University Of Iowa

NIH Research Projects · FY 2026 · 2023-04

ABSTRACT Over the past three decades, there has been an alarming increase in the incidence of childhood obesity. Childhood obesity leads to early onset of cardiovascular risk factors, and both obesity and cardiovascular risk factors track into adulthood and contribute to the epidemic of cardiovascular disease (CVD). The Developmental Origins of Health and Disease theory posits that risk for obesity and CVD is, in part, programmed in utero. To prevent this early entrenchment into obesity and CVD, identification of modifiable maternal factors during pregnancy that later impact offspring risk in early childhood is essential. A surprising lack of research investigates the role of prenatal sedentary behavior (SED), moderate-to-vigorous-intensity physical activity (MVPA), and the novel 24-hour behavior paradigm (the composition of SED, physical activity, and sleep) on these adverse offspring outcomes. This is a critical research gap because there is strong physiological rationale that SED, MVPA, and 24-hour behavior in pregnancy could influence offspring health, and these behaviors are modifiable targets for intervention during pregnancy. The overall goal of this proposal is to examine the associations of SED (Aim 1) and MVPA (Aim 2) across pregnancy with offspring obesity risk and CVD risk through 24 months. We will also use novel statistical methods to determine the optimal 24-hour behavior compositions (Aim 3) during pregnancy associated with reduced risk of these adverse offspring outcomes. We can achieve these aims by leveraging our ongoing, multi-center cohort study Pregnancy 24/7 (R01 HL153095), where we are prospectively measuring SED, physical activity, and sleep in 500 women in each trimester of pregnancy using state-of-the-art monitors (activPAL3 micro and Actiwatch Spectrum Plus). Pregnancy 24/7 also assesses other relevant prenatal exposures that may associate with offspring obesity and CVD risk, i.e., pre-pregnancy obesity, gestational weight gain, diet, smoking, and adverse pregnancy outcomes. In direct response to the NHLBI’s Notice of Special Interest (NOT-HL-19-695), we propose to expand Pregnancy 24/7 by conducting a separate cohort study among the offspring of its participants. In the Offspring Study, we propose to combine maternal exposure data from Pregnancy 24/7 with new, comprehensive assessments of postnatal exposures, obesity, and CVD risk measures in the child through 24 months via medical record abstraction, questionnaires, and an in-person study visit at 24 months. We hypothesize that offspring of women with higher SED or lower MVPA across pregnancy will have more rapid increases in BMI Z-score (primary outcome), and greater adiposity, blood pressure, and pulse wave velocity through 24 months. Further, we hypothesize that statistically reallocating time in SED to physical activity, but not sleep (among adequate duration sleepers) will be associated with more optimal offspring outcomes. By combining prenatal and postnatal exposure data, our approach uniquely allows us to isolate the effects of pregnancy SED, MVPA, and 24-hr behavior on offspring obesity and CVD risk measures in early childhood. This project will inform critically needed primordial prevention interventions to decrease the risk of obesity and CVD.

NIH Research Projects · FY 2026 · 2023-04

ABSTRACT: Sepsis is a dangerous hyper-inflammatory condition that carries a mortality rate of 25% for uncomplicated cases and rises to 80% for patients who develop multiple organ dysfunction syndrome (MODS). No specific therapies for MODS exist, which is why identification of druggable targets and biomarkers for diagnosis/prognosis are urgently needed. During the acute phase response in sepsis, circulating factors such as cytokines and endotoxins cause oxidative stress and derangements in mitochondrial morphology and function in the heart, ultimately leading to septic cardiomyopathy (SepCM), a manifestation of MODS. Prohibitins (PHB1,2) are proteins that assemble in hetero-oligomeric complexes within the mitochondrial inner membrane and in plasma membrane lipid rafts, where studies show they are at the nexus of many vital cellular functions including metabolism, proliferation, oxidative stress and apoptosis. The current proposal stems from our recent findings that PHB1 is a dynamic acute phase reactant protein in sepsis, and its secretion during sepsis is abrogated in mice lacking the anti-inflammatory transcription factor Nrf2 (i.e., NFE2L2). Importantly, bloodborne PHB1 is biologically active, as administration of recombinant human PHB1 (rPHB1) activates PI3K- AKT signaling and enhances aerobic glucose oxidation and pentose phosphate pathway in the heart, and preserves cardiac mitochondrial oxidative phosphorylation (OxPHOS) in mouse models of sepsis. We also have very exciting preliminary evidence that serum PHB1 levels are associated with MODS and mortality in sepsis patients. Experiments outlined in this proposal will test our central hypothesis that bloodborne PHB1 is a stress-induced ‘hepatokine’ that mediates a liver-to-heart protective feedback signal during sepsis by enhancing oxidative glucose metabolism (i.e. suppressing lactate production) and preserving mitochondrial structure and function in the myocardium. This cardioprotective effect of circulating PHB1 can be therapeutically exploited to treat SepCM. Our established interdisciplinary team will test this hypothesis in three Aims. Work in Aim 1 will determine the Nrf2-mediated mechanisms controlling PHB1 secretion in hepatocytes. In Aim 2 we will identify the mechanisms of cardio-protection conferred by circulating PHB1 during sepsis. Work in Aim 3 will validate serum PHB1 as a predictive biomarker of morbidity and mortality in a cohort of patients with established sepsis (INVACS cohort, University of Utah). Each Aim is hypothesis-driven, and the work will be performed using gain/loss-of-function approaches in primary cell culture, clinically relevant mouse models of severe sepsis, and serum samples from a well-characterized cohort of sepsis patients. We will leverage the complementary and uniquely distinct expertise of our research team to elucidate cardioprotective mechanisms of circulating PHB1, and to exploit these mechanisms to treat a very serious and deadly clinical condition.

