University Of Iowa

NIH Research Projects · FY 2025 · 2024-08

Project Summary/Abstract: Superoxide is a toxic molecule that all organisms exposed to oxygen must cope with. This is particularly true for pathogenic microbes, as the host harnesses the toxic properties of superoxide to combat invaders via the oxidative burst. To detoxify superoxide, nearly all forms of life, including strict anaerobes, produce superoxide dismutase (SOD). Convergent evolution has led to the development of three independent SOD families, all of which are dependent on metals for function. The most widely distributed family of SODs are those which depend on iron (Fe) or manganese (Mn) for function. Members of the Fe/Mn superfamily are present in eukaryotes, archaea, and bacteria. Despite over forty years of study, it is not possible to predict accurately the metal utilized by members of the Fe/Mn superfamily of SODs. Difficulties in predicting metalloprotein metal utilization are not confined to the Fe/Mn SOD superfamily but also occur with other classes of metalloenzymes. This deficiency is driven by relatively low levels of protein sequence identity amongst SODs from different organisms that utilize the same metal cofactor. Additionally, the environmental and molecular factors that dictate the metal used by members of this protein superfamily are also unknown. Members of the Fe/Mn SOD superfamily are canonically thought to use either Fe or Mn, but not both, as a cofactor. This idea arose despite early investigations that identified Fe/Mn SOD family members that are active with both Fe and Mn. The ability of these “cambialistic” SODs (able to use either Fe or Mn as a catalytic cofactor) was dismissed as a quirk of chemistry. At the time, it was thought that intracellular metal concentrations did not change enough to alter the metal bound by a SOD. S. aureus possesses two superoxide dismutases, SodA and SodM, which are ~75% identical. Initially, both SODs were reported to be Mn-dependent. During infection, the host restricts the availability of Mn and inactivates Mn-dependent SODs via the Mn-binding immune protein calprotectin. Recent work discovered that SodM critically contributes to the ability of S. aureus to maintain a defense against oxidative stress when Mn-starved, both in culture and during infection, while SodA is important when Mn is freely available. Biochemical analyses revealed that SodM is not strictly Mn-dependent but is instead cambialistic, and the ability to use Fe enables it to promote resistance to oxidative stress when S. aureus is Mn-limited by the host. These observations support a physiological role for cambialism and the hypothesis that metal availability shapes the repertoire of SODs possessed by an organism. The experiments in this proposal will evaluate this hypothesis and elucidate the molecular features that dictate metal utilization in the Fe/Mn SOD superfamily. Aim I: Elucidate the molecular features that dictate metal utilization of Fe/Mn SOD superfamily members. Aim II: Determine if environmental metal availability promotes retention of a metal-specific and cambialistic SOD by S. aureus. Aim III: Elucidate the broader contribution of cambialistic SODs to maintaining a defense against superoxide.

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY Identifying causal disease variants and elucidating how they lead to chronic disease remain important challenges in medicine. Genome-wide association studies have shown that polymorphisms associated with different human chronic diseases such as multiple sclerosis, rheumatoid arthritis and type 1 diabetes map predominantly to noncoding cis-regulatory regions of immune cells. Recent work has shown that a substantial fraction of non-coding variants linked to autoimmune disease lie in cis regulatory elements (CREs) of T lymphocytes, a subset of immune cells that play vital roles in preserving self-tolerance and preventing autoimmunity. However, determining which specific genes are regulated by CREs remains a challenge due to the temporal and spatial contexts in which they are modulate gene expression and the lack of suitable models to assess their activity in a manner that preserves their native chromatin structure. Importantly, T cells from autoimmune patients also exhibit marked changes in DNA methylation. However, the link between epigenetic changes and disease-associated variants is unclear. Our work has shown that T cells undergo significant epigenetic programming via DNA demethylation in the thymus and this programming is essential for long-term gene regulation in T cells. Remarkably, we have found that CREs active during T cell development play a critical role in modulating these epigenetic changes. Furthermore, we have shown that a significant number of genes that have critical roles in regulation of signals received the T cell receptor, which is essential for proper T cell function, are programmed in this manner. The goal of this proposal is to elucidate how CREs modulate epigenetic programming in genes with long-term functionality during thymic development and to define their contribution in chronic diseases. We propose a new model to test how human CREs in which disease- associated variants are present, modulate gene expression during thymic development and affect long-term epigenetic programming. We propose a new conceptual framework and mouse models to then investigate the mechanisms by which these CREs alter T cell function and promote chronic disease. Finally, we will investigate the involvement of newly discovered molecular factors that facilitate DNA demethylation during T cell maturation in the thymus. Understanding these mechanisms not only offers crucial insights into the aberrations of normal gene function in T cell driven diseases but also presents opportunities for the development of innovative approaches to enhance treatments for these illnesses. The comprehensive strategies outlined in this proposal will not only establish the foundation for future investigations into non- coding disease variants in autoimmune disorders driven by T cells but also offer a conceptual framework and new models for future investigations into disease-related variants that are prevalent in other cell types such as B cells. .

NIH Research Projects · FY 2024 · 2024-08

Project Summary/Abstract Alzheimer’s disease and its related dementias (ADRD) are associated with high rates of neuronal death in affected areas, but little is known about the ability of the brain to recover following therapeutic intervention. ADRD are characterized by protein deposits consisting of beta-Amyloid peptide and microtubule-associated protein tau. Tau pathology develops independently of beta-Amyloid deposits, and removal of beta-Amyloid alone is not sufficient to reduce cognitive decline in mice. The dysfunction of tau is characterized by an abnormal state of hyper-phosphorylation (P-tau), induced via a plethora of kinase pathways. This P-tau disrupts cellular function by sequestering other microtubule-associated proteins, directly destabilizing microtubules, and binding normal tau to form paired helical filaments (PHF-tau). Turnover of the tau protein is decreased in this pathology, as PHF-tau is resistant to neuronal proteases and degradation by ubiquitination. In vitro dephosphorylation of P-tau by the phosphoprotein phosphatase PP2A induces dissociation of PHF-tau and restores susceptibility of tau to protease digestion. PP2A activity and expression is diminished in neurons exhibiting P-tau pathology. Preliminary data from our lab indicate that direct delivery of PP2A DNA to the dorsal raphe nucleus (an early presenter of tau pathology) is sufficient to decrease P-tau in ADRD-model mice. To date, no studies have used targeted reversal of tau pathology at different disease-progression stages to investigate ADRD treatment outcomes. This proposal will investigate the reversal of P-tau pathology in serotonergic neurons, to determine any rescue of function or mitigation of P-tau propagation. These findings will further the understanding of early Alzheimer’s Disease, and may identify a clinically-relevant therapeutic intervention. Additionally, this fellowship training plan gives high priority to the professional development and research training of the fellowship recipient. This research training will take place in a highly collaborative and interdisciplinary laboratory setting within the University of Iowa’s department of Neuroscience and Pharmacology.

