University Of California-Irvine

NIH Research Projects · FY 2026 · 2026-05

Project Summary: Chronic metabolic diseases, such as diabetes, are major global health threats and one of the most pressing and costly biomedical challenges today. Developing more effective treatments is essential. Accumulating evidence suggests that the brain, particularly the hypothalamus, plays a vital role in regulating glucose homeostasis. Hypothalamus dysfunction significantly contributes to diabetes. Furthermore, targeting the hypothalamus, especially the arcuate nucleus, shows promise in improving diabetic conditions. Despite its significance, the role of the brain in glucose homeostasis and diabetes pathogenesis remains poorly understood. Recent findings have identified a previously uncharacterized population of leptin receptor-expressing neurons, termed basonuclin 2 (BNC2) neurons, within the hypothalamic arcuate nucleus. These neurons have been implicated in rapid satiety regulation and energy balance, addressing a critical gap in the understanding of hypothalamic control of feeding behavior. Notably, preliminary data suggest that BNC2 neuron activity directly influences peripheral glycemia. Furthermore, genome-wide association studies (GWAS) have established a significant correlation between the Bnc2 gene and metabolic disorders, including diabetes and obesity, underscoring the relevance of BNC2 neurons in metabolic homeostasis and their potential as therapeutic targets. This study aims to elucidate the role of BNC2 neurons in glucose regulation and evaluate their therapeutic potential in diabetes and insulin resistance. Glucose homeostasis is primarily coordinated by hormone-secreting endocrine cells in the pancreas and by glucose production and utilization in peripheral tissues like the liver, muscle, and adipose tissue. Preliminary data suggest that activating BNC2 neurons impacts the function of specific metabolic processes and target organs. To further investigate these mechanisms, this study will first determine whether BNC2 neurons influence target organ function through direct neuronal connections. Next, the molecular pathways underlying BNC2 neuron regulation of these organs will be elucidated. Multiplexed single-nucleus RNA sequencing (snRNA-seq) will be employed to profile cell-specific changes in target organs induced by BNC2 neuronal activity, followed by functional validation using genetic tools. Lastly, the impact of BNC2 neuron modulation on glucose metabolism will be evaluated in diabetic and insulin-resistant conditions using mouse models of both type 1 and type 2 diabetes. Altogether, the successful completion of this project will provide mechanistic insights into how BNC2 neurons regulate glucose homeostasis and potentially identify new therapeutic avenues for diabetes and insulin resistance.

NSF Awards · FY 2026 · 2026-05

As the demand for additional compute power and memory continues to increase, the semiconductor industry is shifting towards ultra-large-scale systems capable of providing orders of magnitude greater compute-memory capacity. Applications such as high-performance compute, neural networks, and large language models, stand to benefit significantly from such systems. Some homogeneous ultra-large-scale systems exist today, however, due to yield challenges and lack of heterogeneity, the industry is clearly shifting towards chiplet-based heterogeneous integration platforms. The technology for chiplet-based systems is becoming rapidly available. However, the design aspects of such systems are yet to be addressed. One of the key challenges of ultra-large-scale systems is the communication among chiplets. To address the communication challenge, a network is required that considers the specificity of the technology, chiplets, and scale of the systems. This project stands to significantly impact the way we design computational systems, stepping away from classic architectures and enabling heterogeneous plug-and-play chiplet-based design. The following are the main thrusts of this project: 1) A communication network architecture for chiplet-based ultra-large-scale systems that includes compatible network topologies and allocation of high-bandwidth domains. 2) Routing and built-in self-test algorithms that will consider the limitations of advanced integration technologies. 3) A unified memory architecture where not only memory is shifted, as is typical in modern architectures, but rather both compute and memory can be relocated to enable efficient computation and enhanced performance. 4) Standards interfacing enabling efficient communication among heterogeneous components such as high-bandwidth memory stacks and compute chiplets. 5) Validation of the proposed topologies, methodologies, and algorithms through circuit design and simulation. 6) A comprehensive education, training, and mentoring plan integrated with the proposed research. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2026 · 2026-05

Enzymes catalyze chemical reactions. They can improve chemical processes, but there are major challenges to realizing their full potential. Most chemical processes involve harsh conditions. These can be high temperatures, extreme pHs, and the presence of organic solvents. This project will identify enzymes that work under harsh conditions by exploiting two characteristics of spores. Spores are highly resistant to harsh conditions, and they can be engineered to display proteins on their surfaces. The experimental strategy will be to generate a large number of mutated enzymes that are displayed on spore surfaces. The spores will then be subjected to a variety of harsh conditions mirroring those found in chemical processing facilities. The mutants that exhibit the desired activity under those conditions will be selected for characterization and additional rounds of mutations. The project will support outreach activities for local high school and community college students that will encourage them to join the biomanufacturing workforce. Combining directed evolution with enzyme immobilization is challenging. Immobilization can cause physical changes that diminish the improvements achieved through enzyme mutation. Traditional evolution methods are low-throughput and incompatible with high-throughput screening due to detrimental effects on cell viability. The overall goal will be to establish a directed evolution workflow for surface-displayed enzymes on Bacillus subtilis spore particles. Directed evolution will be integrated with enzyme immobilization on the spore surface, leveraging the chemical resilience, retained genetic information, and proliferation capability of bacterial spores. The first step will be to develop a high-throughput fluorescence-activated cell sorting (FACS) screening workflow using engineered chemical probes to directly visualize enzymatic activity. Then, a randomized enzyme library will be generated and displayed on the spore surface. This will be followed by identification and characterization of enzyme variants with enhanced performance in harsh environments. The major developments of this research are expected to be three-fold. First, the FACS screening workflow will dramatically improve throughput for directed evolution studies. Second, the spore display strategy will further increase throughput by affording the simultaneous screening for activity in harsh conditions while immobilized. Finally, characterization of mutations that confer enhanced activity under harsh conditions could lead to design rules applicable across a wide range of enzymes with industrial relevance. 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