NIH Research Projects · FY 2026 · 2023-04

PROJECT SUMMARY / ABSTRACT Obesity is a major contributor to the epidemic of metabolic diseases including type II diabetes, hypertension, cardiovascular disease, and liver disease. Excess weight gain is the result of a chronic imbalance between caloric intake and energy expenditure, and while several pharmacological agents target energy intake to promote body weight loss, no current options are successful in the long-term management of obesity. Thus, a greater understanding of the central mechanisms that contribute to obesity are required for both its prevention and treatment. Numerous studies have implicated mitochondrial dysfunction in neurons because of excess consumption of nutrients in the pathogenesis of obesity. Previous publications have demonstrated that the inner mitochondrial membrane protein uncoupling protein 1 (UCP1), renowned for its role in heat production in thermogenic adipose tissue, is also expressed in the central nervous system (CNS), however, the function of neuronal UCP1 is completely unknown. Our preliminary data unexpectedly demonstrates that UCP1 is expressed in the ventromedial hypothalamus (VMH) of adult mice and that its expression is metabolically regulated. Consequently, there is a need to understand how UCP1 functions and whether it’s activation within the CNS can also regulate energy homeostasis as it does in brown adipose tissue. The next steps addressing these needs are to pursue the overall objective of this application: (i) determine the extent to which UCP1 in the VMH influences energy balance, and (ii) investigate if neuronal UCP1 activity attenuates the production of reactive oxygen species (ROS) to regulate energy homeostasis. We will investigate our central hypothesis that activation of UCP1 within the VMH chronically reduces ROS to promote negative energy balance. We will test our hypothesis using novel genetic mouse models and viral vector constructs that knockout or overexpress UCP1 specifically in the VMH to determine whether modulation of neuronal UCP1 activity regulates body weight following cold exposure or consumption of high fat diet. Moreover, we will be able to investigate whether UCP1 in the VMH can chronically reduce ROS to regulate energy homeostasis, as well as determine how modulating its expression regulates mitochondrial dynamics. The experiments proposed in this application are expected to identify novel signaling pathways that provide new insights into the treatment and prevention of obesity. Rationale for this project is that discovering the function of central UCP1 may contribute to future discovery efforts to identify and test new therapeutic targets to treat obesity. In addition, an outlined career development plan to elevate my knowledge of mitochondrial biology by leveraging mentorships, technical training, seminars, conferences, and R01 workshops is described in the application. The University of Iowa has committed its support and facilities to allow Dr. Claflin to complete the proposed research and participate in their extensive training seminars. Completion of the proposed 5-year research and training plans will prepare Dr. Claflin for an independent research career and assist in securing an R01 from the NIDDK.

NIH Research Projects · FY 2025 · 2023-04

Approximately 27% of the 52 million K-12 school-age children (5-18 years) in the United States experience at least one chronic medical condition (CCMC) requiring them to receive medication during the school day. Adherence to the medications and their scheduled dosing is crucial for the CCMC’s health and academic progress. However, primary schools are an understudied community healthcare setting with school nurses (SNs) as the main healthcare provider. Widespread budgetary cuts have left 18% of schools across the nation with no designated SN,2,6 leaving the vast majority (78%) of medication administrations to unlicensed assistive personnel (UAP). Because these individuals are not healthcare providers, medication errors are three times higher when administered by UAP than by a SN. To reduce medication errors in schools, we propose a technology-assisted system to help SNs and UAP with medication administration and documentation. Our proposed computer-based system, the Electronic School Medication Administration Record (eSMAR). Our system prototype was tried in simulated environment. Therefore, the purpose of this demonstration project is to implement eSMAR in a real-world setting (grade schools) and to evaluate the usability and effectiveness of eSMAR on medication administration and documentation in schools. Aim 1: Implement and evaluate the usability of eSMAR in a select sample of K-12 schools in the Iowa City Community School District (ICCSD). We will achieve this aim by analyzing data from a) usability surveys from SNs and UAP, b) eSMAR system usage reports, c) observation, filed notes, and semi-structured interviews during site visits, and c) parent satisfaction survey. Aim 2: Understand contextual factors influencing eSMAR implementation. We will achieve this aim by conducting site visits using rapid ethnographic assessment (REA). Consolidated Framework for Implementation Research (CFIR) and EPIS domains will inform the development of the REA measures. Data from Aims 1&2 will be triangulated to deepen our understanding of contextual variables influencing eSMAR implementation. Aim 3: Evaluate the effectiveness of eSMAR (number of errors intercepted). We will achieve this aim by analyzing data from the eSMAR reports for the number, type, and frequency of errors intercepted by eSMAR. We will compare data on users (SNs vs. UAP), type of medication, time, medical condition, child’s age and grade level. Data from ICCSD incident reports will be collected to identify types of errors not prevented by the eSMAR system.

NIH Research Projects · FY 2026 · 2023-04

PROJECT SUMMARY The airway system is composed of asymmetric dichotomously branching tubes lined with respiratory epithelium that form a barrier at the interface with the environment. The airways carry a simple function of conducting oxygen rich air to the alveolar space where gas exchange with the blood occur. By doing that, pathogens and particles enter the lungs. Mucociliary transport is a host defense mechanism that protect the lungs from invading organisms. Defects in mucociliary transport contributes to many airway diseases such as asthma, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, cystic fibrosis, and primary ciliary dyskinesia. We developed limited understanding of the mechanism of MCT in large airways by investigating the role of submucosal gland secretions. We found that mucus strands secreted by submucosal glands are critical to initiate movement of large particles in large airways. We also found that in CF airways, due to loss of CFTR-mediated anion secretion, mucus strands are abnormally elastic. They fail to detach from submucosal gland duct opening and often recoil backward while transporting on the airway surface. Small airways constitute the majority of the surface airway of the lungs and it is suggested that may contribute to some of the abnormalities seen in several airway diseases. The hypothesis that mucociliary defects in small airways contribute to CF airway disease pathogenesis has largely remained untested. In addition, the characteristic features of MCT in small airways has remained poorly understood. To understand mucociliary transport in the small airways, we developed a positron emission based mucociliary transport assay with high spatial and temporal resolution not achieved before. We used CF airway disease as a disease model of impaired mucociliary transport. To realize our overarching goal of understanding the mechanism of mucociliary transport in both small and large airways, we will test hypotheses in the following Specific Aims: Aim 1. What is the mechanism of metachronal motion in vivo? Does disruption of mucus viscoelastic properties alter metachronal motion? Does loss of submucosal gland mucus secretion affect metachronal motion? Is metachronal motion impaired in CF airways? Aim 2. Is mucociliary clearance defective in CF small airways? Does loss of CFTR cause an MCC defect? Will HEMT correct it? Will an inhaled mucolytic (TCEP) correct it? Aim 3. Is early intervention (at birth) sufficient to prevent/delay CF airway disease? Does HEMT revert CF airway disease back to normal in young piglets? Are mucolytics effective as a bridge therapy until HEMT are initiated? The results are very important in understanding the mechanism of MCT and how MCT is controlled, and ultimately identify desperately new targets for lung diseases. The results will also guide development of newer therapeutics or combination of therapeutics.

NIH Research Projects · FY 2026 · 2023-04

Project Summary A major goal of neuroscience research is to understand how experience reweights the flow of information across brain circuits. This involves plasticity that occurs at across different regions of neurons (i.e., subcellular compartmentalization). Our preliminary data revealed compartmentalization of signaling within neurons that encode olfactory memories, and further found that learning drives spatially broad elevations of Ca2+. This suggests that multiple signals are integrated across different spatial scales during learning events to modulate compartmentalized plasticity. Here we will test how compartmentalized plasticity drives the ensembles of changes across multiple spatial scales in the nervous system that leads to coherent action selection. We will test the mechanisms of compartmentalized presynaptic plasticity down to the subcellular level, using the genetically powerful, highly tractable nervous system of Drosophila melanogaster. The Drosophila mushroom body (MB) carries olfactory information from olfactory projection neurons to downstream circuits that mediate fundamental decision-making processes. We will use this system as a testbed to dissect the mechanisms of compartmentalized plasticity at the molecular levels, examine cellular integration and synaptic plasticity, and probe how these processes modulate behavioral action selection via actions on discrete circuits that modulate behavior. Understanding how memories are encoded in the brain and disrupted in brain disorders is a prerequisite to the rational design of treatments for memory impairment. Results of the present studies will provide guideposts for future research into the molecular biology of memory formation across multiple model organisms (including mammals), as the function of key molecules, cellular mechanisms, cellular compartmentalization and synaptic function, circuit motifs, and computational primitives are both conserved across species and crucial across multiple circuits & types of memory. The project will support our long-term goal of understanding of memory down to the single-cell level, contributing to the knowledge base necessary for the rational development of novel treatments for memory impairment.

