University Of Missouri-Columbia

NSF Awards · FY 2026 · 2026-10

This Research Experiences for Undergraduates Site renewal will engage 10 undergraduate students each year in a 9-week summer research program on artificial intelligence (AI)-enabled operations engineering. Many important systems in transportation, healthcare, manufacturing, and services operate under uncertainty, limited resources, and changing conditions. These systems increasingly depend on analytical and computational methods that combine operations research and artificial intelligence to improve planning, coordination, and real-time decision-making. The project will provide students with mentored research, technical training, and professional development that strengthen preparation for graduate study and technical careers in computing, operations research, analytics, and intelligent systems. The research activities will focus on AI-enabled operations engineering, including prescriptive analytics methods that combine optimization, simulation, machine learning, and related computational tools to support complex operational decisions. Students will engage with decision problems in healthcare, next-generation transportation systems, advanced manufacturing, and contested logistics. They will receive training in problem formulation, data analysis, optimization, simulation, algorithm development, machine learning, computational experimentation, and solution evaluation. Sample projects that are computationally challenging include collaborative blood inventory planning, network-aware drone logistics, urban air mobility coordination, additive manufacturing scheduling, and decision-making for logistics operations under disrupted or contested conditions. The program will strengthen student preparation in both computing and operations research methods while helping build a workforce prepared to address complex real-world challenges in critical operational domains. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2026 · 2026-10

This Research Experience for Undergraduates (REU) Site at the University of Missouri – Columbia will investigate a variety of interesting and challenging problems that involve consumer networking applications and services that are of significance to the economy and quality of life in areas such as public safety, health care, nature conservation and education. The students will participate in the faculty mentors’ on-going funded research, investigate technically challenging issues and develop viable solutions and insights. They will participate in professional development activities to prepare them for future graduate studies and a broad range of emerging computing careers. Using an already established network of recruiting venues, participants will be recruited from a broad range of educational and geographic backgrounds. The intellectual merit of the project rests with the leadership, an experienced research group with excellent expertise and experience in the research area. The research will focus on broad topics such as software-defined networking/virtualization for resource control, resilient visual computing at the drone network edge, secure and artificial intelligence enabled mixed reality, mobile sensing and environment recognition, securing networked consumer applications, and application-aware network performance optimization. The research activities will lead to a better understanding of the multitude of efficiency, performance, reliability, scalability, and security issues and tradeoffs in consumer networking technologies and related applications. Advanced networking environments and software developed in the previous REU site programs as well as novel testbeds such as the NSF-supported AERPAW/FABRIC resources, Mizzou CAVE (mixed reality), smart device equipment, and sensor-based monitoring will be leveraged by the participating students in hands-on experiments within their research projects. 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 · 2026-07

Extreme events such as heat waves and wildfire outbreaks can threaten lives, property, ecosystems, infrastructure, and economic activity. These events often occur quite suddenly, are clustered in space, and arise from complicated interactions among weather, ecosystem, land, and ocean processes. Current forecasting methods can have difficulty detecting when ordinary conditions may rapidly develop into damaging extremes, especially when multiple hidden drivers interact over space and time. This project develops new statistical and deep learning modeling and computational tools to improve understanding and prediction of such events. By linking data-driven forecasting with scientific knowledge about how dynamic systems grow and interact, the work seeks to provide earlier warning of hazards that affect public safety, emergency preparedness, agriculture, energy systems, water resources, and community resilience. The project also advances the national interest by strengthening the mathematical, statistical, machine learning, and artificial intelligence foundations needed to anticipate high-impact risks, producing open-source software for use by other researchers and practitioners, and training students with multidisciplinary expertise spanning statistics, dynamical systems, and artificial intelligence. The resulting methods and tools may also benefit other fields in which rare but extreme events occur, including neuroscience, cardiology, economics, and national security applications involving complex dynamic systems. This project develops a unified framework for modeling and forecasting extremes in spatio-temporal systems by integrating spatio-temporal statistics, extreme value theory, dynamical systems theory, information theory, and neural estimation. The first goal is to characterize transient extremes through efficient statistical proxies for complex nonlinear systems, using linear systems with non-normal transition behavior and heavy-tailed innovation processes. This work develops theory showing how the interaction between transient growth and heavy-tailed disturbances can lead to extremes that are not well represented by standard stationary spatio-temporal dynamic models. The second goal is to identify directed information flow and latent forcing mechanisms that influence both typical behavior and extreme outcomes. The project develops a tail-emphasized spatio-temporal transfer entropy approach, supported by efficient probabilistic density estimation using reservoir computing via echo state networks with heavy-tailed mixture density network output layers. A temporal permutation importance framework is used to identify information gain from potential dynamic drivers of extreme responses. The methods are evaluated through applications to long-lead forecasting of extreme heat waves and wildfire risk. Expected contributions include new theory for transient spatio-temporal extremes, interpretable methods for discovering nonlinear drivers of rare events, and the foundation of a forecasting approach for environmental hazards. The project will produce open-source software, and educational activities that prepare graduate students to work at the intersection of statistics, dynamical systems, information theory, and artificial intelligence. 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 · 2026-06

Summary/Abstract Calcific aortic valve disease (CAVD) is a progressive and life-threatening condition that currently lacks effective pharmacological therapies. Aortic valve calcification (AVC), the central pathological hallmark of CAVD, leads to valve stiffening, reduced cardiac output, and ultimately aortic stenosis, contributing significantly to cardiovascular morbidity and mortality. Despite the clinical burden of AVC, the molecular mechanisms driving calcification remain poorly defined, and no FDA-approved medical therapies exist to halt or reverse disease progression. Key pathological processes in AVC include the osteogenic differentiation of valve interstitial cells (VICs) and the endothelial-to-mesenchymal transition (EndoMT) of valvular endothelial cells (VECs). Emerging evidence identifies Dedicator of Cytokinesis 2 (DOCK2), a guanine nucleotide exchange factor traditionally associated with immune cell signaling, as an important regulator of aortic valve cellular processes. Preliminary data demonstrate that DOCK2 is upregulated in human calcified valves and localizes to both VICs and VECs. DOCK2 deficiency in mouse models significantly reduces AVC, and in vitro knockdown of DOCK2 in VICs and ECs suppresses osteogenic differentiation and EndoMT, respectively. Mechanistic studies implicate two distinct signaling axes: DOCK2 promotes VIC osteogenesis via the PI3K/Akt/GSK3β/β-catenin pathway, and it drives EndoMT through ROS-mediated ERK signaling. The objective of this proposal is to elucidate the cell- specific mechanisms by which DOCK2 contributes to AVC and to evaluate the therapeutic potential of a small molecule DOCK2 inhibitor, cholesterol sulfate. Our central hypothesis is that DOCK2 drives AVC by independently promoting VIC osteogenic reprogramming and EC EndoMT through distinct but targetable signaling pathways. This will be tested through three specific aims: Aim 1 will define the role of DOCK2 in VIC- mediated AVC and determine its signaling mechanism; Aim 2 will establish the contribution of DOCK2 to EndoMT in VECs and elucidate the downstream ROS-ERK pathway; Aim 3 will test whether pharmacologic inhibition of DOCK2 with cholesterol sulfate can prevent or reverse AVC in vivo. The successful completion of this project will identify DOCK2 as a critical molecular driver of AVC, uncover distinct mechanistic pathways in VICs and VECs, and validate a novel small molecule inhibitor as a therapeutic candidate. These studies are expected to significantly advance our understanding of CAVD pathogenesis and provide a foundation for developing targeted, non-surgical interventions to treat or reverse aortic valve calcification.