NIH Research Projects · FY 2024 · 2024-08

PROJECT SUMMARY Stroke commonly disrupts the corticospinal tract (CST) and impairs hand function, but current rehabilitation approaches incompletely restore pre-stroke hand motor control. Transcranial magnetic stimulation (TMS) interventions that target the residual CST and strengthen its neural transmission are promising candidates for enhancing paretic hand muscle activation during rehabilitation and promoting true hand motor recovery. To maximize their therapeutic effects, poststroke TMS interventions must reliably activate the residual CST and enhance residual CST transmission. We and others recently showed that neurotypical adults exhibit spontaneous resting brain activity patterns during which TMS most strongly activates the CST (i.e., strong CST states). When TMS interventions are delivered during these strong CST states, they preferentially enhance CST transmission and enhance motor learning. However, virtually all poststroke TMS interventions are uncoupled from strong CST states, such that only a fraction of TMS stimuli occur when the residual CST is best activated by TMS and neural transmission within it is most likely to be enhanced. Instead, poststroke TMS interventions should be delivered solely during strong CST states. Because each stroke survivor has a unique pattern of brain damage, recovery-related brain reorganization, and motor impairment, these strong CST states must be fully personalized. To address these issues, we developed a novel real-time EEG-informed TMS system that delivers stimulation during personalized strong CST states. Our system uses personalized machine learning classifiers and participant-specific datasets to identify multivariate EEG activity patterns that predict strong CST activation, indexed by large motor-evoked potentials (MEPs). Once these EEG activity patterns are detected in real-time, TMS is delivered. In this project, we will demonstrate the feasibility of real-time EEG-informed personalized brain state-dependent TMS in chronic stroke survivors while also determining hand impairment inclusion criteria for future clinical trials that investigate this promising personalized brain stimulation approach. In Aim 1, we will establish feasibility of real-time personalized brain state-dependent TMS in the poststroke CST system by comparing MEP amplitudes elicited during strong CST states to those elicited during random CST states. In Aim 2, we will correlate differences in MEP amplitudes elicited during strong versus random CST states with poststroke hand impairment. We will then identify the hand impairment levels of stroke survivors who exhibit larger MEPs during personalized strong than random CST states; previous literature suggests that these stroke survivors are most likely to benefit from future personalized poststroke brain state-dependent TMS interventions. Overall, this project will demonstrate feasibility of personalized poststroke brain state-dependent TMS and establish hand impairment inclusion criteria for future clinical trials that test this novel approach. Our results are expected to motivate an R01 proposal that investigates the therapeutic effects of personalized poststroke brain state-dependent TMS interventions.

NSF Awards · FY 2024 · 2024-08

The Pathways to Enable Open-Source Ecosystems (POSE) program seeks to harness the power of open-source development for the creation of new technology solutions to problems of national and societal importance. This project scopes an open-source ecosystem of advanced web technologies for hydrological education, research, and operations (OSE-HERO), that improves water resource management. This open-source ecosystem can empower researchers, educators, and decision-makers with advanced tools for managing, analyzing, and visualizing hydrological data. By leveraging advanced web technologies, OSE-HERO can enhance collaboration, increase data transparency, and promote innovation for hydrological tools, ultimately leading to improved research outcomes, educational resources, and operational practices in water resource management. This initiative addresses critical water-related challenges, fostering a collaborative and open community, and delivering substantial societal benefits. OSE-HERO leverages client-side web technologies to develop a comprehensive suite of web-based libraries and tools to support integration of existing open-source solutions. The project focuses on overcoming the limitations of traditional centralized data management systems by distributing computational load across client devices, enhancing efficiency and scalability. The project team, which possesses extensive expertise in hydrological computing and web-based analytics, conducts community analysis and workshops, and develops training materials to ensure the ecosystem meets the needs of a diverse user base. By promoting the widespread adoption and continuous improvement of these tools, OSE-HERO aims to democratize hydrological research and education, facilitating data-driven decision-making and advancing the field of water resources management. This project is jointly funded by Pathways to Enable Open-Source Ecosystems (POSE) and the Established Program to Stimulate Competitive Research (EPSCoR). This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY Plasmodium parasites, the causative agents of malaria, continue to be major drivers of infectious disease-related morbidity and mortality. Plasmodium evades sterilizing immunity in part by inducing proinflammatory changes that interfere with the orchestration of humoral immunity targeted towards parasite-specific antigens. This is seemingly not limited to parasite-specific immunity, as malaria can interfere with the efficacy of other routine vaccinations; the underlying mechanism of these impairments is poorly understood. Plasmodium parasites are endemic throughout Central and West Africa, regions in which highly pathogenic Zaire Ebola virus (EBOV) episodically causes outbreaks. An FDA-approved, live-attenuated, recombinant vaccine called ERVEBO stimulates antibody responses directed against the EBOV glycoprotein (GP) and has shown promise during EBOV outbreaks in Guinea in 2016 and Democratic Republic of the Congo (DRC) in 2019. Recent studies in the DRC suggest that current ring vaccination with ERVEBO can be highly porous; ~30% of EBOV-infected participants in a recent antiviral trial in the DRC were prior recipients of the vaccine. A possible explanation for this vaccine failure is acute Plasmodium infection of vaccine recipients at the time of vaccination, resulting in reduced immune responses to the vaccine. Utilizing experimental Plasmodium infection and clinically relevant vaccine administration strategies in a mouse model, my preliminary data show that mice that are parasitemic at time of vaccination exhibit dramatically reduced levels of EBOV GP-specific antibodies, reduced vaccine-induced germinal center (GC) formation in the draining lymph node (LN), and reduced vaccine load in the draining LN. These data inform our hypothesis that Plasmodium impairs multiple steps in the generation of a robust humoral response to ERVEBO, which will be tested through the following specific aims: 1) determining the underlying mechanistic impact of Plasmodium infection on ERVEBO-induced GC responses in the draining LN, and 2) determining the impacts of Plasmodium on antibody producing plasma cells and the functionality of EBOV GP- specific antibodies. Success of these studies will reveal mechanisms through which Plasmodium can impair ERVEBO vaccine responses and provide clinically actionable approaches to overcome this impairment. The experiences, techniques, mentoring, and concepts in this proposal were specifically tailored to Mr. Jonah Elliff and his training goals. As a developing researcher interested in improving strategies to treat and prevent severe infectious disease, Mr. Elliff is performing these studies through the Medical Scientist Training Program (MSTP) at University of Iowa under the scientific mentorship of Drs. Wendy Maury and Noah Butler, who provide individualized training at the intersection of virology, immunology, and vaccinology. Longer term plans for Mr. Elliff will be to complete his MSTP training and pursue a research residency in internal medicine, followed by an infectious disease fellowship, and ultimately a faculty position at an academic research center to continue investigating virus-host interactions and immune responses that control viral infections.

