University Of Iowa

NIH Research Projects · FY 2025 · 2016-07

SUMMARY Hearing loss affects 1 in 500 newborns and ~1 in 3 individuals over the age of 65. This disorder is often caused by the loss of mechanosensory hair cells (HCs), a deficiency that is permanent in the mature mammalian cochlea. Therefore, artificial approaches have been developed to regenerate HCs by `converting' non-HCs into HCs; and in mice they have proven successful in generating HC-like cells. However, these cells fail to mature fully and their lifespan is short, indicating that not all major barriers to HC regeneration have been overcome. The HC-regenerating approaches have been based on studies of physiological HC development. These have shown that the transcription factor `Atonal homolog 1' (ATOH1) is fundamental for HC development but that its effects on gene expression are context dependent. These effects differ in HCs versus other ATOH1-expressing cells. Thus, ATOH1 function is fine-tuned by other transcription factors. Harnessing the full potential of ATOH1 for the regeneration of HCs will require the identification of novel modifiers of ATOH1 activity in HCs. Our preliminary data suggest that ATOH1 activity and HC maturation are regulated by the transcription factor `thymocyte selection‐associated HMG box protein' (TOX). Knockout of the Tox gene in mice (Tox∆/∆) caused HC loss and deafness, and RNA-seq analysis of the organ of Corti in these mice revealed that a variety of genes are expressed at abnormal levels. The `abnormally low expression' group includes ATOH1 target genes, `RE1-silencing transcription factor' (REST) target genes, and the transcriptional repressor-encoding gene castor zinc finger 1 (Casz1). Targeted mutagenesis of Casz1 in organ of Corti cultures revealed that CASZ1 is needed for the repression of several genes that are expressed at abnormally high levels in the Tox∆/∆ organ of Corti. Our preliminary characterization of conditional Casz1 knock-out mice revealed that HC-specific deletion of Casz1 causes outer HC (OHC) degeneration and hearing loss. In addition, our previous analyses of REST function showed that perinatal downregulation of REST activity is needed for HC maturation. The objective of the proposed research is to define the role of TOX in the maturation of HCs. Our central hypothesis is that TOX supports cochlear HC maturation by modulating ATOH1, REST, and CASZ1 activities in developing HCs. We propose to test this hypothesis through 2 specific aims: Aim 1) determine the effects of TOX on HC maturation during various phases of cochlear development, and the extent to which it supports ATOH1 activity, REST regulation, and artificially induced production of HC-like cells; Aim 2) determine the effects of CASZ1 on HC morphology and cochlear gene expression, and identify gene repressor complexes that mediate the CASZ1-dependent repression of some of the indirect target genes of TOX in HCs. These aims will be achieved using a variety of methods ranging from RNA-seq to somatic cell genome-editing. The proposed studies are significant because identification of novel modifiers of ATOH1 activity will be necessary for improving the rational design of HC-regenerating approaches.

NIH Research Projects · FY 2026 · 2016-06

PROJECT SUMMARY Plasmodium infections and the disease malaria remain global health emergencies. Plasmodium parasites replicate within and cause the destruction of host red blood cells, which triggers inflammation and causes the symptoms of malarial disease. Parasite-specific antibody responses that develop following infection are critical for controlling parasite burden and limiting disease severity. CD4+ helper T cells are essential for coordinating these protective antibody responses. However, sterilizing anti-Plasmodium immunity rarely develops, even following repeated infection. We hypothesize this is due to deficient Plasmodium-specific effector and memory CD4+ T cell development and function. One of the most critical challenges to developing new immune-based therapies or vaccines against Plasmodium is understanding the mechanisms by which long-lived Plasmodium- specific memory CD4+ T cells develop, function and persist following infection. In the continuation of this project, we apply powerful new cellular and molecular genetic approaches that enable direct, high-resolution analyses of Plasmodium-specific memory CD4+ T cells. These new approaches facilitate our long-term goal to understand the mechanisms governing the development and function of Plasmodium-specific memory CD4+ T cell responses. Our goal is addressed by three specific aims that have evolved to test: 1) how hemozoin, a parasite-derived product of hemoglobin degradation, influences the induction and maintenance of Plasmodium-specific memory CD4+ T cell populations; 2) how constraints on host cellular metabolism shape memory CD4+ T cell formation and function; and 3) how specific epigenetic regulators govern the differentiation and function of CD4+ memory T cells. Our innovative conceptual and technical advances and mechanistic approaches enable us to establish additional new paradigms for understanding and enhancing CD4+ T cell-dependent anti-Plasmodium immunity. Understanding immune memory formation following Plasmodium infection will enable us to identify and develop new immune-based strategies to limit Plasmodium pathogenesis and disease burden.

NIH Research Projects · FY 2025 · 2015-09

PROJECT SUMMARY Pediatric acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP) are rare, but highly burdensome diseases without a cure. ARP progresses to CP complicated by pain, exocrine pancreatic insufficiency (EPI), and diabetes mellitus (DM). Few studies have been performed to characterize the natural history pediatric ARP and CP, to identify its risk factors and to determine predictors of disease course. Most of our current understanding comes from INSPPIRE (INternational Study Group of Pediatric Pancreatitis: In search for a cuRE, PIs: Aliye Uc and Mark Lowe), the first and largest multicenter, multidisciplinary collaboration to carefully phenotype children with ARP and CP, collect longitudinal data and create a network of pediatric centers ready to perform clinical trials. Through INSPPIRE, we have determined for the first time that, contrary to adults with environmental risk factors, genetic or anatomic factors drive the disease in children, with frequent abdominal pain, hospitalizations, emergency room visits missed school days, surgical and endoscopic interventions, costing significant burden to children, families and US health care. Despite this progress, no effective interventions to prevent end-organ failure and complications of CP exist because gaps remain in understanding the determinants and biomarkers for disease progression in pediatric CP. This competitive renewal application is responsive to the objectives of the U01 RFA DK-25-019 to define the profiles of disease progression in pediatric CP through careful longitudinal analysis of the INSPPIRE-2 cohort including innovative approaches to prospectively follow children with ARP and CP into adulthood, to identify diagnostic and prognostic non-invasive biomarkers involved in disease progression, to propose clinical trials to address the underlying causes, improve pain and health related quality of life (HRQOL) and to evaluate treatment response. Our specific aims are: 1) Define the natural history of pediatric ARP and CP and identify variables that drive outcomes.; 2) Develop non- invasive biomarkers of disease progression in pediatric CP; 3) Improve outcomes of childhood CP by addressing drivers of progression. This renewal application will define the natural history of pediatric CP, investigate the impact of risk factors on disease course, study non-invasive biomarkers on disease development and propose two innovative clinical trials of drug repurposing based on novel and exciting preliminary data.