Heat waves are increasing across the U.S., altering the health of coastal ecosystems and, by extension, the health and welfare of the American public who depend on coastal resources. The success of coastal systems may depend on species that create habitat, protecting the overall ecological community from heat-wave impacts. Seaweed canopies and shellfish beds can provide shade and retain moisture, maintaining a cooler, damper environment that buffers the effects of heat waves. This project evaluates the ability of two of the most abundant habitat-forming species on the U.S. coastline – rockweeds and mussels – to maximize the survival of coastal species experiencing increasing heat waves along the west coast of North America from California to Alaska. The project combines observations during natural heat-wave events, heating experiments, and physiological studies of habitat-formers and the plants and animals they support to identify the vulnerabilities and refuges within the coastal ecosystem during these extreme events. The project will also provide training opportunities for students, expand course-based research experiences, and support outreach and knowledge exchange with environmental management agencies and the public. Together, these activities strengthen scientific capacity and improve understanding of coastal ecosystem resilience in a changing environment. To evaluate the ability of coastal foundation species to mitigate impacts of extreme heat events, the investigators test the hypothesis that foundation species are more tolerant of heat waves than the associated species that they support. Rockweeds and mussels are abundant foundation species likely to withstand stressors that other, facilitated species are unable to tolerate. But intensification of heat-wave events could push foundation species beyond their limits. There is a critical need to understand the potential for foundation species to mitigate impacts of heat waves or for cascading local extinctions to occur associated with their losses. The investigators combine observations during natural heat-wave events and in situ heating experiments with measurements of environmental conditions and physiological performance of foundation species and associated species. The objectives are to (i) quantify foundation species’ facilitation of associated communities by mitigating environmental stress; (ii) determine susceptibility of foundation species to heat-wave conditions and how their loss reshapes intertidal communities; (iii) identify physiological mechanisms underlying susceptibility of foundation and associated species to temperature stress; and (iv) predict outcomes of intensifying heat waves for foundation species and associated communities. The results of this research lay a strong foundation for anticipating the impacts of extreme heat events on the health of coastal ecosystems. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY Acute myeloid leukemia (AML) is an aggressive, devastating cancer with limited treatment options. AML progresses rapidly and presents significant treatment challenges due to its immunosuppressive tumor microenvironment , which impairs immune cell function. Group 1 innate lymphoid cells (ILCs), including natural killer (NK) cells and ILC1s, play key roles in immunity. ILC1s reside in tissues and were initially believed to function primarily by secreting cytokines such as IFN-γ, TNF-α, and GM-CSF. However, their anti-tumor activity has been largely unknown. In 2022, we addressed this gap and published our discovery in Nature Immunology as a cover story. We found that ILC1s isolated from AML patients are functionally impaired, whereas ILC1s from healthy mice are significantly more potent. Healthy ILC1s induce the death of leukemia stem cells (LSCs), block LSC differentiation into leukemia progenitor cells, and promote the transition of LSCs into non-leukemic lymphoid progenitors. Mechanistically, normal ILC1s target LSCs by secreting IFN-γ and engaging receptor-ligand interactions (e.g., DNAM-1–CD155 and IL-7 receptor–IL-7). Despite identifying key features of ILC1s and their role in inhibiting LSCs, important questions remain unanswered. It is still unclear how ILC1s develop in vivo under normal or AML conditions, and the mechanisms through which ILC1s induce LSC death and differentiation in humans are largely unexplored. Moreover, the therapeutic potential of ILC1s remains unknown. We hypothesize that ILC1s possess strong anti-LSC activity and unique developmental pathways, offering a novel approach to control or treat AML and potentially prevent its relapse. The goals of this project are to elucidate the mechanisms of ILC1 anti-tumor activity, characterize their developmental pathways, and explore their therapeutic applications. In Aim 1, we will dissect the mechanisms by which ILC1s induce LSC death (e.g., via pyroptosis) and drive M1 polarization of LSC-differentiated myeloid cells in humans. In Aim 2, we will characterize ILC1 developmental pathways in both normal and AML conditions. Leveraging our expertise in developing adoptive cellular therapies, including chimeric antigen receptor (CAR) NK cells for AML, in Aim 3, we will study novel FLT3-targeting CAR ILC1s that we generated. FLT3 is highly and selectively expressed on AML blasts and LSCs, making it an ideal target. We will generate allogeneic, off-the-shelf, ready-to-use FLT3- CAR ILC1s from umbilical cord blood CD34⁺ cells or by converting NK cells into ILC1s, which we demonstrated. These CAR ILC1s will be tested for their anti-AML efficacy in preclinical models and compared to unmodified ILC1s. Additionally, we will combine ILC1s or FLT3-CAR ILC1s with NK cells and an FDA-approved tyrosine kinase inhibitor, which upregulates FLT3 expression on AML cells. Finally, we propose to reprogram endogenous ILC1s by treating them with IL-7 to enhance their activity. A deeper understanding of ILC1 development and function, anticipated through the completion of this study, holds significant promise. The knowledge gained could lay the groundwork for diverse therapeutic strategies that have the potential to reduce mortality in AML patients.

NIH Research Projects · FY 2026 · 2026-04

Protoacoustic Imaging for 3D Mapping the Bragg Peak in Real Time during Proton Therapy, PI: Shawn (Liangzhong) Xiang Proton therapy is witnessing rapid expansion, with 279,455 patients treated globally by 2021 and nearly 110 centers currently operating worldwide. However, accurately localizing the Bragg peak remains substantial challenge. This can require extending the proton beam beyond the tumor, risking damage to healthy tissues, especially when organ movement occurs during therapy. To tackle these issues, this project will develop a novel imaging technology, protoacoustic imaging, designed to precisely verify the Bragg peak's location in real-time during treatment directly on patient. The initiative will create a dual-modality protoacoustic/ultrasound imaging system to: 1. Precisely monitor the Bragg peak's position. 2. Actively manage organ motion during proton therapy. The project's specific aims include: • Aim 1: Evaluate protoacoustic/ultrasound imaging for Bragg peak localization using animal models. • Aim 2: Develop a protoacoustic/ultrasound imaging system for clinical implementation. • Aim 3: Conduct clinical trials (Phase 0) to validate protoacoustic/ultrasound guidance in patients. Achieving these objectives will enhance the precision of proton therapy, allowing for accurate localization of the Bragg peak and real-time radiation dose adjustments, thus maximizing therapeutic benefits and minimizing risks to patients.

