D3: Data Science).

NIH Research Projects · FY 2026 · 2026-06

PROJECT SUMMARY / ABSTRACT This project will improve best practice care delivery and psychosocial outcomes for families of critically ill children hospitalized in the pediatric intensive care unit (PICU). The focus of this proposal is family-centered rounds (FCR), which is recognized as a best practice for hospitalized children. FCR enhances family-centered communication, engagement, understanding of the care plan, and trust in providers. Importantly, these benefits are also strategies to mitigate PICU-related psychosocial harms to family members of the critically ill child. However, FCR is only possible when parents or guardians (“parents” hereafter) can be physically at bedside during rounds. Yet circumstances that prevent physical presence (e.g., work, travel) hinder some families. PICUs lack evidence-based strategies to promote parents’ access to and attendance at FCR. We address this critical gap by testing a telehealth intervention to expand access to and attendance at FCR. We propose a dual cluster randomized trial, which is two simultaneous randomized trials: one testing the intervention of inviting families to use virtual FCR and one testing implementation strategies. Families will be randomized to one of three arms: (1) virtual FCR plus digital navigators (active implementation strategy), (2) virtual FCR plus informative handouts/videos (control implementation strategy), and (3) usual care. In this proposal, we pursue three Specific Aims: Evaluate and compare the impact of providing parents the option of virtual FCR versus usual care on parent FCR attendance, utilization, and psychosocial outcomes (Aim 1). Evaluate and compare two implementation strategies for virtual FCR (Aim 2). Conduct a mixed methods implementation evaluation of the virtual FCR intervention (Aim 3). Aims 1 and 2 will measure heterogeneity of intervention effects and implementation effects, respectively, by pre-specified subgroups. Our team’s preliminary research found that the option to use telehealth to conduct virtual FCR improved parent FCR attendance. All groups benefited from the intervention except for those with the lowest digital literacy and those without a smartphone. We thus build on our prior work to now propose a type 2 hybrid study utilizing the rigorous but underused dual randomized trial design. Our team’s expertise encompasses hospital care delivery interventions, clinical trials, implementation science, community engagement, linguistically appropriate care, mixed methods, and advanced statistics. Our team also includes two patient/provider advisory groups. This application is responsive to NICHD priorities in that it focuses on psychosocial issues related to the care of critically ill children and their families by transforming the delivery of PICU care to be more family- centered and accessible. In summary, this project will advance an innovative FCR solution in the PICU to address families’ unmet needs; and improve parent FCR attendance, healthcare utilization, parent mental health, and sibling well-being.

NIH Research Projects · FY 2026 · 2026-06

Project Summary/ Abstract Liver cancer remains a huge problem in the US and globally, often diagnosed at advanced stages with limited options. This problem is only going to get worse, with diseases such as non-alcoholic fatty liver disease dramatically rising (an alarming 20 million cases is expected in the next 15 years) and leading to cancer. Responding to this need will require establishing new treatments and existing therapies to deploy them a large scale. Transarterial embolization, also called selective internal radiation therapy (SIRT), is a catheter- based therapy for liver cancer with radioactive yttrium-90 (90Y) microspheres. By injecting the microspheres in the liver arterial blood flow, radiation can be directed at tumors, but the targeting is highly patient-dependent and difficult to plan with current imaging techniques. Tumor targeting is established with a day-long procedure combining exploration of the liver vasculature and nuclear imaging to evaluate the risk of microsphere leakage to the lungs (characterized by the lung shunt fraction). This “workup” uses cone-beam CT for vascular imaging and single photon emission computed tomography (SPECT) to image the 99mTc macro- aggregated albumin (MAA) distribution, thus shuttling the patient back and forth between the interventional radiology suite and the nuclear medicine ward. Done 1-2 weeks before treatment, the workup is as long and complex as the treatment itself and represents a huge burden for the patient and healthcare system due its risk, extent, and high cost. Its efficacy to optimize targeting and predict the lung shunt fraction remains limited. We hypothesize that contrast-enhanced perfusion CT can be an alternative to the workup to map the vasculature, predict the lung shunt fraction (LSF), and provide the additional benefit of predicting the 90Y dose distribution. This hypothesis is based on our preliminary results obtained with 4-phase abdominal CT. To test the validity of this approach, three main goals will be evaluated: 1) Perfusion CT allows to visualize the liver arteries in order to select potential 90Y injection sites, 2) perfusion CT can predict the LSF with comparable accuracy as 99m Tc MAA SPECT and 3) novel computational methods based on perfusion can predict the 90Y dose distribution and be used to optimize the injection dosage and locations. As a reference, we will use 90Y positron emission tomography (PET) post treatment to measure the radiation dose distribution and LSF. We will also collect standard-of-care pretreatment 99m Tc MAA SPECT. We are developing a new tensor-based approach that analyzes the blood flow velocity from dynamic perfusion CT to predicts the dose distribution. If successful, treatment planning could be accurately done from an outpatient and non-invasive perfusion CT instead of a day-long workup in interventional radiology and nuclear medicine for some patients. This new paradigm could unlock the use of SIRT in many patients too sick to undergo the workup. While focused on SIRT, these perfusion CT methods could be applied to other embolization techniques and other pathologies for which blood flow plays an important role and for which predictive models remain insufficient.

NIH Research Projects · FY 2026 · 2026-06

We propose implementing a UC Davis Neuroscience Education and Undergraduate Research Opportunities (NEURO) program to enhance the training of a workforce to meet the nation’s biomedical, behavioral and clinical neuroscience research needs. For this, we propose to offer a program that will include activities that are well-evidenced to increase the pipeline of students graduating in science majors who are interested in and prepared for graduate or medical school admissions and/or neuroscience research careers. We will support recruitment for our proposed undergraduate junior and senior training program by incorporating activities that kindle interest and engagement in neuroscience research into our highly successful Biology Undergraduate Scholars Program (BUSP), which serves talented freshmen and sophomores on our campus. We envision BUSP serving as a pre-NEURO curriculum and a vital source of applicants for our NEURO program. We will invite guest speakers to BUSP seminars, who will inform students about the scope and significance of neuroscience research, and about the opportunities offered by the NEURO program. We intend to recruit six UC Davis upper-division students per year to participate in the NEURO program, which will offer a one-year research-intensive experience (10 weeks of full-time research in the summer, and the equivalent of 5 weeks of full-time research during the academic year), advising, professional development opportunities, opportunities to practice science communication, and outreach opportunities. These activities are aimed at cultivating interest in neuroscience, developing scientific and professional skills, and facilitating participants’ advancement to the next step of their education and/or careers. We expect that NEURO participants will a) learn the importance of conducting biomedical research responsibly, ethically, and with integrity; b) increase their scientific expertise with respect to understanding scientific reasoning, rigorous experimental design, data analysis, and interpretation; c) develop skills to communicate scientific research to a variety of audiences, including those at national conferences; d) develop a science identity and sense of belonging within the scientific community; e) develop a professional network that includes supportive mentors at a variety of career stages; f) maintain/enhance interest in pursuing a neuroscience-related career and obtain tools for successful transition to graduate or professional programs and g) graduate with a science degree at a percentage of 90% with a GPA≥3.0. Our ultimate goal is that at least 80% of NEURO participants will enter graduate or medical school programs or research careers focused on neuroscience/neuroscience diseases, ultimately increasing the pool of well-trained neuroscientists.

NIH Research Projects · FY 2026 · 2026-06

Title: Second-generation new-chemical-entity nanomedicine to target treatment resistance in pancreatic cancer Project Summary Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers, with treatment resistance posing a major challenge to effective clinical management. Cells that survive therapy—such as pancreatic cancer stem- like cells (PCSCs) and drug-tolerant persister (DTP) cells—play a critical role in driving drug resistance, tumor recurrence, and metastasis. Notably, both cell populations depend heavily on elevated autophagy, a self- digestion process that enables survival under stress. Therefore, targeting autophagy pathways holds significant promise for improving treatment outcomes in PDAC. Autophagy inhibition with aminoquinoline drugs, such as chloroquine (CQ) or hydroxychloroquine (HCQ), have limited potency for autophagy inhibition, and the concentrations of CQ/HCQ required to inhibit autophagy are not consistently achievable in the clinic. The overall goal of this application is to develop a second-generation new-chemical-entity nanomedicine as an effective autophagy inhibitor to improve the treatment of PDAC in preclinical animal models, providing validation regarding the feasibility for clinical translation. Recently, we have developed an Autophagy inhibitor Self-delivered Nanodrug (AiSN) that offers superior potency for autophagy inhibition and specific drug delivery to improve PDAC treatment to HCQ. AiSN is a self-therapeutic nanoparticle that contains pure bisaminoquinoline (BAQ) derivative as the building block which has outstanding autophagy inhibiting- and lysosomal disrupting- capabilities. AiSN (BAQ13 nanoparticle, BAQ13 NP) is 20-30 times more effective than HCQ in a panel of PDAC cell lines. It preferentially accumulated at PDAC tumor sites with dense fibrotic stromal tissue. It was efficacious in various PDAC models and prevented cancer stem-like cell mediated tumorigenesis in mice. The FDA has recently approved our Investigation New Drug (IND) application (IND#165331) for moving the AiSN (BAQ13 NP) into clinical trials. The FDA has also granted Orphan Drug Designation for BAQ13 for the treatment of pancreatic cancer. Using BAQ13 as the lead compound, we have recently designed and synthesized 30 new compounds as the second-generation AiSNs, among which BAQ42 and BAQ152 have shown better potency than BAQ13, improving the IC50 value from micromolar to nanomolar levels. Furthermore, our study demonstrated that autophagy is significantly upregulated in DTP cells of PDAC. Although DTP cells exhibit resistance to gemcitabine, they can be effectively eliminated by BAQ42. These results have laid a strong foundation for this R01 application, where we plan to: 1) optimize the structure and formulation of second-generation AiSNs to enhance their anti-PDAC potency and nanoparticle-forming properties; 2) characterize their pharmacokinetics and spatiotemporal distribution; and 3) validate their pharmacology and toxicology in various PDAC models. Successful completion of this research will make this new generation AiSN ready for IND-enabling studies seeking IND approval. The novel design of AiSNs, with significantly improved potency and targeted delivery capabilities, is expected to greatly enhance efficacy while minimizing toxicity in PDAC treatment.

NIH Research Projects · FY 2026 · 2026-06

PROJECT SUMMARY The primary mission of the UC Davis Clinical and Translational Science Center (CTSC) Institutional Career Development Core (K12), entitled “Advancing Clinical and Translational Innovation by Vitalizing And Training Early-career faculty” (ACTIVATE), is to cultivate early career scholars into independent investigators who possess the strategic skills, broad perspectives, and methodological expertise necessary to excel as translational science leaders in academic, community, and industry settings. Building upon the nearly two decades of the CTSC’s strong foundation and KL2 successes, we have advanced translational science education and career development across UC Davis. This includes creating comprehensive, tailored training tools and fostering innovative career development initiatives alongside a mentoring team that supports the ongoing growth of both scholars and mentors. Despite these advances, there remains a critical need for exceptional clinical and translational investigators skilled in team science, community engagement, and advanced research techniques. These scholars are essential to advancing human health and healthcare while addressing the broad needs of the communities we serve. Over previous and current KL2 funding periods, we have successfully trained 44 early-career faculty members, most of whom have achieved remarkable success, underscoring the program's effectiveness in preparing scholars for independent careers as translational scientists. To sustain this momentum, the program's goals for the upcoming funding period are: (1) cultivate a new generation of highly skilled translational scientists who will lead transformative, interdisciplinary, community-engaged, and patient- centered research; (2) recruit and mentor early career scholars from broad backgrounds in science and medicine, supporting their success; and (3) to empower ACTIVATE scholars to become leaders and mentors in advancing health through the integration of cutting-edge methodologies.

