University Of California-Irvine

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY Coronary artery disease (CAD) is the most prevalent cardiovascular disease, impacting over 18 million adults and causing more than 350,000 deaths annually in recent years. Acute coronary events are primarily caused by ruptured atherosclerotic plaques, emphasizing the need for early detection and accurate identification of plaque types (stable versus vulnerable) as the first line of defense. Obtaining detailed morphology and functional information on atherosclerotic plaques is crucial for advancing clinical management of atherosclerosis. The objective of this proposal is to develop a single intravascular imaging system incorporating intravascular ultrasound (IVUS), photoacoustic tomography (PAT), optical coherence tomography (OCT), and polarization-sensitive OCT (PSOCT) to study and characterize plaque vulnerability. The multimodal imaging probe, requiring only a single disposable guide wire and catheter, aims to reduce costs, risks, procedure time, and radiation exposure. Building upon integrated IVUS/OCT and IVUS/PAT technology developed in our lab, the proposed OCT/US/PAT system includes significant advancements for enhanced clinical translation. It combines the high molecular sensitivity of PAT at 1720 nm, broad imaging depth of US, high spatial resolution, and extended penetration depth of 1.7-μm OCT, along with mechanical evaluation using PSOCT. The system provides physicians with a powerful clinical instrument for studying, diagnosing, and managing vulnerable plaques. The specific aims are to: 1) Design and construct a multimodal confocal OCT/US/PAT imaging probe; 2) Design and develop the OCT/US/PAT system using a 10-kHz, 1720 nm pulsed laser for PAT and a 100-kHz swept-source laser for OCT/PSOCT; 3) Demonstrate the efficacy of the proposed system via in vivo porcine model. We expect the development of the proposed OCT/US/PAT technology to bring tremendous impact to both basic science and clinical understanding of plaque pathogenesis. This will enhance the clinicians' ability to identify vulnerable lesions, tailor interventional therapy, and monitor disease progression. More importantly, it will be a powerful tool that provides a quantitative means to benchmark and evaluate new medical devices and therapies.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY/ABSTRACT: OVERALL APPLICATION Ninety-eight percent of the human genome is non-coding. Moreover, extensive analyses of common and rare diseases have implicated these noncoding genomic regions as a significant factor. For example, 90% of SNP- disease associations identified through Genome-Wide Association Studies are located in non-coding regions and 60% of genetic tests in rare disease patients produces unresolved associations. Despite this, the link between noncoding variants and human disease remains poorly understood due to challenges in mapping these regions, difficulties in detecting their activity, and a lack of experimental models to dissect their roles in biology. To address these challenges, we propose establishing a Center for Noncoding Disease Variant (NODIVA). We leverage access to national rare and undiagnosed disease consortia as a platform to test high-penetrance disease associations. Our team has been at the forefront of these efforts, generating some of the few available knock-out and knock-in models of non-coding regulatory regions associated with development and disease. In recent years, we have developed innovative tools to improve the ability to 1) detect, 2) quantify, and 3) link to a genomic activity most noncoding loci, as well as high-throughput in vitro and in vivo systems to genetically modulate and mechanistically dissect these regulatory elements. The goal of our Center is to develop targeted experimental disease models of noncoding variants in mice and human pluripotent stem cells (hPSCs) and share the knowledge and resources generated by these models. Our specific aims are to 1) leverage large-scale rare disease discovery cohorts from both internal and external sources; 2) apply novel computational and functional approaches to analyze, prioritize and screen noncoding variants, from variants of unknown significance to likely pathogenic mutations; 3) generate disease models of noncoding variants with high potential for causing disease in mice and model disease mechanisms in hPSCs; and 4) disseminate these models and work with internal and community referral researchers to generate and interpret cellular and molecular phenotypes from patient and animal models. We believe our proposal will be transformative, addressing critical gaps in current rare disease research by providing innovative disease models and integrative frameworks that will advance the field and ultimately improve patient outcomes.

NSF Awards · FY 2025 · 2025-08

This project will contribute to the national need for well-educated scientists, mathematicians, engineers, and technicians by supporting the retention and graduation of high-achieving students with demonstrated financial need at the University of California, Irvine (UCI). Over its 6-year duration, this Track 2 project funds scholarships for 32 unique full-time students who are pursuing Master of Science (MS) degrees in research-focused Biology and Biotechnology programs. These students receive one or two-year scholarships. Scholars are introduced to new curriculum and cohort-based activities that foster resilience, develop research and professional skills, and prepare them to enter the biotechnology workforce. Scholars are paired with both near peer mentors and established faculty mentors to support academic and research progress. This project ultimately seeks to contribute well-prepared individuals to the biotechnology workforce in the region while simultaneously increasing the earning potential of scholars. The overall goal of this project is to increase STEM degree completion among high-achieving Master of Science (MS) students in Biology and Biotechnology with demonstrated financial need. This goal is achieved by awarding scholarships and enhancing curricular and co-curricular activities to foster resilient student cohorts, implement multi-tiered mentoring programs, and develop a new and sustainable MS program in biotechnology that continues beyond the funding period. The new degree program enables high-achieving undergraduate students engaged in research to complete a research-intensive MS degree in a single year instead of the typical two-year duration. The project employs evidence-based strategies to design curricular and co-curricular activities that strengthen resilience in STEM. All participating students receive support throughout their MS studies and transition into the biotechnology workforce or a STEM-related PhD program. An external evaluator monitors scholar recruitment, scholarship distribution, student outcomes from academic and co-curricular engagement, and the impact of holistic mentorship. Project outcomes are shared through social media, conferences, publications, reports, and alumni engagement. This project is funded by NSF's Scholarships in Science, Technology, Engineering, and Mathematics program, which seeks to increase the number of academically talented low-income students with demonstrated financial need who earn degrees in STEM fields. It also aims to improve the education of future STEM workers, and to generate knowledge about academic success, retention, transfer, graduation, and academic/career pathways of low-income students. 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 2025 · 2025-08