NIH Research Projects · FY 2026 · 2026-04

ABSTRACT Checkpoint blockade immunotherapy (CBI) by inhibiting PD1 has provided durable benefits in ~40% of patients with metastatic melanoma and several patients with Merkel cell, non-small cell lung, squamous head and neck, and clear cell kidney cancer. However, PD1 blockade alone and in combination with blockade of other checkpoints (“dual” CBI) still fails in most patients and tumor types. There is an urgent need to understand the underlying reasons; otherwise, CBI will remain ineffective in most cancer patients. One poorly appreciated aspect of PD-1 blockade is that it triggers not only anti-tumor but also immunomodulatory responses, at least partly mediated by T regulatory cells (Tregs). Based on existing literature and extensive preliminary data, we hypothesize that the effect of PD-1 monotherapy on tumor Treg biology depends on the type of antigens expressed by the cancer (CD8-stimulating neoantigens or Treg-supporting dominant autoantigens), the type of DC presenting the antigens to Tregs, and various Treg-supporting pathways instructed by other cells in the tumor immune environment. Moreover, we posit that CBI modulates the spatial organization of the tumor environment and instructs immunosuppression, for instance, by causing the localization of effector T cells to areas of suppressive cytokine or metabolic signaling. The rationale of our study is that understanding the mechanisms of immunosuppression triggered by CBI is a prerequisite to disabling them and increasing the therapeutic efficacy of immunotherapy. Aim 1 will investigate the mechanisms of Treg support enabled by PD-1 blockade. We will study the role of different classes of antigens, and of the DC subtypes presenting them, using functional intravital microscopy. We will also use cell communication analysis of various RNA sequencing data to unbiasedly identify the signaling pathways that support Treg numbers or function after PD-1 blockade. Aim 2 will systematically explore the resistance mechanisms to PD-1 blockade associated with the inhibition of CTLA-4, Lag-3, and ICOSL, specifically focusing on the immunosuppressive spatial reorganizations of the tumor environment that occur after dual CBI. We will stratify animals based on response (or lack thereof) to dual CBI and examine differences in immune cell numbers, phenotype, and spatial organization relative to various intratumor niches via high-resolution spatial sequencing. Finally, we will block the identified mechanisms of adaptive immunosuppression to ameliorate the therapeutic outcome of dual CBI in human-relevant preclinical models. At the conclusion of the proposed project, we would have obtained a mechanistic understanding of the immunosuppressive reactions that cause resistance to PD-1-based CBI. Such knowledge will be instrumental in optimizing clinical immunotherapy and extending its benefits to otherwise resistant patients.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY / ABSTRACT Vaccines have been very effective at protecting against infectious diseases that pose serious threats to human health, but they can also be limited if the pathogens demonstrate antigenic drift, as is the case for influenza. This genetic drift causes mismatches between antigens in the vaccines vs. in the circulating strains, resulting in vaccines that lose neutralization potency against the new variants. Recent studies have shown that the release kinetics of vaccines can be important in establishing lasting and efficacious immunity. In particular, extending the exposure time to antigens can result in higher antibody titers and increase the breadth of neutralizing antibodies that target a broader range of epitopes (relative to conventional bolus vaccination). This can prevent the concern of low vaccine potency after viral mutations. To develop a single-administration vaccine platform based on these premises, we use a H5N1 avian influenza virus model, a pathogen for which the human population currently does not have existing immunity. We have shown that combining the effects of nanoparticles to effectively present H5 hemagglutinin antigen, together with slow release from a thermo-responsive PLGA- PEG-PLGA polymer depot to give extended antigen exposure, will elicit increased durability of the immune response, a broader cross-reactivity for viral variants, and protection from H5N1 infection. Many questions still remain, however, regarding the mechanisms by which this is accomplished and the optimization of this nanoparticle-hydrogel vaccine platform. Our specific aims are to: (1) determine optimized conditions for a nanoparticle-hydrogel vaccine platform and understand the contributing factors of their immune effects, (2) broaden cross-reactivity by incorporating antigens into nanoparticle-hydrogel vaccines that will generate homosubtypic and heterosubtypic responses, and (3) evaluate the cross-reactive and protective effects of combined, optimized vaccine elements. Because these vaccines are modular, and different antigens can be exchanged in a relatively straightforward approach, the successful implementation of this proposed strategy would have wider applicability towards the development of vaccines for other infectious pathogens and for universal flu vaccines.

