University Of Minnesota

NIH Research Projects · FY 2026 · 2013-04

PROJECT SUMMARY/ABSTRACT Prostate cancer (PC) is the most frequently diagnosed male cancer. Surgery or radiation therapy are curative treatments for localized PC while systemic endocrine therapies are standard-of-care for advanced or metastatic PC. The molecular target of endocrine therapy is the androgen receptor (AR), a transcription factor activated by the steroid hormones testosterone and dihydrotestosterone. Because PC cells require AR for proliferation and survival, inhibiting testosterone production (with gonadotropin releasing hormone analogs and/or abiraterone acetate) and using competitive AR antagonists to block testosterone actions (such as enzalutamide, apalutamide, and darolutamide) are the cornerstones of endocrine therapy. Unfortunately, endocrine therapy is not curative and the disease will inevitably progress to advanced castration-resistant PC (CRPC). CRPC is a lethal disease stage for which no curative therapies exist. Our analysis of tumor specimens from patients has shown that one of the most frequent alterations occurring in CRPC is structural rearrangement of the AR gene. Our preliminary data show that AR gene rearrangements uncouple the AR transcription factor from endocrine regulation and also from negative feedback regulation that occurs when tumor suppressor genes like PTEN are lost. This uncoupling renders AR activity insensitive to endocrine therapies and promotes CRPC. The long term goals of this project are to harness AR gene rearrangements as biomarkers to guide more effective use of current and future CRPC therapeutics, and to develop novel therapeutics that can overcome the effects of AR gene rearrangements. To achieve these goals, we will develop new mouse models of CRPC progression that harbor AR gene rearrangements and PTEN loss, and use these models to identify mechanisms by which AR gene rearrangements promote PC progression and therapeutic resistance. These models will fill a long-standing void in the field: a lack of mouse models reflecting clinically-relevant AR alterations. We will test the utility of these models for advancing CRPC research by evaluating CRPC responses to AR-targeted therapeutics in a whole-organism context. We will also use third- generation genome structural variation analysis techniques to interrogate the structure of certain AR gene rearrangements that occur via complex, multi-step mechanisms. This work is expected to provide clarity about the role and origin of the most frequent and complex patterns of AR gene rearrangements in CRPC. Finally, therapeutic vulnerabilities of CRPC models harboring AR gene rearrangements will be evaluated using a set of candidate AR-targeted therapeutics. We will also use computational methods to nominate non-AR-targeted therapeutics that will have efficacy in CRPC tumors harboring AR gene rearrangements. Collectively, this work is expected to enhance understanding of AR gene rearrangements in CRPC progression, and yield new models, biomarkers, and therapeutics that can be used to combat this lethal subset of the disease.

NIH Research Projects · FY 2026 · 2013-03

PROJECT DESCRIPTION Disorders of the nervous system are becoming more prevalent in our society, especially considering the growing elderly population who are more vulnerable to neurodysregulation. To meet the challenge of developing new and effective therapies to treat these disorders, we need to consistently inspire intelligent and talented undergraduate students to enter careers in neuroscience research. This need is particularly acute among populations of students who are currently underrepresented in the field of neuroscience research. Published analyses have made it clear that making students aware of research fields early in their college careers, especially by involving them directly in the research process, is an extremely effective way of developing a student’s interest in research as a future profession. For over 30 years, the University of Minnesota has recognized and met this challenge by offering summer residential research programs in biomedical sciences. This proposal is to fund a neuroscience component of these summer programs in which we will train 8 undergraduate students who have completed their freshman or sophomore years in college. We will recruit students nationally, focusing on students from groups that are underrepresented within the neuroscience research profession, including economically disadvantaged and disabled students. We will provide them with a 10- week intensive residential research experience that will include professional mentoring (academic survival skills and preparation for graduate school) as well as workshops on research ethics. Our goals are to inspire a new generation of neuroscience researchers as well as to create a national mentoring pool who will accept that responsibility for future generations of students. In turn, we expect these individuals to become part of the research infrastructure dedicated to solving medical problems of nervous system dysfunction.

NIH Research Projects · FY 2026 · 2012-09

Project Summary/Abstract—Overall The Caenorhabditis Genetics Center (CGC) is the sole comprehensive repository and distribution center for the nematode Caenorhabditis elegans, a premier model organism for biomedical research studies. The overall objective of this animal resource is to promote research on C. elegans by acquiring, maintaining, and distributing genetically characterized nematode stocks. Researchers in all 50 states and throughout the world use genetic stocks obtained from the CGC in diverse basic and applied research endeavors, as well as for hands-on teaching of experimental science. Studies using C. elegans have led to fundamental insights into basic biological mechanisms, including the genetic basis of programmed cell death, the discovery of microRNAs, and the mechanism of RNA interference in animals. The nematode has also provided key insights into the cell signaling mechanisms, cancer progression, and neurodegenerative diseases. In addition, C. elegans serves as a key model for illuminating our understanding of parasitic nematodes with relevance to human and livestock health. As the only general stock center for C. elegans, the CGC is an extremely important international research resource, supporting research in these diverse areas and in educational endeavors. The CGC provides about 30,000 strains per year to thousands of laboratories; with a collection of 23,000 unique strains, a number still increasing in proportion to the growth of the field, the CGC not only facilitates research, but also ensures that valuable strains are preserved. Strains are distributed upon request through an on-line ordering system with a scheme of user fees in place to help defray costs and support CGC activities. The CGC closely monitors user needs and devises small research projects to support the community. Because essentially every lab uses fluorescent proteins, and there is demand for brighter, more photostable fluorescent proteins, in more colors to allow multi-plexing, the CGC will develop a pipeline to quantitatively evaluate the in vivo properties of a new set of fluorescent proteins in worm, enabling scientists to choose the optimal versions for their applications.

NIH Research Projects · FY 2024 · 2012-08

PROJECT SUMMARY/ABSTRACT The overall goal of this proposal is to examine the changes in cortical network activity in the parkinsonian state and how these are modified during DBS or administration of levodopa and improvement in motor signs. Although multiple studies have examined the changes in basal ganglia activity that occur in the parkinsonian state, there are few studies and little understanding of the changes in cortical neuronal activity, function, how these changes mediate the development of motor signs, or how they are modulated during deep brain stimulation (DBS). In our previous proposal we have made significant strides in characterizing the changes in neuronal activity in the supplementary and motor cortices (SMA and MC) in the parkinsonian condition and during STN or GPi DBS using the MPTP monkey model of PD. The current proposal continues and broadens this work to include the dorsolateral prefrontal and dorsal premotor cortices (DLPFC and PMd), areas with known anatomical connections to the basal ganglia, which are intimately involved in motor control and in the development of parkinsonian motor signs but have been largely ignored in nonhuman primate studies of PD pathophysiology. In this proposal we will examine cortical network function in PD by characterizing the changes in neuronal activity that occur within and across the DLPFC, PMd, SMA and MC in the parkinsonian state using the MPTP monkey model of PD, examine how DBS in the internal and external segments of the globus pallidus (GPi and GPe, respectively) and subthalamic nucleus (STN) modify this activity, and how the changes associated with DBS compare to that which occurs with administration of levodopa. We will simultaneously record from populations of cells in the DLPFC, PMd, SMA and MC using Utah arrays in the DLPFC, PMd, and MC, and Gray Matter devices in the SMA, at rest and during passive and active movement and compare results across the following conditions: normal, parkinsonian, parkinsonian + DBS in three different sites (GPe, GPi and STN), and parkinsonism + L-dopa (alone and in combination with DBS in each of the three sites). We will explore the role of GPe as an alternative target to STN and GPi DBS given our previous studies demonstrating its suppressive effects on both STN and GPi. Characteristics of neuronal activity and connectivity changes will be correlated with the development of parkinsonian motor signs, their amelioration during DBS and L-dopa and to changes in the planning, initiation and execution of movement.

NIH Research Projects · FY 2026 · 2012-05

Project Summary/Abstract This proposal seeks continued funding to expand and enhance IPUMS DHS, which eliminates barriers to over- time and cross-national analyses with the Demographic and Health Surveys (DHS), the world's longest running survey series on health and fertility in low- and middle-income countries. With powerful data discovery tools, thousands of harmonized variables, easy-to-access documentation, and social and environmental context variables linked to individual records, IPUMS DHS dramatically reduces the cost and increases the range, rigor, and reproducibility of research on population health. The temporal and geographic scope of the IPUMS DHS database enables cutting-edge population health research on topics including fertility, contraception, neonatal and under-five mortality, low birth weights, child stunting and wasting, diarrhea, nutrition, food safety, obesity, risky sexual behavior, access to health care, women’s empowerment, intimate partner violence, water and sanitation, and the impact of armed conflict on reproductive choices. The proposed innovations to and expansion of the database in the next phase will exponentially increase the potential research topics enabled by IPUMS DHS. The continuation project has five specific aims: Aim 1. Achieve global coverage. IPUMS DHS now incorporates microdata from 170 DHS surveys from 41 African and Asian countries, but it does not yet cover Latin America, the Caribbean, Central and East Asia, Eastern Europe, or Oceania. The next phase will add survey series from new regions, while also adding the latest surveys from Africa and South Asia. Aim 2. Unlock comparative research across IPUMS global health databases. IPUMS DHS will become even more powerful in the next phase when the database is made interoperable with other global health data series, such as UNICEF’s Multiple Indicator Cluster Surveys (MICS). When coupled with data from MICS, almost 90 percent of DHS countries will have three or more samples to compare across time, and 98 percent will have data from the 21st century. Aim 3. Enable cutting-edge research on the impact of social and environmental context on health. The third project phase will triple the number of social and environmental context variables in IPUMS DHS. With these new data, researchers will conduct path-breaking research, such as global comparisons of the impact of rising sea levels on the health of individuals in communities near coastlines. Aim 4. Expedite data analysis by simplifying or eliminating researchers’ data management tasks. Proposed enhancements will enable users to filter samples based on topical content, variable availability, and country characteristics. We will also develop an Application Programming Interface (API), allowing users to automate the tasks of defining and executing data extracts. Aim 5. Support and expand our user community. IPUMS DHS is committed to democratizing access to population data. The project will continue to provide robust individualized user support, webinars, and workshops at key conferences, while introducing online tutorials and code-sharing opportunities.

NIH Research Projects · FY 2025 · 2011-09

The development of liver metastasis is dependent upon bidirectional interactions between cancer cells and the liver microenvironment. Transforming growth factor beta (TGFβ), released from cancer cells and other resident liver cells, induces activation of hepatic stellate cells (HSCs) into myofibroblasts that in turn promote liver metastasis. The long-term goal of our program is to define mechanisms governing HSC activation and develop strategies to target HSCs and the prometastatic liver microenvironment. Recent advances suggest that HSCs are fueled by aerobic glycolysis, glutaminolysis, and free cholesterol, but mechanistic regulation of HSC metabolism is not fully defined. Glucose transporter 1 (Glut1) is a predominant glucose transporter isoform expressed by hepatic fibroblasts and it has to be on the plasma membrane for glucose to be transported into cells. Our Preliminary Data demonstrate that TGFβ1 induces endosome-to-plasma-membrane translocation of Glut1 and glucose uptake into HSCs by a mechanism dependent on non-receptor tyrosine kinase c-Src (Src) and vasodilator-stimulated phosphoprotein (VASP). While Src interacts with the small Rab GTPase Rab11 and Glut1 at the endosome, VASP interacts with Glut1 at the plasma membrane. Additionally, knockdown of Glut1 suppresses myofibroblastic activation of HSCs in vitro and tumor-promoting effects of HSCs in a tumor/HSC co-implantation mouse model. These findings led to the Central Hypothesis that the TGFβ1-induced localization of Glut1 on the plasma membrane and the subsequent glucose transport into HSCs that fuels HSC activation are mediated by Src at the endosome and VASP at the plasma membrane. In Aim 1, we will study how Src promotes Glut1 trafficking towards the plasma membrane, with a focus on its regulation on Rab11 activation at the endosome. We will also investigate how Src is activated in TGFβ1-stimulated HSCs. In Aim 2, we will elucidate how VASP retains Glut1 at the plasma membrane and promotes glucose transport into HSCs. We will also interrogate whether a lipid signaling pathway induces VASP phosphorylation in TGFβ1-stimulated HSCs. In Aim 3, we will use conditional SLC2A1/Glut1 knockout mice and portal vein tumor injection to test if HSC-specific Glut1 deletion suppresses HSC activation and colorectal liver metastasis in mice. We will also co-inject HSCs and tumor cells into the livers of mice to test if the interplay between Src and VASP modulates plasma membrane Glut1, glucose transport into HSCs, and HSC activation within the hepatic tumor microenvironment. The proposed work will reveal novel mechanisms related to metabolic regulation of HSC activation induced by TGFβ, which will help to identify new targets to inhibit HSC activation and the prometastatic liver microenvironment.

NIH Research Projects · FY 2024 · 2011-08

Nonalcoholic fatty liver disease (NAFLD), including nonalcoholic steatohepatitis (NASH) is the most common cause of liver disease in Western countries. The severity of NAFLD in humans correlates with systemic insulin resistance; risk of type 2 diabetes; and drives downstream complications, including cardiovascular disease, cirrhosis, need for liver transplantation, and liver cancer. As NAFLD progresses, mitochondrial oxidative dysfunction becomes a prominent feature, and human NAFLD exhibits progressive ketogenic deficits. Hepatocyte ketogenesis produces the ketone bodies acetoacetate (AcAc) and D-b-hydroxybutyrate (D-bOHB), which are products of incomplete fat oxidation. Measurements of ketogenesis are often used as a proxy for hepatic fat oxidation, but these measures fail to fully report hepatic fat oxidation, because ketogenesis is blind to complete fat oxidation in the tricarboxylic acid (TCA) cycle, which also varies over the course of NAFLD. Published and unpublished observations generated during the previous funding cycle suggest that ketogenesis provides vital feedback coordinating overall hepatocyte energy supply and demand. When mice are genetically programmed to be devoid of all ketogenesis, the liver compensates by increasing TCA cycle flux, but is predisposed to high fat diet-induced fibrosis, the feature most predictive of adverse outcomes in NASH. Conversely, when mice are genetically programmed to produce only AcAc, but not D-bOHB [via knockout of NAD+/NADH D-bOHB dehydrogenase (BDH1)], the liver compensates by decreasing TCA cycle flux, and is protected from high fat diet-induced fibrosis. These findings reveal unexpected relationships between energy supply and demand in liver that may have profound impact on how metabolic drug targets should be considered in NAFLD. Moreover, recent observations indicate that hepatocyte derived AcAc protects against fibrosis through oxidation in neighboring macrophages. Therefore, the central hypothesis of this proposal is that liver ketone metabolism modulates hepatic fibrogenesis through (a) tuning hepatocyte energy supply/demand balance and (b) metabolism of AcAc in the mitochondria of liver macrophages. This hypothesis will be tested through two Specific Aims. First, to reveal the role of BDH1 in NASH-relevant liver injury, mice lacking BDH1 selectively in hepatocytes will be interrogated using tracer-based mass spectrometry, nuclear magnetic resonance, and mitochondrial bioenergetics studies, together supporting sophisticated quantifications of carbon, electron, proton, and oxygen fluxes to construct relationships between mitochondrial efficiency and NAFLD-like pathogenesis. In the Second Aim, tracer and flux-based approaches will quantify the effects of ketone body exchange between hepatocytes and neighboring macrophages in NASH-like pathogenesis, using mice that lack succinyl-CoA:3-oxoacid-CoA transferase (SCOT), which is required for AcAc oxidation in macrophages. Together, the proposed experiments will define mechanisms through which ketone metabolism can be leveraged to protect the liver from worsening NAFLD injury, a clear unmet need with escalating public health implications.

NIH Research Projects · FY 2026 · 2011-07

PROJECT SUMMARY/ABSTRACT Veterinarian-scientists provide critical disciplinary and technical expertise for advancing biomedical research. Due to their broad understanding of animal anatomy, physiology, pharmacology, and disease, they possess key knowledge for cross-species comparative medicine and for experimentally-induced and naturally occurring animal models of human diseases. Veterinarian-scientists also provide contributions to human welfare through critical roles in One Health initiatives, including in global food security and in emerging and zoonotic diseases and ecosystem health. One key area of importance is that approximately 75% of recenUy emerging infectious diseases affecting humans are diseases of animal origin some of which are in wildlife reservoirs. However, the US National Research Council, an NIH Physician-Scientist Workforce Working Group Report, and the NIH Office of Research Infrastructure Programs have all emphasized that the veterinarian-scientist workforce is far underrepresented and underutilized in biomedical research. Reasons for this include limited access by veterinary students to biomedical research programs and appropriate training. The objective of our "Veterinary Summer Scholars in Comparative Medicine" T35 training program is to provide direct biomedical research experiences to first and second-year veterinary students in order to increase the numbers of researchers in the veterinary-scientist pipeline. Our approach will consist of 1) providing opportunities to conduct comparative biomedical research in an environment of collaboration and discovery by mentors who are basic and clinician-scientists, and 2) providing research training in the form of lectures, discussions and activities focused on responsible conduct and ethics in research, experimental design and quality assurance, conflict management, research communication, and career pathways in the biomedical sciences. New innovations described in this renewal application include additional science communication sessions, increased opportunities for continued research experiences during veterinary school, as well as more interprofessional interactions by our T35 trainees with other health professionals in the university's Clinical and Translational Science Institute (CTSI}, with trainees in our CVM T32 Comparative Medicine Training grant, and other similar health sciences programs to promote team-science. The proposed T35 training program involves a critical mass of faculty mentors from our health sciences schools (Medicine, Dentistry, Pharmacy, and Veterinary Medicine) at the University of Minnesota for providing multidisciplinary and state-of-the-art research experiences.

NIH Research Projects · FY 2025 · 2010-09

Summary Despite advances in tobacco smoking cessation interventions (pharmacological and behavioral), most smokers do not succeed at quitting, creating a major public health burden. Stress is one of the most commonly reported precipitants of tobacco craving and relapse. Tobacco withdrawal is associated with escalation of negative affect symptoms; our research has found multiple stress-related physiological and hormonal alterations during withdrawal that predict relapse. Modifying these stress-related biobehavioral changes may prove useful in reducing effects of stress. Cannabidiol (CBD) is a phytocannabinoid of cannabis with low abuse liability that has received increased attention in the retail market and cannabis research. Although CBD is aggressively marketed for addressing stress, little research has been done to characterize CBD’s physiological and mood effects, their implications in managing tobacco withdrawal symptoms, and the mechanism by which CBD may influence these symptoms. Our research will address these timely issues. This application builds on our current and previous funding periods (PI: al’Absi, R01DA027232) demonstrating that stress-related hormonal changes during tobacco withdrawal predict relapse. We have shown that tobacco dependence is linked with: 1) enhanced basal hypothalamic-pituitary- adrenocortical (HPA) activity; 2) blunted cortisol response to multiple stressors; 3) disrupted opioid regulation of the stress response; 4) association of attenuated stress response and early relapse; and 5) sex differences in changes during withdrawal and predictors of relapse; hormonal responses are better predictors of relapse in men, while withdrawal symptoms and craving are stronger predictors of relapse in women. Our recent research has also documented blunted emotion regulation among cannabis users. In the new cycle, we plan to conduct a multi-site, multi-group, multi-dose, double blind, within-subject study. We will address the following specific aims: 1) Determine the acute effect of CBD on the psychobiological mechanisms of the stress response in healthy participants; 2) Examine how tobacco dependence influences the acute effect of CBD on psychobiological mechanisms of the stress response; 3) