University Of Florida

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY/ABSTRACT The proposed studies will address a major gap in our understanding of T1D, namely, to the mechanisms of  cell failure from a metabolic as well as an immunological perspective. We have proposed this specific project because of a sincere belief that it has high potential to reveal significant, novel, and translatable information regarding  cell dysfunction that will be of therapeutic benefit for individuals with both established T1D as well as persons with pre-diabetes. The goal is to identify components of the glucose sensing and insulin secretory machinery pathways that are altered during the natural history of disease progression in type 1 diabetes (T1D), and to characterize the metabolic and immunological signals responsible for the functional loss in  cell activity that are specifically associated with this disease. This goal will be achieved by performing two lines of experimentation. Specific Aim 1 will determine the specific nature of dysfunctional bioenergetics of β cells in early stages of T1D. Using live human pancreas tissue slices from nPOD, we will employ multi-modal measurements of islet functionality. We will map molecular changes in β cell glucose metabolism to steps in T1D etiology using MALDI imaging (spatial metabolomics) and Akoya PhenoCycler (spatial proteomics). Aim 2 will determine the relationship between immune dysregulation and β cell dysfunction. Using live human pancreas tissue slices from nPOD and mouse models of T1D, we will assess the relationship between islet function and local immune microenvironment using novels tools such as fixable calcium indicators. Our team will leverage combined expertise to synergize the understanding of islet dysfunction in T1D. Phelps has expertise in islet imaging and physiology, Mathews specializes in β cell metabolism and T1D immunology, and Vander Kooi is an expert in spatial metabolomics. Together, we will provide a comprehensive analysis of the metabolic and immunologic mechanisms underlying β cell dysfunction in T1D.

NSF Awards · FY 2026 · 2026-05

Reliable and safe drinking water supplies are important to public health. Water utilities that use chlorine to kill harmful microbes must decide how much chlorine to add and how long it must stay in their systems. Pipe corrosion and microbial biofilms on pipe walls reduce chlorine levels, which can compromise water quality. Biofilms weaken the effects of chlorine, which may enable microorganisms and pathogens to survive. In addition, corrosion can release harmful metals such as lead and copper. Most utilities check chlorine loss, corrosion, and biofilm growth by measuring properties of the bulk water. These tests cannot show the chemical reactions that happen directly on the pipe wall, where chlorine loss begins. This project will study how disinfectants, corrosion inhibitors, and microorganisms interact at the pipe-water surface on a microscopic level. The project will create high-resolution data and combine them with artificial intelligence (AI) tools. This will help water utilities estimate chlorine demand more accurately, improve contact time, and prevent water quality problems. The results will also support better corrosion control and help with regulations such as the Lead and Copper Rule Improvements. The project will also train students in environmental engineering, biotechnology, electrochemistry, and AI, and it will strengthen collaboration between researchers and water utilities. This project will develop a mechanistic and predictive framework linking microscale biofilm-pipe interface processes to disinfectant decay rates, orthophosphate behavior, and localized corrosion in the drinking water distribution system. Controlled biofilm reactors containing ductile iron, copper, galvanic joints, and inert control materials will be operated under free chlorine and monochloramine regimes with defined orthophosphate dosing. Microelectrodes will provide in situ, depth-resolved measurements of pH, dissolved oxygen, oxidation–reduction potential, and disinfectant concentration gradients within biofilms and near metal surfaces. These chemical profiles will be coupled with corrosion metrics (metal release and surface characterization) and microscale multi-omics, including metagenomics and metatranscriptomics, to resolve microbial functional pathways associated with biofilm formation and microbiologically influenced corrosion. The resulting multimodal dataset will be integrated using interpretable machine learning approaches, including random forest, gradient boosting, and neural network models, with SHapley Additive exPlanations (SHAP) analysis to identify dominant predictors of chlorine decay and biofilm resistance. Microscale-derived wall reaction constants will be compared with traditional EPANET formulations to improve predictions of disinfectant decay and chlorine concentration-time requirements. By integrating advanced electrochemical sensing, spatially resolved multi-omics, and AI-driven modeling, the project will establish a mechanistically grounded predictive framework for managing disinfectant stability and corrosion control in water infrastructure. 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

The Security, Privacy, and Trust in Cyberspace (SaTC) program, a flagship initiative by the National Science Foundation (NSF), addresses critical cybersecurity challenges from a socio-technical perspective. By delving into deep scientific and engineering issues and considering human behaviors, SaTC aims to advance the field of cybersecurity and privacy. Given the escalating national significance of cybersecurity, effective communication between program officers, researchers, and government funding agencies becomes paramount. A robust SaTC community will drive innovation, identify novel research avenues, prevent duplication, and enhance graduate education opportunities. This project encompasses the 2026 SaTC PI meeting venue and conference logistics, including registration, audio-visual support, communications, and meeting space in College Park, Maryland. The planning date for the conference is August 6-7, 2026. The 2026 SaTC Principal Investigator (PI) meeting will help as follows. 1) Stimulating research ideas: By bringing together PIs working on different projects, the meeting encourages cross-pollination of ideas. Discussions, workshops, collaborative sessions, and networking opportunities foster creativity and may spark novel research directions. 2) Exploring new opportunities: PIs can explore interdisciplinary collaborations beyond their immediate domains. Interactions between researchers from different disciplines can yield new insights, foster synergies, and prevent redundancy in existing research efforts. 3) Transitioning Research into Practice: Sharing experiences and learning from others helps PIs refine their research approaches. Practical insights gained during the meeting contribute to more effective research outcomes. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2026 · 2026-05