NIH Research Projects · FY 2026 · 2026-06

PROJECT SUMMARY Human gut microbiomes influence health by producing metabolites and enzymes that modulate immunity, transform drugs, and digest nutrients. However, most of these enzymes remain functionally unknown. Current annotation tools rely mainly on sequence similarity searches, which can only assign meaningful functions to less than 30% of microbial proteins. Although recent approaches incorporate protein language models and structural comparison, they still rely on predefined pipelines, manual literature or database searches, and specialized expertise in microbial research. This makes the annotations time-consuming without intelligent automation for context-aware insights and limits their scalability across diverse microbial ecosystems. Large language models (LLMs) have emerged as powerful tools in scientific research by analyzing data, answering complex questions, and generating new hypotheses. Building on these strengths, Artificial Intelligence (AI) agents, which combine LLMs with external resources like databases, tools and APIs, can automate tasks and workflows, mimicking human expert decision-making. Although they are widely used in industry, their potential in bioinformatics has only recently been explored. The overall objective of our project is to develop GENZ-AI (Gut ENZyme AI), a multi-agent AI system for automated curation and functional annotation of gut microbial enzymes. GENZ-AI will leverage LLM and advanced AI agents to autonomously delegate tasks, integrate diverse data sources, and deliver enriched annotations with relevant references. We will use advanced techniques, such as prompt optimization and imitation learning, to continuously refine its performance based on real-world annotation sample workflows and user feedback. The significance of GENZ-AI lies in leveraging these cutting-edge technologies to automate and enhance the data curation and workflow organization for enhanced enzyme annotation. This achievement will also improve gut microbiome-based diagnostics and therapeutics (e.g., dietary interventions, drug enhancement, immune modulation) while substantially reducing the time and effort required. The outcome will be a set of novel computational approaches implemented as user- friendly, reusable, open-source tools, including specialized applications for CAZymes, a class of glycan- metabolism enzymes critical to gut microbiome functions. The CAZyme annotation results and software tools will be integrated into dbCAN-PUL and dbCAN-sub databases. The key innovations of this project include a structure-informed protein language model for generalized EC number prediction, the application of CrewAI framework to build a multi-agent system optimized for enzyme annotation in microbiome, and the in-depth investigation of CAZyme and its glycan substrate utilization through GENZ-AI. The broader impact extends beyond the human gut microbiome, as GENZ-AI can be applied to any microbes, providing a scalable solution for diverse microbial ecosystems and pioneering the adaptation of LLM-powered AI agents in bioinformatics.

NIH Research Projects · FY 2026 · 2026-06

PROJECT SUMMARY/ABSTRACT The sympathetic nervous system is the major regulator of vascular tone. Activity of the sympathetic nervous system increases with age and directly contributes to vascular dysfunction. Norepinephrine released from sympathetic nerve terminals binds vascular α-adrenergic receptors (AR), promoting vasoconstriction and opposing endothelial-mediated vasodilation. Notably, β-AR mediated vasodilation attenuates sympathetic vasoconstriction in young women but not men – eliciting sex-specific vascular protection. Unfortunately, β-AR protection appears lost in women post-menopause. Herein we propose a personalized approach to preserve and restore vascular β-adrenergic receptor (AR) signaling and, in turn, reduce CVD risk in aging women. Our comprehensive experimental approaches will allow us to challenge current thinking as it relates to CVD risk during menopause by addressing a new and unexplored mechanistic and therapeutic option. Our study is framed in the context of the following aims and testable hypotheses: 1) Determine whether acute β3- AR agonism attenuates sympathetic vasoconstriction in aging women. We hypothesize acute treatment with the β3-AR agonist, vibegron (FDA-approved for urinary incontinence), attenuates sympathetic vasoconstriction in aging women as assessed by: a) the vasoconstrictor response to the cold pressor test, b) sympathetic vascular transduction. 2) Determine whether acute β3-AR agonism augments vascular function in aging women. We hypothesize acute treatment with the β3-AR agonist, vibegron, enhances vascular endothelial function in aging women, as assessed by flow mediated dilation (FMD). 3) Characterize vascular endothelial β3-AR expression in aging women. We hypothesize vascular endothelial β3-AR expression, assessed from venous endothelial cells collected from human volunteers, is maintained in aging women. Results of the proposed studies will uniquely determine the direct and modulatory effect of β3-AR on women’s vascular health. If successful, our findings will reveal a potential new area of investigation from which to enhance both mechanistic and therapeutic understanding as it relates to women’s CVD risk.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY/ ABSTRACT Rural individuals with type-2 diabetes mellitus (T2D) face higher rates of complications including amputation, renal failure, and blindness compared to their urban counterparts, which is particularly concerning in Missouri where 99 of 101 rural counties are health professional shortage areas. Our pilot study in the Missouri Bootheel, which has the state’s highest diabetes prevalence rate, revealed that participants experiencing higher stress levels had suboptimal health self-management practices, underscoring the need to integrate stress management into diabetes self-management education programs (DSMEP). This project aims to address this gap by systematically adapting the Stress Process Model (SPM) into the evidence-based Dining with Diabetes (DWD) program for rural Missourians living with T2D. Therefore, in response to PAS-25-102 (Small R01 for Clinical Trials Targeting Disease within the Mission of NIDDK), this research project addresses these intersecting challenges through three specific aims: 1) to systematically adapt SPM into the DWD program for rural populations; to assess the feasibility and preliminary efficacy of the adapted DWD+SPM intervention in rural Missouri by implementing a pilot cluster randomized trial and 3) to evaluate implementation outcomes of the DWD+SPM adapted intervention to inform future scale-up efforts. Using the ADAPT-ITT framework, we will engage Extension Specialists and community partners from six Bootheel Missouri counties to incorporate SPM into the DWD program (DWD+SPM). We will identify rural-specific challenges to diabetes self-management, document necessary adaptations to program content and delivery methods, and develop stress resilience components based on the Stress Process Model. We will assess the acceptability, feasibility, and preliminary efficacy of the adapted DWD+SPM intervention through a pilot hybrid type 1 effectiveness-implementation trial comparing the adapted and traditional DWD programs. Finally, using mixed methods, we will evaluate implementation outcomes to inform future scale-up efforts, measuring implementation outcomes, documenting adaptations, identifying challenges and enablers, and examining how community-specific resources influence program implementation across rural contexts. The expected outcomes will significantly contribute to improving T2D management among rural individuals in Missouri, with underserved rural residents receiving additional stress management services through county extension. Findings will inform the development of a larger-scale R01 randomized controlled trial testing the efficacy and cost-effectiveness of the DWD+SPM intervention across various rural DSMEP delivering settings. This project directly addresses rural health disparities by incorporating stress management into an evidence-based education program to improve T2D outcomes in rural Missouri and responds to the need for interventions specifically effective for rural populations.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY Reproductive aging has long been attributed primarily to declining ovarian function. However, increasing clinical evidence reveals that many individuals experience early fertility loss despite normal ovarian reserve and regular cycles, suggesting that other tissues critical to reproductive success may undergo aging-related dysfunction. Among these, the oviduct (fallopian tube in humans) is essential for early reproductive events such as oocyte pickup, fertilization, and embryo transport, yet remains poorly understood in the context of reproductive aging. This proposal investigates the novel hypothesis that progesterone receptor (PGR) signaling in oviductal ciliated epithelial cells preserves epithelial health and delays reproductive senescence. This work addresses a critical gap in knowledge: how hormonal signaling in extra-ovarian tissues contributes to fertility maintenance across the lifespan. Our preliminary data reveal that conditional deletion of PGR in oviductal ciliated cells results in progressive infertility beginning in mid-reproductive life, despite normal early fecundity. These findings uncover a previously unrecognized role for progesterone in maintaining the epithelial integrity of the oviduct. The proposed research will define how this signaling axis supports long-term reproductive capacity, offering new insight into unexplained infertility and age-associated reproductive decline. In Aim 1, we will determine how loss of PGR in ciliated epithelial cells impairs epithelial function and reproductive longevity by analyzing ciliary beat frequency, particle tracking, epithelial morphology, and in vivo oocyte pickup capacity. In Aim 2, we will define the molecular mechanisms by which PGR maintains ciliated epithelial cell identity and homeostasis, using single- cell RNA sequencing and transcriptional profiling to uncover progesterone-regulated pathways involved in ciliogenesis, anti-senescence, and epithelial maintenance. By integrating cell-type–specific genetic models, advanced imaging, and transcriptomics, this project will uncover a fundamental new mechanism of reproductive aging. The findings are expected to transform our understanding of hormone-regulated epithelial health and inform strategies to preserve fertility across the reproductive lifespan.