NIH Research Projects · FY 2026 · 2026-03

Summary Effective treatment of advanced cancers remains a major challenge due to therapy resistance and limited response rates. This proposal aims to develop a genetic screening approach to systematically identify and exploit drug-diet interactions that enhance cancer therapy efficacy by leveraging cancer- specific metabolic vulnerabilities. By integrating precision dietary interventions with targeted therapies, we seek to improve treatment selectivity, minimize side effects, and expand therapeutic options, particularly for aggressive or treatment-resistant cancers. Our approach is based on the premise that cancer cells exhibit distinct metabolic dependencies, which can be exacerbated under diet-induced metabolic stress. We propose to establish an unbiased, parallel screening platform using syngeneic orthotopic pancreatic ductal adenocarcinoma (PDAC) models to evaluate the interaction of over 2,000 drug targets with a defined dietary intervention that affects cancer cell proliferation. Promising drug-diet synergies identified from this screen will be further validated by assessing the impact of diet on drug efficacy in vivo. By focusing on clinically relevant compounds and personalized dietary strategies, this research has the potential to rapidly translate into novel combination therapies. The proposed study will provide a foundational framework for leveraging metabolic stress to enhance the effectiveness of existing cancer treatments, paving the way for innovative precision medicine approaches in oncology.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY Nitrogenase catalyzes the reduction of atmospheric dinitrogen to bioavailable ammonia, a process that supports the existence of the entire human population. Additionally, nitrogenase reduces carbon monoxide to hydrocarbons, highlighting its potential for coupling environmental health with sustainable energy production. Unlike industrial Haber-Bosch (ammonia synthesis) and Fischer-Tropsch (carbon fuel synthesis) processes, nitrogenase operates at ambient conditions with protons and electrons as reducing agents, making it an attractive model for chemical energy conversion. Our long-term vision is to advance the mechanistic understanding of nitrogenase assembly and reactivity while leveraging its unique properties for innovative, environmental sustainability applications. In the next five years, we propose to use combined genetic, biochemical, spectroscopic and structural approaches to investigate how M-cluster, the unique metallocofactor of the molybdenum nitrogenase, is assembled into a functional unit, with a focus on the radical SAM-dependent carbide insertion concomitant the formation of an 8Fe cofactor core, the in vivo source and insertion mechanism of the ‘9th sulfur’. and the mobilization of Mo for cofactor maturation. Through our proposed studies, we expect to further refine the biosynthetic pathway of the unique metallocofactor of nitrogenase, which will provide crucial insights into the structural-functional relationship of this important enzyme and reveal general principles of the assembly mechanisms of complex metalloclusters in biological systems. Additionally, we will explore the reactivity of the vanadium nitrogenase, notable for surpassing its molybdenum counterpart in its capacity to reduce carbon monoxide to hydrocarbons. This unique trait of vanadium nitrogenase makes it a valuable tool for carbon recycling. In the next 5 years, we will use hybrid systems of vanadium nitrogenase to dissect its reactivity toward carbon monoxide by accumulating intermediates through modulation of electron flux (via heterometal variation), proton flux (via organic compound alteration), and electron availability (via mismatched electron donors). Through our proposed studies, we expect to identify novel strategies that can also be applied to the mechanistic investigations of enzymatic dinitrogen reduction, as well as establish prototype systems for developing nitrogenase-based applications that recycle carbon wastes into useful chemical products.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY Nitrogenase is a complex metalloenzyme central to the global nitrogen cycle, catalyzing the reduction of atmospheric nitrogen to bioavailable ammonia. Termed biological nitrogen fixation, this fundamental process provides ~200 million tons of reduced nitrogen annually, sustaining Earth's ecosystems. Despite decades of research, the (1) enzymatic mechanism and (2) heterologous expression of nitrogenase remain elusive, presenting opportunities for innovation. With respect to 1, the traditional mechanistic thinking of nitrogenase has been driven by the presumption of a structurally ‘static’ cofactor during catalysis. Our recent structural observation of asymmetric belt-sulfur displacements with distinct dinitrogen species in the two cofactors of Mo-nitrogenase invokes a novel mechanism of N2 reduction that necessitates dynamic structural rearrangements of the cofactors during catalysis. In the next 5 years, we will use genetic, biochemical, spectroscopic and structural approaches to probe this novel reaction mechanism, demonstrating the stepwise N2 reduction at the three belt-sulfur sites of each cofactor and illustrating the alternate interaction between the two components of Mo-nitrogenase that drives the coordinated reaction sequences via asynchronous rotation of the two cofactors. These studies will establish a much-needed framework for further exploration of the intricate reaction mechanism of nitrogenase and, in the long run, facilitate the development of nitrogenase-based applications. With respect to 2, efforts to heterologous express nitrogenase have been focused on introducing a complete gene set into a foreign host like E. coli via a ‘top-down’ approach. However, this approach faces challenges in ensuring proper assembly of the key intermediates that eventually give rise to a functional nitrogenase. Our recently developed ‘bottom-up’ strategy allowed a systematic reconstruction of the nitrogenase assembly pathway in E. coli and the ultimate expression of an active prototype nitrogenase, albeit with reduced activity under anaerobic conditions. In the next 5 years, we will use protein-engineering and synthetic-biology methods to enhance the functionality of our prototype nitrogen-fixing system through optimization of the nitrogenase assembly pathway, engineering of the electron and energy supplies in the E. coli host, and implementation of the mechanism of oxygen tolerance in this expression system. These efforts will provide strategies that can also be applied to the heterologous expression of other complex metalloenzymes, thereby advancing both fundamental science and general biotechnological innovation.

NIH Research Projects · FY 2026 · 2026-03

K12 PROJECT SUMMARY The goal of the proposed K12 program is to provide a robust mentored career development environment that pursues the following specific aims. Specific Aim 1: Champion mentored career development by nurturing an integrated K12 program that consists of outstanding leadership and oversight at all levels. Our Education Leadership Team (ELT) consists of Program Directors, Associate Directors, and a Program Administrator. The ELT works closely with the ICTS UM1 Workforce Development Module Team (WDT), the K12 External Advisory Committee (EAC), and a nationally recognized ICTS Survey Evaluation Tracking (SET) Team. The oversight of the program is highlighted by our Scholar-Mentor Alignment and Individual Development Plan meetings, a strong SET process, and a Quality by Design paradigm. Our ICTS partners [Children’s Hospital of Orange County (CHOC) and Long Beach Veterans Association Hospital (LBVA)] will participate in our EAC and quarterly meetings with the ELT. Specific Aim 2: Maximize access to the K12 program, optimize scholar-mentor alignment, and accelerate career development. We will: 1) support the training of four ICTS K12 scholars per year, and 2) continue our Affiliated Scholars Advancement Program (ASAP) which significantly expands training opportunities for unfunded scholars interested in pursuing Clinical Translational Science and Research (CTS&R). Specific Aim 3: Provide a flexible and innovative curriculum that emphasizes both core competencies and advanced concepts in CTS&R. Focused Flexible Accelerated Studies (FFASt) is an immersive set of courses and experiential opportunities developed to expose our scholars to core and advanced competencies in CTS&R. FFASt courses also play a central role in our extensive Responsible Conduct of Research and Reproducibility curriculum. Our FFASt curriculum has always included key elements necessary for nurturing the development of our scholars becoming more proficient as: 1) domain experts, 2) boundary crossers, 3) team players, 4) process innovators, 5) skilled communicators, 6) systems thinkers, and 7) rigorous researchers. Our monthly Journal Clubs include modules which provide additional focus on these key skills. Specific Aim 4: Integrate local, regional, and national insights to transform CTS&R training. The breadth of our program’s integration at the local and regional levels is highlighted by key elements such as: 1) K-ECO, which is a survey of the training landscape at UC Irvine, CHOC, and LBVA, and is used to inform our K12 program and key leaders throughout our campus, 2) a campuswide KT PI Training Council we created and lead, 3) collaboration between the ELT and UC BRAID to create the K Scholar Initiative which will financially support an annual K Scholar Meeting for all CTSAs within the University of California system, and 4) the Western CTSA Education consortium, which consists of 11 CTSAs from California, New Mexico, Oregon, and Washington.