Lafora disease (LD) is a fatal autosomal recessive neurodegenerative disorder characterized by myoclonus, seizures, and a rapid progression to dementia during the teenage years, culminating in death within a decade of onset. LD arises from mutations in genes encoding laforin, a glycogen phosphatase, or malin, an E3 ubiquitin ligase, leading to the accumulation of pathogenic polyglucosan bodies (PGBs) in the brain. Studies in LD mouse models have identified brain PGBs as the primary driver of disease sequalae, identifying the brain PGBs as the critical therapeutic target. Previously, Gentry and Vander Kooi developed an antibody-enzyme fusion (AEF) therapy that degrades brain PGBs and normalizes brain metabolism in LD mice following intracerebroventricular (ICV) administration of the AEF. This work demonstrated impressive proof-of-concept target engagement and brain metabolic recovery. However, clinical translation of this AEF was limited because it does not efficiently cross the blood- brain barrier (BBB). Wang and Gorman recently developed effective antibody-based brain shuttle platforms to allow biologic delivery across the BBB and into the brain parenchyma. This platform utilizes antibodies targeting human transferrin receptor (TfR), which enhance uptake into brain parenchyma by 10-30-fold. This R61/R33 project brings together these two novel technologies. We have engineered a brain-penetrant BBB-AEF therapeutic by fusing the TfR-targeting brain shuttle to the AEF, allowing systemic administration and robust brain PGB clearance. We demonstrate that this BBB-AEF fusion that crosses the BBB, penetrates brain parenchyma, accesses the cytoplasm, and degrades PGBs. A key feature for clinical translation is that the BBB-AEF fusions are humanized. Additionally, we have established a humanized TfR knock-in LD mouse model, designated hTfR-LKO, and developed the needed assays to assess target engagement. Thus, we have already generated preliminary data and necessary tools to develop a translational therapy. The R61 phase (1 year) will establish BBB-AEF target engagement by defining pharmacokinetics, determining an initial effective dose, and assessing PGB clearance in hTfR-LKO mice. Success will be defined by achieving >50% brain PGB degradation. The R33 phase (2 years) will refine dosing regimens to identify the minimum effective dose (MED), optimal treatment duration, and potential sex differences while evaluating physiological outcomes and preliminary safety. Success will be defined by establishing a MED and redosing parameters in both sexes along with defining the therapeutic window and physiological outcomes. This project unites complementary expertise to advance a first-in-class targeted therapeutic for LD and provides the needed data for continued development of this therapeutic. Beyond LD, this platform has the potential to facilitate brain delivery of other biologics, establishing a broadly applicable strategy for treating neurological diseases.

NIH Research Projects · FY 2026 · 2026-04

Project Summary Kaposi’s sarcoma-associated herpesvirus (KSHV) is a gammaherpesvirus responsible for Kaposi’s sarcoma (KS) and primary effusion lymphoma (PEL), malignancies that predominantly affect immunocompromised individuals. The cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) pathway plays a crucial role in antiviral immunity by detecting viral DNA and inducing type I interferon responses. However, KSHV has evolved mechanisms to inhibit this pathway, enabling immune evasion, viral persistence, and tumorigenesis. Despite its importance, the precise KSHV proteins that interact with and suppress cGAS-STING signaling remain largely unidentified. Traditional experimental approaches for mapping host-virus protein-protein interactions (PPIs) are labor-intensive, low-throughput, and often fail to capture the full complexity of viral immune modulation. To address this challenge, we aim to develop an AI-driven computational framework that can systematically identify KSHV-human PPIs, with a focus on viral proteins that inhibit cGAS-STING signaling. Our central hypothesis is that these interactions can be accurately predicted using an AI-based framework and experimentally validated to reveal underlying mechanisms of KSHV-driven pathogenesis. This study aims to uncover novel viral immune evasion mechanisms, enhance our understanding of KSHV pathogenesis, and uncover new therapeutic targets for KSHV-associated cancers by (1) combining deep learning and protein language models to predict high- confidence viral-host interactions using large-scale protein sequences, (2) identifying cGAS/STING-based KSHV proteins with molecular validation, and (3) characterizing functional cGAS/STING inhibitions and evaluating candidate KSHV ORFs in latency establishment or lytic replication. The to-be-developed AI models and tools will be open-sourced and widely disseminated within the community. The success of this project will have broader implications for studying immune evasion mechanisms in other pathogenic viruses, paving the way for innovative antiviral and immunotherapeutic strategies.

NIH Research Projects · FY 2026 · 2026-04

Project Summary/Abstract Lower extremity chronic limb-threatening ischemia (CLTI) is the most advanced form of peripheral arterial disease (PAD) and is a life-limiting condition associated with a 25% risk of mortality and a 20% risk of major limb amputation at one year. CLTI is characterized by a spectrum of findings including non-exertional foot pain (“rest pain”), non-healing wounds, and frank gangrene, and pain is a nearly universal feature. Pain is also an important factor in decision-making around treatment, which may be non-procedural (pain control and wound care), amputation, open surgery (e.g., leg bypass), or endovascular intervention (e.g., angioplasty and stenting). These options necessarily involve substantial tradeoffs among patient goals such as mobility, invasiveness of treatment, likelihood of limb salvage, and post-treatment pain. Despite the centrality of pain in presentation and decision-making, treatment guidelines neglect pain as an outcome and focus on restoration of arterial perfusion to achieve limb salvage. The underlying assumption that treatment of the underlying arterial insufficiency will treat pain is poorly founded. Clinical observation suggests that in many cases pain in CLTI is driven by mechanisms independent of arterial perfusion; however, understanding pain in CLTI has not been a focus of research: there are 0 English-language publications systematically characterizing pain and its features. Furthermore, in a study of PAD patients fewer than half of patients used non-opioid adjuncts (e.g., gabapentin) for pain control, suggesting both a lack of a systematic approach to pain management as well as a lack of understanding of pain mechanisms. Precision treatment of pain and incorporation of pain into prognostication and patient-centered decision-making is impossible without a rigorous real-world characterization of pain in patients with CLTI including its features, such as severity, frequency, and associations with patient and disease-related factors. This knowledge gap directly contributes to deficits in effective decision-making around CLTI treatment and optimal pain management. Therefore, we propose to systematically characterize pain, including identification of clusters of pain features (“pain phenotypes”) in patients living with CLTI and to identify patient and clinical factors associated with these phenotypes. To accomplish this, we will recruit 100 patients living with CLTI facing treatment to 1) characterize pain using validated instruments (e.g., Graded Chronic Pain Scale) and to determine if phenotypes exist and 2) determine the association of phenotypes with patient (e.g., sex) and disease features (e.g., CLTI stage). This work will contribute meaningfully to my development as a leader in patient-centered outcomes and decision-making around CLTI. Most importantly, this proposal lays the groundwork for an R01 focused on 1) understanding the association between pain features and phenotypes and CLTI prognosis, and 2) a granular understanding of pain mechanisms using quantitative sensory testing and other tools with a view towards developing guidelines for precision pain treatment in patients suffering from CLTI.

NIH Research Projects · FY 2026 · 2026-04

ABSTRACT We propose the K12 Career Advancement and Development in Rehabilitation Research (CADRRE) program. The CADRRE program will recruit and train junior faculty who are occupational or physical therapists. The program will support eight K12 Scholars per year who will be recruited from across the nation, and our program will provide them with the skills and research experience necessary to become independent investigators and leaders in rehabilitation. The goal of the CADRRE program is to train leaders who will enable a sustainable and cutting-edge rehabilitation science infrastructure in the United States. The University of Florida (UF) and the University of Southern California (USC) form a partnership that provides a research infrastructure and a critical mass of senior rehabilitation investigators. The strength of this partnership is illustrated by the highly successful K12 program (K12HD055929), that we co-directed from 2007-2024. During that time, we successfully mentored 43 scholars. Building upon that foundation, we propose a new career development program that expands the scope of the mentoring to train scholars at outside institutions in addition to scholars at UF and USC. We have identified 16 highly regarded partner institutions from across the nation that have enthusiastically agreed to participate. We will utilize a two- phase training model which has proven highly successful over a 15-year period of prior K12 support. At the onset of Phase 1, each Scholar will prepare an individualized career development plan under the guidance of an experienced K12 Lead Mentor (i.e., individuals at UF or USC that have a demonstrated record of success in mentoring junior faculty). Scholars at a partner institution (i.e. not at UF or USC) will also have an experienced local Institutional Mentor. The Phase 1 appointment will last up to 3 years and will include a structured didactic program involving research methodology, specialized courses and seminars, training in AI as well as the responsible conduct of research and mentored grant writing experiences. The Phase 1 Scholars will be integrated into an Interdisciplinary Research Team. These teams consist of successful rehabilitation researchers at UF and/or USC with relevant content expertise. The research team members do not replace the Lead and Institutional Mentors, but they will provide a further mentoring resource to assist the Scholars. In Phase 2, Scholars transition to independent research positions and will no longer receive salary support from the K12. Phase 2 Scholars will remain associated with the CADRRE program and continue to be mentored by the Lead Mentor, members of the Interdisciplinary Research Team, and the Institutional Mentor. The entire group of CADRRE scholars (Phase 1 and 2), mentors and advisory boards will gather yearly for an in-person annual meeting in which the research and overall progress will be evaluated and guidance provided by a network of expert advisors in the field. The latter meeting will also serve to help the Scholars network and build strong relationships with peers and senior mentors.

NIH Research Projects · FY 2026 · 2026-04

Project Summary Mechanotransduction and lipid metabolism are fundamental physiological processes essential for maintaining cellular and tissue integrity. Mechanotransduction enables cells to sense and respond to mechanical forces, driving tissue development, homeostasis, and adaptation. Lipid metabolism regulates lipid synthesis, storage, and distribution to maintain energy balance and facilitate cellular signaling. Disruptions in either process can lead to physiological dysfunction and contribute to numerous pathological conditions. Despite their critical biological roles, the molecular and genetic mechanisms that potentially coordinate lipid metabolism and mechanotransduction remain incompletely understood, highlighting the need for further investigation. Our recent findings demonstrate that the mechanosensor PIEZO regulates lipid content and fatty acid-associated prostaglandin synthesis. These findings suggest a potential interplay between mechanotransduction and lipid metabolism, which may function in concert to maintain cellular homeostasis and regulate key physiological processes. This R35 proposal capitalizes on these novel findings linking mechanotransduction and lipid metabolism and outlines two independent yet complementary research directions to address critical knowledge gaps. The first direction focuses on the functional characterization of essential mechanosensitive ion channels, particularly the PIEZO family. By combining forward genetic screens, proximity-labeling proteomics, physiological assays, and transcriptomic analyses, we will identify the interactors and regulatory pathways modulating PIEZO-mediated mechanotransduction. These studies will enhance our understanding of how mechanotransduction influences cellular behavior, calcium-signaling pathways, and inter-tissue communication. The second direction investigates lipid metabolism, emphasizing de novo lipogenesis and lipid droplet (LD) formation — key processes for maintaining lipid homeostasis and supporting metabolic balance. Using genetic screens alongside advanced molecular and biochemistry approaches, we will identify novel genes that could genetically correct lipid metabolic defects, including imbalanced fatty acid synthesis and lipid toxicity, and uncover key regulatory proteins involved in de novo lipogenesis as well as the LD formation and dynamics. This work will define the genetic and molecular networks regulating lipid metabolism and examine how these processes sustain cellular functions under physiological and stress conditions. O ur long-term goal is to unravel these mechanistic connections and provide insights into mitigating the pathogenic impacts of mechanical stress and lipid accumulation, which exacerbate cellular and tissue damage in the liver, cardiac tissues, skeletal muscle, and beyond. Ultimately, this research aims to advance fundamental scientific knowledge and establish a foundation for translational applications.

NIH Research Projects · FY 2026 · 2026-04

ABSTRACT While useful, traditional machine learning and epidemiological prediction models for HIV health outcomes are limited in their ability to capture the complexities of HIV care, typically focusing on single outcomes, and not fully considering the nuisances and multiple health challenges faced by people living with HIV (PLWH). Furthermore, while powerful, traditional machine learning models often times fall short in providing human-interpretable explanations for their choices and predictions. To address this shortfall, we propose the SYNchronized Agentic Prescriptive System for Improving Sequentially HIV Care Continuum (SYNAPSIS-HIV-CC), a comprehensive system to optimize the HIV clinical care continuum. Our approach combines artificial intelligence (AI) agents, large language models, and knowledge graphs to provide individualized healthcare recommendations for multiple endpoints, considering multiple crucial HIV health outcomes: Loss of care (patient dropout from care); viral suppression (undetected viral load); CD4 count levels; a key health monitoring panel; development of new acute events; and development of new comorbidities. The approach also includes the development of an antiretroviral regimen optimization system based on causal AI. SYNAPSIS-HIV-CC outputs will be designed to be interpretable by humans, and supported by causal reasoning. Healthcare providers, such as infectious disease specialists, as well as community healthcare experts will be recruited to help design SYNAPSIS-HIV-CC clinical applications. We will obtain our goals via the following Specific Aims: Aim 1: Agentic AI for multimodal prediction of multiple HIV outcomes Aim 2: A multi-endpoint antiretroviral regimen optimization system via causal AI Aim3: Implementation strategy through qualitative expert assessment By leveraging a multimodal dataset including longitudinal electronic health records, clinical notes, social- behavioral determinants of health, and medical imaging, SYNAPSIS-HIV-CC is designed to help improve PLWH care. Taken together, our three aims will produce an agentic, multimodal, causal AI system for both integrated HIV multi-outcome prediction (Aim 1) and treatment optimization (Aim 2), complete with an implementation plan for real-world applications (Aim 3).

NIH Research Projects · FY 2026 · 2026-04

Post-translational modifications (PTMs) play critical roles in cell biology, drug development, and synthetic biology strategies aimed at advancing human health. While our understanding of PTM diversity continues to grow, deciphering their impact on protein structure, function, and downstream biological processes remains challenging. This project builds on the PI’s research progress in elucidating the diversity, molecular mechanisms, and biological roles of PTMs in archaea. Archaea provide valuable insights into PTM systems, as these microorganisms: i) share evolutionary connections with eukaryotes and are distinct from bacteria, and ii) serve as ideal models for understanding how cells adapt and thrive under extreme environmental conditions that typically damage DNA, RNA, and other biomolecules. This multi-project proposal is integrated around a common goal to address key gaps in understanding how PTM systems work in a coordinated manner to regulate microbial stress response mechanisms. Using the archaeon Haloferax volcanii as a model system, the proposal is focused on advancing knowledge of the biological roles and interactions of the ubiquitin-like proteasome system and lysine acetylation, with an emphasis on how these PTMs regulate DNA replication and repair (DNA/RNA metabolism and chromatin architecture), protein homeostasis (proteasomes), and cellular efficiency (biomolecular condensates). • Project 1 aims to enhance understanding of PTM-mediated regulation of protein-protein interactions (PPIs) and liquid-liquid phase separation (LLPS) of nucleases involved in DNA repair and cell viability. • Project 2 aims to address key gaps in knowledge regarding the function of proteasome assembly chaperones (PACs) in regulating proteasome assembly and activity, with a focus on the role of PTMs and the C-terminal HbYX motif in these processes. • Project 3 aims to deepen our understanding of Sir2-type sirtuin lysine deacetylases and their regulation of chromosome accessibility through their catalytic activity and interaction with thiol-sensing chromatin-binding proteins, such as OxsR. • Project 4 aims to provide insight into how PTM systems work together to control DNA topology, focusing on the interaction of Cdc48-type ATPases, ubiquitin-like ligation, and lysine acetylation in regulating Type 1A topoisomerases in archaea. The long-term goal of this proposal is to enhance our understanding of the interplay of PTM systems in microbial stress responses and translate this knowledge into applications that benefit human health.

NSF Awards · FY 2026 · 2026-04

Plant-based biomass is a potential source of fuels and valuable chemicals. Finding ways to convert biomass to fuels and chemicals could create value and improve U.S. energy security. Lignan is a major component of biomass. Lignan has molecular structures that are precursors to fuels, chemicals and materials used in advanced manufacturing. However, the catalysts that promote the reactions to final products are not selective. They promote both desirable and undesirable reactions. This lowers efficiency and reduces product value. This project will develop new catalyst designs that improve reaction selectivity by controlling the atomic-scale structure of sites where the catalytic reactions take place. The project outcomes will enable more efficient use of biomass and advance sustainable chemical manufacturing by minimizing unwanted side reactions. The project will support education and workforce development by training students in interdisciplinary catalysis research and by engaging K-12 students through STEM outreach activities. This collaborative project will develop a fundamental understanding of oxygen-removal reactions on a class of catalysts known as dilute alloys, which contain isolated early transition metal atoms embedded within copper-, silver-, or gold-based host materials. The project will investigate how the identity and atomic arrangement of these isolated metal sites influence chemical bonding, reaction pathways, and catalyst stability. To achieve this, the researchers will combine controlled surface experiments, catalytic performance measurements at near-ambient pressures, advanced spectroscopic techniques, and computational modeling of reaction mechanisms. By linking insights from well-defined model systems to more complex catalytic materials operating under realistic conditions, the project will establish broadly applicable design principles for catalysts that selectively convert biomass-derived molecules into valuable aromatic hydrocarbons. These principles may also inform the development of cost-effective alternatives to precious-metal catalysts for a wide range of chemical transformations. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2026 · 2026-03

Glucagon-like peptide 1 receptor agonists (GLP-1RAs) have become pivotal in managing diabetes and obesity, with a prescription surge of 300% from 2020-2022, with more than half of the U.S. adult population eligible for therapy, reflecting their potential to impact patient important outcomes. Despite their benefits, concerns about an association between GLP-1RA use and thyroid cancer have emerged, highlighted by low events rates and inconclusive findings from randomized trials and inconsistent results from real-world data. There is an urgent need to address the risk uncertainty regarding GLP-1RA and thyroid cancer to prevent unnecessary evaluation for thyroid cancer or withholding of therapy in otherwise eligible patients. The overarching goal of this study is to enable evidence-based treatment for type 2 diabetes and obesity by clarifying the thyroid cancer risk associated with GLP-1RA therapy. To achieve this goal we will utilize the EPIC COSMOS database and a trial emulation design with active comparators to comprehensively assess thyroid cancer risk post-GLP-1RA initiation, leveraging advanced statistical methods including machine learning, Bayesian methodology and microsimulation. The use of EPIC COSMOS one of the largest databases in the US including electronic health records from 289 million patients provide a unique dataset to overcome the limitations of previous studies. In Aim 1, we will quantify incidence, relative risk, and timing of thyroid cancer diagnosis after GLP-1RA initiation among adults with type 2 diabetes and/or obesity who initiate GLP-1 RA between 2010 and 2025. We will use a Marginal Structural Model combined with inverse probability treatment weights, inverse probability censoring weights, and inverse probability detection weights to adjust for treatment assignment, censoring, and detection bias. Super-learner high-dimensional propensity score and instrumental variable will be used to adjust for residual confounders. In Aim 2, we will investigate the risk and timing of incident thyroid cancer diagnoses within pre-specified high-risk groups and use a novel hybrid interpretable causal artificial intelligence method to investigate if certain variables can serve as thyroid cancer risk modulators and if subgroups at high risk for thyroid cancer exist. Bayesian methods will be used to integrate prior knowledge to derive probability distributions of the relative risk of incident thyroid cancer under GLP-1 RA use in the overall population and identified subgroups. In Aim 3, we will complete a microsimulation experiment using the Building, Relating, Assessing, and Validating Outcomes (BRAVO) model to evaluate the risk-benefit trade-offs between the potential thyroid cancer risk and metabolic benefits conferred by GLP-1 RAs across population subgroups with diverse risk profile, and identify subgroups for whom the benefits significantly outweigh the risks, or vice-versa.

NIH Research Projects · FY 2026 · 2026-03

Summary Brain-derived neurotrophic factor (BDNF) exerts its biological actions mainly through TrkB receptors. BDNF-TrkB signaling plays a crucial role in regulating the development and function of neural circuits. BDNF impacts nearly all stages of neural circuit development by promoting neuronal differentiation, axonal and dendritic growth, synapse formation and maturation, and refinement of neuronal connection. In mature neural circuits, BDNF enhances the efficacy of glutamatergic synapses but weaken the efficacy of GABAergic synapses by changing either activity-induced presynaptic transmitter release or postsynaptic responses. BDNF can also alter the capacity of synapses to express activity-induced long-term potentiation or long-term depression. More recently, substantial evidence has established a crucial role for BDNF in the control of energy balance. Mutations in either the Bdnf gene or the Ntrk2 gene that encodes TrkB cause severe obesity in mice and humans. Given these important roles of BDNF in the nervous system, it is not surprising that hyperphagia, severe obesity, intellectual disability, autism, and impaired nociception are observed in approximately 50% of people with WAGR (Wilms tumor, aniridia, genitourinary abnormalities, and mental retardation) syndrome, due to contiguous gene deletion extended into the BDNF gene, leading to BDNF haploinsufficiency. Thus, a drug that can increase BDNF expression has potentials for treating a subset of WAGR patients with BDNF insufficiency. We have generated a new mouse strain, BdnfNLuc, in which the DNA sequence encoding the highly active nano luciferase (NLuc) was inserted into the Bdnf locus immediately before the stop codon. By using cortical and hippocampal neurons from BdnfNLuc/+ embryos, we developed a highly sensitive and highly reproducible phenotypic assay for detection of BDNF expression in 384-well plates. We had successfully scaled up the assay and performed a pilot screen of the 1280-compound library of pharmacologically active compounds (LOPAC). These results indicate that our assay is ready for high throughput screening. We propose to screen a collection of approved drugs (~4100 compounds) to identify a drug that can increase BDNF expression in both mouse and human neurons in vitro as well as in mice in vivo. We will then determine if administration of the drug can correct several phenotypes observed in Bdnf+/- mice. Findings from these studies could be quickly translated to therapeutic applications for patients with BDNF insufficiency, including the subset of WAGR patients with BDNF deletion. Finally, to find novel chemical structures that may be better suited or more active in increasing BDNF expression, we will screen 20,000 CNS-focused compounds. We aim to find 1-2 lead compounds that can increase BDNF expression in cultured mouse and human neurons and in the mouse brain for future drug development.

NSF Awards · FY 2026 · 2026-03

This award is to support participants at the 2026 Gainesville International Number Theory Conference, which will take place March 18-22, 2026 at the University of Florida, Gainesville. Research in number theory has a long and illustrious history going back to the ancient Greeks. Recent research in number theory has made significant advances that has led to important applications to other areas such as physics, computing, and data security. Two very recent sensational developments have been on the distribution of multiplicative functions in short intervals, and on the Kummer-Patterson Conjecture relating to cubic Gauss sums. The conference will feature three lectures by Maksym Radziwill on these topics. There will be over thirty main lectures and seventy twenty-minute research presentations. Special effort will be made to support students, early career mathematicians and researchers with no other support. The conference will cover the following topics: q-series, partitions and modular forms, analytic number theory, algebraic number theory, irrational and transcendental numbers, arithmetic geometry, and computational number theory. The study of irrational numbers, which dates back to Greek antiquity, continues to be an active area of research. Recently, spectacular advances have been made in the theory of irrational numbers by applying advanced methods. Conference talks by Frank Calegari and Yunqing Tang will report on these exciting new developments. Historically the synergy between analytic number theory and the combinatorial/algebraic world of partitions and q-series has been extremely fruitful, starting with the collaboration of Hardy and Ramanujan. Throughout the twentieth century and into the twenty-first, we have seen each area enrich the other. For example, mid-twentieth century workers like Dyson and Atkin found fruitful interactions between these two areas, and the potential for further interactions along these lines by the participants in this conference is significant and tantalizing. Similarly, L-functions and modular forms have been the catalyst for many developments in computational number theory, and vice versa. The talks and papers of the conference will be widely disseminated by making presentations and abstracts available on the conference web page and by publishing a refereed conference proceedings. More information can be found at https://qseries.org/alladi70. 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 · 2026-03

The International Conference on Complex and Differential Geometry (ICCDG) will take place at the International Centre for Theoretical Physics (ICTP) in Trieste, Italy, on May 25–29, 2026. The conference is organized in partnership with the Clay Mathematics Institute (CMI). This five-day conference will convene leading experts and early-career mathematicians from multiple continents who work in complex and differential geometry. Its primary goals are to disseminate recent research advances, foster interaction across subfields, and promote international scientific collaboration. The requested award will ensure a strong U.S. presence at this global meeting. Complex and differential geometry have experienced significant advances in recent decades, yet many deep and far-reaching questions remain, with important implications for both mathematics and theoretical physics. Through plenary lectures, focused seminars, problem sessions, and informal discussions, the conference will provide U.S. researchers—both established and emerging—with new perspectives and techniques for addressing fundamental geometric problems. Participation by distinguished U.S.-based speakers supported under this proposal will help shape international research directions and reinforce U.S. leadership within the global geometry community. The meeting will also catalyze new international collaborations and strengthen opportunities for the next generation of U.S. geometers. No individual supported by this award will be selected or excluded based on race, national origin, sex, disability, or age. For more information, please visit https://indico.ictp.it/event/11144. 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 · 2026-03

Since much of the coastal population and economic activity is concentrated around bays and inlets, it is important to understand their circulation. Semi-enclosed basins are particularly interesting because their exchange with the open ocean involves the interplay of local wind forcing and conditions over the continental shelf, which may be influenced by larger scale winds elsewhere. This project will explore a dynamical framework to combine such effects and generalize findings to semi-enclosed basins globally. Expected findings will help efforts to predict impacts on coastal environments from extreme weather events, coastal flooding, erosion and water quality threats. This project will address circulation in semi-enclosed basins, investigating the various drivers including tides, density gradients, winds, and remote oceanic influences. While the role of tidal and baroclinic forcing has been extensively studied, the combined effects of local wind stress and remotely driven shelf forcing remain poorly understood. The project will integrate observational and theoretical approaches to advance understanding of wind-driven, including remote forcing from the shelf, and subtidal dynamics in semi-enclosed basins. Field observations, analytical modeling, and machine learning techniques will be combined to examine wind-driven and remotely driven, exchange flows in semi-enclosed basins. A new tetrahedral dynamical framework will facilitate the inter-comparison of semi-enclosed basins. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2026 · 2026-03

Project Summary Over 81,000 Americans died from opioid overdose in 2023. Opioid overdose and opioid use disorder (OUD) impose significant societal and economic burdens, making sustained OUD treatment a critical public health priority. Buprenorphine, an evidence-based therapy for OUD, reduces overdose and mortality risks with >6 months of therapy. Yet, >50% of patients discontinue it within 6 months of initiation, increasing relapse and mortality risks. Primary care providers (PCP) prescribe >60% of buprenorphine prescriptions and are expected to prescribe more following elimination of the federal waiver requirement, highlighting their role in treatment retention. Although PCPs may recognize some patients at risk of discontinuation, they face time constraints, competing demands, and a lack of systematic clinical decision support (CDS) tools to integrate multi-faceted risk factors to efficiently identify patients at high risk of buprenorphine discontinuation. Accurate prediction of buprenorphine discontinuation can better inform tailored interventions, such as long-acting injectable buprenorphine and peer recovery support, to improve retention and outcomes. Prior studies using traditional regression-based methods have identified individual risk factors of buprenorphine discontinuation; however, little is known about whether these single factors accurately predict such risk. In addition, using these methods to predict buprenorphine discontinuation proves to be challenging because of their limited ability to handle complex relationships between predictors and outcomes. Machine learning offers an alternative, uncovering hidden patterns in complex data and generating precise prediction algorithms and risk stratification subgroups to guide clinical care and interventions. Our prior work has successfully applied machine learning to claims data to identify commercially insured patients at high risk of buprenorphine discontinuation. Leveraging our prior work, we propose to develop and evaluate a machine-learning buprenorphine care discontinuity prediction e-tool (BUP-CARE) for PCPs within healthcare systems to identify patients at high risk of buprenorphine care discontinuity. We have 2 specific aims. Aim 1 will use OneFlorida+ electronic health records (EHR) data from 2014 to 2025 in the PCORnet Common Data Model to develop and validate machine-learning prediction algorithms to identify patients at high risk of buprenorphine discontinuation. We will expand our previous work by incorporating advanced deep learning (e.g., recurrent neural network) for risk prediction and by including social determinants of health as predictors. Aim 2 will identify barriers and facilitators for developing a BUP-CARE CDS tool to alert front-line PCPs for patients at high risk of buprenorphine discontinuation. We will use an iterative user-centered design approach to enhance BUP-CARE’s functionality and usability. Our proposed research is highly innovative and clinically relevant in its use of a machine learning- based CDS tool to guide clinical practice and tailor evidence-based interventions, thereby optimizing resource allocation and reducing patients’ buprenorphine care discontinuity.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY/ ABSTRACT: Currently, the therapeutic options available to individuals with inflammatory bowel disorder (IBD) are limited to small molecule drug and biologics with high toxicity and off-target effects. IBD (and gut dysbiosis) have been directly linked to a plethora of metabolic, neural, allergic and autoimmune diseases, further emphasizing the need for effective and safe therapy. Interestingly, gut dysbiosis is distinguished by deficiency in IL-10 in the inflamed areas. Moreover, there are defects in immune regulation affecting regulatory T cell (Treg) activity and IL-10 signaling. Tregs can inhibit inflammatory immune cells such as M1 macrophages and Th17 cells via secretion of anti-inflammatory cytokines (e.g. IL-10). Moreover, Tregs specific for a disease relevant antigen have been shown to be advantageous over polyclonal Tregs. Traditionally, IBD has not been considered an antigen-specific, inflammatory disease. However, groups have shown that there is generation of monoclonal antibodies to epitopes derived from host proteins (e.g. tropomyosin), as well as antibodies against gut pathogens. Ostensibly, localized generation of antigen-specific Tregs can curtail and counter gut dysbiosis. The immunomodulatory biomaterials lab at UF is currently engineering nanoparticles (NPs) from a polymer derived from commensal bacteroides - Polysaccharide A (PSA). PSA is found on the capsule of the commensal bacterium B. fragilis and directly interacts with antigen presenting cells (APCs), particularly dendritic cells (DCs) to direct and maintain the balance of immunity in the gut. Relevant to this application, we have shown that purified PSA can be used to generate nanoparticles with strong and specific activation of TLR2 on DCs, and robust downstream production of interleukin (IL)-10 from regulatory T cells. Here, we propose to develop an off-the-shelf-approach for ulcerative colitis (UC), which involves glycosylated antigen-loaded PSA nanoparticles (NPs) to drive tolerogenic DCs in the mucosal epithelium and induce effective numbers of UC specific-Tregs to ameliorate UC. Our long-term goal is to develop a modular, easily administrable, tolerance-inducing platform for treatment of gut dysbiosis. The overall objective of this R21 proposal is to engineer glycosylated antigen-loaded PSA NPs to attenuate UC in a murine model, and investigate the extent of immune modulation following oral administration. Our central hypothesis is that upon oral delivery, these engineered NPs will resist digestive tract degradation, target inflammation in the intestine and interact with innate immune cells in these areas to induce specific, anti-inflammatory responses and attenuation of gut dysbiosis. The overall objective of this R21 proposal is addressed by the following two specific aims: 1) Engineer glycosylated antigen-loaded PSA NPs and characterize their physico-chemical properties, in vitro modulatory capacity and biodistribution following oral delivery; 2) Evaluate the therapeutic capacity of PSA NPs in an OVA-DSS murine model of Colitis. The proposed research is novel and innovative due to the simplicity of its generation and administration to the patient, and huge potential as a therapeutic agent for IBD.

NIH Research Projects · FY 2026 · 2026-02

SUMMARY The functions of long-noncoding RNAs (lncRNAs) as crucial regulators of transcription, epigenetic modifications, mRNA stability, localization, and translation indicate their potential involvement in Alzheimer's disease (AD) pathogenesis. Given the impairment of these fundamental cellular processes in AD, lncRNAs emerge as plausible targets. Consistent with this possibility, several studies have demonstrated altered expression of specific lncRNAs in various AD models. However, the precise roles, mechanisms, and cell-specific contributions of these lncRNAs in AD development remain unclear. This exploratory/developmental R21 proposal aims to systematically investigate the regulation of expression and function of lncRNA SLAMR in the pathogenesis of AD. SLAMR lncRNA was discovered from an unbiased screen of learning regulated lncRNAs. We find that SLAMR lncRNA in mouse CA1 is critical for synapse density, morphology, plasticity and memory. Importantly, we find that SLAMR functions as a key modulator of translation and structural plasticity. Gain of function of SLAMR resulted in enhanced translation and functional synapses. Our preliminary data show that SLAMR expression is impaired in APP knock-in (App NL-G-F) mouse model of AD. We will now assess the role of SLAMR mediated translation in App NL-G-F model and Tau model (PS19) of AD. Our systematic functional experiments are anticipated to unveil the role of SLAMR in the progression of AD pathogenesis. Successful completion of this proposal will shed light on the significance of lncRNAs in AD pathogenesis and influence the development of lncRNA-based therapeutics for AD.

NIH Research Projects · FY 2026 · 2026-02

Immune responses can be evoked through diverse inducible pathways and several genes in these pathways are under investigation as putative therapeutic targets, yet it is likely that additional regulators of immune responses are present and remain undescribed. Recent data has shown potassium (K+) efflux through ATP-gated inward rectifier potassium (KATP) channels reduces virus replication and virus-mediated mortality in mammals, fruit flies, honey bees, and mosquitoes. These data raise the intriguing question of how ion channels and K+ efflux can regulate the antiviral immune response, which are two seemingly disconnected physiological systems, and is the focus of this proposal. KATP channels act as molecular sensors of the cell by coupling cell metabolism to the electrical activity of the cell via the cell membrane potential. Thus, the premise of this proposal is that KATP channels are functionally coupled to antiviral immunity by K+ efflux controlling neurosecretion, bioavailability of ATP, and kinase activity that are essential for circulatory homeostasis, function of the RNAi machinery, and reactive oxygen species generation, respectively. We will directly test the hypothesis that KATP channels are essential to antiviral immune responses in the vector by regulating 1) circulatory homeostasis 2) antiviral RNAi machinery, and 3) products of aerobic respiration that regulates antiviral immune pathways. The experiments outlined in this proposal will systematically test this hypothesis and delineate the involvement of each physiological system to KATP-mediated viral immunity in model organisms that will yield insights to regulation of antiviral immune responses in humans. In Specific Aim 1, we will test the influence of viral infection and modulation of K+ efflux through KATP channels to dorsal vessel contraction dynamics and circulatory homeostasis through gene silencing and transgenic approaches. The data collected in SA1 will bolster our understanding of physiological systems driving virus infection in a competent vector. In Specific Aim 2, we will expand our preliminary results that clearly indicate KATP channels interact with the antiviral RNAi pathway, but do not define the point of interaction. We will perform small RNA sequencing from transgenic mosquitoes to determine whether the defect is in dicer complex or in downstream steps, such as assembly of RISC complexes. The data collected in SA2 will address the mechanism of how ion channels can alter function of antiviral RNAi machinery, which is currently unresolved. In Specific Aim 3, we will test if reduced DENV-2 replication after KATP channel activation is due to ROS/antioxidant-mediated regulation of antiviral immune pathways. The data collected in SA3 will yield mechanistic insights regarding the functional linkage between KATP channels and antiviral RNAi pathways that can be used to inform downstream therapeutic development. Combined, the data generated in this study will fill fundamental gaps in our knowledge of how antiviral immune responses are triggered and will identify putative intervention points to interrupt viral replication.

NIH Research Projects · FY 2026 · 2026-02

Project Summary / Abstract Bacillary dysentery or shigellosis is caused by bacteria of the Shigella species: S. dysenteriae, S. flexneri, S boydii, and S. sonnei. Infections range from mild or asymptomatic to severe bloody diarrhea, so reported prevalence grossly underestimates actual prevalence. Shigellosis is a global public health concern and antimicrobial resistance has compounded the problem. Moreover, shigellosis is also sexually transmitted in the United States, Europe, and other developed countries. Such outbreaks are driven by the emergence of antibiotic resistant strains of S. flexneri infecting men who have sex with men. The objective of this proof-of-concept study is to demonstrate that wastewater-based epidemiology (WBE) using digital PCR to detect pathogen molecular markers can provide a more accurate picture of community prevalence of bacterial pathogens than traditional case reporting. Wastewater surveillance for viral pathogens has been in use for decades and its use to monitor SARS-CoV-2 is now widely applied globally. Analogous methods for wastewater surveillance of bacterial pathogens by digital PCR has lagged. We will develop and validate methods to detect Shigella, an important bacterial agent of diarrheal disease, in wastewater. We will also field test the methods to assess shigellosis prevalence at community and building scale and link the data to the actual population residing in the wastewater collection area. We will provide actionable data to the local health department which can then develop targeted public health interventions. The independent but complementary aims in demonstrating the proof-of-concept are: 1. Develop and validate sensitive, specific, and reproducible WBE methods for detection of Shigella species in wastewater using digital PCR. Three subaims will: 1.1) optimize methods for extraction and detection of Shigella in wastewater using laboratory-grown strains of Shigella species to “spike” authentic wastewater and laboratory prepared “synthetic” wastewater; 1.2) validate molecular targets for differentiation of S. flexneri from S. sonnei in wastewater; and 1.3) culture of Shigella from wastewater to assess antibiotic resistance genotypes and phenotypes. 2. Assess proof-of-concept of WBE as a public health tool for Shigella at community and building scale with emphasis on high risk congregate populations, i.e., day care centers. Two subaims will: 2.1) measure the prevalence of Shigella species at community scale by sampling at the wastewater treatment plant intake and using wastewater flow rate as a population normalization marker; and 2.2) extend shigellosis surveillance to building scale targeting high risk congregate pediatric populations. Strengths of this proposal are the innovative application of WBE to a bacterial pathogen, our method for population normalization, differentiation of Shigella species, prevalence measurement of Shigella species at community and building scale, and the expertise of our multidisciplinary team.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY Gammaherpesviruses chronically infect more than 90% of all humans worldwide by establishing lifelong latency in B cells. Latent infection is usually asymptomatic, but these viruses can be oncogenic, especially in immunocompromised patients. One example is Epstein Barr Virus (EBV), the cause of Burkitt lymphoma, and the first oncogenic virus ever discovered. No vaccines or antivirals are available to prevent or cure gammaherpesvirus latency, despite the high infection rates and oncogenic potential. One barrier to the development of such interventions is that there is a limited mechanistic understanding of how these viruses establish latency and drive lymphoma. A better understanding of viral and host factors that regulate latency and lymphoma formation would lay the groundwork new vaccines or therapies in the future. A key feature of all gammaherpesviruses is that they infect B cells and drive them through the germinal center activation program before establishing latency in memory B cells. The mouse gammaherpesvirus, MHV68, faithfully reproduces this characteristic, and MHV68 can be used to study viral pathogenesis in vivo. Using this model, we have discovered that the host ubiquitin ligase, Cul4b, is essential for establishment of latency in B cells. Infection of mice that lack Cul4b only in B cells results in a 100-fold reduction in viral latency and also reduces the magnitude of the antiviral humoral response, suggesting that Cul4b is directly needed to support germinal center B cell activation pathways. Our lab is the first to report a role for Cul4b in B cells, but in cell lines and human tumors, Cul4b facilitates proliferation and malignancy. This project will use the MHV68 mouse model of chronic infection and lymphomagenesis to define the role of Cul4b in infected GC B cells, in direct comparison with antigen-activated GC B cells, and we will define the impact of Cul4b on gammaherpesvirus-induced malignancy. The results will shed new light on the understanding of gammaherpesvirus latency establishment, lymphomagenesis, and basic GC B cell biology. This information will be useful for designing strategies to prevent or cure latent infection and gammaherpesvirus induced malignancy, especially in high-risk immunocompromised patients.

NIH Research Projects · FY 2026 · 2026-02

Healthy individuals have strong circadian rhythms in blood pressure and kidney function. Loss of rhythms in blood pressure and renal function causes increased risk for death from cardiovascular disease. The underlying mechanisms of these effects have not been determined but may involve components of the circadian clock. Circadian rhythms in physiological function are driven by a molecular clock present in nearly every cell type. We have identified the molecular clock component PERIOD1 (PER1) as a critical regulator of BP and kidney function using preclinical rodent models. Studies in humans show that PER1 expression is significancy reduced in the kidneys of people with hypertension or kidney disease. Loss of PER1 in rodent models causes disrupted rhythms in blood pressure, increased blood pressure, and impaired renal function in a salt-dependent manner. Salt-sensitive hypertension and kidney disease are public health burdens and there is an urgent need to develop new therapies and improve existing treatments. Based on our published data and exciting new results generated for this proposal, the premise of this application is that increasing PER1 expression in the kidney can prevent salt-sensitive hypertension and kidney disease. A key gap in knowledge is the mechanism by which PER1 mediates its protective effects. We have identified aldosterone signaling through the mineralocorticoid receptor (MR) and endothelin-1 (ET-1) signaling as downstream PER1 targets. The aldosterone/MR and ET-1 pathways are known contributors to salt-sensitive hypertension and kidney disease. Our data demonstrate that loss of PER1 results in adrenal dysfunction as shown by increased production of aldosterone and renal dysfunction including increased expression of MR and ET-1 in the kidney. These data together with our published work support the central hypothesis of this proposal, that PER1 suppresses aldosterone/MR and ET-1 signaling to prevent salt-sensitive hypertension. In Aim 1, we will test the hypothesis that loss of PER1 causes increased aldosterone/MR and ET-1 signaling, leading to salt-sensitive hypertension and renal/adrenal function, using a combination of genetic and pharmacological approaches. In Aim 2, we will test the hypothesis that PER1 expression and activity in the kidney can prevent salt-sensitive hypertension and renal/adrenal dysfunction using a combination of genetic knockout with kidney cross-transplantation or gene therapy to manipulate PER1 expression in the kidney. Understanding the mechanisms by which PER1 mediates its effects on blood pressure and renal/adrenal function will fill a key gap in the field regarding how circadian clock components contribute to physiology and pathophysiology. These studies will also provide important preclinical data to address the premise of this work, that increasing PER1 expression is viable therapeutic option for treating salt-sensitive hypertension and renal/adrenal dysfunction.

NIH Research Projects · FY 2026 · 2026-01

LrgA/B (membrane proteins found in a wide variety of bacteria) has been recently identified as a pyruvate importer in Bacillus subtilis, Staphylococcus aureus, and Streptococcus mutans. An increased appreciation for extracellular pyruvate’s non-traditional and diverse roles in metabolism and stress resistance has emerged in recent years. Although our published and preliminary data demonstrate key roles for LrgAB and/or extracellular pyruvate in modulating S. mutans physiology, oxidative stress resistance, and virulence, the precise mechanism(s) by which extracellular pyruvate exerts these functions in S. mutans remain unknown. Amongst oral streptococci, lrgAB and its upstream two-component regulator lytST, are notably absent from the genomes of non-cariogenic streptococcal species, and likewise extracellular pyruvate supplementation does not confer a strong stationary phase growth advantage in non-cariogenic oral streptococci. Collectively, these observations support the hypothesis that extracellular pyruvate serves as a metabolic signal that enhances stress resistance and metabolic flexibility of S. mutans, contributing to survival in fluctuating host environments. This would provide a distinct competitive advantage to S. mutans in dental plaque biofilm and other pyruvate-replete environments such as the bloodstream. This hypothesis will be addressed by two specific aims. In Aim 1, the metabolic fate of extracellular pyruvate in S. mutans planktonic cultures will be tracked and identified by 13C-labeled pyruvate feeding experiments and NMR spectroscopy. Time-resolved metabolomic and transcriptomic analyses will also be employed to characterize pyruvate-, LytST-, and LrgAB-driven gene expression and metabolic shifts during growth-phase transitions. In Aim 2, fluorescence-based reporters and confocal microscopy will be used to examine the influence of lrgAB and extracellular pyruvate supplementation on S. mutans niche competition and behavior within dual-species biofilms grown in human saliva. Pyruvate supplementation, LrgAB, and LytST effects on S. mutans oxidative stress resistance and survival in human whole blood, plasma and serum will also be assessed. Understanding the interactions between extracellular pyruvate, LytST, and LrgAB could provide new insights into the pathogenesis of S. mutans, its persistence in the oral cavity and bloodstream, and its interactions with other microbial species. This could lead to new targeted therapeutic strategies to control S. mutans infections, both within the oral cavity and in systemic conditions such as infective endocarditis.

NIH Research Projects · FY 2025 · 2026-01

Project Summary and Abstract Inborn errors of metabolism (IEMs) are a diverse group of over 1,000 congenital disorders caused by enzymatic mutation, the vast majority of which prominently affect the nervous system. Phosphoglycerate dehydrogenase (PHGDH) deficiency is a rare IEM caused by loss-of-function mutations in PHGDH, the rate- limiting enzyme in the de novo serine biosynthesis pathway. PHGDH deficiency presents with a clinically heterogeneous spectrum ranging from lethal neonatal Neu-Laxova Syndrome to nonlethal infantile-onset manifestations. While it is understood that PHGDH loss leads to serine and glycine depletion, the mechanisms linking enzyme dysfunction to nervous system phenotypes remain poorly defined. This project investigates how PHGDH loss disrupts metabolic homeostasis during nervous system development by disentangling its dual effects on serine-driven one-carbon, and central carbon metabolism. Preliminary data using [U-13C]glucose tracing in patient-derived PHGDH-deficient cells reveal not only reduced serine synthesis, but also increased pyruvate synthesis and TCA cycle turnover, potentially exacerbating oxidative stress through reactive oxygen species (ROS) overproduction. We hypothesize PHGDH deficiency not only inhibits serine/glycine synthesis, and also increases TCA cycle turnover, predisposing cells to oxidative damage while simultaneously driving global dysregulation of energy metabolism. In Aim 1, we will use inducible PHGDH expression systems in patient-derived fibroblast cell lines and [13C] tracers to define how varying PHGDH levels alter metabolic flux and ROS generation, and test interventions that buffer oxidative stress. In Aim 2, we will characterize the developmental consequences of PHGDH loss in newly developed humanized PHGDH deficiency mouse models. We will leverage spatial metabolic imaging and advanced microscopy to characterize the metabolic functions of PHGDH during nervous system development. Lastly, we will test exogenous, gestational serine supplementation strategies to assess tissue-specific metabolic vulnerability and embryonic lethality rescue in development. This work will provide fundamental insights into how PHGDH loss causes metabolic pathway disruptions leading to nervous system developmental defects. Our work will establish a framework for applying in vitro and in vivo targeted metabolic tracer and gene regulation approaches to study and potentially treat PHGDH deficiency and other IEMs. This proposal comprises of a rigorous and reproducible research strategy and comprehensive training plan that will prepare me to be an independent principal investigator at a tier 1 research institute. This research project will incorporate training in mass spectrometry, isotope tracer analysis, gene regulation, and molecular genetics. The University of Florida, in combination with the exceptional joint mentorship of Dr. Matthew Merritt and Dr. Eric Wang, provides an outstanding research environment that will enable my professional growth and completion of this proposed research.