NIH Research Projects · FY 2025 · 2023-04

PROJECT ABSTRACT Microneedles (MNs) are micron scale projections that allow for improved drug delivery through the skin via formation of transient micropores. For successful transdermal drug delivery, it is crucial that the micropores remain open (drug delivery ceases rapidly after micropore closure, usually within ~48 hrs). Delaying micropore closure would be advantageous by allowing a longer period of drug delivery from each MN treatment. Previous methods that have been explored for delaying micropore closure timeframes did not account for the biochemical differences seen in diverse skin types; further, previous studies did not address the physiological processes that impact micropore closure. We have shown that darker skin types have longer micropore closure timeframes. This could result in altered therapeutic outcomes from unexpected drug delivery windows in diverse skin types, which may be especially problematic for drugs with narrow therapeutic windows. Catecholamines such as dopamine play a role in cutaneous wound healing and may mediate micropore closure, but the direct role of dopamine in micropore closure has never been studied. Dopamine may alter wound healing through dopamine receptor binding and subsequent cAMP modulation. Interestingly, melanin production (responsible for skin color) also relies on the same dopaminergic precursors and alters intracellular cAMP production. Therefore, we hypothesize that drug delivery through micropores in diverse skin types will differ in a manner dependent upon micropore closure times, and variability in micropore closure among skin types is influenced by dopamine secretion and receptor signaling. To test this, we will establish a translational approach through two Aims. In Aim 1 we will assess the impact of differences in micropore closure times on model drug absorption using a pharmacokinetic study. In Aim 2 we will investigate how dopamine D1/D2 receptor signaling alters microwound recovery using a dual in-vitro knockdown approach. The overall goal is to identify a possible pharmaceutical target for delaying micropore closure, ultimately improving MN-assisted transdermal drug delivery and informing development of better MN products for diverse populations.

NIH Research Projects · FY 2026 · 2023-04

ABSTRACT The Institute for Clinical and Translational Science (ICTS) at the University of Iowa (UI) has three aims – (1) to promote an innovative, integrated, geographically distributed framework for conducting clinical and translational research, 2) to create new methods and tools that promote research participation, data collection, and interventions that link the clinic to the home and 3) to develop the multidisciplinary workforce needed to catalyze innovative science throughout populations. ICTS tackles large problems affecting translational science that require institutional solutions, such as transforming regulatory processes for human subjects research, developing an informatics infrastructure for integrating electronic medical record and other health care data, establishing bi-directional relationships with community organizations, and revitalizing the pipeline of well- trained clinical and translational researchers. Our overarching goal is to accelerate integration of research into clinical partnerships around the state and, through team science, bringing our basic, translational and clinical research workforce together to escalate the pace and breadth of scientific discovery to impact healthcare for the state and beyond. Iowa is a rural state, which brings special health care needs and challenges. We have used these rural considerations as a catalyst for driving our approach to clinical and translational research pushing our teams to develop strategies to engage rural populations of all ages and backgrounds and to create new approaches that overcome the geographic barriers in a rural state. We are capitalizing on our established community practice networks of family physicians, clinics, school nurses and pharmacists. We utilize mobile platforms in novel ways and will test the efficacy of these methods of engagement. As we move research to “IMpact Across Geographies using Innovation, Networks and Engagement- IMAG-INE” we have created methods to capture real-time, real-life data from the home and to correlate this environmentally specific, comprehensive data to human health research and outcomes. The ICTS is engaging with other CTSA hubs and national clinical and translational research systems to empirically test different approaches and to develop the evidence base of proven strategies for accelerating translation that can be more broadly disseminated. Though distance and rurality drive our approaches, the strategies that we develop are simply new and potentially better ways to generate broad representation and improved participation by patients, healthcare teams and academicians. Through our local, state and national collaborations, UI and the ICTS are poised to move clinical and translational discovery rapidly into healthcare practice in a variety of clinical settings.

NIH Research Projects · FY 2026 · 2023-04

PROJECT SUMMARY/ABSTRACT Mucus contacted medical devices, such as airway devices and eye prostheses, suffer from mucus accumulation. Plugged mucus causes bacterial infection, airway blockage, and a requirement of frequent device cleaning and replacement, which adds significant care burdens for the patient and support community. Current approaches to mitigate mucus accumulation involve strong mechanical forces or medications, thus having intrinsic limitations and side effects. Mucociliary transport (MCT), a process by which waves of beating cilia move a blanket of mucus, forms the first-line barrier against infection in respiratory and genital tracts. Inspired by the effectiveness of MCT in clearing mucus, the objective of this project is to develop an engineered surface that enables MCT function (i.e., an engineered surface of MCT). Our objective will be achieved through a combination of cilia fabrication, surface modification, and acoustic actuation with the following aims: fabricate engineered surfaces with polarized ciliary structures (Aim 1); understand mucus stickiness on engineered surface of MCT. (Aim 2); develop platforms to test acoustic actuated MCT on engineered surfaces in vitro and in vivo (Aim 3). The proposed research is rationally built on experimental feasibility, investigator expertise, and a supportive research environment. The feasibility is supported by experimental successes in polymer ciliary surfaces, slug and pig models of mucus, and vibration of microstructures with acoustic waves. The team of investigators have expertise in MCT, microfluidics, acoustics, 3D printing, and animal models. The proposed research will be conducted within the environment of the world- renowned Lung Physiology Research Center and Roy J. Carver Department of Biomedical Engineering at the University of Iowa, with broad availability of complementary expertise in biology and engineering. The expected outcomes of this project include revealing the mechanism of MCT on engineered surfaces and delivering an innovative medical device product incorporating an engineered surface of MCT.