NIH Research Projects · FY 2026 · 2026-06

PROJECT SUMMARY Healthy intestines are colonized by a large, diverse population of bacteria, known as the microbiota. During homeostasis, our intestinal cells provide a favorable environment for the microbiota, and in return, the microbiota provides nutritional and immune support to the host, particularly to the epithelial cells of the colon, the colonocytes. Through these interactions, our intestinal cells and the microbiota work together to maintain colonization resistance, an innate immune function that protects against infection by providing an inhospitable environment for intestinal pathogens. Dysbiosis, the disruption of the normal gut microbiota, is increasingly recognized as a major contributor to disease signs and symptoms and can cause a disruption in many of these microbiota-driven intestinal epithelial functions. One result of dysbiosis is the loss of colonization resistance against facultative anaerobes such as E. coli, which can cause dangerous opportunistic infections in people with altered immune function. Current therapies to reduce dysbiosis and intestinal infections involve targeting the microbiota using strategies such as antibiotics, fecal microbiota transplantation, prebiotics, or probiotics. However, these strategies have several weaknesses, including the toxicity of antibiotics for the host; increasing resistance to antibiotics in E. coli; questionable safety of fecal microbiota transplantation for immunosuppressed patients, such as those on chemotherapy; and the need to sustain live bacteria for treatment to be effective, possibly in the face of ongoing microbial disruption. The objective of this application is to investigate whether the restoration of microbiota signaling pathways with non-biotic substitutes will control opportunistic infections during chemotherapy-induced dysbiosis. These non-biotic substitutes, “Faux-biotics,” are drugs that target the host rather than the microbiota and aim to restore colonization resistance by replacing the bacterial signals which are lost during dysbiosis. My overall hypothesis is that restoring host-microbiota signaling will maintain colonization resistance against E. coli during chemotherapy treatment by restoring a healthy intestinal epithelial metabolism during dysbiosis, and that this will reduce the risk of bacteremia during chemotherapy treatment. In Aim 1, we will demonstrate that restoring normal host-microbiota signals by reactivation of the butyrate signaling pathway during chemotherapy reduces the intestinal bloom and systemic spread of E. coli and will assess the pathways altered in colonocytes by chemotherapy-induced dysbiosis. In Aim 2, we will show that maintaining a healthy colonic luminal environment by reactivating the butyrate signaling pathway will promote the faster restoration of a healthy microbiota after chemotherapy is completed and reduce the risk of a post-chemotherapy E. coli bloom. To address these aims, a mouse model of chemotherapy treatment and the transfer of chemotherapy-treated microbiotas into Germ-free mice will be used. Successful completion of the proposed research will establish new therapeutic targets for managing opportunistic infections and will introduce a paradigm shift that establishes the host rather than the microbiota as the treatment target to reduce the effects of dysbiosis.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY/ABSTRACT The World Health Organization classified Candida albicans as a critical pathogen warranting increased research and development needs. C. albicans is the most common etiology of invasive candidiasis, which occurs when C. albicans enters the blood stream (candidemia) and disseminates throughout the body (i.e. the liver and spleen) where mortality approaches 50%. People with hematologic malignancies have the highest risk for invasive candidiasis, and Candida spp. expands in the gastrointestinal tract prior to development of invasive disease. This expansion requires antibiotic mediated loss of Candida spp. colonization resistance. While antifungal prophylaxis has been used in this population to improve outcomes, there are increasing rates of antifungal resistance along with breakthrough infections despite antifungal prophylaxis demonstrating a critical need for new approaches for prevention and better understanding of how C. albicans colonizes the gastrointestinal tract. We recently demonstrated the importance of oxygen availability in allowing C. albicans to colonize the gastrointestinal tract and identified that the inflammatory bowel disease drug, 5-aminosalicyclic acid (5-ASA), restores colonization resistance to C. albicans. We hypothesize that oxygen availability is necessary for C. albicans to colonize the gastrointestinal tract to catabolize available simple sugars in the colon (sorbitol, for example). This will be explored in Aim 1 using C. albicans mutants that are unable to catabolize sorbitol in multiple murine and in vitro models. Antibiotics increase the amount of oxygen available in the colon, and oxygen availability seems vital for C. albicans to colonize the colon. Even though 5-ASA reduces gastrointestinal colonization of C. albicans, it remains unknown if 5-ASA prevents development of invasive candidiasis. It is also unknown if C. albicans oxygen availability in the colon is required for dissemination. In Aim 2, we will answer this question using a C. albicans dissemination model using the cancer therapeutic cyclophosphamide, while also evaluating if C. albicans aerobic respiration is required for dissemination utilizing a C. albicans mutant with impaired aerobic respiration. Successful completion of these aims will provide mechanistic detail into how the critical pathogen C. albicans colonizes the gastrointestinal tract while simultaneously assessing the novel approach to preventing invasive candidiasis via restoration of gastrointestinal epithelial hypoxia.

NIH Research Projects · FY 2026 · 2026-05

ABSTRACT In 1998, the Food and Drug Administration mandated the fortification of grain products with folic acid (FA) to reduce the incidence of neural tube defects. While this mandate has been highly successful, in combination with rising supplementation it has led to a substantial increase in FA consumption in the U.S. At the same time a critical gap exists in our understanding of potentially detrimental effects of high FA intake on neurodevelopment of the fetus. Indeed, a series of epidemiological and experimental observations let us hypothesize that excessive intake of FA during pregnancy poses risks to brain development of the fetus that can predispose to neurodevelopmental disorders. These observations are supported by our own work in mice, which has confirmed that excess prenatal FA exposure can modify developmental neurogenesis and, in the process, alter cortical cytoarchitectural integrity in the offspring. Intriguingly, deviations observed with FA excess closely mimicked those seen in folate deficiency, a recognized cause of neurodevelopmental disorders. A distinct micronutrient, vitamin B12 (B12), has seen population level decreases in intake during the same period FA intake has increased. B12 is critically required for folate cycle progression and regeneration of tetrahydrofolate, which leads us to further hypothesize that neurodevelopmental risk of FA excess is heightened in the face of B12 deficiency. To bridge the gap between preclinical observations in animal models and human neurodevelopment, the research objective of this interdisciplinary proposal is to experimentally test the developmental and biochemical consequences of excessive FA exposure in engineered human cerebral organoids. Such organoids provide an excellent model in the study of early neurodevelopmental events, including those that may be critically disturbed in neurodevelopmental disorders as other studies have suggested. Simultaneously, we will test the effects of B12 deficiency. We will culture cerebral organoids under nine different conditions of folate and B12 supply in the media to measure in Aim 1 their effects on differentiation and growth, rates of neuron generation, and cellular composition at different timepoints. In Aim 2, we propose detailed biochemical investigations of folate pathway dysregulations. In addition, we will test the effects of folate/B12 supply on global and site-specific DNA methylation levels by whole-genome bisulfite sequencing and examine transcriptomic and proteomic dysregulations. In Aim 3, we will measure the effects of folate/B12 imbalance on electrophysiological function of organoid neural networks using high-density microelectrode arrays.