NIH Research Projects · FY 2026 · 2026-03

ABSTRACT Urinary stone disease (USD) is highly prevalent and contributes a substantial proportion of healthcare costs related to kidney and urologic disease. Approximately half of children and adults suffer recurrent symptomatic stone events, resulting in emergency department visits and surgery. More than a condition with episodic occurrence of debilitating events, USD is a disorder of mineral metabolism with substantial morbidity, including increased future risk of chronic kidney disease, fracture, hypertension, and cardiovascular disease. Despite the high prevalence and burden of USD, advances in the understanding, treatment, and prevention of USD have stalled due to deficiencies in available data resources. These critical gaps include lack of clinically important information, lack of longitudinal data, reliance on single-center designs that segregate pediatric and adult patients, and exclusion of key stakeholders in database design. To address this need, this proposal creates the Urinary Stone Disease Hub (USDHub), a readily accessible research resource for the broad research community that would support a wide range of impactful clinical investigation to improve the health of children and adults with USD. USDHub will generated from 10 health systems in the United States that participate in STAR and PEDSnet, two PCORnet clinical research networks that have standardized electronic health record data. We will ensure that the content and structure of USDHub has value to the USD research community by including stakeholders, including patients and caregivers. This work will include the following three Aims: First, we will create a research cohort of >230,000 individuals across the lifespan with USD. We will link extant structured data from the PCORnet common data model to 24-hour urine results and stone composition data. Second, we will enrich USDHub with information extracted from CT images and clinical notes using natural language processing and machine learning methods. Third, we will broadly disseminate USDHub to researchers using sustainable data access model. We will partner the USD research community to user test and refine the data access process. To maximize USDHub’s impact, we will provide pilot grants, clinics to orient researchers to USDHub data, and partner with professional organizations to disseminate USDHub to the broader USD research communities. The outcome of this work will be a new research ecosystem for investigators to generate impactful real-world knowledge that will transform the way USD research is conducted and thereby improve care and outcomes for the growing number of individuals living with the disease. This resource will spur and accelerate hypothesis-testing research and lead to impactful and clinically meaningful discoveries that improve the health of individuals and populations with USD across the lifespan.

NIH Research Projects · FY 2026 · 2026-02

Project Summary / Abstract: Vancomycin-Teixobactin Conjugates Antibiotic resistance is a growing public health crisis, with Gram-positive bacterial infections—including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE)—causing over 2.8 million infections and 35,000 deaths annually in the U.S. Vancomycin has been a mainstay antibiotic for treating Gram-positive infections, but resistance mechanisms such as the D-Ala-D-Lac modification in VRE significantly reduce its efficacy. Teixobactin, a promising antibiotic targeting the pyrophosphate group of lipid II, has potent activity but suffers from poor solubility and aggregation, hindering its clinical translation. This proposal aims to develop novel vancomycin-teixobactin conjugates that combine the strengths of both antibiotics to overcome vancomycin resistance while addressing teixobactin’s formulation challenges. The central hypothesis is that linking vancomycin to the minimal teixobactin pharmacophore will create conjugates with dual lipid II binding capability, restoring activity against resistant Gram-positive pathogens. The proposed research will: 1. Optimize vancomycin-teixobactin conjugates through structure-activity relationship (SAR) studies by modifying key functional groups, linker chemistry, and teixobactin residues to maximize antibacterial activity while minimizing cytotoxicity. 2. Evaluate the in vitro efficacy of lead conjugates against clinically relevant strains of MRSA, VRE, and VISA, and conduct time-kill and resistance studies to identify bactericidal compounds with low resistance potential. 3. Assess in vivo efficacy and pharmacokinetics (PK) using a neutropenic mouse thigh infection model, preliminary ADME (Absorption, Distribution, Metabolism, and Excretion) profiling, and single-dose PK studies, in order to identify a lead compound suitable for further preclinical development. This research is innovative because it leverages synergistic antibiotic targeting by combining vancomycin’s D-Ala-D-Ala binding with teixobactin’s pyrophosphate targeting, thereby restoring vancomycin’s efficacy against resistant pathogens. The successful completion of this study will identify a lead vancomycin-teixobactin conjugate with strong in vitro and in vivo activity, setting the foundation for future preclinical and clinical development. This work has the potential to establish a next-generation antibiotic strategy for treating multidrug- resistant Gram-positive infections, ultimately improving patient outcomes and public health.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY/ABSTRACT Trauma remains a leading cause of death globally, with hemorrhage being a significant contributor. The need for improved trauma care and management is evident, especially in reducing mortality related to hemorrhagic shock and addressing racial disparities in trauma outcomes. This project aims to develop a novel, integrated, wearable hemodynamic platform (iMOMS) designed for the early detection and management of hemorrhage, leveraging advancements in Micro-Electro-Mechanical Systems (MEMS), laser speckle imaging (LSI), and diffuse optical spectroscopy (DOS). By integrating these technologies with machine learning algorithms, iMOMS promises to enhance trauma care through improved monitoring of vital signs and hemodynamic parameters, thus facilitating timely interventions. We will pursue the following Aims: 1) Validate the iMOMS platform in a rabbit model of hemorrhage, focusing on the accurate, continuous measurement of vital signs and hemodynamic parameters. This aim tests iMOMS' ability to monitor and record heart rate, blood pressure, cardiac output, blood flow, hemoglobin oxygen saturation, and oxygen consumption during controlled hemorrhage, leveraging the rabbit model's physiological similarities to humans. 2) Develop and refine a machine learning model to predict hemorrhage by integrating multimodal data streams from humans and rabbits. This includes building an MMML model to identify early indicators of hypovolemia and creating a model for more accurate hemorrhage prediction in humans through transfer learning and domain adaptation from the animal model. 3) Test the iMOMS prototype and ML model in the operating room on patients at high risk for hemorrhage. This includes determining the accuracy of monitored vital signs and testing and refining the ML model developed in Aim 2 for predicting hemorrhage in various surgical patients. The successful completion of this project is expected to have a significant impact on trauma care by providing a reliable, non-invasive, and comprehensive monitoring system capable of early hemorrhage detection. By improving the accuracy and timeliness of interventions, iMOMS has the potential to save lives and advance the field of trauma management significantly.