NSF Awards · FY 2026 · 2026-05

Conference: Enhancing Institutional Capacity Across the Research Ecosystem This project seeks to expand the research, technology transfer, and programmatic capacity of emerging research institutions, and enhance their capacity for sustained cross-sector and multi-institutional partnerships with industry, government, nonprofit, and academic organizations. By equipping institutional leaders from NSF EPIIC awardee institutions, all of which are emerging research institutions, with actionable tools for expanding partnerships and innovation ecosystems, this project aims to promote the progress of science and advance national health, prosperity, and welfare. Emerging research institutions are eager to contribute to the nation’s science, technology, engineering, and mathematics workforce and to the research enterprise but face structural and resource constraints that limit their participation in large-scale, cross-sector collaborations. The conference will enable EPIIC PIs to share institutional capacity building strategies and successes through an interactive workshop structure. The event will emphasize strategies for increasing institutional innovation, entrepreneurship and research capacity, building collaborative network connections, and expanding knowledge of NSF funding opportunities. The program will feature plenary and breakout sessions, structured networking, 1-1 coaching with subject matter experts, and poster sessions. The program also includes a focus on building industry partnerships, providing participants with multiple opportunities to hear from and network with industry leaders and additional experts in technology transfer. Anticipated participant outcomes include acquisition of strategies for enhancing research institutional infrastructure; increased knowledge of future funding opportunities and other sustainability strategies; and increased confidence in each PI team's ability to build strategic partnerships with industry and participate in regional economic growth. Project evaluation will assess progress and success toward project goals, including changes in participant-reported knowledge, network connections, and impacts on strengthening institutional capacity and cross-sector partnerships. The project will culminate in two reports, a conference evaluation report summarizing short-term findings based on conference participation, and an annual evaluation report that summarizes all project activities. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY/ABSTRACT Assisted reproductive technologies (ART) have revolutionized fertility treatments, yet implantation success rates remain suboptimal. Emerging evidence reveals that maternal tubal fluid, specifically extracellular vesicles (EVs), nanoscale membrane-bound carriers rich in bioactive molecules that play a pivotal role in embryo-maternal communication essential for early embryo development and implantation. EVs transport lipids, proteins, and regulatory RNAs, including miRNAs, which influence embryo physiology and developmental competence. Although in vitro studies demonstrate embryo uptake of EVs from reproductive tract cells across species, the physiological relevance of maternal EVs during natural embryo development in vivo remains largely unexplored. Critically, EV populations and cargo profiles differ markedly between in vivo and in vitro conditions, underscoring a pressing need to investigate EVs in their native environment. Our innovative study leverages oviductal epithelial cell-specific CD9-green fluorescent protein (GFP) reporter mice to directly visualize and track maternal EVs within preimplantation embryos in vivo. We have discovered CD9-GFP+ EVs localized in the perivitelline space of 4- to 8-cell stage embryos, providing the first direct in vivo evidence of maternal EV-embryo communication during early development. Building on this, our research pursues two complementary aims: (1) to comprehensively map EV distribution and profile miRNA cargo in oviductal and uterine luminal fluid throughout early pregnancy stages, illuminating dynamic changes in EV-mediated signaling; and (2) to elucidate the functional significance of epithelial cell- derived EVs by employing pharmacological inhibitors to disrupt EV biogenesis and release in vivo, assessing consequent effects on embryo development, implantation, and pregnancy outcomes. This study offers a significant advance in reproductive biology by uncovering the in vivo role of maternal EVs in supporting embryo development and implantation. Our innovative use of epithelial-specific CD9-GFP reporter mice to directly visualize EV transfer to embryos provides valuable new insight into natural embryo-maternal communication. By combining cutting-edge molecular profiling with functional inhibition of EV biogenesis in vivo, this research is uniquely positioned to identify key EV cargos that influence embryo viability and pregnancy outcomes. The results will deepen our fundamental understanding of early developmental processes and enable the development of novel, clinically relevant strategies to improve assisted reproductive technologies. Leveraging maternal EVs as biomarkers or therapeutic agents holds strong potential to enhance ART success rates and promote healthy pregnancies, addressing critical challenges in fertility treatment.