NIH Research Projects · FY 2026 · 2026-05

PROJECT TITLE: Applying Implementation Science to Improve Transitions from Pediatric to Adult Care for Adolescents and Young Adults with Type 1 Diabetes PROJECT SUMMARY The objective of this project is to improve transitions from pediatric to adult care for adolescents and young adults (AYAs) with type 1 diabetes (T1D). The transition from adolescence to adulthood, when people begin to take responsibility for their own healthcare, is a time of increased vulnerability to lapses in routine care. These lapses can lead to worsening health outcomes and increased emergency healthcare use. Transition interventions have been shown to improve rates of successful transition to adult care but are often resource- intensive, inaccessible, and rely heavily on clinician-level or system-level changes. We conducted a human- centered design process to develop a patient-centered virtual intervention to improve the transition process. Our intervention components include peer mentorship, education around navigating the healthcare system and managing diabetes independently, and developing a written transition plan. The proposed research builds on this preliminary work and will provide a strong basis for a future multicenter hybrid effectiveness- implementation trial. We propose three specific aims: Aim 1: Develop implementation strategies using an implementation mapping process grounded in the Capacity, Organization, Motivation- Behavior (COM-B) theoretical constructs. Aim 2: Pilot test a randomized trial of a patient-centered virtual intervention for the transition from pediatric to adult care for AYAs with T1D. Aim 3: Conduct a nationally representative survey of pediatric endocrinology practices to identify the availability, types, and reach of T1D transition resources and to identify barriers to scaling the transition intervention. Together, these aims will result in a well-developed patient-centered intervention based in behavior change theory and knowledge of how to test and scale this intervention in future multisite studies. To ensure the successful completion of the proposed research aims, the candidate has assembled a mentorship team with expertise in implementation science, diabetes clinical trials, diabetes management and education, and survey methodology. The candidate has also proposed a training plan that will leverage her rigorous training in epidemiology and health services research, while allowing her to achieve her long-term career objective of becoming an independent investigator leading research focused on the development, implementation, and evaluation of evidence-based strategies to improve health outcomes for adolescents and young adults with T1D.

NIH Research Projects · FY 2026 · 2026-05

Project Summary Osteoarthritis (OA) is a degenerative disease resulting in irreversible, progressive destruction of hyaline cartilage lining articular joints. A critical challenge for OA management is the development of an effective treatment that reverses cartilage damage. Our previous work indicates the existence of adult skeletal stem cells (SSCs) in postnatal cartilage. These SSCs are dormant yet can potentially repair damaged cartilage when stimulated by surgical procedures such as Microfracture (MF). While MF typically results in the formation of inferior fibrocartilage, we have demonstrated that MF-activated tissue-resident SSCs can be expanded and directed towards the formation of healthy chondrocytes and hyaline cartilage to regenerate full-thickness cartilage defects by pharmacologically modulating SSC activity and the microenvironment surrounding them. This method we termed Growth-factor Enhanced Microfracture (GEM). Our published studies and preliminary data demonstrate that GEM works well in young animals but is less effective in aged mice. Our data supported by recent findings of others further suggest that FGF7 (Fibroblast Growth Factor 7) expression in the SSC lineage is induced by an inflammatory aged and osteoarthritic bone marrow niche, which leads to pro-fibrotic lineage-skewing resulting in cartilage loss. We now build on additional preliminary results showing that direct and indirect blockade of FGF7 during GEM can reinstate stem cell-based cartilage formation in joints of aged and OA mice. The gained insights from the proposed study will help us to develop strategies to efficiently apply GEM even in impaired settings with a cellular microenvironment less conducive to articular cartilage regeneration. To that end, we are elucidating the cellular dynamics and molecular mechanisms that underlie SSC mediated cartilage repair. In Aim 1, we will expand our preliminary findings to confirm and mechanistically dissect how inhibiting FGF7 locally during GEM in aged and osteoarthritic mice can promote hyaline cartilage formation. In Aim 2, we will determine if epigenetic rewiring of local SSCs by a novel therapeutic compound is sufficient to overcome age-related impairments of GEM mediated cartilage regeneration. Our experiments will use state-of-the-art structural and functional readouts at the tissue level as well as latest technology to unravel cellular and molecular changes at the single cell level to assess regenerative properties and provide new biological insights into OA. Our team brings together expertise in skeletal stem cell biology, in-depth basic science and clinical knowledge of OA as well as bioengineering competency. We are using cutting-edge methods to pursue hypothesis-driven questions aimed at unlocking endogenous stem cells for cartilage repair. By taking advantage of a therapeutic window to skew local MF-activated SSC fate we want to generate new cartilage for the resurfacing of OA joints independent of age and disease state. Eventually, we wish to translate these preclinical studies.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY. Whole-body positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG) and other radiotracers has become an essential tool for diagnosing and managing pediatric cancers, such as lymphoma and sarcoma. Current clinical practice relies on static PET imaging to obtain a semi-quantitative standardized uptake value (SUV), which can be affected by scan time and body characteristics. Dynamic PET addresses this issue by using tracer kinetic modeling approaches, such as the standard Patlak plot, to derive a quantitative net influx rate 𝐾i for improved disease characterization compared to SUV. While Patlak parametric imaging has been adopted on certain PET scanners and has demonstrated clinical benefits in adult patients, its use in pediatrics remains severely limited due to the impracticality of acquiring full-length (e.g., 1 hour) dynamic scans and the lack of available pediatric databases for establishing the population-based input functions. The goal of this project is to develop and evaluate a practical parametric imaging method tailored for pediatrics. This method can be directly applied to clinical total-body PET scans (e.g., 10 minutes at 1-hour post-injection) to provide kinetic quantification on top of SUVs. The enabling technique is the Relative Patlak (RP) plot, which relies solely on the late-time input function without the need for the early-time data. This feature makes the RP plot a unique solution for enabling whole-body parametric imaging in pediatrics compared to other streamlined Patlak methods. Our preliminary work with adult patient data has demonstrated the RP method for lesion detection and absolute quantification using the standard Patlak method as a reference. The focus of this R01 grant is to translate the RP technique to enable whole-body parametric imaging in pediatric patients and evaluate its clinical benefits in the context of pediatric oncology. Specifically, we will (1) develop tomographic image reconstruction methods to enable total-body parametric imaging for pediatrics from a 10-minute (or shorter) clinical scan; (2) evaluate total-body RP parametric imaging for lesion detection and treatment response prediction in pediatric cancer patients; (3) extend the RP method to short-axial PET scanners for practical whole- body parametric imaging. Successful completion of this project will develop a new pediatric parametric imaging approach that can be adapted to existing workflows without prolonging scan time. This fills a critical gap in pediatric PET imaging by enabling a safe, efficient, and quantitative kinetic analysis, opening new opportunities for exploring clinical applications that have previously been restricted to adult studies or limited by the complexities of parametric imaging. Moreover, our method is adaptable for both advanced total-body scanners and conventional short-axial scanners, making pediatric whole-body parametric imaging widely accessible.