NIH Research Projects · FY 2026 · 2026-02

The poxviruses comprise a major virus family of medical, ecological and agricultural importance. Although the key family member, smallpox, was eradicated some 45 years ago the risk of reintroduction or reconstruction remains real. The possibility of (enhanced) smallpox re- appearance at a future time has increased substantially with the recent demonstration of the facile recreation, de novo in the laboratory, of a poxvirus genetically very similar to smallpox. Moreover, the cessation of smallpox vaccination has coincided with the progressively more widespread (global) appearance of human Monkeypox (Mpox) with a minor 2003 outbreak reaching the USA and more recently the 2022 clade IIb global outbreak (99,000+ cases, 0.2% cfr). There have been continuing smaller outbreaks since, including a clade Ib outbreak in Central Africa (2023-2024, 29,000+ cases, 43% cfr with cases reported in the US and Canada). Two FDA-approved anti- orthopoxviral drug are TPOXX (stockpiled in the US and with a relatively low barrier to resistance) and Brincidofovir (with a black box warning). Emergency interventions include Vaccinia Immune Globulin. Additional drugs would be valuable for combinatorial or sequential use. Perhaps the richest source of potential viral drug targets is provided by the protein interfaces forming during virion morphogenesis in which the relative complexity of the vaccinia virion presents a therapeutic Achilles heel. This may be an under-exploited environment for rational drug design. Although the ultrastructural transformations occurring during Vaccinia virion morphogenesis are relatively well understood, protein interactions at the molecular level are not. The P.I. has achieved a biochemical affinity purification of the Vaccinia virus nucleus-factory (NF) complex, that now can be characterized at the molecular level. In Aim 1 of this proposal, the P.I will characterize its quantitative proteome to define the proteins present and their relative amounts. In Aim 2, via protein-protein chemical crosslinking mass spectrometry (XLMS), the P.I. will aim to identify protein-protein interfaces in the NF-complex while distinguishing proteins present in the factory from those in the associated nucleus. The P.I. already has successfully applied an XLMS approach to discover domain-level protein interfaces in situ within the vaccinia virion. In Aim 3, the P.I. will attempt to associate specific protein interfaces with specific morphogenic forms in the virus’s developmental pathway, by applying XLMS to the factories of mutant viruses, with repressible genes, that cease morphogenesis while yielding relatively homogeneous populations of morphogenic intermediates.

NIH Research Projects · FY 2026 · 2026-02

New treatments are desperately needed to control the ongoing tuberculosis (TB) pandemic. Newly emergent antibiotic-resistant strains of Mycobacterium tuberculosis (Mtb), the causative agent of TB, are hampering control efforts. Mtb is an unusual pathogen with the remarkable ability to cause both acute life-threatening disease and symptomless latent infections that can last a lifetime. It is estimated that 25% of the world has latent tuberculosis, and in 2023 alone, there were more than 8.2 million TB cases and 1.3 million deaths, making Mtb the leading cause of infectious disease world- wide. Mtb is such a successful pathogen partly due to its extraordinary metabolism; part of its virulence stems from the metabolic flexibility to utilize and scavenge a range of nutrients derived from its human host. A fundamental and currently unanswered question regards how the bacterium regulates its metabolism to cause infection. Answering this question is of therapeutic significance as targeted dysregulation would both starve the bacteria and prevent it from successfully colonizing the human host, effectively killing the bacteria and stalling pathogenesis. We have discovered a novel regulatory system that Mtb requires to consume essential energy sources for its survival in the host and to cause disease. Our hypothesis is that Virulence Associated Dikinase (VadK) coordinates metabolism and virulence by interacting with partner proteins. Importantly, VadK also represents a novel drug target. We will test this hypothesis using a combination of biochemistry, structural biology and microbiology. We will investigate how VadK physically and functionally interacts with its partner proteins to gain insights into how this novel histidine kinase system functions, while also unraveling the mechanism of action of VadK.

NIH Research Projects · FY 2026 · 2026-02

The supplement instructions PA-26-001 state: “At a minimum, the Research Strategy or Program Plan section, as applicable, must be completed and must include a summary or abstract of the funded parent award or project. Other sections should also be included if they are being changed by the proposed supplement activities.” The original Project Summary/Abstract document has not changed as a result of the proposed supplement activities.