NSF Awards · FY 2024 · 2024-08

The 38th Annual Gibbs Conference on Biothermodynamics will be held at the Touch of Nature Outdoor Education Center in Carbondale, Illinois on September 28-October 1, 2024. The Gibbs Conference brings together researchers with similar interests in understanding how changes in structure and energetics manifest in biological function. This conference provides a unique opportunity for scientific exchange and collegial interactions among researchers, while fostering the professional growth of early career trainees and promoting an equitable, accessible, and inclusive biothermodynamics community. The 2024 conference will bring together scientists from across the country as invited speakers and create numerous opportunities for trainees and early-career scientists to connect with peers and mentors. Biological thermodynamics aims to understand the energetics of chemical processes that lead to biological function. Modern biothermodynamics has evolved new ideas with the use of technological advancements to probe the basic tenets of allostery. More broadly, biothermodynamics now includes structural biology to help link the gap between structure, energetics, and function. To move the field forward, there is a need to bring together various disciplines. The field is now at the intersection of computational methodologies, detailed kinetic investigations, structural biology, molecular biology, high- throughput approaches, and classical thermodynamics. Combining these diverse disciplines will lead to new developments in all areas of biology. Developments in modern biothermodynamics will continue to lead to the development of new approaches and methodologies to study protein-protein and protein-ligand interactions, enzymes, and their cellular pathways. This meeting is supported by the Molecular Biophysics Cluster of the Division of Molecular and Cellular Biosciences. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2024 · 2024-08

In-space production application is a national initiative to ensure US leadership of in-space manufacturing in low Earth orbit by demonstrating the production of advanced materials and products for the terrestrial market. However, the zero-gravity environment impairs the product quality of many manufacturing systems that perform efficiently and reliably on-ground. Moreover, the data collection cost of in-space manufacturing is so expensive that commonly used quality control and uncertainty quantification strategies fail for such data-scarce systems. This EArly-concept Grant for Exploratory Research (EAGER) project addresses these fundamental issues by establishing a real-time heterogeneous transfer active learning framework. This framework leverages knowledge from well-studied, data-rich on-ground manufacturing systems to enhance experiment design, uncertainty quantification, and quality control in in-space manufacturing systems. Specifically, this project focuses on the in-space electrohydrodynamic inkjet printing and collaborates with the National Aeronautics and Space Administration to collect both on-ground and parabolic flight test data, develop transfer learning models, and validate their performance. The project also contributes to workforce training by promoting the interdisciplinary research of manufacturing, sensing, and data analytics and integrating the research as project topics into undergraduate/graduate courses and various outreach activities. This project leverages the state-of-the-art transfer learning strategy to resolve the urgent need for reliable in-space manufacturing. While transfer learning is effective for dealing with data scarcity, it faces unique challenges when adapted for integrating on-ground and in-space manufacturing systems: 1) The input values, dimensions, or even data types between the on-ground and in-space systems are different. Such heterogeneity requires not only the adaptation of inputs among systems, but also the identification of useful source systems. 2) The in-situ computational resource is limited. This limitation hampers most active learning methods, where the estimated or predicted uncertainty from training data must be recalculated from scratch whenever new experimental data (identified by active learning) is added. This project facilitates a real-time heterogeneous transfer active learning to conduct the heterogeneous transfer learning batch-by-batch within the context of active learning. This project features 1) a flexible and interpretable transfer learning framework to deal with heterogeneous inputs; 2) a Bayesian mechanism to update experiment design and predictions in real-time; and 3) a tailored experiment validation plan for on-ground and in-space manufacturing systems. The successful implementation of the project fills in the knowledge gaps and challenges when translating a manufacturing system into a different environment where there are unforeseen uncertainties. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2024 · 2024-08

The central U.S. states of Kansas, Arkansas, Nebraska, and Iowa (collectively known as the KANI states) experience some of the most dynamic weather patterns in the nation. This weather affects all walks of life in nearly all economic sectors, especially in agriculture-based communities. Furthermore, the scarcity of observation stations capable of delivering real-time soil and atmospheric data in KANI states make the assessment of climate and weather prediction a challenge. This challenge also co-exists with the high demand of workforce development as well as reliable weather intelligence to increase agriculture-based economy in a changing climate. To address these challenges, this project aims to design and implement the Data-Advanced Research and Education (DARE) infrastructure. The project aims to increase climate change resilience in agriculture-based communities. The DARE infrastructure will be developed and maintained within an integrated workforce development framework, in which classroom teaching, research, extracurricular activities, community engagement and communication work in tandem to identify, assess, and, to some degree, mitigate the localized impacts of climate change and environmental justice issues. The DARE project will contribute to a paradigm shift of readiness and infrastructure development strategy in these agriculture-based communities to embrace new technology for economic growth and adapting to climate change. Its approach to integrate engineering solution, citizen science, and societal impacts will expand both grassroots efforts and research opportunities to increase climate change resilience at local community level. The observation data collected in KANI can be used by broader science community to assess climate change and model predictions in rural and peri-rural areas in the United States. The DARE project is a collaboration among four universities in KANI states, namely the University of Iowa, the University of Arkansas, Kansas State University, and the University of Nebraska-Lincoln. This collaborative project will achieve data acquisition through a citizen science observation network to improve spatial coverage and real-time capacity for weather and soil observations. The network will deploy smart-and-connected low-cost sensors developed in house, enabling the real-time acquisition and delivery of weather and soil data across the KANI states (especially in socioeconomically disadvantaged communities). The DARE project will engage citizens (including K-12 and college students) via summer camps and field campaigns and through statewide agriculture-extension offices for education and communication, community health workers, various organization for growers, offices for Science, Technology, Engineering, and Mathematics (STEM) education, and DARE virtual service system. Data from the citizen science network will be used together with machine-learning method to improve heat index mapping and environmental justice studies; correct weather forecast bias in temperature and precipitation, downscale climate modeling data for subseasonal-to-seasonal (S2S) outlook; and improve efficiency of water use for farming and green space. Upon completion, this project can be a self-sustaining grass-root infrastructure that improves not only higher education and academic research but also participatory research and faculty career development. Through this project, the workforce in agriculture-based communities will not only be increased but also be better equipped with important skills (e.g., sensor design and manufacturing, Unmanned Aerial Vehicle or UAV surveillance, big data analysis) that are in par with modern technologies and in concert with critical thinking of and strategic planning for the resilience to cope with climate change. This project is funded by the EPSCoR Research Infrastructure Improvement-Focused EPSCoR Collaborations (RII-FEC) program. The RII-FEC program builds inter-jurisdictional collaborative teams of EPSCoR investigators in focus areas consistent with the NSF Strategic Plan. RII-FEC projects include researchers from at least two EPSCoR eligible jurisdictions with complementary expertise and resources necessary to address challenges, which neither party could address as well or as rapidly independently. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2024 · 2024-08