NIH Research Projects · FY 2026 · 2026-05

Abstract: This R35 MIRA application represents the five-year program plan for my laboratory. The overarching goal of my laboratory research program focuses on how DNA double-strand breaks (DSBs), a particularly toxic form of DNA damage, induce genome instability and chromosome rearrangements. DSBs are predominantly repaired by non-homologous end joining or homologous recombination. Both pathways are critical for embryonic development, and loss of either increases chromosome rearrangement formation and cancer predisposition. Defects in DSB repair are also potent therapeutic targets, either by traditional chemotherapeutics overwhelming cells with damage or more targeted drugs developed to target cells with specific pathway mutations. In previously published work from my laboratory supported by my NIGMS R01GM134537, we dissected the contribution to R loop metabolism on DSB repair and aberrant CR formation in the immunoglobulin heavy chain locus and genome-wide in activated B cells. DSBs from DNA replication stress and programmed rearrangement events often occur within the same cell and can recombine, driving the formation of chromosome rearrangements. In this R35 MIRA, we investigate how two common secondary structures formed in DNA—R loops and G quadruplexes—impact DSB formation, repair pathway choice, and chromosome rearrangement formation in primary, immortalized and transformed cells. My lab has developed novel methods to measure successful DNA repair at endogenous genomic loci in primary and immortalized cells, and to identify potential sites of transcription-associated replication stress. We have also defined the contribution of cell cycle progression and checkpoint activation on CR formation in both primary and immortalized cells. Here we will: 1) define molecular and genetic factors predisposing specific genomic loci to instability; and 2) functionally dissect the DNA repair pathways driving mutagenic chromosome rearrangement formation. We will use genetic, molecular, cell biological and genomic approaches to study complex rearrangement formation at the single cell and population level, tracking the impact on viability, cell fate, and further genome evolution. This R35 will define the repair pathways driving CR formation, the effect of CR formation on cell survival and cell tetraploidization, and the specific mutagenic signatures associated with G quadruplex stabilization and defective R loop metabolism.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY There is a crucial need in the field of advanced diagnostic tool development for early detection of rare cancers such as osteosarcoma (OSA). Specifically, there is a need to develop platforms that can overcome the limitations of small sample sizes inherent in rare cancers while maintaining generalizability across patient populations for high test accuracy to improve patient outcomes. The long-term objective of this project is to develop a Raman spectroscopy-based liquid biopsy platform which uses a model trained on readily available companion animal biological samples as a basis for cross-species validation using smaller human data sets. To accomplish this objective, the research team will undertake two specific aims. First, Raman spectral signatures of canine OSA will be defined and validated as a foundation for cross-species diagnostic modeling. This will be done by using self-supervised models to train on Raman data generated from 100 canine plasma samples and subsequently using supervised classifiers to detect OSA. Biological interpretability will be validated via targeted lipidomic and metabolomic profiling. Second, the research team will develop and validate a cross-species transfer learning framework by performing Raman spectroscopy on more than 1,000 unannotated canine plasma samples and fine-tuning models on rare cancer–specific data in human patients. By accomplishing these aims, a comparative transfer learning framework will be established that enables label- efficient diagnostic development for rare cancers using abundant veterinary data. This platform has potential for broad extension to other rare cancers with canine analogs, providing a scalable path to early, noninvasive cancer detection in settings where human samples are limited.

NIH Research Projects · FY 2026 · 2026-05

Abstract Total-body (TB) Positron Emission Tomography (PET) is a medical imaging technology that enables comprehensive imaging of metabolic processes across the entire body in a single bed position. It offers substantial advantages for dynamic imaging and kinetic modeling, such as high temporal resolution and multiparametric capabilities, making it invaluable for assessing cancer staging, early treatment response, and distinguishing malignancy from infection/inflammation. However, the widespread adoption of TB PET is limited by its high cost, primarily due to the expense of scintillator material and readout electronics. This proposal seeks to develop an affordable dynamic TB PET system through the use of sparse detector architectures, which will reduce material costs while maintaining the performance benefits of full-body coverage. We hypothesize that sparse designs can produce high-quality dynamic images that allow for kinetic modeling and parametric imaging with minimal loss of quantitative accuracy compared to full-rank TB PET. Our innovative approach combines spatial down sampling of the detector matrix of the 2-m long EXPLORER TB PET scanner with advanced reconstruction algorithms. Classical and deep learning-based Kernel methods will help recover image quality in high-noise, low-count environments. This project will address three specific aims: (1) demonstrating parametric imaging using sparse TB PET, (2) comparing image quality between sparse TB PET and conventional PET scanners, and (3) optimizing reconstruction parameters and detector matrix configurations for high temporal resolution in dynamic imaging. By achieving these aims, we will develop a robust, cost- effective TB PET system with potential to revolutionize both clinical and research applications. The successful implementation of this technology will expand access to dynamic TB PET, enhance diagnostic workflows, and accelerate research in cancer and other diseases.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY/ABSTRACT This shared instrumentation grant proposal seeks funding to upgrade the Bruker 7T preclinical MRI system at the UC Davis Center for Molecular and Genomic Imaging (CMGI), a vital resource supporting a broad community of NIH-funded investigators. The current Bruker AVANCE III console, installed in 2010, has reached end-of-life, with no guaranteed vendor support and limited spare parts, placing the system at significant risk for prolonged downtime. This vulnerability threatens a diverse portfolio of NIH-funded research at UC Davis, encompassing cancer biology, neuroscience, cardiometabolic disease, immunology, molecular imaging, translational nanomedicine, and multi-modal studies integrating MRI with PET and optical imaging. Upgrading to the fully supported AVANCE NEO console is essential to ensure continuity and reliability for these critical research programs. Seamless compatibility with the existing Bruker 7T magnet will enable a smooth transition, minimizing disruption to ongoing studies. With CMGI’s specialized infrastructure and technical expertise in in vivo preclinical imaging, and strong institutional backing for robust operation and long-term maintenance, this upgrade will not only safeguard current research but also empower UC Davis investigators to pursue innovative biomedical studies and accelerate the translation of preclinical discoveries into clinical advances.

