University Of Iowa

NSF Awards · FY 2026 · 2026-12

This REU Site award to the University of Iowa, located in Iowa City, IA, will support the training of 10 students for 10 weeks during the summers of 2027-2029. It is anticipated that a total of 30 students, primarily from schools with limited research opportunities, will be trained in the program. Students will be trained by faculty mentors how research is conducted in evolutionary science, will participate directly in that research, and will learn how to communicate science to public audiences. Potential career paths that exist for evolutionary scientists and for the application of evolutionary science will be discussed and explored. Many participants will present the results of their work at scientific conferences. Required formal mentor training of faculty mentors will have a lasting effect on their future mentoring efforts. Assessment of the program will be done through online surveys. Students will be tracked after the program to determine their career paths. Students should apply to the REU site using NSF ETAP (Education and Training Application: https://etap.nsf.gov). The training students will receive is aligned with NSF priorities in Artificial Intelligence and Biotechnology. The focus of this REU is evolutionary science, with students conducting research projects across several disciplines. Scientist-mentors in seven academic departments will offer research projects that span a wide range of topics, including evolutionary ecology, behavior, paleontology, genomics, bioinformatics, evolution of infectious disease, and developmental biology. Students will work on evolution-themed projects in one of these specific areas and will also work as a cohort to make broad connections among disciplines. As part of the program, students will receive training in ethical and responsible conduct in research, participate in career workshops, make formal research presentations based on their work, and create an interactive digital research poster. All students will be encouraged to participate in a series of three optional short courses in computational methods and phylogenetics. Students will be selected by program directors based on previous academic performance, enthusiasm for conducting research, interest in specific faculty research projects, and potential for future success in a research-related career. Students who have limited research opportunities at their home institution will be especially encouraged to apply. More information about the program is available by visiting https://biology.uiowa.edu/reu, or by contacting the PI (Dr. John Logsdon at john-logsdon@uiowa.edu) or the co-PI (Dr. Andrew Kitchen at andrew-kitchen@uiowa.edu). 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 · 2026-08

The dryness of the Earth's atmosphere (vapor pressure deficit, or VPD) is increasing. Its effects on many plant processes – from leaf photosynthesis, to tree growth and mortality, to forest production and water use – remain poorly understood. How does rising VPD affect different tree species growing in different locations? How do the effects of rising VPD on plants vary depending on the amount of moisture in the soil? How much and how quickly can plants cope with changes in VPD? And how do VPD effects operating on short-term, small-scale leaf processes translate to longer-term and larger-scale impacts on whole forests? Not knowing answers to these questions challenges researchers' ability to predict and manage forest responses to rapid changes in the environment. This project, termed SCALE-UP, is a partnership between institutions funded by the U.S. NSF and the NSF of Switzerland (SNSF) that enables a collaboration between U.S. and Swiss plant scientists and ecologists. This international team will examine the effects of rising VPD across vast distances and time scales using a cutting-edge combination of experiments, observations, and computer models. Not only will the project answer important scientific questions and advance fundamental knowledge about limited forest resources, it will also improve the ability of the U.S. and Switzerland to model, predict, and manage those resources. The scientists will utilize artificial intelligence (AI) approaches in their computer models, and will contribute to the U.S. AI national priority area by training the next generation of researchers in these techniques. By partnering internationally, U.S. researchers will gain access to unique resources, including a forest experiment in Switzerland that manipulates atmosphere and soil moisture, providing benefits to science and society in both countries. SCALE-UP will leverage state-of-the-art controlled seedling experiments, the first in-vivo VPD and soil drought manipulation in a mature forest, globally distributed tree growth datasets across dozens of species at various time resolutions, and mechanistic and scalable models ideally suited for understanding VPD impacts and underlying processes. The approach will thus link experimental insights, large data analyses, and mechanistic model simulations across scales — from minutes to decades, from individual leaves to entire ecosystems, and from seedlings to mature trees. By combining these cutting-edge and cross-scale approaches, SCALE-UP will unravel (1) the mechanisms underlying the diversity of VPD impacts across species on gas exchange, growth, mortality, and ecosystem-scale carbon and water fluxes, (2) the interaction of these responses with soil drought, (3) the potential for acclimation to rising VPD and its role in mitigating impacts of extreme events, and (4) the development of mechanistic insights and predictive models to understand and project VPD effects on forests at multiple scales. The project will therefore enable establishment of a robust empirical and theoretical basis for predictive understanding of VPD impacts on forests. This comprehensive analysis will offer unprecedented insights into the constraints to tree growth, drivers of tree mortality, the diversity of responses across species, and the role of acclimation of plant functional traits in response to exposure to a gradual rise vs. extreme VPD, enabling robust projections of environmental change on water and carbon cycles, and on forest dynamics. Integrated with the experiments and analyses will be training opportunities for five graduate students, and three postdoctoral researchers, and outreach to grade school students and land managers. 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

Project Summary Chlamydia trachomatis (C.t.) is the leading cause of non-congenital blindness and the most prevalent sexually transmitted bacterial infection worldwide. There is no vaccine, and reinfections are common due to the absence of long-term protective immunity. C.t. infection has been associated with supernumerary centrosomes, multipolar spindles, and multinucleation—hallmarks of most tumors, including cervical and ovarian cancers, for which prior or current C.t. infection is a recognized risk factor. However, an important gap in our understanding remains regarding how C.t., orchestrates these host cell changes and whether these events may predispose cells to oncogenic transformation. C.t. delivers an arsenal of effector proteins into the host cell via a type 3 secretion system (T3SS). While progress has been made in elucidating the role some of these proteins play in establishing C.t.’s intracellular niche, the function of most remains unknown. We recently discovered that the T3SS effector protein CteG binds to centrin-2 (CETN2), a core component of centrosomes, and that this interaction induces supernumerary centrosome formation during infection. Although our data indicate that the CteG-CETN2 interaction is necessary for centrosome amplification, it is not sufficient, nor does CteG contribute to other infection-associated cellular abnormalities, suggesting that other bacterial factors contribute. We hypothesize that C.t. employs multiple secreted effectors to disrupt centrosome duplication and to inhibit host cell cytokinesis, promoting chlamydial infection while paradoxically inducing cellular transformation events that may contribute to cellular transformation. In Aim 1, we will use proteomics and advanced microscopy to determine whether CteG mimics Sfi1-like motifs to bind to the C-terminus of CETN2, thereby disrupting canonical CETN2-interactions and promoting centrosome amplification. In Aim 2, we will leverage newly developed C.t. null strains to test whether C.t. interferes with centrosome duplication and host cell cytokinesis to enhance bacterial release via extrusion. In Aim 3, we will examine whether infection-induced cellular abnormalities contribute to transformation using novel cellular and in vivo models. Collectively, our studies will lead to an enhanced understanding of how C.t. perturbs centrosome duplication and host cell cytokinesis, and whether these changes contribute to cellular transformation. Establishing these mechanistic links will be an important step toward understanding the long- term cellular consequences of C.t. infection and their potential impact on women’s health.