Parasitic wasps are critically important predators that control the population sizes of other insects. Why parasitic wasps attack some insect hosts but not others is a key question with major applied implications for control of forest and agricultural pest insects and human disease vectors. This work will involve the study of hundreds of insect species that specialize on oaks - one of the most ecologically important and widespread tree genus in North America. The researchers will document the parasitic wasps that attack each insect and, accordingly, discover which insects those same wasps do not attack. A major goal will be to infer which insect defenses are effective against each type of parasitic wasp, as well as whether, how, and why parasites have shifted among different insect hosts over time. Discoveries resulting from the research will be added to a public facing website, integrated into an urban ecology museum collection in collaboration with a Detroit, MI-based community organization, and incorporated into undergraduate courses. A postdoctoral scholar, three graduate students, and several undergraduate students will be trained as part of this work. The researchers will study the diversity and evolutionary histories of oak gall wasps and seven different genera of their parasitic wasps, all contextualized by the multidimensional trait space of oak galls. Each oak gall wasp induces a gall of a unique and characteristic gall morphology on a specific organ of a specific oak species during a specific time of year. At least seven genera of parasitic wasp are broadly associated with oak galls, with each gall wasp species attacked by several different parasite species. However, not every parasite genus attacks every gall type and individual parasite species have often proved to only attack galls induced by just one or a small number of gall wasp species. The researchers and a team of community scientists will collect, study, and discover new oak gall wasps and parasites from across the continental United States. They will then sequence hundreds of phylogenetically informative genetic loci from thousands of individual insects and infer evolutionary relationships among those insects. They will contextualize galler-parasite interactions by their evolutionary histories, host tree associations, and various dimensions of gall ecology, including phenology, and gall morphology. Questions the study will address include: 1) How do gall wasps escape from parasites? 2) What gall trait changes drive parasitic wasp speciation? The scale of this study (hundreds of host and parasite species) will make it the largest ecologically aware cophylogenetic study of its kind. The project is co-funded by the Systematics and Biodiversity Science program. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2024-08

ABSTRACT The endoplasmic reticulum (ER) plays a pivotal role in maintaining protein homeostasis by implementing crucial quality control mechanisms. Newly synthesized polypeptides that fail to fold correctly, are directed for degradation by the proteasome through ER-associated degradation (ERAD) or transported to the lysosome for degradation via autophagic processes known as ER-autophagy (ER-phagy). Although ERAD and ER-phagy share common features, these pathways function independently to recognize and degrade substrates. Despite the critical role of ER quality control, there are gaps in our understanding of this process including a) how damaged proteins are directed into specific proteostasis pathways and b) the role of cell-type specific proteostasis adaptations. To address these gaps, the overall objective of this application is to understand how ER quality control is regulated in different cell types. Here we outline three goals (1) Establish the principles governing the selection of targets by the ERAD and ER-phagy system; (2) Define how glycan site occupancy regulates the selection of ER quality control pathways; (3) Understand the cell-type specific roles of ER-phagy receptors. We previously found that a disease-causing mutation in the NPC1 protein, an isoleucine-to- threonine substitution mutant at position 1061 (I1061T), is rapidly cleared from the ER by both ERAD and ER- phagy, making I1061T-NPC1 an excellent substrate to study this selection process. Additionally, we found that differences in glycan site occupancy between species alter NPC1 ER degradation. To accomplish the goals, we will leverage our recently developed induced pluripotent stem cells (iPSCs) expressing dCas9, and/or NPC1 variants: WT-NPC1, I1061T-NPC1, or NPC1-null. This isogenic cell system enables the differentiation of iPSCs into hepatocytes or excitatory neurons and modulation of cell type-specific proteostasis through small molecules or by stably reducing specific gene products using dCas9. In goal (1) we will use small molecule inhibitors and dCAS9 to study the role of glycan structures in ERAD and ER-phagy pathway selection. Goal (2) involves introducing human and mouse NPC1 glycan mutants into NPC1-null iPSCs using lentivirus. These cells will be differentiated into neurons and hepatocytes to study the role of glycan sites in NPC1 degradation using biochemical methods. Lastly, in goal (3) we will use dCas9 to stably reduce the expression of a panel of ER-phagy receptors in iPSC derived neurons and hepatocytes. Then we will leverage LC-MS/MS and biochemical methods to study their role in regulating the cell-type specific proteome. The rationale for this project is that understanding the recognition and evasion processes in ER quality control has significant implications for many human disorders, including Cystic Fibrosis (CFTR), alpha-1 antitrypsin deficiency (ATZ), and Gaucher disease (GCase). These insights could potentially lead to novel treatments for these conditions.

NIH Research Projects · FY 2025 · 2024-08

UNIVERSITY OF IOWA (UI) INJURY PREVENTION RESEARCH CENTER (IPRC) ABSTRACT Established in 1991, the UI IPRC aims to prevent, control, and optimize recovery from injuries and violence, especially in rural communities. The UI IPRC has grown to include 70 researchers from 30 departments and nine Colleges across the UI campus, as well as a wide network of practice partners representing local and state government, community organizations, and business. Over the next funding cycle, the UI IPRC will conduct innovative and multidisciplinary research, training and education, and outreach with a focus on reaching populations disproportionately affected by injury and violence. Our research projects will address social and structural factors that create inequities in injury and violence prevention among low-income African American families (Project 1), racial and ethnic minority populations living in rural communities (Project 2), rural residents with substance use disorders (Project 3), and rural older adults (Project 4). The UI IPRC will be led by an efficient organizational structure that promotes engagement and communication across internal and external research and practice partners. A Leadership Team will oversee daily operations, informed by: (1) an Executive Committee of UI IPRC and campus leaders, (2) eight Research and Practice Action Teams organized around our topical areas of interest (suicide prevention, adverse childhood experiences, drug overdose, older adult falls, road safety, trauma care, firearm safety, and intimate partner violence and sexual violence prevention), and (3) the UI Division of Diversity, Equity, and Inclusion to ensure our activities and outputs proactively and purposely promote equity in injury and violence prevention. The Leadership Team will also be informed by two external advisory groups, including the State Injury and Violence Prevention Advisory Committee comprised of public and private stakeholders working in injury and violence prevention practice. The overall aims of the UI IPRC are to: Maintain an efficient, effective management structure that supports and sustains program growth, promotes equitable prevention efforts across populations disproportionately affected by injury and violence, and integrates academic and practice expertise to translate research into effective programs and policies (Administrative Core); Promote and advocate for equitable injury and violence prevention across diverse populations and serve as a trusted information center for partners and the public in the region and nation (Outreach Core); Provide multidisciplinary, inclusive, and accessible academic and professional training and education to advance an equitable field of injury and violence prevention (Training and Education Core) and; Support scientifically rigorous and innovative research through our four Research Projects and competitive Exploratory Research Project program, which is sponsored annually by $90,000 in institutional commitment. A primary goal of the UI IPRC over the next funding cycle is to make significant progress toward closing implementation gaps between injury and violence prevention research and practice in rural populations.

NIH Research Projects · FY 2024 · 2024-08

ABSTRACT Non-invasive recordings of human brain activity – be it of BOLD or neural field potentials – all share a common, insurmountable weakness: it is impossible to identify whether amplitude changes to these signals are due to the excitation or inhibition of their neural generators (i.e., the underlying patches of cortex). Hence, there is a critical need to develop non-invasive measures of the moment-to-moment physiological excitability of the human cortex. Such a method exists for primary motor cortex. The TMS-induced motor evoked potential (MEP) in the electromyogram indexes the physiological excitability of cortico-motor tracts originating in primary motor cortex (M1). The MEP increases alongside motor-neuron firing during movement preparation and decreases alongside reductions in M1 firing during movement cancellation. Here, we aim to test whether a signal with similar properties can be derived outside of M1. Specifically, we aim to test whether the TMS-evoked potential (TEP) in EEG recordings from human cortex similarly reflects changes in the cortical excitability of that underlying cortex evoked by cognitive processes. The TEP is an EEG amplitude deflection that occurs after single pulses of TMS applied anywhere on the brain. We will use a cognitive task to differentially induce the excitation and inhibition of the same cortical region outside of M1: the frontal eye fields (FEF). The firing rate of FEF neurons is known to increase during memory- guided saccades and decrease during the anticipation of anti-saccades (while notably, non-invasive BOLD recordings show signaling increases in both conditions). We will perform an MRI-guided, sham-controlled investigation of combined EEG and TMS to test whether the TEP – unlike fMRI or EEG – faithfully indexes these changes in task-related neuronal firing. If so, this work would provide fundamentally novel, original method to non-invasively measure the excitability and inhibition of cortical areas outside of M1.

NIH Research Projects · FY 2025 · 2024-07

Abstract Influenza A viruses (IAV) pose a constant threat to human health through both seasonal epidemics and occasional pandemics, which are often caused by transmission of IAV strains from zoonotic reservoirs. With the exception of bat IAV, all other IAV strains infect host cells by binding to sialic acid on glycoconjugates (sialoglycans). Various types of cell surface sialoglycans (N-glycans, O-glycans, glycolipids) display significant diversity in both structure and carbohydrate composition. In addition, the sialoglycan repertoire can vary between cell types and across different IAV host species. Thus, defining the structural features in sialoglycans necessary for IAV infection across different host species is critical for our understanding of zoonotic transmission into humans. Importantly, there are no reliable strategies that can comprehensively assess and identify zoonotic IAV strains capable of causing human infections. To define the types of sialoglycans that facilitate IAV infection, we utilized the CRISPR/Cas9 technique and truncated different types of sialoglycans in a human lung epithelial cell line either individually or in combination, by targeting glycosyltransferases essential to biosynthesis. Our studies show that sialic acid on N-glycans, O-glycans and glycolipids can independently serve as a receptor for several IAV strains from both human and zoonotic hosts. Interestingly, truncation of all three types of glycans significantly decreased the replication of human by not avian IAV strains, demonstrating that IAV strains from avian hosts are more flexible in their requirement of sialoglycan structures. Here we propose to utilize the CRISPR/Cas9 technique to define the structural features of sailoglycans necessary for IAV infection and adaptation across various host species using primary differentiated cells. Importantly, we will develop a single cell multi-omics platform to reliably identify zoonotic IAV strains with the potential to cause human infections. These studies will provide significant insights into our understanding of how the sialoglycan repertoire shapes host adaptation and fitness of IAV strains.

NIH Research Projects · FY 2025 · 2024-07

Abstract Pneumonia is the leading cause of infection-related deaths worldwide, a fact that is set to rise exponentially with the SARS-CoV2 pandemic. Recovery from pneumonia requires both clearance of the pathogen and resolution of infection, the latter of which is critical to resume normal lung function. While both processes are important to host health, there is vastly less known about the mechanisms that regulate resistance to and resolution of tissue injury during pneumonia, representing a large knowledge gap in our understanding of the biology of the lung and its repair processes. Here, we propose that lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) modulates acute pulmonary inflammation in way that promotes resolution through reprogramming of leukocyte response. LOX-1 is a class E scavenger receptor, primarily known for its role in promoting vascular inflammation during atherosclerosis. In direct contrast, our data suggests that LOX-1 has a unique function in the lung, where it prevents edematous lung injury and inflammation, independent of bacterial clearance in murine models of Escherichia coli and Streptococcus pneumoniae pneumonia. Moreover, LOX-1 and its major ligand oxidized low-density lipoprotein (oxLDL) are elevated in patients with ARDS as a result of a confirmed diagnosis of pneumonia. Analysis of the cellular expression of LOX-1 in the lung revealed that alveolar macrophages and recruited (airspace) neutrophils are uniquely enriched for LOX-1 expression. Hematopoietic cells are also likely sources of LOX-1-dependent protection, as LOX-1-/- (WT recipient) chimeras are significantly more protected from injury than WT (LOX-1-/- recipient) chimeras during pneumonia. Assessment of the specific effects of LOX-1 inhibition on alveolar macrophages demonstrated that with inhibition macrophages are skewed towards inflammation and exhibit metabolic changes associated with increased glycolysis and lower fatty acid oxidation consistent with inflammatory macrophages. Moreover, we discovered that recruited neutrophils differ in their expression of LOX-1, where about half of neutrophils are positive during infection. Curiously, we also found phenotypic differences associated with LOX-1+ neutrophils that suggest increased cholesterol metabolism, which may uniquely promote tissue resolution. Taken together, leukocytes are an important source of LOX-1 and are likely responsible for LOX-1-dependent protection during pneumonia. However, whether and how LOX-1 elicits its protective effects on leukocytes is not known. Thus, we propose a central hypothesis that LOX-1 signaling evokes tissue-protective mechanisms in leukocytes (K99), that are associated with metabolic changes consistent with reduced inflammation and increased tissue recovery (R00). Results from our investigations will be the first to elucidate how LOX-1 is regulated at the transcriptional and metabolic level in the unique microenvironment of the lung, where it likely facilitates recovery from pneumonia and lung homeostasis.

NSF Awards · FY 2024 · 2024-07

Comprehensive consumer privacy protection regulations are now gaining traction in the United States and globally. These regulations require many organizations to comply with mandates that require disclosure of data gathering and usage practices and allow consumers to control their personally identifiable information by enabling data access, deletion, and usage restrictions. Unfortunately, it is challenging to verify organizations' compliance with these regulations at scale due to limited resources at enforcement agencies. The project team is addressing this challenge by developing a variety of innovative computational techniques to improve the ability of enforcement agencies to conduct large-scale compliance audits. The project is identifying low-cost mechanisms for improving organizations' rates of compliance with these regulations. In addition to advancing the state-of-the-art in Internet measurement and privacy research, the outcome of the project facilitates stronger consumer protections by developing tools that empower privacy regulation enforcement. The integrated education plan is increasing students' awareness and interest in privacy regulatory mechanisms and research. The overarching goal of this project is to facilitate more efficient privacy regulation compliance verification by developing automated audit methodologies. The methods developed use a law-first (i.e., regulation-aware) approach to the construction of a disclosure and data rights auditing framework. This contrasts with the current norm of performing general measurements (i.e., regulation-unaware) and then attempting to make observations about the state of regulatory compliance within an ecosystem. The project team investigates law-aware approaches to automate policy analysis for verifying compliance with common disclosure mandates in privacy regulations, construct methodologies for verifying compliance with common data rights mandates in privacy regulations, and develop low-cost notification-based mechanisms for improving organizations' rate of compliance with privacy regulations. This project is jointly funded by SaTC and the Established Program to Stimulate Competitive Research (EPSCoR). This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2024 · 2024-07

Non-Technical Paragraph: Plant reproductive structures come in many forms from fertile leaves to cones to flowers. The one commonality amongst all of these reproductive structures is the sporangium where the genetic material is halved. The transition to sporangium initiation and its subsequent development are essential for the production of plant genetic diversity, the completion of the plant life cycle, and the production of seeds. The evolution and development of sporangia are key to the success of land plants. Although the molecular genetics of sporangium development have been well studied in flowering plants, there is little comparative data across land plants. This project will investigate the molecular genetics of sporangium development in the model fern Ceratopteris. This research will allow us to understand the evolution of sporangia across plants and will fill a gap in our knowledge about plant reproduction. Furthermore, this knowledge may provide new insight in crop improvement as seed and fruit production is a major aspect of agriculture. This interdisciplinary collaborative project will train participants from high school students to postdoctoral fellows. Technical Paragraph: The sporangium is the fundamental reproductive structure common to all land plants. The evolution and development of sporangia have been key to the reproductive success and diversity of land plants. The evolution of distinct sporangia evolved three times independently and was a necessary innovation for the evolution of the seed. The evolution of smaller sporangia with an effective dehiscence mechanism is key to the reproductive success of leptosporangiate ferns, the largest group of ferns. Therefore, elucidating a core sporangia development network will provide insights into not only the reproductive structure common to all plants but also the evolution and development of structures that are key to agriculture. Despite its fundamental importance, a comprehensive understanding of the evolutionary developmental genetics of the reproductive transition and concomitant sporangia development across land plants is lacking. This project will leverage the unique advantages of the model fern Ceratopteris with a combination of established and emerging technologies to address this major knowledge gap. This project will use a multi-pronged approach combining analyses of candidate gene evolution with phylogenetic, expression, and functional analyses as well as discovering new genes and the genetic network in the model fern Ceratopteris using in situ transcriptomics and LCM RNAseq. In addition, living collections will be leveraged to study the morphological diversity of reproductive structures across ferns. The collaborative project brings together unique skill sets from botany and developmental genetics to plant biotechnology. This project will further develop Ceratopteris as a model species for plant biology studies. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2024 · 2024-07

PROJECT SUMMARY/ABSTRACT Peptide receptor radionuclide therapy (PRRT) with [177Lu]DOTATATE improves quality of life and survival in patients with advanced neuroendocrine tumors; however objective tumor regression is infrequent and complete responses are exceedingly rare. On the other hand, exciting-emerging evidence suggests that PRRT with alpha-emitters has the potential to extend PRRT to tumor regression and even complete response. In this study we propose to develop a new theranostic pair using [203Pb]PSC-TOC (imaging) / [212Pb]PSC-TOC (alpha emitter) for image-guided dosimetry based personalized therapy for neuroendocrine tumors. In Specific Aim 1 of the proposal, we will optimize the radiolabeling and production of [203/212Pb]PSC-TOC to prepare for its use in clinical trials and perform a preclinical dose escalation trial in immune-competent mice to investigate drug toxicity and the relation of toxicity with radiation dose (using residence time as a surrogate) to the organs. The accurate measurement of radiation dose from alpha-emitters is challenging due to dependence of the dose on the distribution of the radiopharmaceutical at cellular and subcellular level. In Specific Aim 2, we propose to develop a surrogate for organ dosimetry based on the residence time of the radiopharmaceutical in a human imaging trial with [203Pb]PSC-TOC, This methodology requires serial imaging over multiple days. We will then extend the dosimetry methodology to develop a predictive model to identify the best single imaging time point that predicts kidney accumulation, similar to our previous work with 90Y-DOTATOC, for translation of the dosimetry procedure into the clinical practice. Finally in Specific Aim 3 we will conduct a Phase 1 dose escalation trial of personalized dosimetry-guided therapy with [212Pb]PSC-TOC in patients with advanced stage NETs who have progressed or are refractory to conventional PRRT with beta emitters. The dose escalation paradigm will be based on escalating critical organ dose limits (using residence time as surrogate for dosimetry). The primary objective of the Phase 1 clinical trial will be the identification of the maximum safe kidney dose surrogate from treatment with [212Pb]PSC-TOC that should be used for a subsequent Phase 2 efficacy trial with the agent. As a secondary objective we will assess objective tumor response to PRRT with [212Pb]PSC-TOC. .

NIH Research Projects · FY 2025 · 2024-07

Project Abstract Salmonellosis continues to be one of the most important causes of food-borne illness in the U.S. Furthermore, multiple-antibiotic resistant Salmonella strains are becoming untreatable infectious diseases. Poultry meat and eggs are major sources of Salmonella food-borne illness, due to carriage of these bacterial pathogens in the intestinal microbiome. The NIH goal to reduce Salmonella human infections is directly linked to the USDA goal of reducing carriage of Salmonella in poultry. While these goals have been high priorities for many years, current control efforts have been uniformly unsuccessful. Accordingly, new approaches are needed to address this infectious disease problem in the United States. The long-term goal of our work is to reduce or eliminate carriage of Salmonella in poultry flocks. The working hypothesis of this proposal is that an engineered probiotic strain that expresses a key Salmonella adherence factor, type 1 fimbriae, can outcompete pathogenic Salmonella strains for position in the intestinal microbiome of poultry. Significant reduction of Salmonella carriage in poultry will significantly improve the food safety of poultry and will decrease the incidence of salmonellosis. There are two specific aims in this proposal: 1) To optimize the binding activity of the type 1 FimH gene expressed in E. coli Nissle 1917, 2) Demonstrate that the hyper adherent E. coli strain can competitively exclude Salmonella strains from colonizing the intestinal epithelium of the poultry host. At the completion of this project, we expect to have demonstrate that an engineered E. coli probiotic strain can significantly reduce intestinal carriage of Salmonella in chickens. The focus of this project is to provide an avenue to reduce cases of human salmonellosis and reduce the human infection risks posed by multiple-antibiotic resistant Gram-negative bacteria.

NIH Research Projects · FY 2025 · 2024-07

Project Summary / Abstract Despite similar obesity rates in both sexes, the underlying biology of excessive weight gain in women and men is believed to differ significantly. Neurons in the ventromedial nucleus of the hypothalamus (VMH) exhibit sexually dimorphic characteristics and play a crucial role in energy balance. However, the signaling pathways within VMH neurons that contribute to sex-specific control of energy balance remain largely unknown. Recently, the primary cilium, a solitary antenna-like sensory organelle found in most mammalian cells, including neurons, has emerged as a critical regulator of metabolic homeostasis. Human genetic studies have identified the cilia-specific adenylate cyclase 3 (Adcy3) as a significant obesity-risk gene and animal studies have further shown that global Adcy3 knockout mice develop severe obesity, particularly in females. However, the mechanism underlying Adcy3's contribution to female-biased weight gain remains unknown. Our recent findings indicate that selective deletion of Adcy3 in VMH neurons leads to female-specific obesity without a significant increase in food intake. Adcy3 is enriched in estrogen receptor alpha (ERα)- and melanocortin 4 receptor (Mc4r)-expressing neurons in the ventrolateral subdivision of VMH (VMHvl), which are known to affect energy expenditure (EE) in female mice. Additionally, we found that ERα binds to a putative promoter region of the Adcy3 gene. Based on these compelling preliminary observations and previous literature suggesting that Mc4r, a Gαs-coupled receptor enriched in primary cilia, is a direct transcriptional target of ERα within VMHvl neurons and increases EE specifically in female mice, we propose a novel hypothesis that Adcy3 functions downstream of ERα-driven Mc4r signaling at the primary cilium of VMHvl neurons to increase EE in females by modulating the excitability and/or neurotransmission of these neurons. This hypothesis will be tested by pursuing following three aims: Aim-1) determine if VMHvl Adcy3 is necessary for metabolic homeostasis by acting downstream of estrogen-ERα and Mc4r signaling, Aim-2) determine if increasing Adcy3 activity in VMHvl ERα+ neurons is sufficient to protect against obesity, and Aim-3) determine if loss of Adcy3 reduce the excitability and/or the neurotransmitter release of VMHvl ERα+ neurons. The proposed research aims to significantly advance our understanding of hypothalamic signaling pathways involved in sex-specific regulation of energy homeostasis. Additionally, it will provide new insights into the largely unknown mechanisms by which ciliary cAMP signaling affects the physiology of key hypothalamic neurons that are crucial for metabolic homeostasis. Such knowledge may ultimately lead to the development of a novel strategy to effectively prevent or treat obesity in females.

NIH Research Projects · FY 2025 · 2024-07

Project Summary/Abstract Hypertension is a common chronic heart condition resulting in cardiac hypertrophy, dysfunction and heart failure. Mediator kinase, Cdk8 expression is increased in human and mouse models of heart failure and is sufficient to induce changes in gene expression networks resulting in cardiac dysfunction. The current proposal has three objectives: 1) determine the therapeutic potential of small-molecule Cdk8 inhibitors. 2) identify Cdk8 kinase substrates that are promising, novel therapeutic targets; and 3) determine how Cdk8 mediates cardiac transcriptional responses in vivo (e.g., by phosphorylating transcription factors and modifiers) using both the small-molecule Cdk8 inhibitors and Cdk8 conditional cardiac knockout mice. Our central hypothesis is that Cdk8 in cardiomyocytes regulates the transition from a steady-state to a hypertrophic gene program, driving functional remodeling and cardiac hypertrophy. Our preliminary data implicate Cdk8 and its substrates as potential therapeutic targets to reduce activation of the hypertrophic gene network, cardiac hypertrophy, and dysfunction in response to pathological hypertrophic stimuli. The central hypothesis will be tested via the following specific aims: (1) Confirm that Cdk8 controls the initial cardiac response to pro- hypertrophic stress [and in the later stage of HF decompensation]. (2) Determine the transcriptional consequences of Cdk8 expression and activity during hypertrophic stress. (3) Identify Cdk8 targets that differentially regulate the cardiac hypertrophic response. At the successful completion of the proposed research, the expected outcomes are: an understanding of the Cdk8 kinase-dependent and kinase-independent mechanisms that serve as a key nodal point in transcription to drive cardiac pathological gene expression networks and contribute to heart disease, and the identification of potential new treatment modalities for pathological cardiac hypertrophy and the subsequent disease. These results will provide a strong basis for further development of therapeutics targeting transcriptional mechanisms that initiate remodeling of gene networks in response to cardiac stressors, which is expected to have a significant impact on treating hypertensive cardiac hypertrophy by potentially reducing cardiac transcriptional remodeling. This research aligns with the NHLBI’s mission to promote the prevention and treatment of heart disease by further defining the activation of the hypertrophic gene network in models of heart disease.

NSF Awards · FY 2024 · 2024-07

The width of tree rings are more sensitive to dry extremes than wet extremes in rainfall. Therefore long-term records from tree rings on past rainfall do not robustly record wet extremes. This bias in the baseline data of the past rainfall variability is problematic for water management and projecting the impact of future rainfall extremes. The goals of this project are to use dendrometers (instruments that record tree growth in real time) to measure the response of tree growth to rainfall at four sites that are part of the AmeriFlux network, sites that have weather stations that measure detailed records of rainfall through time. The investigators will use what they learned from the dendrometer study on how trees respond to wet extremes to refine reconstructions of rainfall and wet extremes from the past from an existing archive of tree ring cores, and use models to study the uncertainty in tree ring reconstructions of rainfall extremes. The project will include training of a postdoc, graduate student and undergraduate students, and public outreach events on climate change through collaboration with a nonprofit cinema's "Science on Screen" series. Tree-ring based hydroclimate records of wet extremes are not as robust, which is problematic for water management and projecting the impacts of future hydroclimate extremes. The goals of this project are to use dendrometers to measure how tree growth responds to changes in the frequency, intensity and timing of precipitation in trees at sites in the AmeriFlux network in Arizona, New Mexico, Colorado and Indiana; reconstruct wet extremes of precipitation from previously collected tree ring width data in the International Tree Ring Database (ITRDB) in a variety of climate zones in the USA; and use forward proxy modeling to evaluate uncertainties in tree-ring hydroclimate reconstructions and estimate the impact of future hydroclimate extremes on forest health. The Broader Impacts consist of training a postdoc, graduate student, and undergraduate students; and climate communication in partnership with a nonprofit cinema’s “Science on Screen” series. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2024-07