NIH Research Projects · FY 2026 · 2026-05

Project Summary Structural variants (SVs) are complex genetic rearrangements of medium to large size (>50 bp) that overall impact more base-pairs of the genome than any other type of genetic variants. These variants are implicated in many diseases, such as neurodevelopmental disorders (NDDs) and cancers. However, our understanding of their contribution to complex diseases remains incomplete. The large-scale studies have mostly focused on non-repetitive regions of genome and coding segments, overlooking potentially relevant areas outside these regions. These limitations are the result of lack of ability to accurately predict and genotype SVs in complex and repetitive regions of the genome, and the complexity of interpreting the functional impact of non-coding SVs. One of the primary objectives of my research is to study the hidden contribution of SVs to complex disorders by addressing these and other shortcomings in our current analysis. Despite the recent advances in computational methods using whole-genome sequencing (WGS) data, accurately predicting and genotyping SVs in repetitive regions of the genome, such as segmental duplications, remains challenging. Even with long-read WGS data, state-of-the-art SV callers are still unable to detect a significant fraction of the SVs in these hard-to-call regions, as demonstrated by the analysis of T2T-CHM13 data. Approximately 15% of the genome comprises regions that are difficult to accurately call variants, and our analysis of the T2T-CHM13 and HG002 assemblies suggests that these regions contain a significant high proportion of SVs. In addition, studying SVs in diseases also requires specialized novel methods, for accurate detection of de novo or somatic SVs. Development of these methods will open the door for comprehensive study of the contribution of SVs in hard-to-call genomic regions to complex disorders. Another major limitation of current studies of SVs in complex disorders is due to challenges in our ability to interpret non-coding SVs. It is hypothesized that non-coding SVs can contribute to complex disorders through a variety of mechanisms. One major such mechanism is the ability of non-coding SVs to disrupt transcriptional regulation. For example, this can occur through changes in the 3D genome architecture, which subsequently modify enhancer-gene interactions and result in ectopic gene expression. Thus, there is a need for development of accurate methods for predicting the impact of non-coding SVs on transcriptional regulation and cell-type specific gene-enhancer interactions. Finally, development of these tools will result in much needed comprehensive investigation of non-coding SVs observed in large-scale complex disorder studies for their impact on transcriptional regulation landscape, 3D genome structure and enhancer-gene interaction. The overall objectives of this proposal are as follows: 1. Dissecting contribution of SVs in hard-to-call genomic regions to complex disorders: Our first objective focuses on deciphering the role of SVs in previously inaccessible and hard-to-call regions of the genome. We will develop innovative methods to enhance the detection and genotyping of SVs, including both de novo and somatic variants, in these regions. We will also leverage these tools to construct a comprehensive catalog of SVs in these regions, utilizing an expanding collection of long-read WGS data from both normal and disease samples. Finally, we will quantify and explore the contribution of SVs in these regions to complex disorders, including autism and cancer. 2. Studying the role of non-coding SVs in complex disorders: Our second objective is to study impact of non-coding SVs to complex disorders. It is hypothesized that certain non-coding SVs can contribute to complex disorders by reshaping the gene regulation landscape. This can involve disrupting 3D genome architecture, altering gene-enhancer interactions, and driving ectopic gene expression. As part of this project we will develop methods to predict the impact of non-coding SVs on the gene-enhancer interactions landscape. We will utilize these methods to study the contribution of non-coding SVs through such a mechanism on complex disorders. In the next five years, my lab's overarching goal is to enhance our understanding of the role of SVs in human diseases and health. The results of this research will expand our understanding of the contribution of SVs to complex disorders, help discovery of novel disease biomarkers, reduce the missing heritability gap in complex disorders, and even discover potential novel drug targets that have been ignored till now.

NIH Research Projects · FY 2026 · 2026-04

Project Summary/Abstract Plastic pollution is a critical environmental and health issue, with global plastic production reaching 390.7 million metric tons in 2021 and climbing. Only a small fraction of plastic waste is recycled, leading to the accumulation of plastics in the environment and the unavoidable generation of microplastics and nanoplastics through various degradation pathways. Nanoplastics are particularly concerning due to their potential to enter the human body through inhalation and subsequently traffic to the brain, inducing neurotoxicity. This study aims to investigate the formation, distribution, and health impacts of pollutant-adsorbed nanoplastics (PANs), which are composite particles formed by the adsorption of airborne pollutants onto nanoplastics. Our central hypothesis is that the physicochemical properties of resulting pollutant/nanoplastic assemblies (i.e., PANs) alter the biodistribution and toxicity of the pollutants, exacerbating their harmful effects upon inhalation. To test this hypothesis, we employ advanced label-free imaging techniques to detect and characterize PANs in environmental and biological samples. The first aim is to develop and optimize label-free methodologies that do not rely on chemical isolations for detecting and quantifying PANs collected in various environments. This includes employing advanced detection techniques such as enhanced dark field/hyperspectral imaging (EDF/HSI) and Raman spectroscopy to analyze size-segregated PANs captured from major roadways, agricultural fields, and industrially adjacent ocean spray. These analyses will inform synthesis of contrived PANs in a controllable fashion. Achieving this aim will establish optimized detection techniques and generate fundamental data on PAN concentrations in real-world environments. The second aim focuses on investigating the biodistribution, accumulation, and organ-specific toxicological impacts of PANs in rodent models. Detailed analyses will be conducted to determine PAN localization and target-specific endpoints in brain tissue using techniques like mass spectrometry imaging (MSI) and transcriptomics. The expected outcomes include a detailed understanding of how PANs travel within the body and their specific impacts on the brain, and how this depends on the specific combinations of pollutants and nanoplastics. We will investigate ubiquitous airborne nanoplastics (e.g., PE, PVC) and pollutants with known neurotoxicity (e.g., mercury, lead, diazinon, chlorpyrifos). The third aim seeks to elucidate the mechanisms by which PANs interact with and traverse the blood-brain barrier (BBB) to yield neurotoxic effects. The proposed research challenges the traditional paradigm of studying nanoplastics and pollutants as isolated entities by investigating their combined effects. By elucidating the mechanisms of PAN transport and their toxicological impacts, this study aims to provide crucial insights into the health risks posed by PANs and inform public health guidelines and regulatory policies. The findings will contribute to the development of effective strategies to mitigate the health risks associated with pollutants and nanoplastics, advancing the fields of human health and toxicology.