PROJECT SUMMARY Mood disorders like major depression are leading contributors to disease burden worldwide. Depression can cause a wide range of symptoms affecting arousal, motivation, mood, and cognition. Unfortunately, current treatment strategies are only effective for a subset of patients. While any individual can develop impairments in these domains of function, there are known risk and protective factors that modify one’s vulnerability. Negative social experiences like bullying are associated with increased risk, while having positive social support is a known protective factor. However, the underlying mechanisms by which these risk and protective factors lead to enduring brain and behavioral changes and how they interact are unknown. To develop more effective therapeutic approaches for depression and related psychiatric disorders, it is necessary to have a more detailed understanding of the ways by which conserved neurobiological systems are altered by them. This proposal will utilize a mouse model of chronic social stress called Vicarious Social Defeat Stress to comprehensively characterize physiological, behavioral, and neural activity changes associated with negative social experiences through Aim 1. This model will then be used to investigate the role of a proposed neural circuit element in the stress ameliorating effects of positive social interactions, commonly referred to as social buffering in Aim 2. Preliminary data suggests the medial amygdala (MeA) is active during acute stress, which is particularly interesting given the various known social functions of this nucleus. Subsequent experiments will test the hypothesis that the MeA is involved in and required for social buffering. In Aim 2, fiber photometry will be used to monitor MeA neural activity dynamics during post-stress social interactions, which will be linked to physiological and behavioral outcomes. In Aim 3, chemogenetics will be used to inhibit the MeA during poststress social interactions followed by assessment of physiological and behavioral outcomes to determine its functional necessity in social buffering. These experiments will improve our understanding of how different social experiences interact to produce complex behavioral responses, laying the groundwork for future research to investigate the potential therapeutic applications of this knowledge.

NIH Research Projects · FY 2025 · 2025-08

ABSTRACT Blinding diseases such as age-related macular degeneration, diabetic retinopathy, and glaucoma, together with ocular infections and dry eye disease represent a public health crisis. The impact of these diseases is compounded by the insufficient number of skilled clinicians and investigators with high quality training and expertise to provide care and conduct translational research. It is vital to foster a new generation of physician researchers that possess a diverse array of knowledge and skills, including understanding basic (genetics, molecular and cellular biology, neuroscience), patient level (clinical care, neuropsychology, fluid biomarkers, neuroimaging, epidemiology), and cross cutting (biostatistics, ethics) research design and methods. Thus, our proposed Summer Mentoring and Research Training in Eye and Vision Research (SMART EVR) T35 program will grow the pipeline of medical students with research experiences inspiring new physician scientists to focus their careers on eye and vision research and ophthalmic care. The low availability of skilled translational physician scientists represents a threat to the national eye and vision research agenda. Therefore, in this T35 application we propose to engage MD students in hands-on research, mentoring, publishing, career development and leadership. Through our leadership expertise in multidisciplinary translational eye and vision research, we aim to enhance the diversity and availability of physician scientists through these three specific aims: 1) Champion mentored career development by providing an integrated program that consists of outstanding leadership and oversight. 2) Create a flexible and innovative curriculum that emphasizes both core and advanced competencies in clinical, translational, and basic science 3) Maximize access to the SMART EVR Program. Through formal check-ins and eye and vision research themed journal clubs, trainees will receive guidance and support from the program directors. Upon the completion of the SMART EVR program, students will be tracked through the four years of medical school to encourage their continued engagement in research activities.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY Natural biomacromolecular interactions utilize non-covalent interactions to generate stable, hierarchically ordered structures critical for their biological function. In this project, we develop a biomolecular-based technology to produce cell-internalizable nanostructures that can locally deliver photocurrents to cardiomyocytes. We aim to address the current limitations associated with bulky electrodes with low spatial resolution for stimulating excitable cells. We will use complementary peptide pairs to drive the sequence- controllable organization of energy transporting organic donor-acceptor units (quaterthiophene and perylene diimide) under physiologically relevant conditions. Molecular to microscale order is critical to the device efficiency of organic electronic materials, therefore highlighting the importance of the role of the self-assembling peptides. Peptides also make these systems water- processable and can include bioactive groups to be recognized by cells. The resulting free-standing nanostructures are designed to be photocurrent-generating and cell-interacting, and thus can be considered as phototransducer cardiac biomaterials. We desire that these peptides exhibit optoelectronic properties while mimicking cues that allow for the directed interactions of materials with cardiac cells. Moreover, the success of demonstrating the efficacy of these materials for cellular photostimulation can complement optogenetic techniques, but without relying on genetic modification techniques nor being limited by the target species. We hypothesize that photoinduced processes by the proposed peptidic coassemblies potentiate surface charging that is sequence/order tunable, leading to visible light cellular depolarization and stimulation of cardiomyocytes and cardiac tissues with high spatiotemporal resolution. To test this hypothesis, we will conduct the following Aims: (1) establish the conditions that allow for ordered coassembly formation and tissue contraction pacing by a model charge complementary donor-acceptor peptide pair with known photocurrent-generating capabilities; and (2) correlate structural order with photostimulation efficiency for a library of designer complementary linear and cyclic peptide pairs. These efforts are rationalized by the established transduction ability of analogous photovoltaic donor-acceptor polymer blends, previously shown to trigger action potential firing in other excitable cells. Our overarching goal is to achieve cell-interacting and photoexcitable peptidic nanostructures as cardiac biomaterials capable of influencing cellular behavior with high spatial resolution. Our vision is that this innovative technology will pave the way for a future where we can wirelessly control, monitor, repair, or regenerate native cells within the human myocardium in real time and in a targeted manner using tissue-penetrating light wavelengths.

NIH Research Projects · FY 2025 · 2025-08

Project Summary/Abstract More than 1.6 million cases of Chlamydia trachomatis infections are reported to the CDC each year, making it the most commonly reported infectious disease in the country. This bacterial pathogen infects human and other eukaryotic cells and only reproduces in a host cell. Chlamydia research has been revolutionized by the recent development of genetic methods to knockout or knockdown specific genes. However, a roadblock in this genetic approach is the limited availability and utility of complementation methods to express an exogenous copy of the gene. Current conditional expression in Chlamydia relies on the Tet promoter, and it is not possible to independently control expression levels for gene knockdown and also for a complementing allele. A further limitation is that expression of the complementing allele from the chlamydial plasmid introduces gene dosage effects. This project will develop new complementation tools that will enhance the rigor of genetic approaches used to study chlamydial gene function. In Aim 1, we will develop new conditional expression methods for C. trachomatis. These studies will test induction systems, including cumate and IPTG, and arabinose, that have been used in other bacteria. In Aim 2, we will identify sites in the C. trachomatis genome where a gene can be inserted without affecting other genes or the intracellular infection. These studies have high potential impact because they will enhance the use of complementation to confirm that a knockout or knockdown phenotype is due to a targeted gene. The ability to independently control the expression of more than one exogenous gene will also be broadly useful for studies of chlamydial gene function and host- Chlamydia interactions. In addition, the identification of neutral sites for gene insertion will be useful for creating C. trachomatis backbone strains that express additional factors, such as Cre-Lox recombination systems or antibiotic resistance markers.

NIH Research Projects · FY 2026 · 2025-08

The overarching goal of this application is to identify environmental factors contributing to the rising mental-emotional-behavioral (MEB) disorders in urban-dwelling children and parental postpartum depression (PPD) in Southern California, and strengthen their respective causal associations. MEB disorders are prevalent among urban-dwelling children and adolescents, causing detrimental and long-lasting impacts on affected individuals and their families. Increased frequencies of MEB disorders have been observed in Southern California; the trend cannot be explained by diagnostic practices alone, yet it tracks well with the concurrent increases in maternal PPD and extreme weather change in Southern California. We hypothesize that neurotoxic environmental exposures increase risks for parental PPD, both contributing to the rising MEB disorders in children and adolescents. The environmental factors of primary interest are extreme heat and wildfire fine particulate matter (PM2.5) and polycyclic aromatic hydrocarbon (PAH). We will examine the effects of both short-term (daily to weekly) and long-term (monthly to yearly; across seven life stages from pre-conception up to adolescence) exposures. Despite strong scientific premises on the effects of extreme heat and wildfire smoke on increasing the risk of parental PPD and child MEB disorders, epidemiologic data remain elusive on linking environmental exposures with adverse mental health in children, and the role of parental PPD in mediating and/or confounding the effects of environmental exposures on MEB health is unclear. The extant literature suffers from several major methodological limitations, lacking high-quality clinical outcome data and missing participant-level exposures estimation particularly for exposures to PAHs from wildfires. This study will address these knowledge gaps and methodological weaknesses by leveraging an established longitudinal pregnancy cohort (2008-2021) based on the comprehensive electronic health record (EHR) of Kaiser Permanente Southern California (KPSC). Children’s MEB outcomes and maternal PPD have been validated. This study will extract relevant paternal data plus 4 more years of birth data (2008-2025; ~600,000 births), continue the outcome follow-up to 2027, and expand the scope of exposure assessment. Spatiotemporally-resolved exposures (extreme heat; wildfire-specific PM2.5 and PAHs) mapped on longitudinal residential histories (from pre-gestational to age 17) will be combined with prospectively recorded and high-quality data on clinical phenotypes, comorbidities, and other relevant covariates. Four aims will respectively focus on MEB disorders (Aim 1), parental PPD (Aim 2), the role of PPD in the putative associations of MEB disorders (Aim 3), and effect modification by neighborhood socio-environment and individual-level factors (Aim 4). This application is highly significant as MEB disorders in children are pressing public health issues. We will advance environmental neurosciences by quantifying the impacts of extreme heat and wildfire smoke on children’s MEB health and parental PPD, clarifying their causal associations including the role of PPD, identifying susceptible time windows, and determining the social-environmental vulnerability.

NIH Research Projects · FY 2025 · 2025-08

Abstract In the demyelinating disease multiple sclerosis (MS), chronic-active brain inflammation, remyelination failure and neurodegeneration remain major issues despite immunotherapy. While B cell depletion and blockade/sequestration of T and B cells potently reduce episodic relapses, they act peripherally to allow persistence of chronic-active brain inflammation and progressive neurological dysfunction. N-acetyglucosamine (GlcNAc) is a triple modulator of inflammation, myelination and neurodegeneration. GlcNAc promotes biosynthesis of Asn (N)-linked-glycans, which interact with galectins to co-regulate the clustering/signaling/endocytosis of multiple glycoproteins simultaneously. In mice, GlcNAc crosses the blood brain barrier to raise N-glycan branching, suppress inflammatory demyelination by T and B cells and trigger stem/progenitor cell mediated myelin repair. MS clinical severity, demyelination lesion size and neurodegeneration inversely associate with a marker of endogenous GlcNAc, while in healthy humans age- associated increases in endogenous GlcNAc promote T cell senescence. A polymorphism linked to dysregulation of GlcNAc metabolism most strongly associates with MS severity. In a recent mechanistic open- label trial assessing oral GlcNAc at 6g (n=18) and 12g daily for four weeks in MS patients not in relapse and on the immunomodulator glatiramer acetate, we reported that oral GlcNAc therapy was safe, raised serum levels, modulated N-glycan branching in lymphocytes and lowered serum levels of pro-inflammatory IFNg, IL-17 and IL- 6. Oral GlcNAc also dose-dependently reduced serum levels of the anti-inflammatory cytokine IL-10, which is elevated in the brain of MS patients. As glatiramer acetate acts peripherally, the reduction in inflammatory cytokines and IL-10 by oral GlcNAc may arise from crossing the BBB to target chronic-active CNS inflammation. Consistent with this, oral GlcNAc dose-dependently reduced serum neurofilament light chain (sNfL), a specific marker of brain inflammation/neurodegeneration. Moreover, 30% of treated patients displayed confirmed improvement in neurological disability; consistent with reduced brain inflammation and/or re-myelination. As these observations were based on unblinded analysis, no placebo and small sample sizes, here we propose to develop a multi-center double-blind randomized control trial to validate GlcNAc’s potential to improve residual brain inflammation, myelin repair, neurodegeneration and neurological function. The study “Oral N- Acetylglucosamine as Anti-Neuroinflammatory Add-on therapy for Multiple Sclerosis” (NANA-MS) will include MS patients with ongoing chronic-active CNS inflammation (i.e. non-gadolinium enhancing paramagnetic rim lesions (PRLs) on brain MRI) despite best available or no therapy. Primary outcome is the number of patients with reductions in disability of at least 0.5 EDSS points. Secondary outcomes are change in 1) chronic CNS inflammation based on brain MRI (i.e. decreased PRLs) and/or cerebrospinal fluid analysis, 2) peripheral inflammatory markers, 3) myelination as assessed by Visual Evoked Potentials and 4) Quality of life measures.

NSF Awards · FY 2025 · 2025-08

This project investigates splicing, a fundamental cellular process where RNA molecules from the same gene are processed to produce multiple distinct proteins. This flexibility is essential for healthy development, and splicing errors are linked to numerous human diseases, including cancer and neurodegenerative disorders. A major obstacle in understanding splicing control is that traditional live-cell imaging interferes with the very dynamics under observation. This research overcomes this limitation through a tightly integrated experimental-theoretical approach that infers molecular dynamics from spatial patterns in static, high-resolution cellular images. By combining advanced microscopy with predictive mathematical modeling, the investigators will uncover the rules governing RNA splicing. This work will advance biological understanding and national health by providing deeper, quantitative insights into gene regulation to inform future therapies. The project also trains interdisciplinary scientists and produces open-source software for the research community. This research quantifies the kinetic rates governing RNA fate, including co-transcriptional splicing, post-transcriptional splicing, and degradation. The project's central strategy is the close, iterative integration of experimental imaging and mechanistic modeling to infer these dynamics from static, single-molecule images. Experimentally, fluorescence in-situ hybridization (FISH) generates high-resolution spatial maps of RNA isoforms that directly inform and validate computational models. Computationally, this project develops novel spatial stochastic models based on reaction-diffusion processes to describe RNA dynamics within spatially heterogeneous cellular environments. Bespoke inference pipelines will connect these models to imaging data for robust parameter estimation and hypothesis testing between competing splicing mechanisms. This synergistic approach will yield dual impacts for biology and mathematics, providing biological resolution to RNA splicing dynamics while establishing new mathematical theory and a powerful paradigm for inferring dynamics from static data. 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 2025 · 2025-08

The University of California Irvine will organize and the University of California Santa Barbara will host the third Cal-Bridge Summer Institute Alumni Conference, July 20-26, 2025. Participants will be doctoral students who are alumni of Cal-Bridge, a partnership between the University of California (UC) and the California State University (CSU) systems designed to provide pathways into research and the professorate for students from CSU and California community college campuses. Participating scholars will form a peer learning community built on a community-of-practice model. The summer program will focus on how people learn and effective learning strategies, along with facilitating teaching and learning. The group will continue with regular virtual meetings throughout the academic year to promote the exchange of ideas and best practices. The portion of the workshop costs funded by the NSF will support funding for 25 Cal-Bridge Doctoral Scholars to participate in the Summer Institute. The Cal-Bridge Summer Institute, a series of professional development workshops, will have two major thrusts: 1) developing effective pedagogues, and 2) developing effective research leaders. In addition to these, the conference will include a variety of shorter professional development mentorship sessions, and community and cohort building activities. This conference aims to address two systemic points of loss along the professorial and professional researcher pathway for Cal-Bridge Alumni currently in PhD programs outside of the University of California system: completion of the PhD and entrance into the workforce. Specifically, the award will: 1) Broaden the impact of the professional development being offered to a larger group of doctoral scholars, and 2) Provide space for Cal-Bridge Doctoral students to hold discussions and activities to build up their professional network and community. 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 2025 · 2025-08

Abstract Sulfur mustard, also known as mustard gas, is a threat in chemical warfare and terrorism. Although major advances have been made in understanding mustard-induced skin injury, effective countermeasures are lacking. Under an R34 grant, we have been investigating shared and unique mechanisms of mustard- and arsenical- induced skin injury with single cell tanscriptomics and fluorescence lifetime imaging microscopy. Using nitrogen mustard as a surrogate for sulfur mustard, we unexpectedly found that dermal fibroblasts are damaged early after mustard exposure and that CDK8, a kinase component of the Mediator transcription complex, is a potential new treatment target in mustard-induced skin injury. We also found that the vitamin B12 analog cobinamide, a new and potent antioxidant that neutralizes both reactive oxygen and nitrogen species, effectively counters the skin and systemic toxicity of nitrogen mustard and phenylarsine oxide, a common research surrogate for lewisite. Furthermore, we found that cobinamide is more effective than N-acetyl-cysteine (NAC) in countering nitrogen mustard-induced skin damage. The goals of this project are to understand the mechanisms of mustard-induced skin injury and how cobinamide affects these mechanisms. Ultimately, insights from this research could be used to develop new countermeasures that will be effective on their own or in combination with cobinamide. The Specific Aims are: 1. To understand the variable sensitivity of different skin cells to mustard-induced cell death. This Aim focuses on the early loss of fibroblasts and tests the hypothesis that different skin cells have differential sensitivity to mustard-induced injury: whereas some cells initiate a cell death program, other cells are more resistant and may ultimately recover. We will combine single cell RNA sequencing with spatial transcriptomics and we will test whether CDK8 contributes to mustard-induced injury. The studies will be done on SKH-1 mice, initially with nitrogen mustard and then with sulfur mustard. 2. To understand mustard-induced effects on skin fibroblasts and their interactions with immune cells. This Aim tests the hypothesis that skin fibroblasts play an important role as early sensors of mustard exposure and that they activate and recruit neutrophils and macrophages. We will use multiphoton intravital microscopy to study the dynamics of myeloid cell accumulation, and as in Aim 1, studies will be done with nitrogen mustard in mice. In both Aims, we will test how cobinamide affects the mechanisms under study. This research is innovative because cellular heterogeneity in response to mustard-induced skin injury and the role of dermal fibroblasts during mustard-induced injury are under-investigated. Moreover, we are using state-of-the-art techniques, we have assembled a talented multi- disciplinary team, and we are testing cobinamide, a new type of antioxidant that is bifunctional for reactive oxygen and nitrogen species and has not been previously evaluated in vesicant-induced skin injury. The studies are significant because no effective countermeasures exist against mustard-induced skin injury.

NSF Awards · FY 2025 · 2025-08

This doctoral dissertation research studies how students actively participate with teachers and other adults in shaping science education and curriculum in K-12 school settings. The investigators specifically test the impacts of student knowledge and lived social experience on a future-oriented science curriculum. The research expands our understandings of the important role of students and children in developing science curriculum that is relevant to student experience and that expands their capacity to make future impact. In addition to providing scientific training for a graduate student in anthropology and interdisciplinary research in education, the broader impacts of this research also involve a participatory methodology that will introduce K-12 students to the methods of social science data collection. The results will inform the development of an enrichment program on science education and will be disseminated through a digital archive of findings developed by students. In order to understand the impacts of lived experiences of children and students on their education, investigators utilize multiple qualitative and spatial methods including semi-structured interviews, participant observation, photography, drawing, and landscape mapping. K-12 students at various grade levels will be involved closely in data collection using a participatory methodology that will include and train students in the methods of anthropological data collection. The research offers clear contributions to the anthropology of childhood and education through an innovative approach that draws on the expertise and capacities of students in developing and refining a future-oriented scientific education. 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 2025 · 2025-08

Filipp Furche of the University of California, Irvine (UCI), is supported by an award from the Chemical Theory, Models and Computational Methods Program in the Division of Chemistry to develop, implement, and apply a new approach to strong electron correlation based on natural determinant functional theory (NDFT). Strong correlation is central to overcoming roadblocks in areas of critical scientific and technological importance, such as organometallic rare-earth and actinide chemistry, metal-metal interactions, reactive intermediates, single-molecular magnets and other quantum materials and devices; however, existing methodology either fails or is computationally prohibitive for real-world applications featuring strong correlation. Furche and his research group will develop, implement, and test NDFT-based approaches addressing these limitations. The computational methods resulting from this project will be widely disseminated through both proprietary and open-source codes. The program supports education and workforce readiness through undergraduate curriculum development at UCI, as well as outreach to high-school students. The project will start from single-reference NDFT developed during the prior funding period, which "exactifies" the popular but empirical generalized Kohn-Sham approaches, including (local) hybrid functionals and fifth-rung random-phase approximation (RPA) methods. NDFT will be extended using a single real parameter s defining an active space through an interval of (interacting) natural occupation numbers around the Fermi occupation number. Strong correlation within the active space will be treated explicitly by configuration interaction, whereas "dynamic" correlation should be accurately captured using appropriately generalized NDFT functionals. This approach does not (i) rely on perturbation theory, and (ii) require problematic active space selections. In parallel, new dynamic correlation functionals based on RPA with local field corrections will be developed. These methods will enable Furche and his group to extend applications to organometallic d and f element compounds with unprecedented electronic structure and properties. Low-power-low-cost single-board computers will be used to bring theoretical and computational chemistry to high-school students nationwide. 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 2025 · 2025-08

This research project explores fundamental principles underlying how groups of intelligent decision-makers—called "agents"—interact and learn within shared environments. Understanding these interactions is increasingly important because they directly impact critical areas such as autonomous driving, economics, evolutionary biology, robotics, artificial intelligence safety, and strategic decision-making. By developing theoretical insights and efficient learning algorithms, the project aims to determine when and how these complex multi-agent systems can reach equilibrium, resulting in predictable and stable outcomes. Beyond scientific advancement, the project will actively integrate its research findings into undergraduate and graduate curricula. Additionally, through the organization of workshops, the project will provide students hands-on opportunities to engage with current research, thus preparing students to effectively tackle emerging challenges at the intersection of multi-agent systems and game theory. This research project aims to develop a robust theoretical framework for analyzing learning processes in multi-agent systems—environments in which independent agents interact repeatedly to achieve their objectives. The project's primary goals include designing computationally efficient algorithms that provably converge to equilibrium states, particularly in scenarios characterized by both cooperative and competitive interactions and in games where agents have large action spaces. Additionally, the project seeks to address long-standing open problems concerning classical learning methods, specifically the rate of convergence for well-known learning algorithms, such as fictitious play. Methodologically, the research will leverage approaches from algorithmic game theory, optimization theory, and dynamical systems analysis. The outcomes of this work are expected to significantly advance the understanding of multi-agent learning dynamics, offer new algorithmic solutions for structured games, and impact applications in artificial intelligence and online decision-making. 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 2025 · 2025-08

Rainfall during the Asian summer monsoon (ASM) is a critical water resource for human use, ecosystems, agriculture, energy and industry. The behavior of the ASM varies regionally, and there is a gap in understanding of the variability through time of ASM and the Asian Winter Monsoon (AWM) in mainland Southeast Asia (MSEA), where a greater proportion of rainfall is during the autumn and winter months. This project will reconstruct rainfall intensity on timescales of decades to tens of thousands of years through geochemical measurements of cave deposits from Laos and Vietnam. These measurements, along will climate model simulations, will improve understanding the mechanisms that drive variability of the ASM and AWM, and how this system responds to climate variations through time. This project will use oxygen, carbon, calcium stable isotope ratios and trace elements measured in speleothems, cave monitoring, and hydrogeochemical modeling to reconstruct ASM and autumn/winter monsoon AWM circulation and regional precipitation patterns in MSEA over the last 200 ky. These new data will be synthesized with existing data and isotope-enabled and high-resolution climate model simulations to determine drivers of MSEA hydroclimate variability on millennial to orbital timescales and characterize decadal scale hydroclimate variability and the impacts of coupled ocean-atmosphere dynamics and hydrological extremes on ASM and AWM in different climate states. The project includes support for undergraduate students and PhD students and K-12 outreach events. 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 2025 · 2025-08

Artificial Intelligence (AI) and the Internet of Things (IoT) are reshaping the way people interact with technology. Everyday devices—from home sensors and wearable monitors to industrial systems—are now capable of gathering data and making decisions in real time. When AI is embedded into these connected systems, a powerful combination emerges: the ability to detect patterns, respond to changes, and automate functions that once required human oversight. This blend, known as AIoT, has the potential to improve safety, efficiency, and responsiveness across many sectors, including transportation, healthcare, and environmental monitoring. However, to fully realize these benefits, there is a growing need for well-prepared engineers and computer scientists who can design, analyze, and manage these complex systems. This project helps meet that need by offering research experiences to undergraduate students who may not otherwise have access to high-impact scientific opportunities. Through mentorship, project-based learning, and exposure to advanced tools, participants will gain the knowledge and confidence to pursue careers at the forefront of technological innovation. The project, titled “REU Site Renewal: Enhancing AI-Driven Insights Within IoT-Enabled Ecosystems (AIoT-Sys)”, is based at the University of California, Irvine and builds on prior success training students in IoT systems research. During the eight-week program, undergraduate participants will engage in applied research projects led by faculty from computer science, electrical engineering, and health sciences. Technical focus areas include: (1) the development of secure, low-latency communication protocols for wearable medical sensors and implantable monitoring devices; (2) the optimization of distributed energy management algorithms in building automation systems; and (3) the application of supervised and unsupervised machine learning techniques for the interpretation of large-scale environmental data collected from remote sensor networks. Students will perform a progression of tasks: reviewing existing literature, implementing prototypes using microcontroller-based hardware platforms, collecting and analyzing experimental data, and presenting their findings through oral presentations and written reports. Participants will design and evaluate their systems using professional-grade computing tools and cloud-based resources. The program also includes training sessions on technical communication, ethics in research, and strategies for pursuing graduate education. Assessment will be conducted through surveys, mentor evaluations, and tracking of participant outcomes to measure the impact on academic and career trajectories. By equipping students with foundational knowledge and practical experience in AI-integrated sensing and control systems, this program supports the development of a highly skilled technical workforce prepared to contribute to critical areas of science and engineering. 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 2025 · 2025-08

The Chem-SURF program at the University of California, Irvine, is a Research Experiences for Undergraduates (REU) site funded by the NSF Division of Chemistry. Chem-SURF supports eight students for 9 weeks of undergraduate research during the summers of 2025-2027. The purpose of this REU site is to bring together a group of talented students from different backgrounds to develop collaboration, communication, and critical thinking skills, as well as learn experimental and computational techniques in chemistry. The Chem-SURF program prepares students to pursue graduate education and to become leaders in the chemical sciences and related STEM disciplines and will solidify their identities as scientists. It will accomplish this by emphasizing faculty-student interactions; quality mentorship from faculty, graduate students and peer-mentors; supportive community; and hands-on research training in a large selection of chemistry research projects. Chem-SURF provides participants an opportunity to interact with mentors and peers in both professional and social environments that have been designed to increase students’ chemistry knowledge, research skills, and identities as scientists. The students participate in exciting and transformative research in laboratories with state-of-the-art equipment and with support of campus-wide research facilities. Students are mentored by faculty, postdoctoral fellows, and graduate students in laboratories conducting chemistry research in a wide variety of specializations. They also attend professional development workshops and seminars, including ethics training, graduate school and fellowship application preparation, and communication skills. REU students interact with other on-campus summer research programs and graduate school preparation programs during shared and crossover activities including conferences, seminars, and symposia. Students leave the program well-prepared to present their results at scientific meetings and to continue on to graduate study. This site is supported by the Department of Defense in partnership with the NSF REU program. 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 2025 · 2025-08

Individuals can vary greatly in their response to the same infection. This variation can be caused by many factors, including genetics, life experiences, and environmental conditions. By using fruit flies (Drosophila) as a model, researchers can control for many of these factors, allowing them to focus on the roles of genetics and other factors in infection outcomes. However, due to technical limitations, traditional infection studies typically rely on measurements of the infection progression at a single time point, making it difficult to track the infection’s dynamic progression in an individual over time. This project aims to solve that problem by developing new light-based tools to monitor infections in living animals. By using glowing bacteria and glowing proteins that show an animal’s immune response, researchers will measure both bacterial growth and the host’s immune response in individual flies. This will allow them to identify genetic and other factors that influence infection outcomes in different animals. This research will introduce new biotechnology i.e., innovative imaging techniques, that will contribute to the bioeconomy and could reshape our understanding of disease progression, potentially revealing immune genes conserved across species. The project also provides hands-on training for students and postdoctoral researchers in genetics, computational modeling, and imaging. Additionally, the team will create educational materials and outreach programs to inspire the next generation of American scientists. By advancing both research and education, this work has the potential to improve our ability to predict, understand, and ultimately control infections. This research aims to uncover genetic and stochastic factors that influence infection survival by tracking microbial dynamics and host responses in individual animals. Using the Drosophila model system, researchers will develop bioluminescence imaging (BLI) tools for real-time, longitudinal monitoring of infection. This approach will allow direct observation of infection progression and help identify novel immune genes. The project has two main goals. Goal 1: Uncover the genetic drivers of infection resistance, tolerance, and outcome. Different fly genotypes show significant variation in survival, but infection resistance at a single time point does not always predict survival. This may be because immune responses unfold over time and immune tolerance mechanisms also influence survival. By monitoring infection dynamics in genetically diverse individuals, researchers aim to identify genetic factors that affect resistance, tolerance, and overall survival. Goal 2: Uncover the stochastic contributions to infection outcome. Current technologies do not allow observation of microbial growth dynamics and host responses in a single animal. To address this void, researchers will develop orthogonal luciferase-luciferin pairs that report on microbial load and host gene expression. A simple model of bacterial growth and host response will be compared to those with more complex dynamics, including feedback and fluctuations, to find which fit the data best. Such work will reveal the role of fluctuations in microbial growth and host response to infection outcome, providing potentially novel strategies for infection control. 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 · 2025-07

PROJECT SUMMARY/ABSTRACT Cyclic adenosine monophosphate (cAMP) is a key signaling molecule that is essential for pancreatic beta- cell gene expression, function, and survival. Recent studies indicate that the cellular response to cAMP signaling varies based on the location within the cell where cAMP is generated. Important targets of diabetes therapy are G-protein coupled incretin hormone receptors located on beta-cells. Upon ligand binding on the cell surface, the incretin hormone receptors glucagon like peptide-1 (GLP-1R), glucagon (GCGR), and glucose dependent insulinotropic peptide (GIPR) activate the G-protein Gas-to stimulate cAMP synthesis at the inner surface of the cytoplasmic membrane. Furthermore, these ligand-bound receptors are internalized into early endosomes within the cell body, from where they continue to generate cAMP before recycling to the cell surface or before being degraded through the ubiquitination pathway. Although incretin hormone receptor agonists are central to diabetes treatment and generate cAMP from different locations within the beta-cell, very little is understood about the differential role of cAMP signaling events that originate from different intracellular compartments. Furthermore, therapeutic incretin receptor agonists are designed to potentiate insulin secretion, while their effects on beta-cell gene expression remain poorly defined. Based on our preliminary studies, we hypothesize that the beta-cell differentially interprets cAMP signaling based on the spatial location of cAMP synthesis. We hypothesize that incretin hormone GPCR-stimulated cAMP signaling from the cell surface predominantly potentiates glucose-stimulated insulin secretion (GSIS) with little effects on gene expression in the nucleus. Conversely, cAMP generated at endosomes has minimal effects on GSIS potentiation, but potently regulates cAMP-dependent gene expression in the nucleus. We also find that in mice that are fed a diabetogenic diet, incretin hormones retain their ability to potentiate GSIS (cAMP from the plasma membrane) but lose their ability to regulate beta-cell gene expression (cAMP from the endosome). Thus, beta-cell endosomal cAMP signaling is defective early in diabetes pathogenesis, thereby leading to altered gene expression. We now seek to expand our novel and exciting findings specifically a) to understand the differential roles of cAMP generated from different cellular locations in regulating beta-cell function and gene expression; b) to understand the consequences of selective disruption of endosome-derived cAMP signaling on beta-cell function and gene expression Our studies will yield important and fundamental insights into the role of cAMP signaling in beta-cell biology. Furthermore, our studies have the potential to identify new molecular mechanisms that can be targeted in order to prevent and/or reverse the relentlessly progressive beta-cell deterioration in diabetes mellitus.

NIH Research Projects · FY 2025 · 2025-07

The protein kinase superfamily is rich in disease-driving mutations. Experiments described here focus on the catalytic domain of cAMP-dependent protein kinase A (PKA-C). This enzyme catalyzes the phosphorylation of numerous proteins during the excitation-contraction coupling mechanism of normal heart muscle function. Mutation-driven, aberrant phosphorylation by PKA-C is directly linked to various cardiac dysfunctions, including dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), and diabetic cardiomyopathy. We will observe at the single molecule level the catalytic subunit of PKA-C operating on physiological proteins in both functional and cardiac disease-associated situations. PKA-C, the best characterized protein kinase, is ideal for novel, single molecule studies. Its catalytic steps have been well-studied including X-ray structures of all steps during catalysis. The dynamic features of catalysis and allostery as well as inhibition by pseudo-substrates have been characterized by NMR and classic kinetics. We will use well-defined cardiac proteins (RyR, PLN, and Troponin C) as substrates for phosphorylation by both wild-type and cardiac disease-associated mutants of PKA- C. Sub-microsecond empirical data will be combined with the computational tools of MD simulations integrated into a graphical tool (Local Spatial Patterning) for mapping entropic changes that correlate with allosteric control over this highly regulated, enzymatic switch. Thus, the approach will uncover a dynamic portrait of PKA-C in both diseased and normal physiologies. In Specific Aim 1, we will engineer a single-walled carbon nanotube field effect transistor (SWNT FET) system to record single molecule dynamics with unprecedented, 35 ns time resolution. This approach will be combined with inkjet- and 3D-printing to allow rapid design-build-test cycles and broad adoption of the technique beyond this project. In Specific Aim 2, we bioconjugate wild-type PKA-C to the SWNT FET and characterize the catalytic machinery of PKA-C using three peptides – the substrates Kemptide and SP20, along with the pseudosubstrate IP20 from the heat stable protein kinase inhibitor (PKI). Nucleotide binding, opening and closing of the catalytic cleft, requirements for pH and metal ions (Ca++ vs. Mg++) will establish a baseline set of motions at sub-microsecond timescales. In Specific Aim 3, we will characterize the phosphorylation of three well-studied, cardiac substrates, an activity critical to healthy heart physiology. We first define the motions that correlate with phosphorylation using peptides that flank both sides of the P-3-P+1 P site when docked to the active site cleft. These flanking regions are docked onto allosteric sites in the C-lobe. We will then examine mutations in the C-lobe of PKA-C that drive Cushing’s syndrome and a set of recently described PKA-C mutations that drive the formation of potentially lethal cardiac myxomas. The studies outlined here leverage recent advancements in nanotechnology, and the approach can be adopted by other laboratories, promising broad impact within the biomedical community.

NIH Research Projects · FY 2025 · 2025-07

Summary Large-scale biological studies along with routine use of digital sensors and mobile devices to collect medical data have created a data deluge, imposing new challenges on scientists and practitioners to process and analyze a large amount of data for information extraction, discovery, and decision making. Tackling these emerging challenges requires interdisciplinary teams of scientists with complementary domain knowledge and analytical skills, who can work together effectively toward the common goal of understanding complex biological phenomena and improving treatment effectiveness. To develop such a framework for sustainable support of collaborative environments at the intersection of biomedical sciences and biostatistics, we propose to create an integrative, interdisciplinary, and interactive training program called Statistical Training to Enhance the Excellence of Research (STEER) in Biomedical Sciences. At its core, STEER provides PhD students with the required training on statistical thinking for biomedical data analysis. We will also prepare our trainees with the required skills to handle big data problems and the associated computational challenges, given that the emerging biomedical studies have become increasingly data-intensive. Additionally, we will introduce trainees to state- of-the-art statistical machine learning techniques and their role in biomedical research. Our program's overall goal is to teach students the underlying principles of statistical analysis so they can solve real-world biomedical problems. STEER will foster a stimulating environment for training and mentoring the next generation of biomedical scientists with proper exposure to modern developments in biostatistics, and biostatisticians with expertise in solving complex and data-intensive problems for fundamental research in biomedical sciences. To this end, our research training program's main objectives are as follows: Obj 1: Use the science of team science to create a stimulating collaborative environment at the interface of biomedical sciences and biostatistics; Obj 2: Develop an interdisciplinary education framework to cultivate an exceptional learning environment for training a new generation of scientists with a deep understanding of modern biostatistical techniques and complex biomedical systems; Obj 3: Create a collaborative research framework where our trainees learn to develop innovative data analysis methods that are fundamentally sound, methodologically robust, and computationally feasible for investigating biomedical problems; Obj 4: Provide professional development training and organize career planning activities to prepare our students for a variety of academic and nonacademic career options, while ensuring a high level of PhD completion rate and appropriate time to degree.

NSF Awards · FY 2025 · 2025-07

This project addresses theoretical challenges in high-dimensional probability, with a particular focus on those arising in data science. It aims to develop rigorous mathematical foundations for understanding the authenticity and privacy of synthetic data, tackling questions such as “What is artificial, mathematically?” and “How can we distinguish artificial data from real?” As a related aim, the project will broaden the reach of random matrix theory in data science by developing new geometric approaches to random matrices and random tensors. By establishing a probabilistic framework for detecting synthetic data, the project will develop an adversarial classification model and characterize the regimes where artificial data can be reliably identified. This analysis will draw on connections to high-dimensional Gaussian geometry and convexity. To develop a mathematical framework for private synthetic data, the project will explore metric-based characterizations of the privacy-accuracy tradeoff, grounded in the methodology of high-dimensional probability. Furthermore, this project will advance non-spectral random matrix theory by developing and applying high-dimensional probability methods to study approximation numbers, general operator norms, and norms of the inverse of random matrices. 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 · 2025-07

With approximately 296 million people (5.8% of the global population aged 15–64) having used drugs at least once, the world is facing an unprecedented opioid epidemic. Chronic opioid exposure can lead to long-term brain function changes and opioid use disorder (OUD). Concurrently, despite advancements in treatment that have transformed HIV into a manageable chronic disease, evidence shows that opioid use in HIV-infected individuals can further weaken immune function and exacerbate HIV-related central nervous system (CNS) impairments. To unravel the intricate interplay between these conditions, several SCORCH data generation and analysis centers have been funded to generate large-scale molecular profiling data at single-nuclei resolution, allowing the revelation of cell-type-specific molecular alterations due to chronic opioid exposure and/or HIV infection. However, the driving forces behind these molecular changes and their underlying regulatory mechanisms remain elusive, hindering our understanding of these factors and limiting the development of effective therapeutic strategies. To address this gap, we propose the DMFV-SCORCH project, an interdisciplinary initiative aimed at uncovering multi-scale dysregulations resulting from HIV and OUD through population-scale single-nuclei sequencing data, and validating our findings with advanced genomic assays. Specifically, we aim to identify intra- and inter-cellular dysregulations that lead to transcriptomic alterations and brain dysfunctions in OUD and HIV. We will address three key questions: 1) Which cell types are significantly affected, and what epigenetic changes lead to differentially expressed genes (DEGs) in these cell types? 2) Within a cell, what alterations in the gene regulatory network (GRN) and 3D chromatin conformation contribute to the DEGs? 3) How do regulatory changes in the CNS microenvironment, via cell-cell communications (CCC), impact DEGs? To achieve this goal, we will: 1) develop advanced Artificial Intelligence (AI) methods for data mining on SCORCH and atlas-level public CNS single-nuclei sequencing data, highlighting multi-scale dysregulations due to HIV/OUD; and 2) conduct functional validations through advanced genomic assays, such as epigenetic and transcriptomic manipulations via CRISPR followed by snRNA-seq (e.g., CROP-seq) and high-throughput screenings using massively parallel reporter assays (MPRA). Collectively, our examination of the interrelationships among genetic, epigenetic, transcriptional, network, and inter-cellular dysregulations will offer a robust translational approach to unravel the independent and synergistic mechanisms of OUD and HIV.

NIH Research Projects · FY 2025 · 2025-07

PROJECT SUMMARY Smoking has been demonstrated to induce oxidative stress, which is compounded with significantly reduced antioxidant availability, increased production of inflammatory cytokines as well as neutrophilic infiltration that are implicated in pathogenic processes in the lungs. Additionally, studies involving mice exposed to cigarette smoke reveal impaired pulmonary anti-bacterial and anti-viral defenses in response to infections. Other research has found that smokers also exhibit increased susceptibility to infections including influenza and SARS-CoV2. Investigations concerning the harmful effects that tobacco use exerts to lower bodily defenses are undeniably urgent, particularly those that address strategies for amelioration of smoking-induced health risks. Nicotine is the main component among the thousands of chemicals in all tobacco products including e-cigarettes. Nicotine binds to a family of nicotinic acetylcholine receptors (nAChRs) like acetylcholine (ACh). nAChRs are highly expressed in the lung fibroblasts and epithelial cells. Nicotine functions as an immunomodulator and has been reported to impair the immune response of smokers to infections. Vitamin C (vitC; ascorbic acid: AA) is an essential water- soluble vitamin with known respiratory health enhancing properties. Humans cannot synthesize vitC endogenously and thus obtain it from dietary sources via intestinal absorption. Dietary vitC is absorbed from the intestine via carrier-mediated sodium-dependent vitC transporters (SVCT1 and SVCT2, the products of the SLC23A1 and SLC23A2 genes, respectively). Low plasma levels of vitC have been found in patients with viral infections and other critical illnesses. Many previous studies have highlighted the role of vitC in protection against lung infections. Administration of vitC to patients with pneumonia, for example, can reduce the severity and duration of the disease. Pneumonia and influenza infections and related pathologies are also more severe in Gulo KO mice (a mouse model that cannot synthesize vitC endogenously, similar to humans). Both smokers and passive smokers have lower plasma and leukocyte vitC levels than non-smokers. Mean serum concentrations of vitC in adults who smoke have been found to be one-third lower than those of non-smokers. Our preliminary studies showed that nicotine reduces the functional expression of vitC transporters in the intestine and lung epithelial cells. We therefore hypothesize that nicotine induced vitC deficiency/insufficiency is a major factor in increasing the risk of respiratory viral infections in smokers. To test this hypothesis we propose two specific aims: Aim 1: To determine the mechanisms underlying nicotine-mediated impaired uptake of vitC by intestinal and lung epithelial cells using in vitro and in vivo models. Aim 2: To determine whether vitC supplementation is able to overcome the increased susceptibility to viral infections induced by nicotine. The expected outcomes of this project will advance our knowledge regarding the changes in uptake of vitC in the intestine and in the lungs, which is essential to develop novel therapeutics to improve vitC deficiency and insufficiency while also addressing ensuing lung viral infections and injury found in smoking population.