5T32GM149386-02 Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. The interface of Behavioral and Biomedical sciences is one of the most vibrant frontiers of science today. The overarching objective of our proposed predoctoral Training Program, Understanding Health and Disease at the Behavioral-Biomedical Interface, is to train the next generation of behavioral science researchers to utilize rigorous biomedical methodologies and conceptual frameworks that stretch the boundaries of their thinking and research to position them to make transformative breakthroughs in addressing issues of health and disease. The program is built on the foundation of an existing NIGMS-funded T32 established in 2014, adding new programmatic, evaluation, and curricular plans, which bring greater evidence-based focus on mentorship, rigorous and reproducible research, and career development. The Program provides predoctoral behavioral science students in the Department of Psychological and Brain Sciences (PBS) at the University of Iowa with an integrated program of coursework and laboratory experiences. These include: (1) Broad-based training in the fundamentals of behavioral science including rigor, transparency, and reproducible science, quantitative methodology and experimental design, responsible conduct of research, and key issues in health psychology and neuroscience; (2) In-depth training in pathophysiology and specific biomedical research areas (including conceptual frameworks, driving hypotheses, and laboratory techniques); (3) Guidance and mentoring for development and implementation of an innovative independent research program that spans both behavioral and biomedical science; (4) Career development; and (5) Cohort building activities that support development of a supportive peer group. Behavioral mentors are from PBS; biomedical mentors are from the Colleges of Medicine and Public Health. In the current grant, we have used the T32 support and two matching slots from the Graduate College to recruit outstanding students and to provide a catalyst for the Program, which has matured into a dynamic setting for scientific exchange between behavioral science students and biomedical mentors and their labs. Since the start of the current program, 51 outstanding students have participated in the Training Program. (19 have had T32 support) We have developed Seminars and Retreats, featuring career development, science communication, manuscript and grant writing, cohort-building, networking, and discussions of cutting-edge research at the Behavioral-Biomedical interface, which we will continue in the new Program. The application requests 6 slots/year to provide these impactful training experiences for our talented pool of trainees. The program is highly relevant to public health, as training at the Behavioral-Biomedical interface will enable these scientists to innovatively address mechanisms influencing human health and disease.

NIH Research Projects · FY 2025 · 2024-07

Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. This application requests support for nine trainees for a Predoctoral Training Program in Biotechnology, the University of Iowa Biotech-TP. These nine lines will be matched by six more lines by the University of Iowa through its Center for Biocatalysis and Bioprocessing (CBB). Combined, the NIH and CBB fellowships will provide training in the applications of biological and physical sciences to biotechnology-related research. The CBB and Iowa Biotech-TP create a vibrant community of trainees and dedicated faculty trainers from four University of Iowa colleges and ten academic departments. The Iowa Biotech-TP is administered by a Leadership Team and an Executive Committee. An External Advisory Board of biotechnology industry leaders provides independent input to assure relevance to the needs of the biotechnology industry and research. Our Iowa Biotech-TP will train future leaders in biotechnology-related research and will equip them to succeed in industrial, academic and governmental research enterprises. Our cohort of trainees will come from different scientific backgrounds and will be trained in a way that fosters effective communication with one another, which is critical to our ability to make significant advances in biotechnology in the future. The Iowa Biotech-TP is designed to provide an extensive education to trainees, including academic training covering qualitative and quantitative aspects of biotechnology, hands-on introduction to industrial methods, and preparation for professional life in biotechnology. Trainees are required to: a) complete an industrial internship lasting three months; b) must complete at least three (3) semester hours of coursework in four of five core areas of biotechnology (Biocatalytic Sciences, Bioprocessing, Molecular and Synthetic Biology, Data Handling and Computational Analysis, and Professional Development); c) take courses in Responsible Conduct of Research and Mastering Reproducible Science; d) participate in the “Perspectives in Biotechnology” class and activities every semester including presentations at the annual CBB and the annual Iowa Biotech-TP Spring Symposium; e) participate in TP’s seminars; and f) participate in various trainee-cohort career building and networking activities. Our fifteen proposed trainees (9 NIH and 6 CBB fellows) will be selected annually toward the end of their first year in graduate school, and support for trainees may be renewed for up to two years, however all trainees continue in the program until graduation. The recruiting pool is based not on departmental affiliation but on interest in biotechnology and graduate training. In addition to six fellowships, the CBB will provide administrative support, as well as financial support to offset the effort of the Iowa Biotech-TP leadership team. The CBB will also provide training in industrial settings and will expose trainees to commercial aspects of biotechnology. These CBB matching funds will greatly increase the effectiveness of the funds requested from NIH and ensure an extensive emphasis on industrial training.

NIH Research Projects · FY 2025 · 2024-07

Compelling evidence highlights the central role of islet β-cell failure in the transition from insulin resistance to Type 2 diabetes (T2D). Defects in the β-cell's secretory pathway accompany T2D onset and include changes to insulin trafficking, reduced insulin storage, and impaired proinsulin processing. The cellular mechanisms underlying these defects are not completely understood, yet could have considerable therapeutic value if β-cell function could be restored. Our data highlight altered ER redox homeostasis as a novel mechanism that contributes to β-cell dysfunction in human and rodent diabetes models. Using novel proinsulin trafficking reporters, we identified a delay in the ER export of proinsulin that leads to inadequate insulin granule production. We linked delayed proinsulin export to hyperoxidation of the ER lumen and showed that restoration of ER redox homeostasis rescued proinsulin export and insulin granule formation. The hyperoxidized ER environment may interfere with proinsulin export by contributing to the formation of misfolded disulfide-linked proinsulin oligomers previously reported in human T2D β-cells. Ultimately, this proinsulin trafficking delay limits the production of insulin granules, which may explain the increase of proinsulin and loss of insulin granules prominent in T2D. Our proposed studies are designed to define the molecular mediators of β-cell ER redox control and address how ER hyperoxidation develops in T2D. Our preliminary data have identified a novel mechanism linking defects in mitochondrial and redox metabolism with changes to ER function in the decline of insulin production in T2D. Our central hypothesis is that metabolically supplied reductive redox donors are necessary for the β-cell's ER redox buffering capacity to sustain efficient proinsulin folding for insulin production. The goals of this proposal are to establish a critical link between glucose metabolism and ER redox control (Aim 1), define key mediators that buffer ER redox capacity (Aim 2), and determine how proinsulin folding impacts ER redox homeostasis (Aim 3).