NIH Research Projects · FY 2026 · 2026-04

Abstract Adeno-associated viral (AAV) vectors have become the gold standard for delivery of genetic cargo the central nervous system. Remarkable efficacy and strong safety profiles have led to FDA approval of multiple AAV gene therapies for genetic disorders validating this platform as a key leader in the space. However, AAV gene therapies are still limited in certain aspects as it pertains to broadly treating and advancing to clinical trials for brain disorders. One of the key factors that determines clinical efficacy and success is related to transduction efficiency, biodistribution, and efficient transgene expression. Revolutionary progress has been made on the first two fronts through the identification of naturally occurring serotypes with CNS tropism and through capsid evolution to increase blood-brain barrier permeability and distribution, however increasing transgene expression has been limited to studies of promoter optimization. The critical barrier for transgene expression following AAV transduction is mediated through the single strand DNA virus undergoing double-strand DNA synthesis allowing for mRNA to be transcribed. This process is mediated by the only non-optimized, wild-type sequence within the AAV process, the inverted terminal repeats (ITR). This proposal aims to modernize and engineer better transgene expression through the identification and screening of a large library of ITR domains in the mouse brain. These library screens will allow for the high throughput identification of optimal ITR domains that outperform the natural ITR found in AAV plasmids and at least equivalent if not improved performance when compared to self-complementary ITR. Additionally, this proposal will explore novel mechanisms in which to enhance AAV production through increased particle secretion into the extracellular space. Through this high-risk/high-reward project we aim to provide the foundational information needed to improve upon specific aspects of AAV gene therapy effectiveness and translational capabilities. While the primary goal is to increase the efficiency in which a single strand DNA virus can efficiently form the double- strand substrate needed for transcription, this system may also enable and unlock additional benefits as it relates to AAV gene therapy such as reduced innate immune response, shorter timeframe to express therapeutic transgene therefore shorting the treatment window in which an organism could receive therapeutic rescue, improved packaging and manufacturing metrics, and the ability to lower the vector genome dose needed to achieve therapeutic efficacy thereby making these treatments safer for the patient population. Taken together, this initial screen and optimization of ITR may have an outsized impact on AAV gene therapy for those suffering from genetic neurological conditions.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY/ABSTRACT The ubiquitin-proteasome system is a cornerstone of eukaryotic cellular regulation, orchestrating critical processes such as protein homeostasis, signal transduction, cell cycle progression, and stress responses. Central to this system are E3 ubiquitin ligases, which determine substrate specificity and mediate the transfer of ubiquitin from E2 enzymes to target proteins. This research focuses on unraveling the molecular mechanisms, structural dynamics, and regulatory networks of two highly conserved and essential classes of E3 ligases: Plant U-box (PUB) ligases and a specific family of RING ligases, with a particular emphasis on their roles under biotic stress conditions. U-box and RING ligases are conserved across eukaryotes, including humans, where their dysregulation is associated with various diseases. In plants and human U-box and specific RING ligases are integral to immunity, development, and stress adaptation, yet their precise biochemical mechanisms, including substrate recognition and regulation, remain poorly understood. Our preliminary studies have provided significant insights into these ligases. We determined the crystal structure of the U-box domain of a PUB E3 ligase in complex with E2 enzyme that represents a large and highly conserved class of E2s in eukaryotes, revealing a novel dimeric interface. We discovered a redox- sensitive disulfide bond switch in the E2 enzyme that dynamically modulates ubiquitin transfer and chain formation, both in vitro and particularly under biotic oxidative stress conditions. Using proximity labeling coupled with mass spectrometry, we performed distinct experiments including mapping the interactome of a PUB E3 ligase, and investigating the RING complex module under both normal and pathogen-exposed conditions. The experiment informed dynamic proteome changes in response to pathogen exposure, uncovering new relationships and previously unknown target substrates. Additionally, our CryoEM studies of the RING complex module provided critical insights into its dynamic substrate recognition mechanisms, proposing how structural adaptations can drive ubiquitination activity. Together, these findings provide a strong foundation to scale up and expand our studies, enabling deeper exploration of structure-function relationships as well as interactome networks to reveal novel regulatory pathways and mechanisms. This project seeks to decode how U-box and RING ligases integrate into and regulate broader cellular processes. It aims to uncover the molecular mechanisms of substrate specificity, ubiquitin transfer dynamics, and regulatory networks of these ligases. Leveraging structural and functional approaches in vitro and in planta, this research will elucidate plant stress responses and reveal conserved ubiquitination pathways with broad implications for eukaryotic biology and therapeutic innovation.

NIH Research Projects · FY 2026 · 2026-04

PROJECT ABSTRACT Identifying individuals likely to respond to a specific intervention is a critical challenge in medical research. In the age of big data, where vast amounts of information are accessible, the potential for personalized interventions based on individual characteristics has become increasingly feasible. However, advancement comes with significant challenges. The sheer volume of data often leads to datasets with numerous factors which might influence outcomes. Moreover, the data may exhibit clustering or repeated measurements, with potentially informative cluster sizes, adding complexity to the analysis. For instance, researchers are interested in understanding why some pregnancies are more vulnerable to maternal immune activation (MIA), which impacts brain and behavioral development in offspring and increases the risk of autism, schizophrenia and other neurodevelopmental disorders. However, this task is complex due to the multitude of biomarkers and clustered or repeatedly measured outcomes over time and brain regions. Current statistical tools available are inadequate for handling the complexities of such data, thus impeding the progress of precision medicine. To address this significant gap, this proposal underscores the urgent need for innovative statistical methodologies that can adeptly handle the complexity of clustered and longitudinal datasets with numerous covariates, thereby advancing the field of precision medicine. By developing novel methods building on our preliminary statistical framework, integrating machine learning techniques, rigorously evaluating these methods through simulation studies that mimic real data, and applying these methodologies to real-world longitudinal and clustered datasets, we aim to make significant contributions to this field. Our preliminary simulation results and real-world examples demonstrate both the scientific merit and computational feasibility of these methods. We will apply these newly developed statistical tools to existing datasets as a proof-of-concept to uncover factors that predict susceptibility and resilience to MIA regarding the brain and behavior development outcomes in offspring. The innovative statistical methods developed hold significant promise for identifying biomarkers that elucidate the link between environmental exposure during human pregnancy and brain mechanisms associated with neurodevelopmental disorders. This advancement will assist in identifying high- risk pregnancies and tailoring interventions for offspring at risk due to MIA exposure. Furthermore, these innovative statistical approaches can be adapted to various interventions and a wide range of medical conditions. We will provide free, user-friendly programs and software to enable research communities to apply these methods easily. Consequently, this project presents a unique opportunity to tackle a complex issue in precision medicine and leverage existing datasets for groundbreaking insights.

NIH Research Projects · FY 2026 · 2026-04

Project Summary /Abstract Gd3+-based contrast agent (GBCA) enables enhanced MRI images for visualizing internal organs, tissues, and blood vessels. While GBCA is primarily considered safe, trace amounts of Gd have been detected in the bones and brains of patients after multiple administration of GBCA. Additionally, a life-threatening but rare nephrogenic systemic fibrosis disease can occur in patients with chronic kidney disease after exposure to GBCA. Currently, the use of GBCA is restricted against patients who are at risk. Hence, developing a new GBCA is of high interest from the perspective of contrasting capability and safety. However, such development requires the ability to diagnose GBCA stability both in vitro and in vivo. In this proposal, we will develop a unique high-powered 263 GHz Electron Paramagnetic Resonance (EPR) spectrometer that will enable sensitive detection and highly- resolved characterization of the Gd3+ coordination environment in both test tubes and cells. The new spectrometer will be at the forefront of Gd3+-based magnetic resonance, paving the way for describing the physical chemistry of Gd3+. We will also establish the EPR spectral features associated with Gd3+ bound to its chelating carrier or dissociated Gd3+ that has interacted with endogenous proteins. Specifically, we will use a class of lanthanide-binding peptides known as Lanthanide-Binding Tag (LBT3) and a recently discovered picomolar lanthanide-binding protein, LanM, which has invigorated the field of lanthanide biochemistry. The high- frequency Gd3+ EPR spectra contain zero-field splitting features that serve as the spectral 'fingerprint' of different Gd3+-protein interactions, crucial for diagnosing either ligand-bound or protein-bound Gd3+. Finally, we will use LanM and engineered LBT3 as candidates for new GBCAs. The picomolar affinities of these proteins, which have been exploited for commercial lanthanide extraction strategies, are also highly promising for carriers of GBCA. This research plan aims to integrate EPR methodologies to gain insight into the structural features of Gd3+-ligand and Gd3+-protein interactions for future GBCA development. The long-term goal is to develop a method that can identify the different Gd3+ complexes, either to assess the stability of GBCA in a biological context or to create new GBCAs with new coordination environments. The fellowship will support the applicant in gaining expertise in microwave engineering and protein engineering, preparing him for a well-rounded career as an investigator at the front line of magnetic resonance spectroscopy and lanthanide-related structural biology.

NIH Research Projects · FY 2026 · 2026-04

Summary Glycolysis, the fundamental metabolic process in which glucose is converted to lactate, lies at the core of diabetes and metabolic dysfunction, as well as cancer and immune function. Regulation of glycolytic rate by insulin and other endocrine signals is essential for bodily metabolic homeostasis and also plays important cell-intrinsic roles in regulating cellular proliferation, apoptosis, and differentiation. While there is a long history of quantitative modeling of glycolysis in bulk, regulation at the single-cell level has been explored in much less depth. This lack of understanding makes it impossible to know whether glucose disposal and lactate production are distributed evenly across tissues or are selectively performed by cellular subpopulations. Our lab has made significant progress in single-cell metabolism using multiplexed live-cell measurements for key points of glycolytic flux and regulation, including fructose 1,6-bisphosphate (FBP), NADH/NAD+, ADP/ATP, and kinase activities of AKT, AMPK, and mTOR. Our preliminary data in epithelial, muscle, and liver cell lines indicate an extensive degree of glycolytic heterogeneity and motivate our overall hypothesis that a small number of live-cell measurements can adequately constrain mathematical models of the glycolytic rate distributions. Specifically, we hypothesize that dual measurements of FBP and NADH/NAD+ ratio will provide strong modeling constraints that will enable the distribution of single-cell glucose disposal and lactate production rates. We further hypothesize that signaling by the AKT/AMPK/mTOR network links glycolysis rates to protein synthesis rates to create time-dependent variation and metabolic microenvironments that affect cellular processes including cell death and differentiation. In this project, we will 1) use multiplexed live-cell measurements to constrain models of single-cell glycolytic distributions and identify optimal sets of observables; 2) Measure the single-cell linkage of glycolysis and protein synthesis rates via the AKT, AMPK, and mTOR activities, and 3) create an integrated model of glycolytic flux and signaling network regulation that is currently lacking in the field. The computational models generated in these aims will fill an important gap, enabling an understanding of how glycolytic flux acts as a key information-carrying process integrated with signaling network activity. These models will make it possible to predict how cellular and tissue- level metabolism are affected by the many pharmacological signaling modulators for PI3K, AKT, mTOR, and AMPK now available. We will also gain a greater understanding of how individual cell glycolysis rates participate in cell-intrinsic processes including cell proliferation, death, and differentiation, which are central in diabetes, cancer and other diseases.

NIH Research Projects · FY 2026 · 2026-04

Project Summary Up to 40% of the U.S. population is exposed to unhealthy air pollution, with particulate matter (PM) being a major contributor. PM exposure induces oxidative stress and inflammation and leads to severe lung diseases, which is mediated by the Aryl-hydrocarbon receptor (AhR) pathway and epithelial cytokines. Despite growing evidence, the underlying molecular mechanisms are not fully understood, limiting the development of targeted interventions. Emerging research suggests that PM exposure influences N6-methyladenosine (m6A) RNA modification, which regulates RNA stability and translation, through altering the expression of proteins adding, removing and binding to this modification ("Readers", "Writers", and "Erasers", abbreviated as "RWEs"). Intriguingly, RNA m6A "read- ers" can recruit epigenomic regulators such as DNA demethylase TET1 to alter DNA methylation and chromatin accessibility, highlighting crosstalk between RNA m6A and TET1-mediated epigenomic mechanisms. Whether RNA m6A interacts with TET1 and TET1-mediated epigenomic mechanisms in airway epithelial cells, how they interact and contribute to PM-induced lung inflammation remain as significant research gaps. In response to NIEHS RFA-ES-25-001 (EPCOT), this proposal aims to investigate the interactions between TET1-mediated epigenomic mechanisms and RNA m6A in PM-induced lung inflammation. Our preliminary data established a novel role of TET1 in protecting against PM-induced lung inflammation and remodeling, through promoting the expression of detoxifying enzymes downstream AhR signaling and restricting proinflammatory cytokines. Our data also suggest a novel, noncanonical role of TET1 in regulating chromatin accessibility and CTCF looping to regulate gene expression, in addition to DNA methylation and histone modification, in human bronchial epi- thelial cells. Importantly, we found that TET1 regulates the expression of RNA m6A RWEs in HBECs and mouse lungs, through both canonical and non-canonical roles, resulting in changes in global RNA m6A. Collectively, we hypothesize that TET1 mediates interactions between multiple epigenomic mechanisms and RNA m6A to re- strict PM-induced lung inflammation. To test this hypothesis, we will examine how TET1 regulates m6A RWEs in airway epithelial cells by analyzing 5mC/5hmC, histone modifications, chromatin accessibility, and CTCF-medi- ated looping in response to PM exposure in Aim 1. In Aim 2, we will identify genome-wide RNA m6A changes following PM exposure and TET1 loss and determine the impact of these changes on mRNA stability and protein translation of target genes, especially those contributing to lung inflammation. In Aim 3, we will identify genomic locations with both RNA m6A and TET1-regulated epigenomic features, investigate interactions between TET1 and m6A readers at these locations, and evaluate the impact of PM exposures on these interactions. Leveraging a highly collaborative research team with complementary expertise, unique PM samples and resources, and state-of-the-art technologies, the proposed research is expected to provide novel mechanistic insights into PM- induced pulmonary toxicity and disease, potentially leading to targeted interventional strategies.