NIH Research Projects · FY 2026 · 2014-08

ABSTRACT Age-related macular degeneration (AMD) is a major cause of blindness worldwide that is characterized by pathologic changes at the retinal pigment epithelium-choriocapillaris interface. We recently found that loss of endothelial cells of the choriocapillaris is related to the earliest clinical signs of AMD, and that a reduced vascular density and increased number of “ghost” vessels are related to the size and number of drusen and other sub-RPE deposits. Compelling evidence suggest that activation of the terminal complement pathway and formation of the membrane attack complex (MAC) at the level of the choriocapillaris is a likely cause of vascular loss and AMD pathogenesis. In this proposal we seek to identify the molecular and cellular responses of choroidal endothelial cells to MAC assembly; to determine what makes choroidal endothelial cells susceptible to MAC attack; and to determine if donor cell CFH genotype has an impact on integrative capacity, function and longevity of iPSC-derived choroidal endothelial cells following transplantation. We anticipate that completion of the aims outlined in this application will result in an important new understanding of disease pathophysiology, which will allow us to further develop treatments focused on protecting and replacing damaged blood vessels in AMD.

NIH Research Projects · FY 2025 · 2013-07

This competitive renewal application proposes to continue our program to provide comprehensive, integrated training in dental and craniofacial research at the University of Iowa (UI) to a cohort of basic, clinical, and translational researchers and dental scholars. It will provide dentists and non-dentists with a comprehensive skillset to meet the challenges of oral health research in academia for the 21st century. Outstanding interdisciplinary didactic training and rigorous research mentoring will emphasize ongoing review and critique. The proposed program builds on 37 years of research training success, with several major enhancements listed briefly below. The program addresses 7 major research training areas: 1) Craniofacial, Oral Biology, Genetics, and Dental Development; 2) Bioengineering, Tissue Engineering, Stem Cells, Biomaterials, and Materials; 3) Immunology, Inflammation, Microbiology, Caries, and Microbiome; 4) Oral Cancer; 5) Public Health, Epidemiology, and Behavioral Sciences; 6) Oral Health Policy; and 7) Clinical, Translational, and Big Data Research, reflecting the strengths of the College of Dentistry, UI health science colleges, and collaborative institutes and centers. Trainees in the proposed program will pursue a PhD in Oral Science (or in one of the 13 other affiliated PhD programs) or a post-doctoral fellowship. In addition, trainees now will be able to obtain a Graduate Certificate in College Teaching, Biostatistics, or Translational and Clinical Investigation or an MS in Dental Public Health. The T90 will support 4 non-dentist predocs and 2 dentists for the PhD (3 years each) and 1 non-dentist postdoc (2 years). The R90 component reflects the importance international dentists have in U.S. oral health research programs and will support 2 dentists for the PhD (3 years each). A group of 28 experienced program faculty from a variety of disciplines is available to mentor trainees. The success of our program over the past 4+ years is seen in 5 trainees receiving F- or Kawards since 2019 and trainees’ successful career placement. To build on this success, we propose several improvements/new major components of this Institutional Training Program. The successful Grant-Writing Workshop Series has been updated and enhanced. Additionally, we propose several new programs, including ones in Research Rigor, Research Leadership Development, and Interdisciplinary Faculty Mentoring. Training will be supervised by the experienced Director and Associate Director and implemented in concert with a Faculty Leadership Team. Future participant selection will be made solely on the basis of merit. Several committees will support the program: internal and external advisory committees, and other componentspecific committees. In summary, the program brings together productive, well-funded mentors with pre- and post-doctoral trainees in an environment with a strong institutional commitment, outstanding interdisciplinary research training in relevant disciplines, and excellent educational and research facilities. The outcome will be a cadre of oral health researchers ready to function at the cutting edge of their disciplines.

NIH Research Projects · FY 2025 · 2013-07

This competitive renewal application proposes to continue our program to provide comprehensive, integrated training in dental and craniofacial research at the University of Iowa (UI) to a cohort of basic, clinical, and translational researchers and dental scholars. It will provide dentists and non-dentists with a comprehensive skillset to meet the challenges of oral health research in academia for the 21st century. Outstanding interdisciplinary didactic training and rigorous research mentoring will emphasize ongoing review and critique. The proposed program builds on 37 years of research training success, with several major enhancements listed briefly below. The program addresses 7 major research training areas: 1) Craniofacial, Oral Biology, Genetics, and Dental Development; 2) Bioengineering, Tissue Engineering, Stem Cells, Biomaterials, and Materials; 3) Immunology, Inflammation, Microbiology, Caries, and Microbiome; 4) Oral Cancer; 5) Public Health, Epidemiology, and Behavioral Sciences; 6) Oral Health Policy; and 7) Clinical, Translational, and Big Data Research, reflecting the strengths of the College of Dentistry, UI health science colleges, and collaborative institutes and centers. Trainees in the proposed program will pursue a PhD in Oral Science (or in one of the 13 other affiliated PhD programs) or a post-doctoral fellowship. In addition, trainees now will be able to obtain a Graduate Certificate in College Teaching, Biostatistics, or Translational and Clinical Investigation or an MS in Dental Public Health. The T90 will support 4 non-dentist predocs and 2 dentists for the PhD (3 years each) and 1 non-dentist postdoc (2 years). The R90 component reflects the importance international dentists have in U.S. oral health research programs and will support 2 dentists for the PhD (3 years each). A group of 28 experienced program faculty from a variety of disciplines is available to mentor trainees. The success of our program over the past 4+ years is seen in 5 trainees receiving F- or Kawards since 2019 and trainees’ successful career placement. To build on this success, we propose several improvements/new major components of this Institutional Training Program. The successful Grant-Writing Workshop Series has been updated and enhanced. Additionally, we propose several new programs, including ones in Research Rigor, Research Leadership Development, and Interdisciplinary Faculty Mentoring. Training will be supervised by the experienced Director and Associate Director and implemented in concert with a Faculty Leadership Team. Future participant selection will be made solely on the basis of merit. Several committees will support the program: internal and external advisory committees, and other componentspecific committees. In summary, the program brings together productive, well-funded mentors with pre- and post-doctoral trainees in an environment with a strong institutional commitment, outstanding interdisciplinary research training in relevant disciplines, and excellent educational and research facilities. The outcome will be a cadre of oral health researchers ready to function at the cutting edge of their disciplines.

NIH Research Projects · FY 2025 · 2013-03

Project Summary Cochlear implant (CI) electrode arrays are made of platinum wires and contacts encased in a silastic housing. These materials provide mechanical stability and flexibility critical to the long-term function of the CI. However, they also induce local tissue reactions that can have detrimental effects. For example, trauma from insertion of the CI can damage cochlear health and any residual acoustic hearing. Further, the fibrotic capsule that encases CI electrode arrays leads to increased impedances and decreased signal resolution which reduce CI effectiveness. Intracochlear fibrosis is also implicated in the loss of acoustic hearing that can occur months to years after implantation. Thus, developing materials that mitigate insertion trauma and the inflammatory, fibrous response to CI materials could significantly improve device function and safety. Ultra-low fouling zwitterionic polymers are a new class of materials that show significant promise to eliminate fibrosis. However as bulk materials they lack mechanical properties and long term durability suitable for use in CIs. To leverage the ultra-low fouling surface properties of zwitterionic polymers while maintaining the proven mechanical properties of current CI materials, we recently established a novel, patented photochemical process for simultaneous polymerization, grafting and cross-linking of zwitterionic thin films on relevant CI materials. We now leverage the mechanical advantages of recently developed dual network polymer technology to enhance the strength of the thin films. We also use the thin films as novel drug delivery platforms with controlled and sustained kinetics. We hypothesize that robust dual network, zwitterionic thin film coatings will maintain long- term anti-fouling properties; reduce friction, insertion trauma, and intracochlear fibrosis; and provide controlled sustained release of glucocorticoids. Accordingly, in Aim 1 we engineer robust, dual network zwitterionic thin films for ultra-low fouling CI biomaterial coatings. Aim 2 investigates the effect of dual network, zwitterionic thin film hydrogel CI coatings on tissue friction, insertion forces, cochlear trauma, and fibrosis using human cadaver and sheep models. Finally, Aim 3 develops zwitterionic thin film hydrogel coatings with controllable, sustained glucocorticoid delivery systems to reduce intracochlear inflammation and fibrosis in reporter mouse CI models. Development of robust zwitterionic thin film coatings on implanted biomaterials that are lubricious, ultra-low fouling, and capable of controlled and sustained drug delivery represents a transformative advance to prevent trauma, reduce fibrosis, and improve the functional outcomes associated with placement of medical devices, such as CIs, in the body.

NIH Research Projects · FY 2025 · 2012-06

PROJECT SUMMARY Brain diseases such as Alzheimer's disease, glioma, Parkinson's disease, epilepsy, stroke and amyotrophic lateral sclerosis devastate the lives of millions of patients and their families. Despite decades of research costing billions of dollars, these and other brain diseases still lack accurate diagnostic tools, effective disease- modifying therapies, adequate symptomatic managements, or even well-defined mechanistic causes. These failures stand out particularly in light of incredible advances in basic scientific knowledge. Thus, there is a critical need for clinicians to be involved in basic research on human brain disease since they are well suited to identify new approaches. The University of Iowa Clinical Neuroscientist Training Program (CNS-TP) is designed as an efficient pathway to train outstanding neurology, neurosurgery and neuropathology residents in basic research, with the goal of increasing the percentage of trainees who continue in a long career as productive clinician-scientists.

NIH Research Projects · FY 2026 · 2011-09

Project Summary Hearing loss is the most common sensory deficit in humans. It affects more than 360 million people worldwide and broadly impacts their quality of life. Although causality is multifactorial, in developed countries a large fraction of hearing loss is genetic and non-syndromic, i.e. not associated with other phenotypes. During the prior granting period (12/01/16-11/20/21), we focused on three specific aims: 1) To optimize phenotype-genotype integration in the analysis of hereditary hearing loss by implementing hierarchical surface clustering and audioprofile surface analysis in AudioGene; 2) To explore physics-based protein modeling as a tool within the Deafness Variation Database; and 3) To determine whether genetic modifiers of specific deafness-causing genes can be predicted by hierarchical surface clustering In this competitive renewal, our overarching goals are to further improve the clinical care of persons with hearing loss and to provide a more robust foundation for gene-specific precision medicine for this population. We will achieve these goals by addressing current knowledge gaps as reflected in the following specific aims:  Specific Aim 1. To complete gene-specific natural history studies (NHS) of non-syndromic forms of hearing loss by integrating phenotypic and genotypic data using AudioGene and OtoSCOPE Hypothesis: The natural history of non-syndromic hearing loss is gene specific and can be defined by integrating the hearing loss phenotype (phenome) with the associated genotype (genome) for the various types of non-syndromic hearing loss.  Specific Aim 2. To refine ACMG guidelines for hearing loss by making them gene specific and by implementing a combination of deep learning and physics-based protein modeling to improve variant classification Hypothesis: While general guidelines exist for variant classification, guidelines that are disease- specific and even within a disease, gene specific, will facilitate variant annotation. In particular, variant calling for missense variants can be refined by applying deep learning and physics-based modeling to predict free-energy changes associated with missense variants.  Specific Aim 3. To identify genetic modifiers of select types of non-syndromic hearing loss Hypothesis: The presence of genetic modifiers is supported by gene-specific differences in ethnically- based population studies and can be validated using murine models of hearing loss. The successful completion of these specific aims will refine our understanding of the biology of hearing and deafness, improve the clinical care of persons with hearing loss, provide a strong foundation for gene- based precision medicine for the hearing impaired, facilitate the design of clinical trials to test novel therapies to treat gene-specific types of hearing loss, and potentially identify new targets for gene therapy for deafness.

NIH Research Projects · FY 2025 · 2011-02

Type 2 diabetes (T2D) is the major health problem in the US that imposes significant physical, financial, and emotional tolls. Thus, there is a strong and urgent need for an effective and widely applicable therapy. Excessive accumulation of lipids in beta cells is considered to contribute to the development of T2D. At the same time, lipids supports insulin secretion. We aim to understand how an intracellular organelle termed lipid droplets (LDs) in beta cells regulate a double-edged sword action of lipids. Our work to date has shown that lipid droplet protein perilipin 2 and 5 (PLIN2 and 5) each has a unique role in beta cells to support insulin secretion and protects beta cells from nutritional stress. PLIN5 interacts with adipose triglycerides lipase (ATGL) and supports insulin secretion. PLIN2 sequestrates lipids as an inert pool and protects beta cells from lipid overload. However, beta cells cannot continue to accumulate lipids indefinitely. Thus, a pathway of LD clearance is important to maintain beta cell health under nutritional stress. Lipophagy is self-digestion of LDs at lysosome and known to play a role in LD clearance in a wide range of cells. Importantly, dysregulation of lipophagy has been associated with obese adipocytes and fatty liver. However, little is known regarding a role of lipophagy in beta cells. Our preliminary data showed that lipophagy is constitutively active in beta cells without nutrient deprivation. Interestingly, chronic suppression of LIPA in INS1 cells, rat islets, and human non- diabetic islets impairs insulin secretion. Therefore, we hypothesize that lysosomal degradation of LDs is critical for LD homeostasis and insulin secretion in beta cells, and that the impairment in lipophagy accelerates beta cell demise in T2D. The following three aims will test our hypothesis. Specific Aim 1: Determine how LIPA regulates LD catabolism and lipid metabolism in beta cells under regular and glucolipotoxic conditions: Our preliminary data indicates that LIPA and ATGL each has a distinct role in mobilization of LDs in beta cells. We will clarify how LIPA and ATGL confer the spatial and temporal regulation of lipid metabolism at LDs using beta cells in which LIPA and ATGL are down-regulated. Specific Aim 2: Determine a role of LIPA in the maintenance of beta cell function and health: Our preliminary data indicates that prolonged suppression of lipophagy negatively affects insulin secretion. We will address how LIPA deficiency affect beta cell health and function at regular and glucolipotoxic conditions. Specific Aim 3: Determine whether lipophagy dysfunction contributes to beta cell failure in T2D. It has been proposed that lysosome becomes dysfunctional in beta cells during the development of T2D. This could create functional deficiency of LIPA that requires the acidity of lysosome. In addition, nutritional stress may increase demand for clearance of LDs by lipophagy during the development of T2D. Here, we will test the relationship between nutritional stress and lipophagy in beta cells using in vitro and in vivo models. We will learn whether impaired lipophagy contributes to beta cell demise in T2D.

NIH Research Projects · FY 2025 · 2011-02

Project Summary Clostridioides (Clostridium) difficile causes nearly 500,000 infections a year in the United States, leading to nearly 30,000 deaths. The CDC has declared C. difficile an “urgent” threat to public health, the highest threat category. New treatments are sorely needed. Many of our most useful antibiotics target the cell envelope. However, little is known about cell envelope biogenesis or cell envelope stress response in C. difficile. These cell envelope stress response systems may play an important role in antibiotic resistance. By understanding how C. difficile responds to cell envelope stress we may uncover better treatment options for C. difficile infections. Surotomycin, a daptomycin derivative, which targets peptidoglycan synthesis showed promise as a potential treatment for C. difficile. However, conflicting phase 3 clinical trials have halted development of surotomycin as a treatment for C. difficile infections. We used multiple genetic approaches to identify key factors involved in daptomycin resistance. By isolating spontaneous daptomycin resistant mutants and performing Tn-seq we identified two different two component regulatory systems, DraRS and DapRS, that are involved in daptomycin resistance. We will pursue three specific aims to dissect the role of these regulators in controlling daptomycin resistance and cell envelope stress response. In Aim 1 we will define how the DraRS regulatory system contributes to antibiotic resistance. We will test both gain-of-function and loss-of-function draRS mutants for their effect on resistance to a number of cell envelope stresses and on cell envelope biogenesis. We will also define the DraR regulon and determine the contribution of individual genes to antibiotic resistance and cell envelope biogenesis and stress response. In Aim 2 we will dissect how activity of DraR is controlled in response to cell envelope stress. Our preliminary data suggest DraRS is activated by antibiotics disrupt the lipid-II cycle. We will use CRISPRi to test this model by genetically recapitulating the effects of antibiotics and determining the effect on DraR activation. We will also isolate mutants of DraS that are unable to respond to cell envelope stress. In Aim 3 we will define the role of DapRS and the DapRS-regulated genes hexSDF in cell envelope biogenesis. Our data suggest they are required for production of a unique glycolipid which makes up 16% of the polar lipids in the C. difficile membrane. We will define the DapR regulon and how individual regulon members contribute to daptomycin resistance, cell charge, and lipid content and cell envelope stress response. Together these aims will advance our understanding of C. difficile by defining how it resists cell-wall acting antibiotics like daptomycin and vancomycin.

NIH Research Projects · FY 2025 · 2010-07

Project Summary / Abstract In the hours after learning, the activation of gene expression follows a specific pattern, producing transient waves of expression needed for long-term memory consolidation. These changes require non-genetic (i.e., “epigenetic”) events, including modifications to: DNA-organizing proteins known as histones, the DNA itself, and the accessibility of DNA to proteins. Additionally, the molecular changes necessary for memory require a form of RNA-based regulation. In the absence of such changes, the long-lasting regulation of gene expression during memory storage fails, and this could account for defects in memory that accompany many psychiatric disorders. Our long-term goal is to define novel epigenetic mechanisms underlying memory storage and synaptic plasticity by taking advantage of recent advances in our understanding of histone modifications, in the development of single-cell RNA technology, and in the function of regulatory mechanisms mediated by small noncoding RNAs. During the previous funding period, we defined a novel metabolic source of acetyl-CoA in the nucleus and have obtained preliminary data about new forms of histone acylation and crotonylation associated with spatial learning. We also developed bioinformatic tools to analyze single nuclear RNA sequencing data to identify neurons activated by learning. We further established the reversal of microRNA (miRNA)-mediated mRNA silencing as a novel epigenetic means of regulating activity-dependent translation, linking synaptic activity to translational upregulation of key memory-related targets. These major findings provide the basis of our proposed experiments that we believe will define the next frontiers in our understanding of the epigenetic mechanisms of memory consolidation. In Specific Aim 1, we will examine the impact of a novel histone modification, histone crotonylation, on the epigenetic landscape and gene expression during memory consolidation. In Specific Aim 2, we will define cell type-specific transcriptional signatures of the hippocampal neurons during memory consolidation and retrieval. In Specific Aim 3, we will elucidate the microRNA- dependent mechanisms that regulate long-term memory and synaptic plasticity driven by a microRNA processing complex. An understanding of these key epigenetic regulatory mechanisms involved in the consolidation and storage of long-term memories is expected to ultimately lead to the development of new treatments for the debilitating cognitive deficits associated with psychiatric disorders such as schizophrenia, autism, bipolar disorder, post-traumatic stress disorder and depression.

NIH Research Projects · FY 2025 · 2009-03

PROJECT SUMMARY This proposal is a competitive renewal for a unique study that measures the volume, function, and development of striatal-cerebellar circuity in children at risk for Huntington's Disease (HD). The standard assumption is that HD is a degenerative disease of the striatum. However, research supports supported the notion that a crucial component of the pathoetiology of HD is abnormal brain development. The grant was originally funded in 2009 and dubbed the Kids-HD program, designed to investigate this hypothesis by the study of children at risk for HD (those with a parent or grandparent with HD). The at-risk participants are genotyped and those who are gene-expanded (GE) are compared to those who are gene non-expanded (GNE). Gene knock-down therapy – Antisense Oligonucleotides or ASOs – are currently entering Phase III studies and hold promise for treatment of patients in early stages of disease (by preventing further decline). If ASOs fulfill that promise, the next step will be preventive therapy – giving the ASO early enough (potentially to children) to prevent symptoms from occurring. The growth and development of the striatum is vital to understand as this is the primary site of disease pathology. Yet, knocking down a gene that is vital to development of these structures must be approached with an abundance of caution. Human brain development is prolonged, with striatal maturational changes occurring up through 30 years of age. Therefore, discriminating ongoing development/maturation with the degenerative phase of the disease may be key in knowing when to administer and ASO. Our preliminary data suggest that a novel blood biomarker – Neurofilament light (NfL) rises within roughly 20 years of onset but is normal prior to that, suggesting it is not present in development, but is seen at the very beginning phases of degeneration. Rationale for renewal and expansion (5 sites across the US) include: 1) increase sample size for replication of original findings with sufficient power to detect CAG-specific effects and 2) model the entire period of brain development (up to age 30 rather than only up to age 18); 3) evaluate the utility of a blood biomarker of neural dysfunction, Neurofilament light (NFl) that may help delineate the earliest phases of degeneration.

NIH Research Projects · FY 2026 · 2006-05

The Iowa Superfund Research Program (ISRP) is a center of research excellence focused on polychlorinated biphenyls (PCBs). PCBs mixtures called Aroclors were added to thousands of products, including construction materials, until their sales were banned more than 40 years ago. Today, people are still exposed to PCBs indoors and in communities surrounding Superfund sites. Recent ISRP research demonstrated that airborne PCBs present an especially urgent problem: Inhalation of airborne PCBs may be the most significant route for human exposure to these important toxic chemicals. The ISRP’s long-term goal is to develop recommendations to prevent and/or limit human exposure to airborne PCBs and to improve the health and well-being of the population. The ISRP renewal will focus on PCBs in air, particularly in schools and those emitted from contaminated soils and water of Superfund sites. We will examine the health impacts of inhaled PCBs, particularly on adolescents, with a focus on neurodevelopmental and metabolic effects. The ISRP will accomplish its long-term goal through the following integrated Specific Aims: 1) Identify community-supported strategies that address concerns about exposure to airborne PCBs and methods for remediation. We will leverage established and developing partnerships with communities to design and conduct research that responds to community concerns about PCB emissions in Vermont schools and Portland Harbor, Oregon. 2) Determine how lower-chlorinated PCBs cause toxicity during adolescence. We will address how PCBs and their metabolites are risk factors for altered neurodevelopment during adolescence and the mechanisms by which these compounds interfere with lipid metabolism. 3) Reduce airborne PCBs in schools. We will design and test novel sampling methods to directly measure and predict emissions of gas-phase PCBs from building materials in school rooms; distinguish primary, secondary, and tertiary sources; and identify cost-effective strategies to remove or reduce airborne PCBs in schools 4) Define concentrations of airborne PCBs in contaminated water, soil, and sediment and identify mechanisms to reduce their emission. In collaboration with communities in Portland, Oregon, and elsewhere, we will determine the magnitude of emissions from contaminated waters and soils surrounding a Superfund site and evaluate the short-term emissions of PCBs due to sediment dredging. We will also develop novel materials and methods to reduce emissions of PCBs using molecular mechanisms by which microbial populations, including bacteria and fungi, metabolize these compounds in sediments. 5) Train scientists and attract new scientists to environmental health sciences. We will recruit trainees, build on an existing training program offered through the RETCC, and provide trainees and established scientists with new research skills in data science, chemical analysis, community engagement, and research translation.

NIH Research Projects · FY 2026 · 2006-04

Project Summary The University of Iowa submits this renewal application for continued participation in the NICHD Neonatal Research Network (RFA-HD-23-002). We seek to continue to support the mission of the NRN to improve healthcare and outcomes for newborns, seeking solutions to increase survival without neurodevelopmental impairment or chronic illness for premature and critically ill newborn infants. We have several strengths that will advance the collaborative work of the NRN. 1. Our NICU is a world leader in the care of periviable infants, born at 22 and 23 weeks’ gestation. The survival rate of this population at the University of Iowa is the best in the United States, and the majority of these survivors are free of neurodevelopmental impairment. We bring expertise to inform research design as well as a relatively large periviable population available to participate in NRN studies. Our mortality for extremely low birth weight infants is perennially among the lowest in the NRN. 2. We have a strong tradition and culture of clinical research in infants. Our clinical research infrastructure in the NICU has a decades-long track record of successful participation in multicenter studies and contributions to important neonatal study findings. 3. Our NICU is the leading US center in the emerging neonatal subspecialty of neonatal hemodynamics. Our Hemodynamics group has developed the study methods and echocardiographic measurement standards for this modality and are global experts in its use both clinically and in physiologic and interventional research. That expertise can be harnessed in the NRN to pursue novel study designs. 4. As the only academic medical center in a largely rural state with an economy based in agriculture, we represent a population that is not otherwise well represented in the NICHD Network. Our partner site at Sanford Health in Sioux Falls, SD further enhances this diversity with the addition of a Native American population to our combined rural population. If the results of Network studies are to be generalized to patients throughout the country, this large area of the country should be represented. The University of Iowa Network center represents this region and population. 5. We have contributed significantly to the NRN’s work through the last 7 years. We have been among the highest enrolling sites in several studies despite our relatively low population, and we have had excellent follow-up rates for infants both in trials and in the Follow-up observational study.

NIH Research Projects · FY 2026 · 2005-08

Children who experience prenatal alcohol exposure may develop Fetal Alcohol Spectrum Disorders (FASD) and the central nervous system (CNS) is particularly susceptible to alcohol-induced damage. Children of FASD have significant neurobehavioral deficits. FASD is diagnosed at an alarmingly high rate making it the most common non-heritable cause of mental disability and resulting in tremendous personal and societal costs. It is therefore important to understand mechanisms that contribute to these adverse effects and find ways to improve outcomes in these individuals. The neurobehavioral deficits observed in FASD results from structural damages in the brain. It has been well-established that there is a temporal and spatial vulnerability to alcohol-induced neuronal damage during the development. That is, neurons at the different developmental stage display differential sensitivity to alcohol-induced damage. Even at the same developmental stage, neurons in different structures are differentially impacted by alcohol exposure. However, the underlying mechanisms are unclear. The endoplasmic reticulum (ER) is an important organelle involved in protein quality control. The accumulation of improperly folded proteins within the ER lumen results in ER stress, and sustained ER stress causes cell death. Neuronal cells are particularly sensitive to ER stress. Recently it is shown that ER stress plays an important and more specific role in alcohol-induced CNS damage. The ability of immature neurons to maintain ER homeostasis develops gradually and heterogeneously. We hypothesize that the temporal and spatial vulnerability of developing brain to alcohol-induced neuronal damage is mediated by the sensitivity to ER stress. That is, the differential sensitivity of neurons to alcohol neurotoxicity during the development is due to the difference of neuronal ability to maintain ER homeostasis and mitigate ER stress. We further hypothesize that enhancing neuronal ability to maintain ER homeostasis will make immature neurons resistant to alcohol-induced neurodegeneration and improve neurobehavioral deficits. We propose three specific aims to test these hypotheses. Specific Aim 1 will determine whether the temporal and spatial vulnerability to alcohol-induced neuronal damage is mediated by the sensitivity to ER stress in the developing brain. Specific Aim 2 will determine whether enhancing neuronal ability to maintain ER homeostasis can protect immature neurons against alcohol- induced ER stress and neurodegeneration in the developing brain. Specific Aim 3 will determine whether enhancing neuronal ability to maintain neuronal ER homeostasis can improve alcohol-induced neurobehavioral deficits. This proposal will use both in vitro and in vivo approaches to investigate how ER stress contributes to neuronal vulnerability to alcohol. It will employ genetic manipulations and chemical intervention by FDA-approved drugs to mitigate ER stress in immature neurons. The cohesive specific aims will not only elucidate the cellular and molecular mechanisms underlying the temporal and spatial vulnerability to alcohol, but also open a novel avenue for the intervention/therapy of FASD.

NIH Research Projects · FY 2025 · 2005-06

OVERALL SUMMARY The overall goal of the University of Iowa Wellstone Muscular Dystrophy Specialized Research Center (MDSRC) is to perform research on muscular dystrophies (called dystroglycanopathies) that arise from absence or reduction in matriglycan on α-dystroglycan (α-DG). Dystroglycanopathies are a group of congenital/limb-girdle muscular dystrophies that lead to progressive skeletal muscle weakness and a decline in respiratory function. Project 1 (Campbell and Richerson) using mouse models of dystroglycanopathy will define the cellular and molecular mechanisms that underlie respiratory complications. Additional studies will determine the relationship between matriglycan length, laminin binding and α-DG receptor dysfunction in respiratory muscles; they will also determine the ability of potential therapies already in clinical trials to restore full-length matriglycan and normal respiratory function. Project 2 (Mathews and Saade) will define the natural histories of FKRP-related and non-FKRP-related dystroglycanopathies derived from an established, unique cohort of patients using established and evolving clinical measures, to optimize clinical care and facilitate clinical trial design, with a focus on those who might be excluded from current trials due to rare genotypes, young age or advanced disease. Extended follow up of non-FKRP genotypes will identify cohorts that share similar rates of motor progression who might be studied together in gene non-specific clinical trials. Novel potential biomarkers (electroretinograms and urine proteomics) identified in pilot work will be tested for relationship to motor manifestations. Core A (Campbell and Moore) is an administrative core that will coordinate the activities within and outside the Center to promote an interactive and collaborative research environment, and to engage patients in muscular dystrophy research. Core B (Moore), a Muscle-Tissue/Cell- Culture/Diagnostics Core, will support Projects 1 and 2, serve as a national tissue and cell-culture resource for research, provide specialized diagnostic testing for a wide range of muscular dystrophies, and maintain the infrastructure needed to evaluate muscle biopsies in support of clinical trials. Finally, Core C (Mathews and Campbell) will coordinate our Training initiatives. This Core will support basic science and clinical research training for medical students, postdoctoral trainees, graduate students, and undergraduate students who will conduct research in the Center and participate care of patients. Dr. Mathews and Saade will provide clinical research mentorship, Dr. Campbell will provide basic science training, and Dr. Moore will mentor neuromuscular pathology students. Core C will engage the wider MDSRC and neuromuscular disease communities by sponsoring annual symposia in coordination with the patient and family conference and by hosting pediatric muscular dystrophy conferences. The highly integrated cores and projects of this Center will accelerate the tempo of discovery in preclinical translational research and broadly impact the care of patients, from managing individuals to changing treatment paradigms affecting patient groups.

NIH Research Projects · FY 2025 · 2005-05

Project Summary/Abstract The global injury burden is disproportionately concentrated in low and middle income countries. This project, named ICREATE: Injury Capacity in Research in EAsTern Europe, expands on five successful years of building injury research and education capacity in the countries of Armenia, Georgia, and Moldova. These countries are strategic global priorities due to their political and economic ties to the Middle East, Russia, and Europe. Through a European Union TEMPUS grant, our partner institutions established MPH programs in 2010, but at that time no programs had injury or violence course content or research. After our first cycle of funding, all MPH programs, as well as one new undergraduate program in Moldova, have injury content in the core curricula. We have built data capacity through the establishment of an 8-hospital emergency department trauma registry and an NIH-funded prospective brain injury registry; these databases have been used for student projects, and trainee publications and presentations. In our first cycle, we trained 40 MPH students, 9 PhD students, mentored 43 experiential learning projects, and published 13 papers. In the next funding cycle, we propose the following aims: train a critical mass of researchers from Armenia, Georgia, and Moldova to conduct innovative research; facilitate the transition of trainees to positions of leadership; develop our partner institutions as sustainable centers of excellence in injury research and education; and, engage partners to translate research into effective prevention and treatment programs. Our original topic areas of focus on road traffic injury, interpersonal violence, and acute care will be expanded to include alcohol use, and we will expand our methodologic focus on data and analytic capacity to include implementation science. Our program will prioritize MPH and PhD training to build research and leadership skills focused on injury and violence prevention. Through a credit-sharing agreement, trainees will be able to study at multiple institutions during their degree program. Now that partner institutions have implemented injury curricula, PhD degree training will shift from the University of Iowa to partner countries. Our Injury Prevention Summer Course, previously hosted at the University of Babes-Bolyai, will now circulate between partner institutions, taught by trainee alumni appointed as faculty. Partner countries will continue to host annual research symposia to highlight trainee research and to promote the field of injury and violence research. We plan for these activities to build sustainable research and education capacity that will lead to reductions in the burden of traumatic injuries and violence. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page

NIH Research Projects · FY 2025 · 2004-07

ABSTRACT The United States faces a crisis due to the high prevalence of chronic pain and associated opioid use disorder and overdose deaths. This crisis highlights the need for advanced and cross-disciplinary pain science training in our emerging basic and clinical scientists. Thus, the goal of our training program is to enable a new generation of young investigators with the expertise necessary to make substantial impact on pain science and treatment. This application seeks renewal of funding for an Interdisciplinary Training Program in Pain Research at the University of Iowa, requesting support for two predoctoral and two postdoctoral trainees for this award period. The program has been highly successful during its 15 years of funding, providing training to pre- and postdoctoral fellows of exemplary quality that have gone on to develop strong independent research careers in pain research and are actively involved in pain societies world-wide. The program will continue to provide basic training in the cellular and molecular mechanisms that underlie acute and chronic pain, as well as translational and clinical pain research. The 23 faculty of our multidisciplinary training program is a balanced representation of basic scientists, translational and clinical scientists from 12 departments and programs across 4 colleges at the University of Iowa. Our clinical trainers include faculty with expertise in medicine, physical therapy, and nursing, with strong emphasis on non-pharmacological approaches to pain management. Our more senior trainers with strong record of training both predoctoral and postdoctoral fellows will also be responsible for mentoring junior trainers. The training program provides a highly structured and diverse program of didactic coursework, including monthly seminars, weekly journal clubs and work-in-progress meetings, that is coupled with research training in a highly collaborative and interactive environment. In the next funding period, we propose to add several new features to the program that are aimed at strengthening training in rigor and reproducibility, at enhancing quantitative literacy and competence in biostatistics, and at expanding experience-based learning in basic, translational and clinical pain research. The specific goals of the proposed training program are to: (1) assist trainees in developing an individualized curriculum that provides a solid knowledge base in pain science appropriate to their career goals; (2) provide formal instruction in rigor and reproducibility in biomedical pain research, including working knowledge in biostatistics and quantitative approaches; (3) provide rigorous training in the elements of scientific investigation including the formulation of research hypotheses, experimental design and analysis; (4) assist trainees in developing their written and verbal scientific communication skills; (5) enable trainees to interact and collaborate with basic and clinical pain researchers both within and outside the institution. It is expected that the trainees in this program will acquire the knowledge, experience, and skill sets necessary for successful transition to an independent research career in academia, industry or government.

NIH Research Projects · FY 2026 · 2002-02

The University of Iowa Child Health Research Career Development Award (CHRCDA) entitled “Molecular and Cellular Research to Advance Child Health” was originally established in 1990 when NICHD first developed the program. Since inception, our CHRCDA program has facilitated the career development of 43 junior pediatric faculty. Our program is designed to support the academic career development of promising junior pediatric faculty. Given our history, we anticipate training 8-10 Scholars for the 5-year duration of this award. This program takes advantage of our present strengths, existing research programs, and established investigators by placing particular emphasis on three major areas of pediatric research, namely Molecular Genetics, Neurosciences, and Inflammation/Host Defenses. Specifically, this program will support and foster research training of junior pediatric physician-scientists in cellular and molecular biology, applied genetics and genomics, animal models of human disease, and translational research. The specific long-term goals and objectives of this program are: (1) to provide junior pediatric physician scientists with research experiences and technical training that they will then apply to current and future studies of the genetics and functional basis of diseases that impact broadly on children’s health; (2) to provide junior pediatric physician-scientists with a systematic curriculum of formal instruction in fundamental skills that are necessary for the development of a successful academic research career; (3) to provide a unique environment for junior pediatric physician- scientists to study gene function across the biological spectrum from regulation at the molecular level thorough to whole organism physiology; (4) to provide junior pediatric physician-scientists with an opportunity to acquire new, innovative and state-of-the-art scientific research expertise in molecular and cellular biology, physiologic genomics, neuroscience and translational research to bridge the gap between basic science research and clinical pediatric medicine; (5) to attract the most talented junior pediatric physician-scientists as independent investigators. To achieve these aims we have recruited a cadre of senior faculty Mentors from diverse departments and units throughout the Department of Pediatrics, the Howard Hughes Medical Institute, and the College of Medicine. Oversight of the program will be achieved through regularly scheduled meetings of an Internal Advisory Committee and presentations by each of the Scholars. In addition, an External Advisory Committee will meet annually to review the program, assess progress of the Scholars, and provide feedback regarding the effectiveness and operations of the program. This program will ultimately improve the health and well-being of children through innovative research fostered by the development of newly trained and highly effective pediatric physician--scientists.

NIH Research Projects · FY 2025 · 2000-08

PROJECT SUMMARY/ABSTRACT Speech sounds are the most important sounds that humans hear, yet our knowledge of how the complex cortical network of auditory and auditory-related brain regions subserves speech perception is limited. Our overarching goal is to understand where and how speech information is represented within this network. The focus of this proposal is to test directly predictive coding models of speech perception. In predictive coding hypotheses, the brain minimizes the differences between internally generated expectations and sensory observations through an ongoing interaction between sensory and higher-order cortical regions. We use novel combinations of complementary invasive and non-invasive experimental methods to study these brain regions in neurosurgery patients who require placement of chronic intracranial electrodes. These experiments involve combining direct cortical electrophysiological recording methods with non-invasive electroencephalography, electrical stimulation techniques and anatomical and functional neuroimaging methods. We also obtain causal evidence of network functional properties by studying the effects of selectively disrupting the function of specific components of this network. Our investigative strategy makes use of these unique experimental opportunities to overcome long-standing barriers to progress in this research field. We will pursue our goals by testing hypotheses regarding: (1) the locations, functional properties and connectivity patterns of auditory cortical fields and auditory-related cortices of the temporal and frontal lobes that are engaged in speech processing, (2) predictive coding models of speech signaling within this network, and (3) the behavioral consequences and neural signatures of selective disruption of the network. These objectives are pursued by an experienced multidisciplinary group of investigators with expertise encompassing all required clinical and research topic areas. To our knowledge, the resulting data will be the first of its kind to directly demonstrate how speech information is processed at all levels of auditory cortical hierarchy and provide causal evidence of the role of feedback projections on speech information processing within canonical auditory cortex. Detailed characterization of this network will improve our understanding of the pathophysiology of disease states affecting this system and will provide mechanistic insights that are required to inform the design of new treatment strategies.

NIH Research Projects · FY 2026 · 2000-07

ABSTRACT Holden Comprehensive Cancer Center (HCCC) at the University of Iowa (UI) is the only NCI designated cancer center in the state of Iowa, a highly rural state that serves as the HCCC catchment area. The HCCC leverages its highly collaborative culture to advance transdisciplinary, cancer research that is particularly relevant to the people of Iowa. This includes basic cancer research, a strong portfolio of translational multi-investigator grants including the nations only Specialized Program of Research Excellence (SPORE) P50 grant focused on Neuroendocrine Tumors, a new NCI P01 and population science research addressing prevention, cancer control and survivorship. HCCC has a growing portfolio of early phase clinical trials including studies based on discovery science emerging from the HCCC. The HCCC functions administratively as a matrix Cancer Center with 174 Center members from seven UI colleges. The members of the HCCC have $20.6 million in direct annual cancer-related, peer-reviewed, external research support. Of this, $11.0 million comes from the NCI. The HCCC is organized into three research programs. Cancer Genes and Pathways (CGP) is the basic science program of the HCCC. Experimental Redox Therapeutics (ERT) is the translational program, and Cancer Epidemiology and Population Science (CEPS) is a population science program. HCCC members benefit from seven HCCC managed shared resources including Biostatistics, Biospecimen Procurement & Molecular Epidemiology, Flow Cytometry, Genomics, Population Research, Radiation Free Radical Research, Viral Vector and one developing shared resource, Translational Immunology Core. The HCCC has a robust Community Outreach and Engagement effort that facilitates bidirectional interactions between the HCCC and the people of Iowa. It leverages the resources of the Iowa Cancer Consortium (ICC) and research infrastructure that extends into the community. It also has a comprehensive Career Enhancement (CE) Program. In summary, the HCCC provides a collaborative environment, infrastructure and resources to strengthen all aspects of interdisciplinary cancer research taking place at UI.

NIH Research Projects · FY 2025 · 1999-07

This renewal application requests support for integrated, broad-based, fundamental, multidisciplinary predoctoral training of first- and second-year students in Neuroscience at the University of Iowa. The application builds on more than three and a half decades of success in matriculating, training, and placing top-caliber PhD students. Our Program features mature leadership, with Daniel Tranel, PhD, having led the Program and T32 since 2000. For the next cycle, in response to Program growth, leadership will be enhanced by the addition of an MPI, Sheila Baker, PhD. During the past 5 years, the Program has seen sharp increases in student enrollment and funded neuroscience faculty, reflecting the strong institutional emphasis on Neuroscience and the major infusion of resources from the Iowa Neuroscience Institute (including new buildings and numerous new faculty hires). The Program draws on a long Iowa tradition of collaborations between basic and clinical scientists (many of our preceptors are clinician-scientists), a strong translational focus, and a major emphasis on quantitative training. The Training Faculty is comprised by 79 experienced, well-funded, neuroscientists with research interests that span the gamut of neuroscience. Students participate in a carefully honed curriculum that offers broad and fundamental training in levels of analysis and breadth of approaches, with a special focus on the neuroscience of disease and disorders (including a highly successful Neurobiology of Disease course). There is intensive training in experimental design, statistical methodology, quantitative skills, reproducibility, and professional skills development (enhanced by new curricular components in teaching, oral/written communication, networking/skill building, and grantsmanship), and detailed annual student evaluation using the Individual Developmental Plan. The Program incorporates three laboratory rotations, regular programmatic activities (Seminar, Research Day, journal clubs), and comprehensive training in responsible conduct of research and reproducibility. Program evaluation includes detailed internal and external reviews that evaluate all aspects of the Program and recommend changes. The “value-added” is especially compelling—NIH training grant dollars enhance every aspect of our Program and have contributed directly to sustained successes marked by outstanding time to degree (5.1 years), productivity (5.8 publications per student, 2.4 as first author), completion rate (86%), and placement of graduates in stellar neuroscience careers (54% of our graduates are in tenured or tenure-track academic positions). To maintain and extend these accomplishments, this renewal request asks for 10 slots per year to support first- and secondyear students.

NIH Research Projects · FY 2024 · 1999-07

Project Summary/Abstract: The Free Radical and Radiation Biology Training Program in the Department of Radiation Oncology and the Holden Comprehensive Cancer Center was established in 1998 to provide interdisciplinary graduate and post- graduate training with a focus on six goals including: 1) Impart a fundamental understanding of radiation biology, free radical biology, and cancer biology; 2) Provide opportunities to achieve excellence in experimental radiation biology, free radical biology, and molecular oncology; 3) Provide trainees with skills in hypothesis driven research, execution of rigorous experimental designs, and rigorous evaluation of scientific results for peer-reviewed publication; 4) Offer real-world experiences in collaborative basic and translational research involving both clinical and basic science faculty to facilitate the movement of knowledge in free radical and radiation biology from the bench-to-bedside; 5) Provide trainees with the critical thinking skills necessary to effectively communicate scientific knowledge in both oral and written presentations; and 6) Encourage trainees to pursue innovative approaches to test basic mechanisms underlying radiobiology and redox cancer biology emphasizing the development of novel interventions to limit the health impact of cancer. We are proposing to support three predoctoral and three postdoctoral trainees per year. We have an internationally recognized faculty with a consistent track record of success in peer reviewed funded research/publications in radiobiology, redox biology, and cancer biology. We propose to have 26 well-funded and dedicated program faculty members (both junior and senior faculty) embracing a diverse knowledge base that synergistically integrates both the interdisciplinary graduate programs in Free Radical and Radiation Biology as well as Cancer Biology in the Biomedical Sciences Umbrella program at the University of Iowa. The 26 program faculty members consist of 15 Professors, 8 Associate Professors, and 3 Assistant Professors of which 5 are from Radiation Oncology, 3 from Surgery, 5 from Internal Medicine, 3 from Biochemistry, 2 from Pharmacology, 2 from Anatomy and Cell Biology, 3 from Pediatrics and 1 each from Microbiology/Immunology, Radiology, and Molecular Physiology and Biophysics. Educational activities include one-on-one mentoring by faculty, cancer-related nationally recognized research projects, presenting work and receiving feedback at national meetings, 2 program specific journal clubs/week, 1 seminar/week, 1 translational research meeting/week, and technical training in the state of-the-art Radiation and Free Radical Research core lab based in the program. Formal graduate level coursework includes classes in radiation, redox, and cancer biology as well as a course in medical physics with an emphasis on image guided cancer therapy. The interdisciplinary cancer related research being pursued by the faculty spans a wide spectrum from basic mechanistic studies to translational preclinical as well as clinical studies. The program was established in 1961 and has trained more that 150 scientists working in cancer research, redox biology, and biomedical sciences.

NIH Research Projects · FY 2025 · 1998-09

PROJECT SUMMARY/ABSTRACT (PRECISION MEDICINE CENTER FOR CF – OVERALL) For the past 25 years, the P30 Center for Gene Therapy of CF has concentrated on advancing CF treatments through enhanced understanding of disease mechanisms, identifying key targets for gene and cell manipulation, and developing technologies for CFTR gene delivery and editing in vivo. As of 2024, the Center will transition leadership and become the Precision Medicine Center for Cystic Fibrosis, reflecting updated patient needs and investigator expertise. The landscape of CF has evolved significantly with the introduction of highly effective modulator therapy (HEMT), which has resulted in new challenges such as increased prevalence of multisystem effects in aging CF patients. Complications like CF-related diabetes (CFRD), pancreatitis, kidney dysfunction, liver issues, obesity, and shifts in dynamics of the gut microbiome are now critically influencing quality of life. As individuals with CF age, the variability and organ-specific nature of CF-associated diseases are influenced by the involvement of diverse CFTR gene mutations across patients, interactions with modifier genes, and environmental factors. The Center uses a bedside-to-bench-to-bedside approach in CF management and research, integrating clinical observations, experimental research, and clinical applications. This iterative process ensures that insights from work with patients drive the development of new therapies, bridging clinical practice with scientific discoveries. The highly collaborative environment at the University of Iowa fosters rapid CF research aligned with the NIDDK mission, focusing on innovative therapies. Key research areas that build on the center’s strengths include CF pancreatic disease, CFRD, CF gallbladder disease, and CF intestinal disease. The Center has effectively supported CF research through several mechanisms: 1) Its Pilot and Feasibility Program, which has sponsored 74 pilots over the previous 25 years of funding, has brought numerous new Members and expertise into the Center, and has facilitated the maturation of talented junior Associate Members into independent tenure-track faculty. 2) The establishment or expansion of several core facilities (Viral and Non-Viral Vector Core; Cell, Tissues, and Models Core; Comparative Pathology and Animal Models Core; and Clinical Phenotyping Core) dedicated to CF research has provided Center investigators with specialized vectors, CF model systems (human, pig, ferret, and mouse), and approaches suitable for testing important hypotheses about CF pathogenesis and developing effective therapies. These resources have also enabled the Center to serve as a resource for the distribution of viral vectors, cells, tissues, and CF pig resources to numerous outside institutions. 3) The Center’s Enrichment Programs have promoted interdisciplinary interactions and training. 4) Formal internal and external mechanisms for review of the Center, the Cores, and the Pilot and Feasibility projects has ensured a high level of excellence and the most appropriate utilization of the Center’s resources. In summary, the Center has significantly enhanced CF research at UI and serves as a valuable resource for institutions worldwide engaged in CF research.