NIH Research Projects · FY 2026 · 2026-06

Abstract: In recent studies, we have demonstrated that viruses encoding Marburg virus (MARV) glycoprotein (GP) are less sensitive to type I and II interferon (IFN)-dependent inhibition than the same viruses encoding Ebola virus (EBOV) GP. Our preliminary findings indicate that one or more interferon stimulated genes (ISGs) inhibits EBOV GP dependent entry, but not MARV-dependent entry. Our new-found appreciation for the differential IFN control of viruses encoding EBOV and MARV GPs identifies an additional layer of complexity to the ongoing war between filoviruses and host innate immunity. Identifying ISG(s) that selectively restrict EBOV, but not MARV, would yield fundamental insights into the molecular determinants of species barriers to filovirus infection, inform the mechanisms underlying viral spillover events, and highlight potential targets for therapeutic intervention. This application seeks to elucidate those interactions and may identify new strategies for combating the episodic, devastating outbreaks caused by these viruses. During these proposed Aim 1 studies, we will characterize which human and mouse cells inhibit EBOV GP, but not MARV GP, dependent entry when pretreated with type I or II IFN. We will also define which filovirus GPs are sensitive to IFN pretreatment. In Aim 2, we will use two different strategies to identify and characterize host factors that are responsible for this differential effect on filovirus GPs. By the successful completion of these studies, a clear understanding of a newly appreciated mechanism of IFN inhibition of EBOV GP entry will be achieved. These studies are significant and innovative as they investigate a previously unappreciated antiviral mechanism that controls entry of some, but not other, members of this deadly family of viruses. These studies may provide the basis for future antiviral approaches.

NSF Awards · FY 2026 · 2026-06

DNA mutation is a fundamental biological process that drives evolution, adaptation, and human health challenges such as cancer and antibiotic resistance. Understanding how and why mutation rates vary across cells, organelles, and species remains a major open question in biology. This project investigates how mode of reproduction shapes the evolution of mutation rate. By determining how reproductive strategies influence the origin of new genetic variation, this research provides foundational insights that can help predict how natural populations will adapt to novel environments and assist in managing invasive species, which are frequently clonal or highly self-fertilizing. Because human cells proliferate clonally, understanding mutational processes in clonal lineages sheds light on aging and cancer development. This project also supports education and public engagement by providing STEM activities for communities in Iowa and Texas. This initiative will also train graduate, undergraduate, and high school students, offering them vital career development and mentorship in science and community outreach and building a biotechnology workforce. The primary goal of this project is to model and empirically test the evolutionary consequences of reproductive mode variation on mutation rates. The project aims to build on the drift-barrier hypothesis to develop new theory exploring the short- and long-term impacts of reproductive mode variation, polyploidy, and beneficial mutations on mutation rate evolution. Empirically, the research measures base-pair substitution and structural mutation rates across three different types of organisms that have undergone independent transitions in reproductive mode. The study systems include the snail Potamopyrgus antipodarum (outcrossing to obligate clonal), the ciliate Tetrahymena (facultative outcrossing to clonal), and plants in the Brassicaceae family (outcrossing to highly selfing). The investigators will use mutation accumulation experiments and parent-offspring analyses, combined with whole-genome sequencing, to estimate de novo mutation rates and mutational spectra. By comparing mutation parameters in closely related lineages with multiple independent transitions in reproductive strategies, this project will help illuminate factors driving mutation rate variation across the tree of life. 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 · 2026-06

From yeast to humans, actin – a protein best known for its role in forming cytoskeletal filaments that give cells their shape and allow them to move – also localizes to and functions inside the nucleus. This nuclear localization of actin was controversial initially, so the functions of nuclear actin are only just now being uncovered. This project will define functions of nuclear actin within the nucleolus, a subcompartment of the nucleus. The nucleolus is a non-membrane bound organelle that is the site of ribosomal RNA (rRNA) synthesis and, so, mediates ribosome formation; ribosomes produce proteins, the factors that mediate cellular functions. Thus, too little or too much nucleolar activity has deleterious outcomes, from cell dysfunction to cell or organism death. The project will use Drosophila, a robust genetic system, and the non-essential tissues of oogenesis (egg development) to advance understanding of how nuclear actin tightly controls nucleolar functions, providing insights into normal cellular function and development, as well as into how misregulation can contribute to diseases. This project will also train the next generation of biologists by developing undergraduate laboratory course modules that bring this research into the classroom and by mentoring trainees in the research lab. The functions of actin in both the cytoplasm and the nucleus depend on the form of actin – monomers, polymers, filaments, and networks of filaments. The objective of this proposal is to define the form-specific roles of nuclear actin in the nucleolus. Actin localizes to the nucleolus and regulates RNA polymerase I (RNAPI) activity across organisms. The team discovered that during Drosophila oogenesis, monomeric and polymeric nuclear actin localize to the nucleoli with distinct developmental patterns, suggesting that nuclear actin has stage-specific and form-specific roles in regulating nucleolar functions. Indeed, increasing nuclear actin results in increased ribosomal RNA (rRNA), abnormal nucleolar morphology, and increased protein translation. However, the roles of the different forms of nuclear actin in modulating the nucleolus remain unknown. The project will uncover how monomeric vs polymeric actin regulate RNAPI activity – from licensing of rRNA genes to functioning within the RNAPI complex – and the downstream effects on cellular function. It will also use two unbiased approaches – proteomics and a targeted genetic screen – to identify new regulators of nuclear actin and nucleolar activity. As the nucleolus is a key regulator of cellular homeostasis, uncovering the connections between the nucleolus and nuclear actin is critical for understanding both normal cell function, and how misregulation of nuclear actin contributes to cellular dysfunction. 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 Major depressive disorder (MDD) is a leading and rising cause of disability in adolescents, a group undergoing rapid brain development and therefore uniquely vulnerable to environmental stressors that increase psychiatric risk. Chlorpyrifos, a widely used organophosphate pesticide, has been linked to neuropsychiatric symptoms in adolescents, but whether it directly induces symptoms or instead produces latent neurobiological changes that increase vulnerability to future stressors remains unclear. Most animal studies have focused on prenatal or adult exposures, leaving a critical gap in understanding how chlorpyrifos affects the adolescent brain and shapes long-term psychiatric risk. Preliminary data demonstrate subtle but consistent anhedonia-relevant behaviors following adolescent chlorpyrifos exposure; while these changes do not constitute full pathology, they suggest chlorpyrifos alters brain function in ways consistent with a latent vulnerability state—sensitizing the brain in ways that predispose the brain to exhibit MDD-relevant outcomes following subsequent stressors. Social stressors such as bullying and isolation, which are well-established contributors to adolescent-onset MDD, are also on the rise. Real-world exposures often involve multiple, co-occuring risks, underscoring the need to investigate their combined impact on the developing brain. The objective of this research is to use a translational mouse exposure model to identify MDD-relevant behavioral, immunological, and brain circuit changes following adolescent chlorpyrifos alone and in combination with social stress. I hypothesize that chlorpyrifos induces a vulnerability state, producing brain circuit and immune changes with minimal MDD- relevant behaviors, and that co-exposure with social stress leads to susceptibility, marked by the active emergence of MDD-relevant behaviors and pathology. In Aim 1, I will test whether chlorpyrifos alone induces neurophysiological and immunological changes without many behavioral effects. In Aim 2, I will assess how combined chlorpyrifos and social stress exposures influence MDD-relevant behavioral, brain circuit, and immune outcomes. This project will uncover, for the first time, how adolescent chlorpyrifos exposure changes brain-wide mechanisms relevant to MDD, both independently and in interaction with social stress. More broadly, this fellowship will provide integrated training in psychiatry, neuroscience, and environmental toxicology through individualized mentorship and guided research. The highly collaborative and interdisciplinary environment at the University of Iowa through the Iowa Neuroscience Institute and Environmental Health Science Research Center offers an ideal setting for this work. This training plan will support my development as a physician-scientist focused on how environmental exposures during sensitive developmental windows shape long-term brain health. My long-term goal is to help advance environmental health approaches within psychiatry and neuroscience to better protect child and adolescent mental health.

NIH Research Projects · FY 2026 · 2026-05

The cerebellum has traditionally been viewed as a motor structure, but recent research indicates that it contributes to various aspects of cognition, emotion, and social behavior. These non-motor functions are thought to be generated through interactions with forebrain areas such as the prefrontal cortex, amygdala, and hippocampus; however, there has been surprisingly little research on the mechanisms underlying cerebellum- forebrain interactions. We aim to address this gap in knowledge with a systematic analysis of cerebellum- forebrain interactions during learning in rats. We will examine cerebellum-forebrain interactions using trace conditioning. Trace conditioning requires the anterior cingulate (ACC), dorsal hippocampus (HPC), and cerebellum. Moreover, neurons in the ACC, HPC, and cerebellum show learning-related increases in activity during trace conditioning – these neural signatures of learning are not seen in control conditions such as unpaired training. Thus, trace conditioning is an ideal paradigm for investigating the mechanisms underlying cerebellar interactions with the forebrain. The main goal of the current proposal is to leverage the findings of our previous research toward a more comprehensive analysis of cerebellar interactions with the ACC and HPC during learning. Our general hypothesis is that the cerebellum receives inputs from the HPC and ACC and it then sends feedback to these forebrain areas to facilitate learning. We will use multi-site electrophysiology and optogenetics to test this hypothesis. We have extensive experience with these techniques and preliminary data demonstrate feasibility for the proposed experiments. In Aim 1 we will determine the dynamic nature of interactions among the ACC, HPC, and cerebellum during learning using multiple tetrodes to simultaneously record spike and local field potential (LFP) activity from these areas to examine feedforward and feedback interactions during learning. We hypothesize that the cerebellum has bidirectional interactions with the ACC and HPC throughout learning. In Aim 2 we will examine the role of cerebellar projections to the ACC and HPC during learning. We will use optogenetics to manipulate cerebellar output while simultaneously recording neural activity from the ACC and HPC. We hypothesize that cerebellar output to the ACC and HPC during training trials facilitates trace conditioning. In Aim 3 we will determine the role of post-trial cerebellar activity in learning. We hypothesize that the cerebellum sends feedback to the HPC and ACC after training trials, and that the post-trial cerebellar signal facilitates learning by increasing forebrain neural responses to the training stimulus on subsequent trials. To test this hypothesis, we will manipulate cerebellar output with optogenetics in the post-US period while recording spikes and LFPs in the ACC and HPC during learning. The findings from this fundamental science project will provide a clearer understanding of how the cerebellum communicates with forebrain areas. The results may have implications for developing treatments for cognitive deficits associated with neurological disorders and stroke such as stimulation of cerebellar output to the forebrain.

NIH Research Projects · FY 2026 · 2026-05

Project Summary Vision is our primary sense. We rely on vision for everything from building our sense of reality, to navigating obstacles, identifying threats, and reading text and emotions. Untreatable vision loss beginning in childhood is often emotionally devastating and incurs a lifetime of healthcare expenses. This is the situation for people with Cone Dystrophy with Supernormal Rod Response (CDSRR), alternatively referred to as KCNV2 Retinopathy. In CDSRR there is a decline of vision in early childhood, followed by progressive macular degeneration by early adulthood. The hindrance to developing sight preserving treatments for CDSRR is that the etiology of macular degeneration is unknown. CDSRR is caused by mutations in a photoreceptor-specific potassium channel, Kv2.1/Kv8.2. As such CDSRR can be considered a disease of disrupted potassium homeostasis in the outer retina. Regulated potassium flux is essential for the electrical response of photoreceptors to light and can create osmotic gradients that drive water transport. Since photoreceptors have a high rate of mitochondrial respiration, generating excess metabolic wastewater that must be exported, we propose that loss of Kv2.1/Kv8.2 potassium channels in CDSRR reduces clearance of wastewater from photoreceptors, activating chronic osmotic stress signaling. In this project, we will use state-of- the-art imaging biomarkers and transcriptomics to evaluate osmotic regulation in mouse models of CDSRR.

NIH Research Projects · FY 2026 · 2026-05

Abstract Phosphorous in the form of phosphate, with numerous critical roles, is essential for life. Inorganic phosphate (Pi) is the main assimilable form of phosphorus. Despite possessing dedicated Pi uptake systems, Staphylococcus aureus and other pathogens experience Pi starvation. In addition to Pi uptake systems based on studies primarily using non-pathogenic model systems, bacteria must possess additional strategies for overcoming Pi starvation including metabolic adaptations and scavenging of Pi from organophosphates. S. aureus lacks the established metabolic adaptation, thus, to overcome Pi limitation S. aureus obtains Pi from organophosphates. This is accomplished by cleaving the Pi moiety from organophosphates and importing it using the Pi-transporters. Alkaline phosphatase (PhoB) can liberate Pi from many organophosphates. However, prior work revealed that S. aureus consumes numerous organophosphates including those that are highly abundant within the host such as nucleotides, in a PhoB-independent and Pi-transporter-dependent manner. It is also clear that S. aureus must utilize more than Pi transporters to overcome Pi limitation during infection, as the ΔphoPR mutant has a more severe virulence defect than the Pi-transporter double mutant ΔpstSΔnptA. To better understand how S. aureus overcomes Pi limitation during infection, the staphylococcal genes induced by Pi limitation and PhoPR were determined. This analysis identified AdsA (adenosine synthase), which catalyzes the conversion of extracellular adenosine mono-, di- and triphosphates into adenosine and free Pi. AdsA can also catalyze a similar reaction with other nucleotides. Further work confirmed that AdsA is expressed in a PhoPR-dependent manner in response to Pi limitation and that it enables S. aureus to use adenosine mono- and diphosphates as Pi sources. PhoB can catalyze the same reaction as AdsA and further investigation revealed that the relative contribution of these two enzymes to using nucleotides as a Pi source is environment dependent. Extracellular adenosine suppresses the immune response and deoxyadenosine triggers macrophage death, with previous work revealing that loss of AdsA reduces S. aureus virulence and increases the inflammatory response. Combined, these observations lead to the hypothesis that Pi limitation increases the expression of AdsA and PhoB, which contribute to both suppression of the immune response and acquisition of Pi during infection. The Aims of this this proposal will test this hypothesis: Aim 1: Establish if Pi limitation enhances immunomodulation by AdsA and PhoB. Aim 2: Determine if environment modulates the contribution of AdsA and PhoB to phosphate uptake. Aim 3: Elucidate the in vivo impact of AdsA and PhoB on Pi uptake and immunomodulation during infection. The support of this fellowship will facilitate my doctoral training in the Department of Microbiology and Immunology at the University of Iowa (UI). All my time will be dedicated to research, obtaining an MS in Science Education, presentation of my work, and professional development.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY Fuchs Endothelial corneal dystrophy is a blinding disease for which there is no cure. This condition affects 4- 7% of individuals over 40, and results in an economic burden of $300 million. Corneal transplantation is the prevalent treatment which has several disadvantages such as graft rejection, and secondary ocular complications. A major hindrance to the development of therapies for FECD is the lack of understanding of the molecular mechanisms which lead to the onset and progression of this condition. The non-existence of an animal model that had all the FECD phenotypes was a major cause behind this. We recently developed a mouse model that contains the major features of FECD – guttae (sub-endothelial blebs), corneal endothelial cell loss, and corneal edema. Using this animal model, we plan to elucidate the signals leading to the onset and progression of FECD phenotypes using the following specific aims. Aim 1 will determine the role of Descemet’s membrane changes in corneal endothelial functions. Aim 2 will determine the role of ubiquitin- proteasome system inactivity in development of FECD phenotypes.

NSF Awards · FY 2026 · 2026-05

The 2026 Great Plains Operator Theory Symposium (GPOTS) is a conference to be held at the University of Iowa in Iowa City, May 26–30, 2026. GPOTS is a major international conference series in operator theory and operator algebras, attracting mathematicians at all career stages from around the world each year. The 2026 meeting will feature invited and contributed talks spanning a broad range of topics in these areas. Participants will present significant new developments and identify directions and open problems for future research. GPOTS highlights recent advances in operator algebras and operator theory, including the structure and classification of C*-algebras and von Neumann algebras, free probability, operator theory, noncommutative geometry, the theory of operator spaces, and quantum information theory. These areas have a rich history within analysis and provide deep connections to other fields, including dynamical systems, group theory, logic, differential geometry, quantum computing, and mathematical physics. The conference offers a dynamic forum for collaboration and exchange: plenary speakers will present the latest developments and trends in the field, while contributed sessions will allow participants at all career stages to share their research and engage with colleagues. The conference website is https://sites.google.com/view/gpots-2026 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

Bridges that traverse streams or rivers are susceptible to degradation or collapse due to riverbed erosion (i.e. “scour”) around bridge-supporting piers. Erosion is induced by rapidly moving currents that accelerate as they pass the piers. It is usually studied in small-scale experiments in laboratory flumes with a layer of sand placed on the flume bottom. However, wide piers are difficult to study in this configuration because they partially block flow through the flume, which is not representative of piers in natural streams. As a result, erosion around a wide pier in a narrow laboratory flume differs from erosion observed around piers in rivers. This is problematic because these results are used to improve the design of bridges over streams and rivers. This project will quantify how flow blockage affects scour around piers in laboratory experiments, develop a methodology to correct for these effects, and incorporate this correction to obtain more accurate predictions of scour for full-scale piers. The results will enhance the resiliency and safety of current U.S. bridges and the future manufacturing of other similar structures. The overall objective of this project is to gain new insights into the effect of flow blockage on the physics of local scour due to large-scale turbulent flows around bridge piers, using circular cylinders placed on an erodible bed. The research will evaluate the influence of blockage ratio (the ratio between pier width and flume width) on the flow field around bluff bodies in mobile beds. Experiments and numerical simulations will be conducted for select bluff body geometries and bed coarseness values to identify the physics-based parameters related to channel blockage. Time-resolved particle image velocimetry measurements will be acquired to capture the size, circulation, and location of horseshoe vortices, the width, circulation, and length of wake vortices, and the magnitude of the “contracted jet region” in the streamwise-vertical plane around the cylinders. Numerical simulations will elucidate additional three-dimensional characteristics of the flow. The effect of blockage ratio will be used to identify the dimensionless parameters that are linked to blockage effects. These results will be used to establish a framework of conditions to mitigate blockage effects in future experiments and to develop correction factors. This approach can be applied to future testing other bluff bodies in a flume test involving an erodible bed (e.g. aquatic vegetation patches and marine infrastructure components). The results will also be used to develop an improved bridge scour design methodology and introduce STEM students to bridge design at the undergraduate level. The project will train STEM students in numerical modeling and experimental testing and improve the resiliency of the bridge infrastructure for public safety. 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

This innovative study will address suboptimal outcomes (readmission, morality, and loss of function) consistently associated with older adult hospital-to-home transitions by integrating elements of age- friendly care into structures and processes of evidence-based hospital-to-home transition interventions. Existing hospital-to-home transition interventions include aspects of safe transitions, and they provide evidence-based structures and processes of effective transitions. However, existing hospital-to-home transition interventions have lacked elements of high-quality geriatric (i.e., “age-friendly”) care. These include what matters to the individual, and key safety issues (potentially inappropriate medications, falls, cognitive impairment, depression) contributing to loss of function, readmission, and mortality. The 4Ms framework is an ideal starting point for refocusing hospital-to-home transitions because it: 1) starts with “what matters” to the older person and caregivers and 2) outlines best practices for addressing safety issues (medications, mobility, mentation) contributing to suboptimal outcomes during hospital-to- home transitions. The critical gap in the science is how to integrate elements of age-friendly care into older adult hospital-to-home transitions. We propose to conduct stage 0 and 1A research to create the Age-Friendly Hospital-to-Home Transition Intervention (ARRIVE-AT-HOME). We will use a systems engineering, human-centered design process to integrate elements of age-friendly care into structures and processes of evidence-based hospital-to-home transition interventions. Aims of this study are to: 1) identify and prioritize barriers and facilitators to integrating elements of age-friendly care (4Ms) into hospital-to-home transitions from the perspective of multiple key stakeholders; and 2) co-design an adaptable Age-Friendly Hospital-to-Home Transition Intervention (ARRIVE-AT-HOME). In Aim 1, we will conduct interviews with key stakeholders (recently hospitalized older adults, caregivers, healthcare professionals, administrators, and community-based service professionals) to identify barriers and facilitators and then apply systems engineering risk prioritization methods, surveying stakeholders to rate identified barriers and facilitators on frequency, modifiability, and importance. In Aim 2, two design teams will participate in parallel co-design sessions guided by our five-stage design process. One team will include recently hospitalized older adults and unpaid caregivers and the other will include professionals and administrators from hospitals/primary care and community-based services. The expected outcome of this research is an intervention ready for feasibility testing and subsequently a hybrid efficacy/ effectiveness trial testing the intervention’s effectiveness on individual and healthcare utilization outcomes. The proposed aims directly address National Institute on Aging priorities to develop effective interventions to maintain health, well-being, and function.

NIH Research Projects · FY 2026 · 2026-04

ABSTRACT Chorioamnionitis is infection and/or inflammation of the fetal membranes and the placenta and is one of the most common complications during pregnancy. Chorioamnionitis is an independent risk factor for several im- mune-mediated morbidities, including neonatal sepsis, chronic lung disease of prematurity, and asthma devel- opment in childhood. Although the risks associated with chorioamnionitis are severe, our understanding of the impact of this perinatal inflammatory exposure on offspring immune cell function remains incomplete. Current treatment approaches for chorioamnionitis are non-specific, including broad spectrum antibiotics and supportive care, which may independently increase the risk of asthma development. Therefore, there is a critical need to identify new therapeutic targets that address the underlying immune alterations that occur during chorioamni- onitis. This proposal investigates the central hypothesis that fetal interleukin (IL)-1 receptor (IL-1R) signaling drives chorioamnionitis-induced bacterial tolerance in neonatal offspring by upregulating the toll-like receptor (TLR) regulator Tollip. This hypothesis is supported by published data demonstrating that chorioamnionitis is dependent on IL-1 and that chorioamnionitis results in post-birth neonatal hyporesponsiveness to bacteria in animals and in humans. My robust preliminary data demonstrates that murine chorioamnionitis-exposed neona- tal offspring have hyporesponsive splenic macrophages, decreased systemic inflammation, and decreased mor- tality during neonatal E. coli sepsis. Additionally, murine chorioamnionitis-exposed neonatal macrophages dis- play increased chromatin accessibility at the promoter of Tollip, which is associated with increased gene expres- sion. The overall objective of my proposal is to determine how chorioamnionitis impacts offspring innate im- mune function and leads to an increased risk of immune-mediated morbidities. I will address this objective through two specific aims that test 1) the role of IL-1R signaling and 2) the role of Tollip in chorioamnionitis- associated neonatal hyporesponsiveness. Upon completion of this project, the expected outcome is that the mechanism(s) underlying chorioamnionitis-induced alterations in macrophage antibacterial responses will be better understood. The broader impact is that this project has the potential to alter current clinical practice by informing therapeutic and preventative approaches for chorioamnionitis that will address the underlying inflam- matory insult.

NIH Research Projects · FY 2026 · 2026-04

Summary / Abstract Atypical carcinoids of the lung and neuroendocrine carcinomas (NECs) are currently incurable with most patients succumbing to disease within five years. A subset of pulmonary neuroendocrine tumors (NETs) and NECs (including small cell lung cancer [SCLC]) initially respond to chemotherapy or to radioligand therapy (RLT) targeting somatostatin receptor type 2 (SSTR2). However, resistance to therapy invariably develops and many of these tumors lack or lose SSTR2 expression such that metastases, progression, and mortality occurs in most cases. This creates a critical need for new therapeutic strategies. Our exciting preliminary data show these lung tumors highly express the G protein coupled receptor, C-X-C chemokine receptor 4 (CXCR4), and can be effectively suppressed using 212Pb-pentixather (212Pb-pent) in preclinical models. Other data using 203Pb-pent show this theragnostic pair (203Pb/212Pb) can be used in preclinical models to calculate radiation doses to tumor and normal target organs (kidney, liver, bone marrow) to maximize tumor dosing with acceptable bone marrow toxicity. Importantly, the high linear energy transfer (LET) unique to alpha particles from 212Pb-pent generate dense ionization tracts in the cytoplasm that damage metabolic structures such as mitochondria, leading to metabolic generation of hydroperoxides. The presence of hydroperoxides can selectively enhance tumor cell kill when combined with inhibition of hydroperoxide metabolism using an FDA approved, thioredoxin reductase inhibitor (Auranofin; Aur) while causing minimal normal tissue injury. The overall hypothesis is targeting CXCR4 with 212Pb-pent in atypical carcinoids and lung NECs combined with inhibition of hydroperoxide detoxification will enhance the responses to 212Pb-pent alpha particle radiation therapy. Our hypothesis is tested in 3 Aims. Aim 1 and Aim 2: Determine if inhibiting hydroperoxide metabolism with Aur induces selective enhancement of 212Pb-pent alpha particle therapeutic efficacy in vitro and in vivo preclinical models of lung NETs and NECs by hydroperoxide mediated oxidative stress with tolerable bone marrow and kidney toxicities. Aim 3: Conduct a Phase 1 trial of alpha emitter dosimetry guided PRRT with 212Pb-pent in patients with atypical lung NETs and pulmonary NECs including SCLC. SIGNIFICANCE: Successful completion of Aims 1 and 2 will result in a high impact biochemical-based paradigm shift in the treatment of lung NETs and NECs. CXCR4 will be targeted with high LET 212Pb-pent and the anti-tumor effects enhanced by exploiting cancer cell-specific hydroperoxide-mediated metabolic oxidative stress. Aim 3 will optimize safety, clinical imaging, and dosimetry for evaluation of CXCR4 receptors for targeting of atypical carcinoids and NECs with 212Pb-pent in anticipation of future Phase 2 clinical trials. Overall, these studies will provide mechanistic and clinical information that will have a lasting impact on the development of 212Pb-pent for improving outcomes in currently incurable neuroendocrine lung cancers.

NIH Research Projects · FY 2026 · 2026-04

RESEARCH SUMMARY Lymphangioleiomyomatosis (LAM) is a debilitating, progressive lung disease for which few therapeutic options are available because of a lack mechanistic knowledge of the pathogenesis. The hallmark of LAM is the formation of neoplastic lesions (nodules) composed of smooth muscle-like epithelioid-like cells (LAM cells), followed by destruction of lung tissue and invasion of both bronchioles and lymphatic vessels. LAM cells are enveloped by lymphatic endothelial cells (LECs) and interact with activated LAM fibroblasts (LAMFs), which resemble carcinoma-associated fibroblasts. A critical knowledge gap is how interactions among these cell types drive LAM pathogenesis, and filling this gap will be key to developing effective treatments for LAM. Our long-term goal is to contribute to the design of new therapies for LAM by identifying candidate targets. The objective of the proposed research is to identify the cellular mechanisms that govern functional changes in the cell populations that contribute to pulmonary dysfunction in LAM. Our central hypothesis, based on the literature and our strong preliminary data, is that intercellular signaling within LAM nodules is dependent on TGF-β signaling and inhibition of the mTOR pathway, and it contributes to the hallmarks of LAM: fibroblast activation, endothelial-cell recruitment, and alveolar simplification. We will test the ability of changes TGF-β signaling in LAM-cells to contribute to LAM pathogenesis by activating surrounding fibroblasts, dysregulating differentiation of the alveolar epithelium, and promoting the growth and migration of cells within LAM nodules. To this end, we will engineer novel, multicellular 3-D organoid and lung-on-chip models that will enable us to test the effects of TGF-β signaling on the growth of LAM nodules, and to identify mechanisms that drive both this growth and alveolar simplification. We will do so by determining the extent to which LAM-cell dependent upregulation of TGF-β signaling drives disease-associated phenotypic changes in lung fibroblasts and lymphatic endothelial cells (Aim 1); and defining the cellular interactions that govern TGF-β signaling in TSC2 mutation-associated LAM and their impact on the differentiation of alveolar cells (Aim 2). This study will be possible because of our unique access to non-diseased and LAM-patient tissues and cells, as well as to immortalized cell lines derived from renal angiomyolipoma (AML) of LAM origin. The expected outcomes are (1) a novel and reproducible 3D culture system in which TSC2-null (and control) cells are co-cultured with both primary human lung fibroblasts and transitional alveolar cells, as well as LAM-chips produced from these, which will enable the study of LAM onset, and (2) knowledge of mechanisms by which TGF-β signaling and mTOR inhibition contribute to LAM pathogenesis. These outcomes put us in an excellent position to pursue support for future studies designed to understand the intercellular signaling that leads to LAM initiation and progression and to screen for therapeutic approaches that impact aspects of disease progression in the multiple cell types involved.

NIH Research Projects · FY 2026 · 2026-03

Summary: Chronic stress is a growing public health problem that contributes to the development of mental illnesses such as major depressive disorder (MDD). While maladaptive responses to environmental stressors are clearly fundamental to some individuals developing pathology, we still do not know why others remain resilient to chronic stress. Recently, using recording electrodes in a mouse model of chronic stress-induced maladaptation, we identified a robust and specific brain network signature prior to chronic stress exposure that predicts which animals will show a susceptible behavioral phenotype following chronic stress. Animals with this predictive pattern of network activity before stress exposure have been termed vulnerable while animals with a depressive-like phenotype after chronic stress are termed susceptible. This study opens the door for identifying underlying mechanistic causes of stress vulnerability-conferring neural signature that may be useful for the development of therapeutics targeting specific brain networks. It also enables us to study a brain state that has largely not been characterized: stress-naïve vulnerability to chronic stress. To examine the naturally occurring regulation of the stress-naïve vulnerable brain state, our specific aims combine the use of multi-site in vivo neurophysiology, fMRI, behavioral and telemetric measurements, single cell RNA-Seq, spatial transcriptomics, epigenetic investigations, and viral manipulations. This project will help us to better understand and quantify the relationship between our brain network signature and behavior following chronic stress. Further, it will provide an in-depth assessment of the similarities and differences in brain networks that predispose males and females to the ill effects of chronic stress. It will also reveal new insight into how individual differences in gene expression and epigenetics can produce such brain network signatures. These studies will provide an important first step in the development of therapeutics that are designed to target specific network activity that can prevent network activity that confers vulnerability. We will apply molecular profiling and validations to the stress-naïve vulnerable brain to determine pre-existing molecular alterations that predict stress susceptibility. This work fills an important gap in stress neurobiology, which has focused primarily on defining the molecular hallmarks of stress susceptibility (i.e., compensatory changes after stress), not vulnerability (i.e., before stress exposure). Identifying the molecular signatures of the vulnerable brain state enables the possibility of preventative therapeutic approaches. Furthermore, by identifying molecular contributions to brain network activity, this study enables the possibility of brain network-based pharmacotherapeutics, which could be useful for targeting medications to specific individuals (i.e. precision medicine).

NIH Research Projects · FY 2026 · 2026-03

Abstract Chronic pancreatitis (CP) is a fibro-inflammatory disorder of the pancreas which is histologically characterized by acinar cell loss, inflammation and fibrosis. Studies suggest that pancreatitis is also a risk factor for pancreatic cancer. Despite decades of research there is no specific therapy for CP. Recent studies point towards a central role of activated pancreatic stellate cells (PSCs) in the pathogenesis of CP-associated fibrogenesis. Activated PSCs have been shown to not only regulate the synthesis and degradation of extracellular matrix proteins but also modulate the immune system to a more pro-fibrogenic state. Elucidation of the pathways which drive the activation of PSCs will lead to the development of novel therapies. Notch signaling pathway, a highly conserved developmental pathway, has been shown to be upregulated in fibrotic diseases of liver4 and other organs. While activation of Notch pathway has been observed in human CP5, its role in pathogenesis of CP, and whether its inhibition can be used as a therapeutic strategy has not been explored. Our preliminary data curated from in-vitro and in-vivo studies suggest that - 1) Activated PSCs exhibit pro-fibrogenic characteristics in a Notch-pathway dependent fashion 2) Notch pathway is activated in multiple animal models of CP; 3) this activation is observed in the PSC and the acinar compartment; 4) PSC- specific deletion of Notch-signaling improves outcomes in CP, whereas acinar-specific Notch-pathway deletion has no role (neither improves nor worsens) in CP pathogenesis or recovery 5) Notch pathway inhibition with pharmacological inhibitors reduce CP severity. Based on these data, we hypothesize that “Notch pathway in PSCs is involved in the pathogenesis of chronic pancreatitis. Notch pathway in PSCs drives the pro- fibrogenic response and modulates the immune environment to a pro-fibrotic state.” The current proposal is focused towards evaluating the role of Notch pathway in the pathogenesis of CP as well as progression of recurrent acute pancreatitis (RAP) to CP. In specific aim 1, using mouse models with stellate cell specific Notch pathway knock-out or knock-in strategies as well as using in-vitro setup, we will evaluate the role of Notch pathway in PSCs in the pathogenesis of CP. In specific aim 2, we will elucidate the effect of Notch pathway in PSCs on the immune environment in CP. Finally, in specific aim 3 we will confirm the activation of Notch pathway in pancreatectomy specimen from patients with CP. Furthermore, the ability of clinically relevant pharmacologic inhibitors of Notch pathway to improve CP in mouse models as well as to prevent progression of recurrent acute pancreatitis (RAP) to CP will be evaluated. Successful execution of these studies will not only elucidate novel pathways involved in the pathogenesis of CP, but will also generate pre-clinical data for a future clinical trial of Notch pathway inhibition in the treatment of CP.

NIH Research Projects · FY 2026 · 2026-02

SUMMARY T follicular helper (Tfh) cells are a subset of CD4+ T cells that specialize in communicating with germinal center (GC) B cells to facilitate B cell differentiation into either Memory B cells or Plasma cells that secrete high-affinity class-switched antibodies. As a key regulator of both antibody quantity and quality, coupled to the crucial role antibodies play in mediating pathogen control following immunization or infection, or in driving autoimmune or allergic diseases respectively, Tfh cells directly contribute to either protective or pathological B cell responses depending on the context of the disease. Notably, Tfh cells play an especially important role during chronic viral infections, such as during HIV-1 and hepatitis C virus infection, or during chronic lymphocytic choriomeningitis (LCMV) infection in mice, all of which critically depend on Tfh-mediated antibody responses for viral control. Moreover, recent evidence indicates that Tfh cell-derived IL-21 functions to sustain the effector function of CD8+ T cells during chronic viral infection and cancer. However, despite their essential role, the precise molecular circuits underpinning Tfh cell differentiation remain unclear. Moreover, in settings of persistent infection, the development of neutralizing antibodies is often delayed for several months, and the initial wave of antibodies that do develop are often of low-affinity and poor quality. Furthermore, hypergammaglobulinemia, or the overproduction of non-specific antibodies, and impaired FCγ receptor effector functions are hallmarks of chronic viral infections in both mice and humans, indicating that dysregulated humoral immunity is a generalizable feature of persistent viral infection. We hypothesize that persistent exposure to antigen and inflammation perturbs functional Tfh cell responses, thereby resulting in insufficient “help” signals to both B cells and CD8+ T cells, suboptimal antibody responses and impaired viral control during chronic infection. Herein, I will employ cutting-edge technologies, including single cell profiling of T cell transcriptomes and epigenomes, innovative bioinformatic pipelines, and CRISPR/Cas9 screening and genetic mouse models to identify novel and conserved regulators of Tfh cell differentiation across different infections and species, as well as determine how persistent exposure to antigen and inflammation perturbs the transcriptional and epigenetic program of Tfh cells and their functional capacity to provide “help” to B cells. Additionally, using computational approaches to integrate publicly available single-cell RNA-sequencing datasets containing human CD4+ T cell populations, accompanied by a creative in vitro Tfh:B cell co-culture system, we will extend our findings from experimental models to further delineate critical regulators of human Tfh cells. Successful completion of this project will provide mechanistic insight into the molecular circuitry underpinning Tfh cell development and aid in the identification of novel strategies aimed at targeting Tfh cells to modulate their function for therapeutic benefit during chronic viral infection and/or other diseases.

NIH Research Projects · FY 2026 · 2026-02

Accidental or deliberate radiation exposure of humans remains a major health concern, due to the paucity of medical countermeasures (MCMs) to ameliorate radiation-induced damage. While high dose radiation exposure is generally fatal, even low dose whole body (WBI) or partial radiation exposure can have acute- and/or delayed- negative impacts that appear to act through disruption of the immune system. The cytoreductive effects of WBI have long been exploited in conjunction with chemotherapy as a preparative regimen prior to hematopoietic stem cell transplant in patients with blood cancer to deplete malignant cells and suppress the immune system. While there is strong evidence that radiation kills rapidly dividing cells, a hallmark of the immune system, and induces inflammation that can mediate tissue destruction, the precise nature of radiation induced immune-dysfunction is not well understood. This knowledge gap is a key impediment to development of MCMs to treat radiation exposure. For one example, memory CD8 T cells provide enhanced resistance to re-infection and malignancies. However, most studies in the literature examine the impact of radiation exposure on the capacity of the host’s naïve CD8 T cells to mount a new (primary) immune response and just a few reports have looked at how radiation exposure influences the longevity and protective capacity of pre-existing pathogen or vaccine-induced CD8 T cell memory. Memory CD8 T cell populations have the job of surveying the entire body for signs of re-infection. They accomplish this task using two complimentary and interactive strategies. This first strategy involves populations of memory CD8 T cells that survey the body by using the circulatory system (circulating memory CD8 T cells - Tcircm). The second strategy involves the generation of a population of non-circulating memory CD8 T cells (called T resident memory, Trm), generally in the tissue of pathogen entry. These cells, which persist long-term in tissues, provide rapid detection of re-invading pathogens and then send out mediators to recruit other cells of the immune system to the site of infection. Importantly, our recent data obtained after WBI or partial (targeted) thorax radiation suggest that sublethal ionizing radiation inflicted numerical and functional damage to Tcircm and Trm cells that diminished their ability to provide protection to pathogen-re-encounter. Our long-term goal is to precisely identify mechanisms that govern maintenance, differentiation and function of infection and/or vaccine- induced memory CD8 T cell subsets and explore modalities to recover memory CD8 T cell responses in radiation survivors. We will address our long-term goal through the following specific aims: SA1 - Delineate the tissue-specific impact of WBI on pathogen-specific Trm and evaluate targeted vaccine strategies to restore memory CD8 T cell numbers and function after irradiation. SA 2 - Define mechanisms underlying WBI-induced numerical and functional diminishment of Tcircm and exhausted (Tex) CD8 T cells generated after acute or chronic viral infections.

NIH Research Projects · FY 2026 · 2026-02

Project Summary/Abstract Neuronal plasticity is fundamental for cognitive and behavioral processes. Emerging evidence has shed light on the role of oligodendrocytes in regulating activity-dependent plasticity. Although primarily recognized for their role in forming myelin, mature oligodendrocytes also perform additional metabolic functions that facilitate energy- efficient and rapid saltatory conduction in white matter tracts across neuronal circuits. Although it is established that myelin plasticity can influence neurophysiology and behavior, a comprehensive understanding of the molecular mechanisms by which mature oligodendrocytes regulate hippocampal function remain elusive. Recent reports have identified the presence of distinct mature oligodendroglial subtypes within the hippocampus that differ in their transcriptomic profiles, topographical distribution, and myelination characteristics, and it is likely that these mature oligodendroglial subclasses also exhibit differences in cell-type-specific and spatial molecular signatures during long-term memory storage. Our preliminary findings provide evidence of rapid changes in transcriptomic signatures in mature myelinating oligodendrocytes within the first hour after spatial learning, likely reflecting myelin-independent aspects of mature oligodendroglial function. The rapid and dynamic changes observed in the transcriptomic landscape, coupled with the diversity in mature oligodendroglial cell types, necessitate a thorough molecular investigation to fully comprehend the role of these cells in hippocampal function. This proposal aims to elucidate the molecular signatures of mature oligodendroglial subtypes at single- cell and spatial resolution during memory consolidation and investigate the functional consequences of manipulating mature oligodendroglial gene expression on activity-dependent oligodendroglial plasticity underlying hippocampal memory consolidation. The research will be conducted in two aims. In Specific Aim 1, we will identify learning-induced molecular signatures in mature oligodendrocyte subtypes using cutting-edge single-cell multiomics and high-plex in situ approaches. In Specific Aim 2, we will develop in vivo strategies of gene manipulation specifically targeting mature myelinating oligodendrocytes. We will then examine functional signatures of activity-dependent oligodendroglial plasticity in vivo, by quantifying myelination changes after learning and utilizing fiber-photometry to investigate the dynamics of calcium and glucose in mature myelinating oligodendrocytes during spatial learning. The expected outcomes of this exploratory/developmental R21 proposal will provide unprecedented insights into the functional heterogeneity of mature oligodendrocytes during memory consolidation, laying the groundwork for future research to investigate the mechanistic relationship between transcriptomic changes that underlie learning-dependent oligodendroglial plasticity and hippocampal memory consolidation. These findings will significantly advance our understanding of long-term memory and offer novel avenues for therapeutic interventions for cognitive impairments associated with neurodevelopmental, neuropsychiatric, and neurodegenerative disorders.

NIH Research Projects · FY 2026 · 2026-02

Abstract Having a stroke is a frightening experience for the individual and their loved ones. A major source of anxiety is not knowing what stroke-related deficits will persist – will my loved one ever be able to talk again or understand me? The likelihood for recovery is estimated by the treating neurologist or rehabilitation specialist based on their personal experience. Much of the variance in outcomes depends on the location of the stroke in the brain. Currently, however, there are no tools available that can utilize this lesion location information for the purposes of improving the accuracy of prognostication. The focus of our research program is developing such a tool. Specifically, we have developed a method that uses the location of the stroke, queries it against outcome data from hundreds or thousands of other individuals, and generates a personalized, quantitative prediction of long- term stroke-related cognitive deficits. At the University of Iowa, we have one of the most comprehensive ‘lesion’ registries in the world. In patients with ischemic stroke, it includes demographics, neuroimaging, and extensive cognitive outcome information. We propose to capitalize on this unique resource in developing a tool to predict cognitive outcomes from stroke across 7 independent stroke cohorts. First, using existing data we will generate lesion-symptom maps, which identify brain regions associated with cognitive impairment. We will also use an innovative strategy that links lesion-associated deficits to specific patterns of brain network disconnection, called lesion network mapping. This method infers what networks are disrupted by brain lesions in association with specific symptoms, which improves the accuracy of cognitive outcome predictions. A major goal of this proposal is to optimize cognitive outcome predictions by evaluating novel approaches to lesion- symptom mapping and lesion-network mapping in comparison to existing methods, with the goal of identifying the approach that explains the most variance in cognitive outcomes. A second major objective is to combine different modalities of predictive information within ensemble machine learning models – both lesion and non- lesion predictors. The third major objective is to engineer a fully automated pipeline for generating these predictions, such that clinically acquired MRI data can be used as input to an algorithm that generates a report of personalized cognitive outcome information based on lesion location and lesion-associated network disruption, which will contribute to statistical models that also include non-lesion predictive information. By addressing these objectives, we will lay a strong foundation for developing a clinical tool that uses clinically acquired brain MRI data to generate personalized cognitive outcome predictions based on ischemic stroke lesion location. This will improve stroke management by informing early intervention decisions and helping to guide rehabilitation and life planning for patients with stroke.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY/ABSTRACT: Our goal is to understand why measles virus (MeV) is the most contagious human virus. MeV is a worldwide leading cause of vaccine-preventable deaths. Understanding what sets its mechanism of transmission apart from other viruses is important. Humans are the only natural reservoir for MeV. Thus, a critical challenge for MeV study is identification of representative model systems. Well-differentiated primary cultures of airways epithelial cells from human donors (HAE) provide a physiological relevant model of human airways. In HAE, direct cell-to-cell spread of MeV results in well-defined foci termed infectious centers that ultimately dislodge from the epithelial layer en masse. Of the many respiratory viruses screened to date, only MeV results in infectious center formation in HAE. We hypothesize that infectious center formation, release, and environmental contamination are vital steps for efficient host-to-host spread of MeV. In Aim 1, we address fundamental questions about the formation of infectious centers. We hypothesize that MeV targets mitochondria and induces mitophagy. Release of mitochondrial DNA into the cytoplasm is detected by the DNA sensing molecule cGAS which initiates a cascade that stimulates antiviral genes. Next, we ask where intracellular assembly of MeV occur in HAE. Again, preliminary data suggest that mitochondria may play an important role in this process. This model will challenge the currently accepted paradigm of how MeV replicates in airway epithelial cells. In Aim 2, we demonstrate that infectious center formation can be approximated by expression of only 2 MeV proteins: Fusion (F) and Hemagglutinin (H). We use replication deficient adenoviral vectors for delivery. Modular expression of adenoviral expressed viral proteins allows numerous advantages including: 1) rapid generation of recombinant expression vectors; 2) low risk that genetic manipulations of transgenes will impact vector titer; and 3) many combinations of viral protein comparisons are possible. This novel tool will allow for the substitution of proteins with known mutations that will alter complex formation; as well as, substitution of orthologous proteins from other viruses, such as respiratory syncytial virus, Nipah virus, and Sendai virus. In Aim 3 we determine how long aerosolized MeV remains viable under common environmental conditions. Dislodged infectious centers could protect the virus from desiccation and prolong the infectious period. We develop tools to aerosolize cell-associated or cell-free MeV. Subsequently, the infectivity will be compared following exposure to environmental conditions, (e.g., desiccation or temperature). Defining the stability of MeV across different environmental conditions could inform policy to reduce transmission. In summary, fundamental biological questions remain about the highly contagious MeV. Within airway epithelial cells, MeV undergoes its final amplification and prepares itself for spread to the next host. This final step is likely key to the contagious nature of MeV.

NIH Research Projects · FY 2026 · 2026-02

ABSTRACT This proposal addresses the need to investigate understudied proteins associated with rare diseases, such as Brugada Syndrome (PAR-25-122). One class of proteins highlighted in this RFA—Scn2b, Scn3b, and Scn4b— belongs to a family of β subunits that associate with the large pore-forming α subunits of voltage-gated sodium channels (NaV), which regulate electrical excitability throughout the body. In total, there are four distinct β subunits that can mix and match with nine different α subunits. Beta subunits are widely recognized for their ability to regulate the gating properties, trafficking, and pharmacology of Nav channel complexes. Dysfunction of these subunits has been linked to several human diseases, including epilepsy and cardiac arrhythmias such as long QT syndrome, atrial fibrillation, and Brugada syndrome. Additionally, mutations in NaV α subunits have been implicated in rare diseases, including SCN8A encephalopathy (SCN8A/ NaV 1.6), hereditary sensory and autonomic neuropathy type 7 (SCN11A/ NaV1.9), and dilated cardiomyopathy-1E (SCN5A/ NaV1.5). A critical step in understanding how beta subunits contribute to disease is elucidating their precise modulatory effects on NaV function. Electrophysiological studies in heterologous cells have demonstrated the ability of beta subunits to influence channel gating, pharmacology, and trafficking. However, results across multiple studies have been inconsistent, often due to variability in the cell lines used. A major confounding factor is that many cell lines endogenously express beta subunits, which can interfere with exogenously introduced β subunits under investigation. To overcome this limitation, we developed a specialized cell line lacking all β subunits, including Scn2b, Scn3b, and Scn4b, as well as Scn1b, MPZ, MPZL1, MPZL2, and MPZL3. These cells, termed beHAPe cells (beta- eliminated haploid cells for expression), provide a controlled system to study NaV channel regulation. Our initial electrophysiological studies using beHAPe cells reveal novel properties of beta subunits in modulating NaV1.5, the primary α subunit in cardiac tissue. Building on these findings, we propose to produce stably-expressing human (HEK) cell lines to systematically define the roles of Scn2b, Scn3b, and Scn4b in modulating additional α subunits, including NaV1.6 (a key subunit in the central nervous system) and NaV1.7, NaV 1.8, and NaV 1.9 (which are predominant in the peripheral nervous system). This work will provide deeper insights into their function in these tissues and their associated diseases. Additionally, our new data suggest that Nav1.8 plays a previously unrecognized role in cardiac function alongside NaV1.5. Understanding how β subunits modulate pore-forming subunits could provide new insights into their involvement in cardiac arrhythmias, expanding their known roles beyond the nervous system. Taken together, in addition to providing new information on the understudied Scn2b, Scn3b, and Scn4b proteins, our newly generated stable cell lines will enable studies for the development of novel therapeutics for isoform specific modulation of specific α- and β-subunit pairs.