NIH Research Projects · FY 2026 · 2026-05

ABSTRACT Traumatic brain injury (TBI) often leads to vision loss and damage to cranial dura mater (CDM), the outermost brain meningeal covering, which regulates the brain’s metabolic waste and cerebrospinal fluid outflow. The incidence of TBI- related disability in men is 2.2 times higher than in women, but reasons for this disparity remain unknown. CDM shares sensory innervation with cornea through trigeminal ganglion system forming anatomo- physiological link between easily accessible cornea and unreachable CDM. Our resent collaborative study identified a connection between corneal injury and alterations in the connective tissue and microvasculature of the CDM. Additional pilot data support these findings and show delayed time-dependent corneal damage in response to mild TBI. Importantly, we reveal the involvement of decorin, a small leucine-rich extracellular matrix proteoglycan, in cornea-CDM crosstalk post injury. Our recent novel in vivo findings and human clinical literature led us to hypothesis that TBI-induced insult to CDM leads to neuroinflammatory alterations in cornea via ophthalmic division of the trigeminal ganglion supplying sensory innervation to cornea and this pathological event is modulated by the decorin. The primary goal of the project is to identify mechanism of TBI/CDM-injury to cornea and test if decorin can serve as a therapeutic target to regulate this pathological process. The results of study will lead to identification of mechanisms mediating corneal dysfunction post TBI/CDM injury and uncovering of strategies for treating TBI/CDM-induced corneal damage resulting vision loss in vivo. The two Specific Aims will test novel hypothesis and accomplish goal of current project. Specific Aim 1 elucidates how TBI/CDM-injury alters neuroinflammatory responses in cornea in vivo using a well-established mouse model. Specific Aim 2 tests if decorin has therapeutic potential to regulate TBI/CDM-mediated pathological responses in cornea in vivo using decorin-knockout (loss-of-function) mouse model and insult to CDM. Our multidisciplinary team has cornea and CDM experts with experience in TBI/CDM-injury in vivo mouse model, and has established methods, published protocols, and vast expertise in corneal and CDM research with experience in clinical eye imaging, quantitative computer-based image analysis, and molecular techniques. The scientific impact of project is high as successful will (a) advance understanding of the anatomo-physiological connection between cornea and CDM provided by trigeminal system, (b) unveil neuroinflammatory link between cornea and CDM, (c) improve clinical diagnostic approach for pathophysiology of cornea and TBI disorders associated with the activation of trigeminal system, (d) fill knowledge gaps regarding the sex-based differences in anatomo-physiological connection between cornea and CDM, and (e) allow us to collect pilot data for R01 application to extend this research.

NSF Awards · FY 2026 · 2026-05

Many energy and cooling technologies rely on boiling a liquid inside channels to remove large amounts of heat. Examples include nuclear power systems, advanced manufacturing, and electronics and data centers. Thin films of liquid form on the inside channel walls while fast-moving vapor occupies the interior of the channel. The details of liquid motion in the films can strongly affect rates of heat removal. The films can rupture in spots and then reform, which is called re-wetting. Small droplets of liquid can be ejected from the film and carried into the vapor, which is called droplet entrainment. These processes are difficult to predict in practice, even though they are important for heat removal. This CAREER project will use advanced visualization techniques to study re-wetting and droplet entrainment during flow boiling. The techniques will be able to resolve very fast processes at very small scales. The results will be used to develop models and heat transfer numerical tools that engineers can use to design efficient thermal systems. The project will also provide multidisciplinary research training for undergraduate and graduate students and broaden participation through education and outreach activities. This CAREER project will quantify droplet entrainment mechanisms during annular-film boiling and rewetting-front dynamics and develop first-principles models that link interfacial behavior to droplet formation and heat-transfer performance. The research will combine advanced laser-based visualization and measurement techniques to observe microscale liquid-film motion, temperature fields, interfacial waves, and droplet behavior under carefully controlled boiling and rewetting conditions relevant to advanced energy and thermal-management systems. Through statistically consistent data integration, physics-based theoretical models will describe how interfacial dynamics govern droplet formation, providing a foundation for improved engineering simulations of two-phase heat transfer. The project will create a predictive framework that connects microscopic interfacial physics to system-level thermal behavior, reducing reliance on empirical correlations and improving simulation reliability. The project will also train students in advanced experimental and data-analysis methods, develop an elective course on modern fluid diagnostics, conduct annual outreach activities for high-school students focused on energy and thermal science, and disseminate open datasets and educational resources through an online platform. Collaboration with federal regulatory stakeholders and national laboratories will help translate research outcomes to practical applications while strengthening workforce development in thermal-fluid 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.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY Membranes are central to life. These vital biological structures define cellular perimeters, control intercellular fluxes, and enable intracellular compartmentalization. Despite fundamental and pharmaceutical importance many gaps exist in our knowledge of membranes and in their diverse activities. This research project addresses shortcomings of knowledge in two key areas: we seek to (i) understand the mechanism of host cell membrane attack by candidalysin (CL), the recently discovered peptide virulence factor of Candida albicans, and to (ii) define the mechanism of protein translocation across membranes in the general secretory (Sec) system of Escherichia coli. The first focus area centers on the yeast C. albicans, which infects human cells by releasing CL. We recently showed that the CL toxin readily self-assembles into polymers in solution which then create pores in lipid bilayers. However, knowledge in this area is incipient and many critical questions remain open. We seek to determine the formation mechanism of CL pores and understand the physiological factors that control the extent of membrane damage that CL inflicts. The second area of research centers on understanding protein export through the translocon, SecYEG. This heterotrimeric transmembrane complex is homologous to eukaryotic Sec61. Though the translocation mechanism is understood only superficially, it is certain that the macromolecules involved, including peripheral ATPase SecA, undergo large conformational changes and do so in a highly coordinated fashion. Our direct imaging of the Sec system at work in close-to-native conditions revealed precursor-dependent translocase conformations, challenging conventional models which assume a single transportation mechanism for all precursors. We seek to expand upon these results and define the mode(s) of protein transportation across the membrane. A variety of techniques will be deployed to address these gaps in understanding including single molecule atomic force microscopy (AFM), electron microscopy, mutagenesis, and neutron reflectometry. The biophysical analyses will be pushed further towards in vivo conditions. Results will be verified biologically. This research will provide new insights into mechanisms underlying a key fungal virulence factor and a ubiquitous protein translocation apparatus. The information garnered is expected to accelerate the development of novel therapeutics.

NIH Research Projects · FY 2026 · 2026-04

Project Summary Title: Explore niche-leukemic stem cell interactions and evaluate niche-directed leukemia treatments. Retention of minimal residual leukemic stem cells (LSCs) within the bone marrow (BM) microenvironment, known as the niche, plays a pivotal role in therapeutic resistance and leukemia relapse. Our long-term goal is to unravel the intricacies of the niche and regulatory mechanisms governing human LSCs, identifying potential therapeutic targets within the tumor microenvironment to enhance leukemia treatment efficacy. We observed that dipeptidyl peptidase 4 (DPP4) deletion significantly alters LSC distribution in the AML BM and identified N-cadherin-expressing BM mesenchymal stem cells (N-cad+ MSCs) as critical in shaping LSC localization, essential for AML cell migration, stemness, and survival. We also discovered significant interactions between DPP4 on AML cells and glypican-3 (GPC3) on N-cad+ MSCs, regulating Cxcl12 activity and gradient. We hypothesize that molecular interactions between N-cad+ MSCs and LSCs are crucial for orchestrating LSC properties and are essential for effective human AML treatment. The objectives of this proposal are to elucidate the intricate crosstalk between N-cad+ MSCs and LSCs and evaluate niche-directed treatment strategies in both human and mouse AML models. Aim 1: Elucidate the molecular interactions between LSCs and niche cells. We will use inducible Gpc3 knockout in N-cad+ MSC mouse models to determine GPC3's role in AML development and LSC properties and study its impact on the crosstalk between N-cad+ MSCs and LSCs. Histological imaging and functional assays using AML patient BM biopsies will explore GPC3's role in the human LSC niche. Aim 2: Investigate the impact of N-cad+ MSC-derived Cxcl12 signaling on human LSC activity. We will perform scRNA-seq and histological imaging analysis of patient BM biopsies to identify whether N-cad+ MSCs are major CXCL12 sources in the BM niche for human LSCs. We will use AMD3100 treatment to block CXCL12 signaling in human LSCs, enabling us to evaluate the distinct properties of DPP4high and DPP4low LSCs in response to CXCL12. Aim 3: Evaluate niche-directed treatment strategies. We will compare chemotherapy efficacy between N-cad+ Cxcl12−/− and control AML mice and evaluate the stemness, survival, and localization of residual LSCs post- chemotherapy. Preclinical trials will assess the effects of niche-directed therapies on LSC activity, disease progression, and overall survival in AML patient-derived xenograft models using chemotherapy- resistant/relapsed AML cells.

NIH Research Projects · FY 2026 · 2026-04

Project Summary The objective of this supplement project is to perform a side-by-side assessment of various gene editing (GE) formulations to identify those most effective as reagents for tissue editing. The project involves the delivery of CRISPR/Cas9 gene editing ribonucleoprotein complexes intravenously to pigs. Fluorescent reporter pigs will be used to detect editing activity and cell transduction efficiency. Successful targeting in cells and tissues by the formulations will be demonstrated by the induced expression of a red fluorescent protein (tdTomato). The work focuses on two efforts 1) ‘Programmable Delivery System for Gene Editing’, which will evaluate organ-specific delivery and 2) ‘Crossing the Blood Brain Barrier (BBB)’, which will evaluate the relative efficiency of reagents to circumvent the BBB to deliver editors to neural tissue. Both project efforts are structured into three parts: 1) In Vitro evaluations of test reagents, 2) In Vivo Toxicity Pilot delivery, and 3) final In Vivo Delivery to complete the animal studies. Importantly, all the reagents will utilize the same guide RNA from a common source that will target the same sites for editing. After each delivery, the pigs will be monitored daily, and blood will be drawn frequently. Inflammatory cytokines will be measured as well as serum chemistry levels and blood CBC and differentials, using the standard toxicology package provided by the University of Missouri Veterinary Medicine Diagnostic Laboratory (VMDL). At the close of the study (4 weeks ±2 days post-delivery), animals will be euthanized, and gross necropsies will be performed by the Testing Center staff. Tissues will be harvested, fixed, embedded, and sectioned for histopathology evaluation and imaging of tdTomato (or other immunostaining, based on project needs). For ‘Programmable Delivery’, three project-defined target tissues, along with the Liver and Thoracic Dorsal Root Ganglion will be evaluated. For ‘Crossing BBB’, two coronal brain slices (A&B) will be hemisected into the left and right hemisphere resulting in four brain areas to be evaluated; additionally, the Liver and Thoracic Dorsal Root Ganglion will be evaluated. Ultimately, these evaluations will include H&E, cell-specific markers in serial sections to determine which cell type(s) were transduced, and high-resolution fluorescent imaging of the most targeted tissues. A detailed summary of the imaging assessments, blood panels, and circulating inflammatory markers will be provided to the targeted challenge board for their rankings. At the end of the study, the results and tissues will be provided to the submitting investigator teams.

NIH Research Projects · FY 2026 · 2026-04

HIV remains a significant problem worldwide. The CA protein of HIV is involved in several critical replication events, including Gag oligomerization and viral assembly, maturation, reverse transcription (RT), trafficking to the nucleus via interaction with host factors, nuclear import, integration, and evasion of host immune responses. CA’s numerous roles are facilitated by its ability to adopt distinct structural forms at different steps of replication. Despite significant advances in our understanding of the role of CA in replication, there are many unresolved questions regarding CA structural dynamics during viral assembly and post-entry replication steps, CA-host factor interactions, and the impact of these interactions on virus biology. The genetic fragility of CA, a lack of tools for specific CA structural forms, and difficulty of examining CA-host interactions in cells represent significant barriers to the resolution of these questions. To address these challenges, have developed novel RNA aptamer tools capable of discriminating among distinct CA structural forms. Aptamers are uniquely well-suited to the study of CA, as they bind targets with high specificity, discriminate among different conformations of the same protein, can be expressed in or delivered to cells, and are amenable to a variety of different modifications. Further, they have significant applications for biosensing due to their dynamic conformational variability, for which we provide proof-of-concept. This proposal will 1) elucidate the molecular basis for aptamer-CA interactions, 2) leverage aptamer programmability and specificity for the development of cutting-edge molecular tools, and) determine the biological significance of aptamer-CA interactions to inform novel therapeutic targets. If successful, this work will provide a complete panel of CA structure form-specific aptamers, including those that bind pentamer or in the presence of LEN and/or host factors, provide aptamer-CA interaction maps that define aptamer-targeted epitopes along with the biological significance of these interactions, develop aptamer-based biosensor technology for detection of CA structural forms in specific cellular compartments, and resolve key questions regarding proposed CA structure form-specific host interactions. Importantly, this work will set the stage for future innovations in CA structure form-specific detection, including high throughput mapping of accessible CA epitopes using aptamer barcoding, multiplexed detection of CA structural forms using aptamer- based biosensors, in-home diagnostics with improved sensitivity, and cost-effective, aptamer-based detection methods to measure CA structural forms or detect viral resistance, among others. Collectively, this study will provide exciting new molecular tools and insights into CA, informing future drug design strategies, as well as biological interactions and mechanisms.

NSF Awards · FY 2026 · 2026-04

This Faculty Early Career Development Program (CAREER) award supports fundamental research to establish an innovative multiphysics-assisted 3D printing technology for high-precision, stable fabrication of functional microstructures both on Earth and in space. As space exploration expands, there is an increasing need for reliable in-space manufacturing technologies capable of producing high-performance microstructures under reduced or altered gravity conditions. However, achieving high-precision, stable, and continuous 3D printing across a broad range of ink properties, particularly for high-viscosity, high-volatility inks dispensed through fine nozzles, remains a major challenge both on Earth and in space. This project aims to investigate a novel ultrasonic vibration-enhanced electrohydrodynamic printing technology uniquely configured for anti-gravity operation, thereby advancing the fundamental science of multiphysics-assisted micro-additive manufacturing. The outcomes will establish both the scientific and technological foundations for future in-space manufacturing and advanced functional microstructure fabrication across a wide range of applications, such as energy harvesters, etc. This project will also integrate research and education by developing an immersive mixed reality learning platform that visualizes complex printing processes in virtual space station environments, making additive manufacturing concepts freely accessible to K–12 and the general public, thereby promoting STEM interest, creativity, and workforce development. Outreach efforts will engage K–12 students through summer camps and pre-college programs, while also supporting Missouri’s Industry 4.0 workforce initiative to train the next generation of STEM professionals. The research aims to establish a comprehensive theoretical, computational, and experimental framework to understand vibration-enhanced electrohydrodynamic printing under anti-gravity conditions. The anti-gravity setup not only helps validate the potential for in-space manufacturing but also enables precise “isolation and amplification” of physical field effects on printing dynamics, providing a unique platform to understand and validate the fundamental mechanisms of the printing technology. In this project, both analytical and computational models will be developed to investigate the fundamental printing dynamics governing stable cone–jet formation under the influence of multiple coupled physical fields. Systematic experiments will then be designed and conducted to validate and improve the models using both in-situ and ex-situ characterization and analysis techniques, thereby deepening the understanding of the multiphysics-coupled cone–jet dynamics. To elucidate the relationship between process parameters and the resulting structural and functional performance, high-viscosity, high-volatile piezoelectric inks will be printed to demonstrate enhanced printing stability, resolution, and functional performance. The outcome of this CAREER project will unravel the fundamental mechanisms of this multiphysics-assisted printing and develop working diagrams to optimize processing parameters for high-precision, high-performance fabrication of functional materials both on Earth and in space. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY This research seeks to elucidate the fundamental role of post-translational protein modifications in bacterial cellular signaling. To adapt to environmental changes, bacteria must rapidly sense and respond to stimuli in order to appropriately modify their cellular physiology. To achieve this, bacteria have evolved intricate signaling networks to maintain homeostasis under stress conditions, including those that promote evasion of host immune responses and resistance to antibiotics. One subset of these systems are serine-threonine (S/T) and serine-threonine-tyrosine (S/T/Y) kinases, which have been shown to be critical, and often essential, for bacterial growth and division, antibiotic resistance, virulence, and biofilm formation. Members of this group include the highly conserved Hanks-type eukaryotic-like penicillin-binding and serine-threonine associated (PASTA) kinases that are found almost exclusively in single copy across Gram-positive bacteria and regulate a wide range of physiological processes, including carbon metabolism, cell signaling, peptidoglycan biosynthesis, virulence, and biofilm formation. As such, PASTA kinases and their transduction pathways represent attractive targets for novel antimicrobials, however these signaling systems remain poorly understood. Non-Hanks-type S/T and S/T/Y kinases have also been shown to be important determinants for resisting oxidative, pH, and osmotic stress, yet the molecular mechanisms underlying these phenotypes and the regulation of these signaling systems remain unknown. The long-term goal of my laboratory is to explore how bacteria employ post- translational modifications to fine-tune their cellular physiology and how multiple transduction pathways are coordinated and integrated to respond to environmental changes. Such information is essential to understand bacterial contributions to human health and disease. To do so, we propose to combine complementary biochemical, genetic, and proteomic approaches to 1) define the PASTA kinase signal cascades and metabolic rewiring that enables bacteria to resist cell envelope stress, 2) decipher the role of non-Hanks-type S/T and S/T/Y kinases in bacterial stress responses, and 3) understand how bacteria integrate signals across multiple kinase signaling pathways to produce a coordinated physiological response. Results of the proposed experiments will advance knowledge of how bacteria sense and respond to environmental stimuli and ultimately inform efforts to develop new antimicrobial therapies targeting bacterial signal transduction systems.

NIH Research Projects · FY 2026 · 2026-03

Project Summary/Abstract Lipoproteins (LPs) are heterogeneous macromolecular nanoparticles that play a central role in transporting lipids and cholesterol between the gut, liver, and other tissues. Apolipoprotein B (apoB), one of the largest proteins known, serves three main functions: (1) coordinating the synthesis of LP particles; (2) acting as the primary structural component of all non-high-density LPs to maintain particle integrity; and (3) providing the binding domain for receptors, enabling cellular uptake. Dysregulation of apoB-containing LP metabolism and mutations in apoB contribute to atherosclerosis, metabolic diseases, and a range of inherited lipid disorders. Despite its pivotal role in fundamental lipid biochemistry and physiology, significant gaps remain in our understanding of apoB structure and function, hindering progress toward a comprehensive understanding of lipid and cholesterol metabolism and associated disease mechanisms. Progress toward understanding apoB's structure and function has been slow due to its large size, complex membrane associations, and the inherent heterogeneity of LPs. The Berndsen group recently made a seminal contribution by solving the structure of apoB, revealing an unexpected multi-domain architecture and complex arrangement on the LP surface. This breakthrough uniquely positions us to address some of the most pressing unanswered questions about apoB, including: How does apoB change conformation to accommodate LPs of varying size and composition, and how do these changes influence its interactions with receptors? What roles do the individual apoB domains play in its three primary functions? How do naturally occurring genetic variants impact apoB’s structure and function? Our approach will be primarily biophysical, with a focus on state-of-the-art electron microscopy, including both single-particle analysis and tomographic techniques, which were instrumental in resolving the apoB structure. Secondary objectives include the continued development and dissemination of these experimental methods, as well as the application of advanced computational modeling techniques. To probe the structure- function relationship of apoB, we will build on insights gained from our recently solved structure and leverage extensive resources cataloging the phenotypes of naturally occurring mutations. We will determine the structure of apoB from heterogeneous LPs isolated from human serum and mutant apoB-containing LPs generated through recombinant expression, both alone and in complex with their cellular receptor. To complement these structural studies, we will measure LP size, mass, lipid composition, receptor-binding thermodynamics, and the efficiency of cellular assembly and secretion to construct a comprehensive understanding apoB function. The outcomes of these experiments and the technologies we develop will advance our fundamental understanding of apoB structure and LP metabolism, provide valuable tools and knowledge to the broader research community, and yield critical insights into the molecular mechanisms underlying various diseases.

NIH Research Projects · FY 2026 · 2026-03

Project Summary: Charcot-Marie-Tooth (CMT) is one of the most common inherited neurological disorders affecting 1 in 2,500 people in the U.S. and nearly 3 million people worldwide. There are five main types of CMT with each type having numerous subtypes, such as CMT type 2E (CMT2E), and more than 100 different disease-causing genes have been identified. While most types of CMT are not lethal, these diseases significantly impact the quality of life of individuals with CMT and their families. To address CMT disease, several animal models associated with distinct genetic mutations have been developed that faithfully mimic CMT pathology providing tremendous value to our understanding of CMT disease initiation and progression. Despite these advances, no cures for any CMT subtype have been approved. We are proposing to develop a precision medicine-based approach to treating CMT2E, using a specific patient-derived mutation as the pre-clinical model developed in the Lorson laboratory. CMT2E is caused by mutations in the neurofilament light gene (NEFL). NEFL codes for the neurofilament light protein (NF-L), which, along with other intermediate filaments, including neurofilament middle and heavy, are involved in maintaining structural stability of neurons among other roles. Neurofilament aggregation is also a pathology of several neurodegenerative diseases. CMT2E-causing missense mutations have been identified throughout the various functional domains within the NF-L protein. To address the extent of NEFL mutations, we developed a mutation agnostic therapeutic approach; therefore, our therapeutic vector should address disease associated with most NEFL mutations. We developed a novel CMT2E animal model that represents a specific human patient mutation (NEFL- E396K) within the mouse Nefl gene (E397K). The Nefl-E397K mouse model faithfully recapitulates CMT2E disease. Using this disease context, we will leverage the AAV9 gene therapy system to deliver a dual cargo therapeutic vector developed in the Lorson laboratory. This vector delivers two complementary therapeutic “payloads” designed to reduce mutant NEFL, restore healthy/functional NF-L protein and prevent disease development. This project is a collaboration between several labs that bring together ideally suited areas of expertise: 1) the Lorson lab which has a long-standing interest in developing therapeutics and viral vectors for SMA, SMARD1 and other neurodegenerative diseases; 2) the Arnold lab which brings CMT experience in pre- clinical models as well as within the clinic; and 3) Dr. Hong An, an expert in bioinformatic analysis. This is a project focused upon furthering our understanding of CMT2E disease progression as well as further optimizing and validating a therapeutic for this important disease. This cross-disciplinary team is well positioned to successfully complete this project.

NIH Research Projects · FY 2026 · 2026-03

Project Summary Heart disease is the leading cause of death in the U.S., accounting for ~655,000 deaths annually and over $219 billion in healthcare costs each year. Continuous ambulatory monitoring with wearable devices is vital for early detection, prevention of life-threatening events, and reducing healthcare burdens. However, existing heart mon- itors face three critical limitations: (1) they primarily focus on cardiac electrical activity via electrocardiography (ECG) and lack the ability to assess mechanical function (e.g., seismocardiography, SCG and gyrocardiography, GCG), restricting diagnostic depth and overall accuracy; (2) they perform reliably at rest but are prone to motion artifacts, limiting their utility during daily activities; and (3) they are typically made from nonporous materials with poor long-term biocompatibility, often leading to discomfort, skin irritation, inflammation, and even infections over long-term wear, reducing user adherence. Together, these limitations hinder reliable, continuous cardiac moni- toring throughout daily life—an essential feature given that cardiac events can occur unpredictably at any time. To address the challenges, this project aims to develop multimodal, porous, starfish-like, soft wearable systems for high-fidelity recordings of cardiac electrical (five-electrode ECG) and mechanical (SCG and GCG) biosignals even during motion, enabling real-time, continuous, reliable monitoring of heart conditions across daily activities. The device features a pentaradial, starfish-like configuration with five free-standing arms, each equipped with sensing elements (electrodes and accelerometer-gyroscopes) at its tips (sensing pads), all connected to a cen- tral electronic hub. This device configuration minimizes mechanical coupling at the system level, ensuring high- fidelity cardiac biosignal acquisition during motion when combined with signal compensation and machine learn- ing (ML)-driven data processing. The five-electrode recording configuration enables 7-channel ECG data collec- tion, while SCG and GCG offer complementary mechanical insights, providing a holistic view of cardiac function and enhancing diagnostic accuracy. ML algorithms on smartphones will process the data in real time, enabling timely and accurate heart condition diagnosis. Our innovative multifunctional porous soft materials will serve as the skin-interfaced device substrate, ensuring long-term biocompatibility and user comfort. Atrial fibrillation (AFib) will be used as the disease model to validate our approach. During our preliminary studies, we have developed the proposed device using polyimide as substrates and initially verify its ability to record high-fidelity cardiac electrical and mechanical signals during motion and to improve heart disease diagnostic accuracy using three cardiac signal types as inputs for ML models. Building on this promising foundation, we aim to fully achieve our research objectives through two specific aims: (i) develop multimodal, starfish-like wearable cardiac monitors with our innovative multifunctional porous materials and evaluate their performance on 20 healthy individuals during motion and over 7-day wear; and (ii) evaluate the device on 20 AFib patients during motion and over 7- day wear and investigate heart disease diagnosis using multimodal cardiac signals as inputs for ML models.

NIH Research Projects · FY 2026 · 2026-03

Project Summary/Abstract Plants synthesize a diverse array of specialized (secondary) steroidal metabolites that are of high value pharmaceutically and nutritionally. Examples include cardenolides, bufadienolides, as well as steroidal saponins and alkaloids, many of which have been used to treat variety of human diseases. Plants natively synthesize specialized steroids, but usually in small amounts and as constituents of complex mixtures. Structural complexity often renders the chemical synthesis of steroids challenging and expensive. Therefore, our access to wide range of bioactive steroids in natural and synthetic systems remains restricted. Metabolic engineering approaches potentially can provide a new way to access steroidal molecules. However, knowledge gaps in our fundamental understanding of plant derived steroidal specialized metabolic pathways, and associated enzymes have hampered application of these approaches towards the production of steroidal compounds at scale for medicinal applications. The proposed research aims to elucidate complex steroidal biosynthetic pathways from plants and to provide access of high value steroids in sustainable bioproduction platform. Our research program starts with identification and characterization of biosynthetic enzymes that convert simple sterols to specialized steroids, for example cardenolides and bufadienolides. These classes of steroidal metabolites are produced in a wide array of plants and are known for their use in treating of congenital heart conditions, cancers and other chronic diseases. Our expertise in comparative metabolomics, genomics and transcriptomics across a diverse spectrum of plants enable us to identify candidate genes involved in biosynthetic pathway of complex steroidal molecules (e.g. cardenolides). By including plant species with both overlapping and divergent steroidal metabolite profiles, we expect to rapidly filter out large number of gene candidates for further functional characterization. The prioritized candidates will be then tested in different heterologous expression systems (e.g. E. coli, yeast, tobacco plants) to confirm their role in biosynthetic pathways (e.g. cardenolides). Our strategy will support accelerated discovery of steroidal pathways and associated enzymes across multiple plants. Building on this foundation, metabolic engineering will be used to develop efficient and sustainable ‘Plant’ based expression chassis for reconstitution of complex steroidal pathways to generate both natural and new-to-nature steroids with potential biological activity. A practical goal is to unlock the biosynthesis of steroidal metabolites with pharmacologically relevant bioactivities. Long term goals include a comprehensive understanding of the molecular mechanisms in cells through which remarkable metabolic diversity is generated in chemical structure and biological activity, laying a foundation for exploiting nature-inspired diversity in development of new medicinals.

NIH Research Projects · FY 2026 · 2026-02

Voltage-gated sodium (NaV) channels are essential membrane proteins that mediate sodium ion (Na⁺) influx in response to membrane depolarization. This rapid Na⁺ entry is critical for generating and propagating action potentials in excitable cells, including neurons, skeletal muscle, and cardiac muscle. The nine functionally characterized NaV isoforms (NaV1.1–NaV1.9), encoded by SCN genes, exhibit distinct tissue distributions and physiological functions. Mutations in NaV channels contribute to a range of neonatal and adult diseases, highlighting their role in pathological processes. While their contributions to neuronal and cardiac excitability are well established, NaV channels are also expressed in the vasculature, where their pathophysiological significance remains unclear. Although NaV channels have been identified in mesenteric, pulmonary, coronary, and femoral arteries, their regulation and function in the renal preglomerular microvasculature remain unexplored. Our preliminary findings suggest that NaV1.5 contributes to the regulation of intrarenal arterial tone in the neonatal kidney, revealing a previously underappreciated role for this channel in neonatal vascular physiology. In neonatal pig renal vascular smooth muscle cells (VSMCs), NaV1.5 channels are spatially localized in close proximity to the Na⁺-Ca²⁺ exchanger (NCX). Activation of NaV channels promotes Ca²⁺ influx and vasoconstriction through reverse-mode NCX activity and L-type Ca²⁺ channels (LTCCs). Additionally, hypoxia/reoxygenation (H/R) stimulates contraction of the neonatal pig renal artery through the NaV-NCX-LTCC axis. Our pilot studies further suggest that nitric oxide (NO) regulates NaV1.5 expression in neonatal renal VSMCs via the forkhead box protein O1 signaling pathway, a mechanism that may drive alterations in endothelial-to-VSMC signal transduction and contribute to renal ischemia-reperfusion (IR)-induced hypoperfusion—a key factor in the development of acute kidney injury (AKI). This project aims to (1) elucidate the regulation of NaV1.5 expression and activity in renal VSMCs by NO-dependent signaling; (2) determine the role of NaV1.5 in H/R-induced intracellular Na⁺ and Ca²⁺ overload in renal VSMCs and its contribution to renal vasoconstriction; and (3) assess whether NaV-mediated increases in renal vascular resistance contribute to IR-induced kidney hypoperfusion and AKI. To accomplish these objectives, we will employ a multidisciplinary approach that integrates biochemical analyses, liquid chromatography-tandem mass spectrometry, intracellular ion measurements, patch-clamp electrophysiology, vessel myography, and neonatal pig models of renal IR. We will evaluate the therapeutic potential of clinical NaV channel modulators and utilize a transgenic SCN5A neonatal pig model. Findings from this study will provide fundamental insights into the regulatory mechanisms and functional significance of renal vascular NaV1.5, establishing its potential as a therapeutic target for mitigating neonatal AKI.

NIH Research Projects · FY 2026 · 2026-02

Project Summary Alzheimer’s disease (AD) is the most common form of dementia with hallmarks of extracellular beta amyloid (A) plaques (A), intraneuronal tau tangles (T), and neurodegeneration (N), known as the A/T/N framework, a descriptive classification for AD biomarkers. Accumulating evidence shows that a severely imbalanced microbial community, or dysbiosis, is associated with A/T/N and neuroinflammation in AD patients compared with healthy controls (HC). However, it remains unknown how individual microbiota correlates with regional A/T/N neuroimaging markers in AD and HC. It is also unknown if dysbiosis directly promotes and accelerates A/T/N at early stage and whether there are effective interventions available to mitigate the dysbiosis and thus AD risk. Therefore, the goal of the project is to design a translational study, employing parallel human and preclinical animal experiments to understand mechanism and identify interventions for filling these knowledge gaps. The central hypothesis is that severity of dysbiosis between AD and HC individuals will correlate with their regional A/T/N imaging markers and cognitive status; young healthy triple transgenic AD (3xTg-AD) mice received fecal microbiome transplantation (FMT) from AD patients (FMT-AD) will have reproduced dysbiosis as the donors, which will accelerate A/T/N, neuroinflammation and cognitive impairment of the mice. Interventions with inducible nitric oxide synthase (iNOS) inhibition will mitigate A/T/N and neuroinflammation, and prebiotic diet (inulin) supplementation can further restore microbiome balance to protect brain physiology and cognition. The central hypothesis will be tested by the following three Specific Aims: (1) Identify longitudinal correlation of dysbiosis, A/T/N imaging markers and cognition in humans; (2) Reveal impact of iNOS on mitigating A/T/N in the presence of dysbiosis; (3) Determine ability of inulin, either in conjunction with or separate from iNOS, to rescue dysbiosis- induced A/T/N and cognitive impairment. Participants who had PET scans for “A/T” will be recruited for the study, and ultrahigh resolution 7T MRI will be used to determine “N”. Translational 7T MRI, gut microbiome sequencing and cognitive assessments will be applied to both humans and mice to determine longitudinal effects of gut-brain interactions. A novel iNOS knockout triple transgenic AD (iNOS-KO/3xTg-AD) mouse model has been created for the project to study the iNOS effects on mitigating A/T/N despite of gut dysbiosis. Biochemical assays and brain staining will be used to determine “A/T” in the mice. Inflammatory gene expression will be identified by transcriptomics. We expect that findings from this study will have tremendous positive impact as they will enhance our understanding of gut-brain dynamics related to A/T/N in AD. This may set the stage for potential novel interventions for AD through the microbiome-gut-brain axis.

NIH Research Projects · FY 2026 · 2026-02

Project Summary Hypospadias is one of the most common birth defects in the world, affecting nearly 1% of newborn boys. Hypospadias is abnormal urethra closure, where the urethra exits ventrally along the shaft of the penis, and not the tip. Although hypospadias is common, the origin of 70% of urethral closure defects remains unknown. During urethra closure there are extensive changes in the extracellular matrix composition. Prior to urethra closure, basement membrane surrounding the urethral epithelium is one continuous sheet. As the urethra closes, the basement membrane becomes fragmented. This allows the surrounding mesenchymal cells to invade and support urethra closure. This process is dependent on normal androgen signaling. In the absence of testis-derived testosterone, there is no basement membrane breakdown, no mesenchymal invasion, and the urethra remains open along the ventral aspect of the penis. Surprisingly, the genetic regulation of extracellular matrix modification and the diversity of cell populations involved in urethral closure are not well understood. Recently, my lab discovered a unique cell population in the penis that expresses the gene, Forkhead Box L2 (Foxl2). These cells are located immediately next to the urethral epithelium, express androgen receptor and enzymes that modify extracellular matrix, and are closely associated with urethra closure. My central hypothesis is that the Foxl2 gene, and the cell population that expresses FOXL2, are essential for urethra formation by remodeling the urethral epithelium and responding to androgens. Guided by strong preliminary data and pre-existing publications, we will address this hypothesis in three main aims. In aim 1, well define the role of Foxl2, the gene, in urethra closure. We will investigate the hypothesis that Foxl2 expression is essential for regulating genes required for urethra closure. Hypospadias defects will be investigated in Foxl2-/- mice and the molecular action of FOXL2 will be determined with transcription factor binding assays. Aim 2 will determine the role of FOXL2+ cells during urethra closure, by using a cell ablation mouse model. Aim 3 will reveal how androgen signaling influences FOXL2+ cell differentiation and urethral closure. To test the hypothesis that androgens are directly involved in FOXL2+ cell function and differentiation, we will use FOXL2 conditional androgen receptor knockouts, chromatin accessibility assay, and chromatin binding assays. Results from these studies will establish the role of the gene, Foxl2; the role of a novel group cells; and the role androgen signaling in FOXL2+ cells in penile urethra closure. Our lab has the conceptual and technical expertise to successfully complete the proposed aims. This attained knowledge will provide new avenues in understanding the origins of hypospadias within the human populations. With a more comprehensive understanding of urethra closure, we can begin to develop surgical alternatives, or preventatives for this common birth defects.