NIH Research Projects · FY 2026 · 2023-03

Abstract: Primary open angle glaucoma (POAG) is a potentially blinding ocular disease that affects 60 million people world-wide. Reduction of IOP is currently the only glaucoma treatment, but fails to preserve vision in a significant fraction of patients, suggesting that other –currently untreated- factors contribute to the disease. Therefore, there is a critical need to identify these additional pathomechanisms to aid the development of new therapeutic approaches that directly support survival and function of retinal ganglion cells (RGC). Our recently published studies have demonstrated that adoptive transfer of T-cells from glaucomatous mice into normal recipients causes RGC loss in the recipients. We have also demonstrated that the absence of T- and B-cells profoundly protects RGC in a mouse glaucoma model. Preliminary data included in this application demonstrates that peripheral blood mononuclear cells (PBMC) of glaucoma patients contain a higher fraction of CD4 cells synthesizing TNFα and exhibit a higher activation state than those of controls. We further demonstrate that glaucoma PBMC have a heightened propensity to damage RGC in an ex vivo assay when compared to controls. Together, these findings strongly suggest that T-cell mediated damage is one of the mechanisms contributing to RGC loss in both animal models and in human patients. This project is designed with the long-term goal to determine whether modulation of immune responses provides vision saving benefits to glaucoma patients. The objective of this application is to establish which subtype of CD4 T-cells mediates damage in the glaucoma retina and to determine the functional significance of CD4 cell derived TNFα. To test our novel hypothesis we will employ a transgenic mouse model of myocilin-associated spontaneous glaucoma that we previously developed (Tg-MYOCY437H) containing an inducible Tnf knockout allele. We have also developed a novel in vitro assay allowing the quantitation of the cytotoxic activity of patient PBMC targeted toward RGC. Finally we propose to determine the activities T cells extravasated in the glaucoma retina, as well as those in lymph nodes and PBMC by establishing detailed gene transcription profiles. Experimental proof that CD4 T-cell mediated mechanisms contribute to vision loss in patients would establish new targets for the medical treatment of glaucoma. These in turn will pave a way for future clinical studies with the ultimate aim of preserving the sight and improving the quality of life of patients with primary open angle glaucoma.

NIH Research Projects · FY 2026 · 2023-03

The aim of this training program is to foster the development of medical students into physician- scientists that positively impact human health through rigorous investigation of pathways that can be exploited to treat or cure cardiovascular, pulmonary, hematology and sleep diseases. The Iowa Medical Student Research Program (IMSRP) achieves this transformative goal by leveraging institutional strengths in student recruitment and interdepartmental collaboration to create immersive mentored research opportunities. This training grant proposal seeks funding for 16 students to participate in a 12-week summer fellowship in a heart, lung, blood or sleep-related research project between their first two years of medical school. Students will work with one of the 66 enthusiastic and experienced mentors listed on our curated roster of Participating Faculty to draft and submit a proposal which is then expertly reviewed by two members of the College of Medicine’s research committee. Outstanding submissions with strong mentorship plans and a clear pathway to presentation and publication are selected by the Research Council for funding. The funds provided through this training grant would be matched by the Carver College of Medicine, amplifying the impact of the award. Program leadership will fully onboard students and monitor their progress closely. In synergy with extensive opportunities provided through relevant Centers and Institutes of excellence, scholars will receive Instruction in Methods for Enhancing Reproducibility and the Responsible Conduct of Research, as well as mentor-guided journal clubs and research seminars. The summer fellowship will be followed by a Medical Student Research Conference and surveys of all participants to allow ongoing program evolution. In the years that follow, students are strongly encouraged to enroll in the IMSRP’s research skills course, year- long research opportunities, the Research Distinction Track, and dual degree programs. We monitor students alongside their mentors as they continue their pathway towards a research career with incremental advancement through the continuity of support that is available at our institution, including funding during residency, fellowship, and junior faculty appointments. Challenging ourselves and our students to make meaningful change at every opportunity, we critically evaluate our program each year, and use a combination of formative feedback and self- reflection to enhance the breadth and depth of a program that is designed to fully expose students to the entire research process, from writing a proposal to analyzing data, presenting at local and national meetings, and ultimately disseminating the results in peer reviewed journals. The long-term impact of this program is the nationwide dissemination of a cadre of physicians, who developed an appreciation for team-based science early in their career, and are equipped to make discoveries and evidence-based decisions that will improve public health.

NIH Research Projects · FY 2026 · 2023-02

Abstract Lewy-Body dementias, including Parkinson’s disease Dementia and Dementia with Lewy Bodies, are devastating, multi-system diseases and a major cause of dementia worldwide. Patients have characteristic symptoms that suggest dysfunction of the frontal-network, including difficulty with planning, fluctuating attention and impaired flexible learning. The pathology of patients with dementia includes widespread aggregates of the protein alpha-synuclein (𝛼-syn) in the frontal cortex and other extra-nigral regions. Despite this association, the role of 𝛼-syn pathology beyond the dopaminergic system remains unclear. There is a critical need to understand how -syn affects network function to develop treatments for Lewy Body dementias. Our long-term goal is to develop treatments for Lewy Body Dementia by targeting circuit-level dysfunction. Our overall hypothesis is that local -syn aggregation in the cortex disrupts prefrontal circuits, leading to executive dysfunction. Testing this overall hypothesis requires determining the regional effect of 𝛼-syn on cellular activity and neuronal plasticity in isolation from deficits secondary to other major neurotransmitter systems that project to cortex. To accomplish this goal, this proposal uses viral overexpression of -syn localized to the prefrontal cortex. By imaging the activity of individual neurons and the plasticity of dendritic spines, we can learn how cortical cells respond to this enigmatic, disease-associated protein. We propose to use 2-photon transcranial microscopy to determine how neuronal activity (Aim 1) and synaptic plasticity (Aim 2) respond to regional overexpression of -syn over the course of aging. In Aim 3, we will use a rule-learning, reversal and rule- shifting tasks adapted for head-fixed applications to determine how prefrontal-dependent learning and flexibility respond to cortical -syn. In parallel, we will correlate cognitive performance with anatomical plasticity and neuronal activity. Findings from this proposed research will provide targets for future studies to restore cortical function and treat symptoms through circuit-level manipulation. In addition, by comparing outcomes across the three aims, we will be able to connect structural plasticity, neuronal activity and frontal-cognitive behavior to provide broad insights into the prefrontal cortex.

NIH Research Projects · FY 2026 · 2023-02

Project Summary A key aspect of stressor adaptation in humans and other mammals involves the selection of appropriate coping responses. The active coping response set allows for the maintenance of lower levels of glucocorticoid stress hormones and sympathetic activity, due in part to the actual or perceived agency over aversive stimuli, and when active responses are restricted, such as in the passive coping set, behavioral passivity increases and HPA and sympathetic responses are exaggerated. In this regard, elevations in HPA and autonomic systems resulting from over-biasing toward passive coping contribute to psychiatric and systemic disease pathogenesis. Our unpublished data using pathway-specific optogenetic circuit analyses have revealed that two parallel pathways from caudal and rostral prelimbic (cPL and rPL) cortex, innervating dorsolateral and ventrolateral subdivisions of periaqueductal gray (dlPAG and vlPAG), that promote active and prevent passive behaviors, respectively, in response to acute stressors. Based on these preliminary data, we will examine the hypotheses that one or both of these pathways are required to promote an active coping set, whereas their diminished influence under chronic stress conditions biases the animal toward a passive coping set. The first aim will determine how activity changes in PAG projector neurons in PL correlate with active and passive coping behavior following chronic stress compared to rats with no previous exposure. Aims 2 and 3 will utilize pathway specific optogenetic manipulations to evaluate whether inactivation of either cPL–dlPAG or rPL–vlPAG pathways under acute stress conditions increases passive behavior and exaggerated HPA and sympathetic activation. Conversely, we will evaluate whether increasing activity in either of these pathways in chronically stressed rats can rescue an active coping set involving increased active behavior, and attenuated HPA and sympathetic output. In the fourth aim, we will address the complementary relationship between each circuit’s function (i.e., cPL–dlPAG pathway promotes an active coping set; rPL–vlPAG pathway prevents a passive coping set), since these data implicate the predominance of one circuit over the other. Here, we will utilize an anterograde transsynaptic viral strategy to optogenetically test whether the cPL–dlPAG pathway engages vlPAG as a downstream mediator for restraining passive behavior and preventing exaggerated HPA and sympathetic activation under CVS conditions. These studies will advance a new framework for understanding the neural regulation of stress coping for translation to stress-related psychiatric diseases— by elucidating a novel circuitry and activity patterns of responses under acute and chronic conditions, and the expansion of the concepts of susceptibility and resilience to encompass behavioral, endocrine and physiological features.

NIH Research Projects · FY 2026 · 2023-02

PROJECT SUMMARY/ABSTRACT Staphylococcus aureus infections are a major global health problem and remain a significant health burden to society. In the U.S. alone it is estimated that over three-hundred thousand cases of hospital-associated S. aureus infections occur yearly at the cost of $2 billion. These infections also contribute to pneumonia, sepsis, infective endocarditis, osteomyelitis, and other diseases. S. aureus infections and associated diseases result from secreted virulence factors and the ability of the bacterium to survive in a wide range of environmental niches, including hypoxic conditions. Importantly, growth and virulence are regulated by two-component systems (TCS), which are composed of a membrane-bound sensor histidine kinase (HK) and a cytoplasmic response regulator protein. The kinase senses the extracellular environment, and under the appropriate stimuli transmits a signal across the cell membrane to induce phosphorylation of the response regulator, resulting in changes in gene expression. The staphylococcus respiratory response AB (SrrAB) TCS is activated under hypoxic conditions or in the presence of nitrosative stress and coordinates the regulation of virulence factors, fermentation enzymes, nitric oxide detoxifying enzymes and biofilm formation. In this proposal, the PI will pursue three aims designed to reveal the regulatory mechanisms of the SrrB sensor histidine kinase. The SrrB HK is a transmembrane protein that contains an N-terminal extracellular Cache domain and a cytoplasmic catalytic region (HAMP-PAS-DHpCA) containing a PAS domain. The first aim is to determine the role of the SrrB PAS domain and how binding to heme impacts SrrB function. The second aim will identify ligands that bind to the Cache domain and elucidate its sensing mechanism and role in virulence. The third aim will determine the structural basis for SrrB enzymatic regulation using X-ray crystallography, SAXS and cryogenic electron microscopy of full-length SrrB reconstituted in nanometer-scale lipid discs. Successful completion of these studies will provide the molecular mechanism(s) by which SrrB senses extracellular ligands and cellular redox to regulate catalytic function, and the biological consequences for disrupting this regulation. Our results will have important implications for the design of novel therapeutic strategies targeting the SrrAB TCS to combat antibiotic resistant S. aureus strains.

NIH Research Projects · FY 2026 · 2023-02

Two key transcription factors, homeodomain protein CRX and basic leucine zipper protein NRL, are at the center of gene regulation during photoreceptor differentiation and homeostasis. CRX is essential for specifying commitment of postmitotic photoreceptor precursors to the development of photoreceptor cells, whereas NRL determines the rod cell fate. In orchestrating the transcriptional program of photoreceptor development, CRX and NRL cooperate functionally and physically via a direct protein-protein interaction. Defects in photoreceptor transcriptional regulation due to mutations in the genes encoding CRX and NRL cause severe retinal diseases including retinitis pigmentosa, cone-rod dystrophy, and Leber congenital amaurosis. Despite our advanced understanding of the biology and transcriptional networks of CRX and NRL, mechanistic insight into the functions and unique synergy of these transcription factors at the atomic level is lacking. In the proposed studies, we seek to determine the crystal and solution structures of the individual DNA-bound complexes of CRX and NRL, as well as the structure of the ternary CRX/NRL/DNA complex. Although mutations in these TFs have been identified, they have not been mechanistically linked to regulation of key genes. The mechanistic predictions from the structures on how disease-causing mutations in CRX and NRL may alter DNA-binding specificity at cis-regulatory elements will be validated in the follow-up assays, including high- throughput approaches such as Spec-seq. These studies will enhance our knowledge of the functions of CRX and NRL, define the molecular nature of their synergy, and allow us to delineate specific mechanisms whereby mutant CRX and NRL proteins cause retinal diseases. We hypothesize that ultimately the structures of CRX and NRL complexed with their cis-regulatory elements will enable targeted design of therapeutics to treat visual disorders via modulation of transcriptional activities at specific promoters.

NIH Research Projects · FY 2026 · 2023-02

Project Summary/Abstract DNA damage is a serious threat to genome stability. This is because it interferes with DNA replication leading to mutations and chromosomal rearrangements – the hallmarks of cancer, aging, and other diseases. To ensure genome stability, cells utilize DNA damage bypass pathways to cope with DNA damage during replication. The long-term goal of our research program is to understand how DNA damage bypass is carried out in eukaryotic systems at the structural and mechanistic level. Our research will focus on two damage bypass pathways: translesion synthesis and template switching. Progress in this field has slowed recently because of the challenges associated with studying how the various bypass components assemble into and function within large, dynamic, multi-protein complexes. We have developed the biochemical, biological, biophysical, computational, and structural tools needed to overcome these challenges. This puts us in a unique position to answer many fundamental questions about damage bypass. Our future research plan is organized into three broad projects. First, we will study the regulation of DNA damage bypass. This will be done by determining how bypass complexes are assembled at stalled replication forks and by determining how this assembly is controlled by PCNA-ubiquitylating enzymes. Second, we will study the mechanisms of translesion synthesis. This will be done by determining how the most appropriate non-classical polymerase is chosen to bypass the damage and by determining how each non-classical polymerase accommodates damaged DNA templates. Third, we will study the mechanisms of template switching. This will be done by determining how the remodeling of the replication fork allows for the bypass of DNA damage and by determining how this process is carried out by fork-remodeling DNA helicases. In answering these questions, we will gain important new insights into the maintenance of genome stability.

NIH Research Projects · FY 2026 · 2023-02

Pulmonary morbidity and mortality are increasingly impacted by the environment. The harms disproportionately affect children, older people, the socioeconomically disadvantaged, and people with underlying lung disease. Although we have known this for some time, efforts to understand the pulmonary responses and injuries have been woefully inadequate. There are multiple explanations for why we have not made more progress, but one contributor is that we have not been training the next generation to tackle the consequences of the environment on lung health. Thus, our goal is to train students and postdoctoral fellows for cutting edge research in the effects of the environment on pulmonary health. We have outstanding leadership with complementary and synergistic skills: Dr. David Stoltz in the College of Medicine in basic and translational lung biology, and Dr. Peter Thorne in the College of Public Health in pulmonary toxicology and environmental epidemiology. We have creative and innovative mentors in several areas of emphasis: air pollution; allergens, airway biology, and environmental challenges; extreme weather/disasters; and lung infections. In addition to accepting post-doctoral fellows, we take a forward-looking approach by accepting predoctoral graduate students and offering a summer program for medical students. We strive to recruit, train, and retain a group of trainees who are prepared to tackle the effects of the environment on lung health. Our existing expertise, programs and interests position us exceedingly well for this direction, and our trainees will benefit from multidisciplinary research teams and programs including the Environmental Health Sciences Research Center, Iowa Superfund Research Program, Center for Emerging Infectious Diseases, and the Center for Global & Regional Environmental Research. Our program is focused on comprehensive training in research to understand and mitigate the impact of the environment on lung health via multiple modalities that include active mentored research, didactic courses, activities that enhance writing and presentation skills, community engagement, and endeavors that facilitate career development. We encourage collaboration, networking, and creative partnerships with multiple scientists, healthcare providers, and community members to advance solutions to the pulmonary harms of the environment. The program also benefits from the perspective and advice of an External Advisory Committee composed of world leaders in the health risks of the environment and lung biology.

NIH Research Projects · FY 2026 · 2023-02

Voltage-gated ion channels shape electrical signaling in the excitable cells of nerve and muscle. Sodium (NaV) and calcium channels (CaV) drive membrane depolarization and activate second messenger pathways via gated cellular entry of their namesake ions. In skeletal and cardiac cells, CaV channels trigger muscle contraction. Voltage-gated potassium channels (KV) allow the release of potassium ions from within the cell to drive membrane repolarization. In concert, these channels provide the molecular foundation for thought, perception, and contraction. High-resolution protein structures of human voltage-gated channels are now providing the first glimpses of the types of poses they may adopt in cellular environments. However, understanding the ultimate link between how these proteins look and how they support physiological mechanisms is a major challenge that will require innovative approaches. For one, transmembrane voltage is absent in a structural experiment thus depicting voltage-gated channels in an essentially non-physiological environment. We are therefore developing photochemical `stapling' approaches to covalently trap high-value protein conformations in live cell membranes prior to purification for structural determination. Further, we have begun to identify mechanisms of channel function by introducing modified chemistries at the peptide backbone in the transmembrane segments that form voltage-sensors and channel gates. In cellular settings, ion channels are also critical amplifiers of transduction pathways. During the fight-or-fight response, for instance, the near instantaneous phosphorylation of CaV1.2 channels results in faster and sustained channel opening, leading to a more forceful and rapid heart rate. Yet the absolute speed and complexity of the process is a challenge to experimentally parse individual molecular events that result in channel gating modifications. We describe newly validated methods that enable light controlled, site-specific phosphorylation, for the careful deconstruction and identification of key steps and players is this process. Lastly, CaV channels can be therapeutically inhibited to manage pain, epilepsy, arrythmia, high blood pressure, and alternatively, activated to treat heart failure. Surprisingly, both of these effects (channel activation and inactivation) can be elicited by medicines binding a common extracellular binding site on the channel. Conversely, unintended blockade of cardiac hERG potassium channels by otherwise useful therapeutics cause 90% of drug induced long-QT syndrome, a potentially lethal cardiac arrhythmia. All of these chemical binding events rely on aromatic rich binding sites formed by the side-chains of phenylalanine and tyrosine residues in CaV and hERG channels. To better understand these chemical interactions, we have developed a high-resolution method that allows for energetic and nuanced dissection of these aromatics within the CaV and KV drug binding aromatic boxes in the environment of mammalian cells. The successful execution of this research program will provide cutting edge training opportunities, advance the molecular understanding of channel gating, and will reveal the binding modes of clinical drugs with high therapeutic value.

NIH Research Projects · FY 2026 · 2023-01

PROJECT SUMMARY Despite currently available treatments, cardiovascular disease remains the leading cause of death in the United States. As dysregulated lipoprotein metabolism contribute to cardiovascular disease, there is a critical need to decipher the lipoprotein pathways, including those regulated by ANGPTL proteins, that drive cardiovascular pathologies. The long-term goal of the proposed research is to understand how ANGPTL proteins regulate lipid homeostasis and how these proteins become dysregulated in disease. One ANGPTL protein, the hepatokine ANGPTL3, inhibits both endothelial lipase (EL) and lipoprotein lipase, and thus regulates both plasma cholesterol and triglycerides. The objective in this application is to identify the mechanisms by which ANGPTL3 regulates EL and how this regulation affects HDL metabolism and cardiovascular disease. The central hypothesis of this study is that ANGPTL3 inhibits EL by promoting structural changes that disrupt its stability, and that this inhibition prevents the pathologic remodeling of HDL that contributes to atherosclerosis. This hypothesis will be tested by pursuing two specific aims: 1) Determine the effects of ANGPTL3-mediated EL inhibition on atherosclerosis and HDL function; and 2) Identify the mechanism by which ANGPTL3 inhibits EL. The studies in aim 1 use mice that express mutant ANGPTL3 alleles that only inhibit EL or LPL. These mice will be crossed with ApoE knockout mice to determine the respective contributions of ANGPTL3-mediated EL inhibition and LPL inhibition to atherosclerosis. These mice will also be used to determine the physiologic locations of EL inhibition using tissue phospholipase activity assays. Radioactive tracer experiments will be used to determine how inhibition of EL by ANGPTL3 alters HDL-lipid partitioning, and a variety of HDL functional assays will be used to determine how this inhibition alters the anti-atherogenic functions of HDL. In aim 2, various biochemical analyses, including phospholipase activity assays, site-directed mutagenesis, and hydrogen-deuterium exchange mass spectrometry, will be used to probe the functional interactions of ANGPTL3 with EL. The proposed studies are innovative in their use of ANGPTL3 alleles that only inhibit LPL or only inhibit EL to decouple the physiological effects of LPL and EL inhibition. The proposed studies are significant because lipoprotein homeostasis is essential for cardiovascular health. Therefore, uncovering how and where ANGPTL3 inhibits EL activity, and how this inhibition impacts HDL function, HDL metabolism, and the progression of atherosclerosis will increase our fundamental understanding of how lipoprotein metabolism is regulated. Completion of the aims outlined in this study will have a broad positive impact as lipoprotein metabolism contributes to many metabolic diseases, and thus understanding how the regulators of these pathways, including ANGPTL3, can best be therapeutically targeted may have wide-reaching implications for improved outcomes for these diseases.

NIH Research Projects · FY 2025 · 2023-01

PROJECT SUMMARY/ABSTRACT Alzheimer’s Disease (AD) is the most common cause of dementia in the elderly, and it is the sixth leading cause of death in the United States. AD currently cannot be prevented, cured, or even slowed, and it has a significant public health impact in terms of health care dollars and quality of life for those affected and their family members. Experimental models of ADRD have implicated the gut microbiome-bile acid-brain axis in the development and progression of ADRD. Neurotoxic environmental toxicants, such as polychlorinated biphenyls (PCBs), alter the function of the microbiome, resulting in an altered bile acid homeostasis; however, it is unknown if PCB-mediated changes in the gut microbiome-bile acid-brain axis play a role in the etiology of ADRD. Furthermore, epidemiological studies have major limitations assessing the complex effects of PCB exposure on the gut microbiome-bile acid-brain axis across the lifespan. Thus, there is a critical need to assess how human-relevant PCB mixtures alter the development and progression of ADRD-like phenotypes in experimental models of ADRD via the gut microbiome-bile acid-brain axis. The long-term goal of the transdisciplinary team assembled for this project is to characterize how environmental exposures contribute to ADRD and ultimately prevent ADRD through a precision environmental health paradigm. The translational objective is to demonstrate with a systems biology approach that exposure to a human-relevant PCBs mixture contributes to and accelerates the etiology of ADRD-type outcomes in vivo. The central hypothesis is that exposure to PCBs adversely affects the ADRD phenotype in rTg4510 and APP/PS1 mice, two experimental models of ADRD, by causing microbiome-mediated alterations in the bile acid homeostasis and affecting vascular function in a dose and exposure time-dependent manner. This hypothesis integrates strong preliminary data from the research team showing that PCBs are present in the human brain, affect the microbiome, alter bile acid homeostasis, and cause vascular dysfunction. The hypothesis will be tested using a systems biology approach by assessing how exposure to a human-relevant PCB mixture affects ADRD-related outcomes in experimental models of ADRD. The Specific Aims are to a) characterize effects of PCB exposure on gut microbiome composition and circulating bile acids; b) study the effects of PCB exposure on vascular function, and c) identify ADRD-type pathological changes and memory loss in the brain of PCB exposed rTg4510 or APP/PS1 mice. To ensure integration across all Aims, mediation analysis will be used to demonstrate that the microbiome and/or vascular dysfunction mediates the effects of PCBs on ADRD-type outcomes. These studies will demonstrate that PCB exposure leads to accelerated progression and more severe disease pathology in experimental ADRD models. Identifying PCBs as environmental risk factors that alter ADRD-related outcomes will lay the groundwork for mechanistic studies and inform translational studies for preventing ADRD mediated by environmental toxicants using a precision environmental health paradigm.

NIH Research Projects · FY 2026 · 2023-01

The future of Neuroscience must include a broad workforce to fuel the innovation required to meet current scientific and healthcare challenges facing neuroscientists. In response to RFA-NS-22-035, we propose a Doctoral Readiness training program – the Iowa Discovering Research And Mentorship (iDREAM) program. The iDREAM program leverages the power of (1) an outstanding Neuroscience Graduate Program with long-running T32 support (JSPTPN), and (2) a strong institutional unit, the Iowa Neuroscience Institute, which supports rigorous faculty mentoring development and will provide crucial administrative support for iDREAM. We have formed a compelling MPI leadership plan with a blend of experience, skills sets, and energy. We will train four iDREAM post-bac scholars per year, for two years each, drawn from a large pool of applicants from schools without substantial research opportunities. Our Neuroscience Graduate Program has a stellar track record of training future tenure-track faculty (>50%). iDREAM scholars will be introduced to Neuroscience research via high-quality, hands-on research experiences in the laboratories of carefully selected preceptors with steadfast commitments to the iDREAM mission. Scholars will receive rigorous training in the responsible conduct of research, evidence-based didactic training in the critical thinking and communication skills necessary for a successful research career, and programmatic experiences designed to cultivate a strong training environment within the local and global Neuroscience communities. iDREAM scholars will partner with grad students in the Neuroscience Program for near-peer mentorship experiences. Faculty research mentors are 28 well-funded neuroscientists with strong mentorship training and experience. The mentors will be matched with trainees through a guided interview process with careful oversight from the MPIs and Executive Committee. iDREAM scholars will attend career development workshops, weekly scientific seminars and laboratory meetings, and present their research at multiple local and one national meeting per year. iDREAM scholars will also be guided through all aspects of the graduate school application process. Long term goals of the program include: 1) empowering post-bac trainees to be competitive at rigorous, top-tier graduate programs in Neuroscience (including at Iowa) and to lead successful scientific careers; 2) catalyzing progress of enhancing excellence within the Neuroscience community at Iowa and beyond; and 3) reinforcing and strengthening existing partnerships between the Neuroscience community at Iowa and schools without substantial research opportunities. Metrics of success include the number of participants who apply for and are accepted in a rigorous neuroscience graduate program, and students reported outcomes in the Neuroscience community.

NIH Research Projects · FY 2026 · 2023-01

Project Summary Periodontitis, which results in irreversible damage in hard and soft tooth-supporting tissues, affects 42% US adults. This extremely prevalent inflammatory oral disease is also tightly associated with systemic diseases such as diabetes. Clinical studies have shown that periodontitis contains mixed disease phenotypes. For example, the disease progression pattern in about 20% of periodontitis patients is clearly distinct from that of the majority in a population. Recently, we used a data-driven approach to create a periodontal profile classification (PPC)-Staging system by integrating periodontal measurements and indices from a closely followed up community cohort. After validation, we demonstrated that this new PPC-Staging tool has drastically improved clinical associations with several systemic diseases including diabetes, stroke, and coronary heart disease due to the improved homogeneity of each PPC-Stage (I to VII). Through a proteomic biomarker analysis in the gingival crevicular fluid of a patient pool from the cohort, we found that the expression pattern of the interferon-β (IFN-β) cytokine, a classical member of type I interferon (IFN-I), in PPC-Stages mimics that of interleukin-1 receptor antagonist (IL-1RA), a well-described classical anti-inflammatory cytokine. This novel finding prompted us to evaluate the role of IFN-I in periodontitis. Using a mouse periodontitis model, we found that IFN-I plays a protective role in alveolar bone loss. We further found that such a protective role of IFN-I is associated with a dampening of an interleukin (IL)-17-neutropphil axis, while the transcription of Il27 in local gingiva was upregulated. The role of IL-27 in an integral IFN-I pathway has yet remained to be elucidated in periodontitis. We further showed that IFN-β signaling suppressed the lipopolysaccharide-induced proinflammatory cytokine production in and potently inhibited osteoclast differentiation from bone marrow- derived monocytes. We therefore hypothesize that an integral IFN-I response in monocytic lineage plays a protective role in periodontitis by deactivating an IL-17-neurophil axis through an IL-27 pathway. We seek to gain insight into the mechanism of IFN-I in modulating innate and adaptive immune responses in periodontal disease. We propose to test this central hypothesis by the following approaches: 1) we will first define the role of Type I IFN- IL-27 pathway in IL-17-neutrophil axis using the animal periodontitis model; 2) we will then assess the specific role of IFN-I signaling in myeloid lineage that contains monocytic /osteoclast precursor cells in the periodontitis model; 3) we will also evaluate the effect of a locally delivered novel nanoparticle-mediated sustained release of IFN-β/IFN-I stimulator in the periodontitis model. Our goal of this project is to advance the understanding of INF-I, a clinically relevant yet under-investigated molecule, in periodontal disease, and to leverage IFN-β or IFN-I-centered inflammatory networks as biomarkers to further refine the clinical periodontal disease classification. In addition, this research proposal will provide evidence to target IFN-Is as an adjunctive therapeutic measure in a subset of patients to improve precision periodontal health.

NIH Research Projects · FY 2026 · 2022-12

Abstract The voltage-gated sodium channel NaV1.5 controls cardiac excitability and is an established therapeutic target. Mutations in the SCN5A gene, which encodes NaV1.5, are associated with inherited arrhythmia syndromes (long QT syndrome, Brugada syndrome, congenital heart block) and dilated cardiomyopathy. While gain of function mutations that disrupt NaV1.5 inactivation explain action potential duration (APD) and QTc prolongation, the mechanisms by which loss of function NaV1.5 mutations cause the other diverse pathogenic outcomes are unresolved. The physiological significance of other Na+ channel genes expressed in the heart are also uncertain. Rodent models with gene-targeted Scn5a mutations can recapitulate some clinical features of disease, but their use is complicated by compensatory mechanisms that may occur early in development. In addition, the available pharmacological blockers of NaV1.5 block brain Na+ channels and other potential cardiac Na+ channels with equal or greater potency, limiting their utility. In order to advance our understanding of NaV1.5-related biology, we have developed a chemical-genetic model to achieve acute and reversible silencing of NaV1.5 in situ. We engineered a NaV1.5 channel that contains a high-affinity, isoform-specific binding site for acylsulfonamide (GX) drugs, enabling chemical strategies to pharmacologically drive nonconducting channel conformations. The NaV1.5-GX channel has WT voltage-dependent gating and, unlike WT NaV1.5 and most other putative cardiac Na+ channels, is blocked by nanomolar concentrations of GX compounds. We have used CRISPR gene-editing to replace the endogenous Scn5a locus with the GX binding site in mice, creating a novel NaV1.5GX strain. Homozygous NaV1.5GX/GX mice have normal cardiac phenotypes, yet the acute application of nanomolar GX compounds to NaV1.5GX/GX isolated cardiac myocytes ablates Na+ current (INa). Systemic drug application in vivo results in conduction slowing in NaV1.5GX/WT mice, and conduction block and sudden death in NaV1.5GX/GX mice, thus providing a facile means to study NaV1.5 function and SCN5A-mediated disease. We propose first to examine the effects of acute Nav1.5 blockade by GX compounds on gene expression, Ca2+ handling, ROS production, fibrosis, cardiac function and arrythmias will be studied using NaV1.5GX/WT and NaV1.5GX/GX cardiac myocytes and mice, and compared to chronic Nav1.5 blockade using Scn5a+/- heterozygous knockout mice. We will then identify the effects of Na+ channel blockade on structural and electrophysiological remodeling, and on arrhythmia susceptibility following Transverse Aortic Constriction (TAC). Lastly, we will develop in vivo and ex vivo platforms to study SCN5A mutations identified in patients. The Scn5aGX mouse presents a unique opportunity to examine the phenotypes of human SCN5A mutations in a cardiac environment. In total, we anticipate these efforts will reveal novel molecular mechanisms of genotype-phenotype coupling stemming from SCN5A's role in controlling cardiac excitability.

NIH Research Projects · FY 2026 · 2022-12

Project Summary / Abstract Hypertension affects one billion people and is a principal reversible risk factor for cardiovascular disease. Obesity which has become common in the US and throughout the world is a major cause of hypertension, but the mechanisms underlying the relationship between obesity and hypertension remain largely unknown. The goal of this proposal is to identify the neuronal and molecular processes that control blood pressure and how dysregulation in these processes contribute to obesity-associated cardiovascular risks. This proposal is based on the hypothesis that obesity-induced elevation in the hormone fibroblast growth factor 21 (FGF21) promotes hypertension by activating ventromedial hypothalamic neurons expressing steroidogenic factor 1 (SF1) to increase sympathetic nerve activity. We will use a multidisciplinary strategy combining cutting edge neuro- technologies to precisely and remotely modulate or monitor the activity of SF1 neurons in freely moving animals with unique genetically engineered mouse models that permit selective modulation of FGF21 signaling in SF1 neurons and sophisticated integrative physiology for sympathetic and cardiovascular phenotyping. We plan to test our central hypothesis by determining how chemogenetic- or optogenetic-mediated activation or inhibition of SF1 neuron activity affects sympathetic outflow and arterial pressure under normal conditions as well as in obesity. We will also explore the contribution of FGF21 signaling in ventromedial hypothalamus including SF1 neurons to sympathetic and arterial pressure control and obesity-associated hypertension and sympathetic nerve activation. This work should unravel novel mechanisms that underlie obesity-associated sympathetic activation and hypertension, making our work of high clinical relevance. Insights into the cellular and molecular processes that control the sympathetic tone that regulates cardiovascular function may make it possible to selectively interfere with the damage obesity inflicts on cardiovascular sympathetic functions.

NIH Research Projects · FY 2025 · 2022-12

Project Summary The University of Iowa (UIowa) is poised to advance the field of cerebroprotection in patients with acute ischemic stroke by remaining as a site for the NIH Stroke Preclinical Assessment Network (SPAN)’s translational research infrastructure to efficiently conduct rigorous and innovative comparative studies of cerebroprotection in the context of reperfusion. UIowa-SPAN has consistently followed a rigorous, clinical trial-like approach to avoid the methodological mistakes of past cerebroprotection research. Specifically, we use randomization, blinded intervention, independent outcome adjudications, and intention-to-treat analyses to interpret and report our animal studies. We also address the effect of sex and comorbidities to increase the translational value of our research. UIowa-SPAN brings together a team of basic and translational scientists that integrates technical expertise with logistics. This has resulted in the top performance during the first iteration of SPAN, consistently leading the enrollment efficiency of the network while producing the highest quality data based on the metrics. We aim to maintain or exceed this performance if selected as a site in the new iteration of the network. Notably, the goals of UIowa-SPAN are aligned with those of UIowa’s regional coordinating center for StrokeNet, a NIH clinical trial network with the mission of identifying and testing promising stroke therapies. We are also proposing innovations to multiple aspects of the SPAN, including minimizing overall data variability, technical improvements in the embolic clot rodent model, and improvements to the internal validity of the current outcome measures, using artificial intelligence to interpret corner tests and alternative computation methods for the grid walk test. Our goal is to rigorously and efficiently identify which cerebroprotective interventions are likely to succeed in clinical trials in order to improve the outcomes of the 800,000 Americans who suffer a stroke and are currently treated with reperfusion strategies that have limited effectiveness.