NIH Research Projects · FY 2026 · 2026-02

PROPOSAL SUMMARY Autoimmune diseases remain challenging to treat due to a lack of therapies that specifically target immune dysregulation without inducing generalized immunosuppression. Dysregulated immunoregulatory networks drive autoimmune disorders and are often associated with imbalances in regulatory T (Treg) and effector T (Teff) cells. Treg cell therapy or selective expansion of Treg cells in vivo can shift the Treg/Teff balance towards Treg cells to resolve ongoing inflammation and promote tissue repair to restore function and improve overall quality of life. However, selective and functional expansion of Treg cells during ongoing autoimmune conditions (i.e., therapeutic use) has been challenging. This is mainly because immune regulatory networks are complex, and our knowledge of the cellular and molecular choreography of Tregs in tissues is still evolving, particularly in the context of autoinflammatory disorders of the central nervous system (CNS). Treg cells hold tremendous potential to not only stop the course of the disease but also to restore neuronal function by inducing the repair of damaged axons. Therefore, our main objective is to investigate key principles of expansion of Treg cells to limit the pathophysiology of CNS autoimmunity and promote myelin repair. Capitalizing on the multiphoton imaging, state-of-the-art ratiometric calcium indicator, Salsa6f, label-free detection of myelin lesions, we aim to identify the role of combinatorial activation of T cell receptor (TCR), IL-2 signaling, and TGF-beta signaling for expansion of Treg cells in vivo. Using immunomodulatory Treg expanding biologics (TREBs) and experimental autoimmune encephalomyelitis (EAE), a model of MS-like disease, we will determine target engagement, biodistribution, and immunosafety of combinatorial Treg-expanding biologics (Aim 1); and define cellular and molecular determinants of Treg expansion and evaluate therapeutic efficacy in models of CNS autoimmunity (Aim 2). We postulate that selective expansion of Treg cells is an ideal strategy to curb ongoing autoinflammatory responses while preserving the immune system’s ability to fight new infections and promoting tissue repair for functional recovery. Although our exploratory/developmental project aims to establish a mechanistic link between Treg expansion and clinical improvement during CNS autoimmunity, in a broader context, our studies will guide the rational design of Treg-targeting immunotherapies, accelerating translation into effective and safe treatments for MS and several other autoimmune conditions.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY Proper skin restoration after the damage is vital for organismal survival. The lymphatic vascular system is spread throughout the human body and has a critical function in mammalian physiology. In physiological conditions, its main function is the regulation of tissue drainage, immunosurveillance, and regeneration. Lymphatic dysfunction causes lymphedema a medical condition that manifests as tissue swelling and fibrosis. This serious condition results in profound severe delays in wound repair and the formation of chronic non-healing wounds. The mechanism by which lymphatic vessels regulate skin repair is unexplored. Additionally, while the role of lymphatic vessels in immune cell egress from tissues is well-established, how lymphatic vessels may directly modulate immune function in damaged tissues is poorly-defined. Recently, I discovered that lymphatic vessels are actively remodeled during wound healing to form small capillaries which are present in close localization to the wound front and hair follicles. This remodeling is critical for optimal repair as skin-specific loss of lymphatic vessels results in a significant delay in wound closure accompanied by a massive infiltration of immune cells. This proposal aims to leverage these observations by 1) delineating the mechanisms and consequences of lymphatic vessel remodeling during skin repair, and 2) determining the role of lymphatic vessels and fluid pressure in macrophage behavior during skin repair. This research stands to have a significant clinical impact because it can serve as a basis for developing new therapeutic avenues for lymphedema ulcers and chronic wound management. In addition, career-oriented guidance from my mentor and advisors, along with career development activated during the K99 phase that includes formal coursework on grant writing and project management, will further facilitate my transition to the R00 phase and my long-term productivity as an independent academic investigator. Collectively, the proposed research and career development plans are expected to generate data with a significant impact on understanding the repair and immunomodulatory functions of lymphatic vessels in skin repair and setting the basis of my future research as an independent researcher.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid-β (Aβ) plaques, brain inflammation, and neurofibrillary tau tangles beginning up to two decades prior to clinical symptom onset. Increasing evidence indicates that sleep disturbance may be a modifiable risk factor impacting Alzheimer’s disease risk. Recent cross-sectional data has identified signature deficits in the local expression of sleep that may track with the buildup of Aβ, brain inflammation, and tau. However, typical approaches quantifying local sleep expression conflate contributions from distinct biological sources, including the overall rate of background spiking activity in brain cells, the balance between excitatory and inhibitory neurons, and the regulation of brain oscillations, all of which may be differentially impacted by distinct components of Alzheimer’s disease pathophysiology. For example, Aβ and tau impact the excitability of brain cells in opposing ways. This means that local sleep deficits likely change longitudinally as AD biomarkers buildup in the brain. Careful characterization of these effects longitudinally are critical to isolate the biological mechanisms linking local sleep expression with the evolution of Alzheimer’s disease pathophysiology throughout the brain and impairments in cognitive function. However, there are no published data linking longitudinal changes in local sleep expression with the progression of AD pathophysiology over time. To address this critical knowledge gap, we will use an innovative multimodal neuroimaging design combining polysomnography with high-density electroencephalography and high-resolution structural magnetic resonance imaging of medial temporal lobe (MTL) neurite density and structural volume combined with fluid biomarkers of brain inflammation, AD pathology, and neuronal integrity and episodic and procedural sleep-dependent memory tasks. Using these methods, we will map how local sleep changes in relation to the buildup of AD pathophysiology and memory decline over a two-year period. We will test the following hypotheses. (1) Increasing frontal deficits in slow waves will be apparent in individuals with Aβ plaques, while deficits in sleep spindles, slow wave-sleep spindle coupling, and measures of background spiking activity and the balance between excitatory and inhibitory neuron firing over parietal cortex will be more apparent in those with more brain inflammation, tau pathology, and MTL atrophy. (2) Distinct local deficits in sleep expression will predict longitudinal episodic and procedural memory decline. Findings from the proposed study will provide novel insight into how the buildup of AD pathophysiology relates to the change in local sleep expression and sleep-dependent memory over time, providing a map of candidate modifiable sleep targets for interventions to preserve cognition in a manner specific to AD pathophysiological feature and biomarker-defined preclinical stage.

NSF Awards · FY 2026 · 2026-02

This award a conference taking place at University of California, Irvine from February 9 to February 12, 2026. The title is: Set Theory: Larger Cardinals, Forcing and Higher Order Languages. The meeting is devoted to advances in finding a critical understanding the underlying assumptions and logic that mathematicians use. What separates mathematics from other fields of science is that mathematical facts are known for certain, and not subject to data errors, or a changing environment. The method used for this is that of proofs. For a mathematical fact (such as the Central Limit Theorem) to be known, there has to be a proof of it. But Proofs are divided into assumptions A and consequences B and a proof that A implies B. What constitutes a proof is well understood, but there are many unknown questions about what the appropriate assumptions are. Most of mathematics follows from the collection of assumptions referred to as ZFC. But important questions cannot be settled by ZFC. This meeting studies the relationships between the assumptions that can be added to augment the ZFC assumptions and clarifies what they imply. There are three well-accepted methods for adding and comparing axiom systems for mathematics. They are: adding Large Cardinal assumptions, using the method of Forcing to alter examples where ZFC plus the additional axioms hold and a method called Inner Model Theory. Some of the assumptions combine both Large Cardinals and Forcing (these are called Strong Forcing Axioms). Much of the conference will be devoted to understanding the relationship between Forcing, Large Cardinals and how the power set operation behaves. This will be related to the use of powerful languages (Strong Logics) to construct inner models, and the construction of mathematical trees with strong properties. Organizers expect to be able to support about ten graduate students and postdocs and similar number of senior mathematicians. 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 · 2026-01

It is estimated that 1.2 percent of Americans have active epilepsy, and the annual cost for treating these cases is estimated at $12.5 billion. While brain stimulation is routinely used in clinical practice, stimulation signals and parameters are often applied and tuned empirically, and can be substantially improved by a quantitative model of the brain network dynamics. Indeed, human brain function function arises from complex dynamics between intricate and time-varying interconnection of dynamically rich neural components, and multiple neurological disorders are linked to disruptions of these network mechanisms. This project will develop new theories and tools to predict the onset and spreading of epileptic seizures and to inform the use of novel electrical brain stimulation strategies to treat neurological disorders. By constructing mathematical models that incorporate epileptic data and dynamical analysis, this work aims at uncovering the phenomena that underlie epileptic events and linking them to features of the anatomy of the brain. The intended outcome will be a novel theoretical basis to analyze and optimize practical noninvasive stimulation of brain networks. This project will also pursue educational initiatives at the graduate and undergraduate levels that will contribute to the growth of a large and diverse STEM workforce, outreach activities to engage the local community, and dissemination activities to promote multi-disciplinary approaches to problems in neuroscience. The project will develop novel methods to analyze the spreading of oscillations in complex networks and derive control mechanisms to regulate the spatiotemporal evolution of network dynamics, such as neurological oscillations. In particular, the research will aim to (i) characterize a novel set of dynamical biomarkers that explain qualitative changes in neurological recordings during epileptic events -- these biomarkers provide a quantitative link between the structure and parameters of nonlinear, networked, neural mass models and the features of epileptic recordings; (ii) reveal the structural properties that allow healthy, localized neural oscillations to cascade into brain-wide pathological seizures, and (iii) develop spatiotemporal control strategies to regulate the spreading of oscillatory dynamics over networks, which will provide a solid theoretical basis to analyze and optimize practical noninvasive brain stimulation. In addition to contributing to the fields of network control and dynamical systems, this project will also contribute to the integration of these disciplines with computational neuroscience and promote the translation of control-theoretic tools towards the design of novel, targeted, non-invasive, and highly effective treatments for neurological disorders. 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 · 2026-01

When transitioning into a dark room most people initially struggle to see, but are quickly able to adjust and see in the new setting. In fact, people continue to see and understand the world around them even as the appearance of the world changes in many different ways. In contrast, our computer vision systems have limited ability to understand the world if it changes. Imagine if the first time one drove at twilight or in the snow one could no longer recognize the road. No doubt, driver’s training would require many hours of sitting in the passenger seat at all times of day, within different weather conditions, across different cities, and so on before allowing a new driver behind the wheel. This project aims to study and build new models, algorithms, and measures of success enabling the next generation of visual recognition systems to be resilient to an evolving visual world. The project will integrate research with education and outreach to K-12 students. This project advocates for resilient vision systems through a new integrated approach which iterates between generalizing across available visual domains and rapidly adapting given new domain data. Prior approaches optimize for independent criteria, either generalization across multiple domains, or adaptation to a new target domain, which limits advancement towards the larger goal of creating vision systems that can operate in more domains over time. Further, existing solutions are slow to adapt, relying on substantial new observations before updates can be made. The project will work on: 1) Model design and learning approaches for multi-domain generalization that facilitates future adaptation. 2) Transformative visual domain adaptation algorithms that are capable of rapidly adapting to a target domain using limited target observations and without accessing a large auxiliary source of data, reducing compute demands. 3) Algorithms that enable vision systems to expand the set of domains they can successfully operate in over time. Finally, this project will introduce a benchmark and new evaluation protocols to measure the resilience of visual recognition models to changing domains. 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 · 2026-01

Human Resources (HR) Specialists fulfill a range of critical staffing functions in organizations. This project focuses on supporting HR Specialists in the technology and “big-box” retail industries, who source and screen candidates for entry- to mid-level positions. These HR Specialists often find themselves under enormous pressure to fill roles, and they turn to automated decision systems (ADS) for managing the meticulous balancing act of talent acquisition: sifting through pools of candidates to find people who meet job requirements and have the “right” culture fit, while adhering to ethical standards and legal compliance. AI models that match and rank candidates are at the heart of these ADS. Poorly designed models can produce incorrect and inconsistent results that fail to match candidates appropriately to job requirements, or that limit the visibility of well-suited candidates. Together, these problems can lead to unaccountable decision-making processes and unfair decision outcomes, harming individual job seekers and members of already disadvantaged communities, and putting employers at risk of litigation. This project reimagines the role of HR Specialists (future worker), empowering them with the agency to reason about, validate, audit, and influence the ADS-assisted hiring process (future work context). These interventions are supported by a human-in-the-loop framework called Trapeze (future technology) that supports transparent automation in talent acquisition, along with innovative educational materials and methodologies that train HR Specialists to become better informed about AI and accountability in ADS-assisted decisions. Outcomes of Trapeze include open-source software, allowing the broad and diverse community of responsible AI researchers and practitioners to build and evaluate tools for sourcing and screening more effectively. This project also advances the understanding of the behavioral, social, legal, and technical contexts in which HR Specialists in the technology and retail domains make ADS-assisted decisions. Publicly available training materials and methodologies from this project help HR Specialists become more informed, responsible, efficient, and effective in their use of ADS. All shared materials, taken together, serve as a strong blueprint for strengthening accountability in ADS use within other high-stakes sectors of industry. 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.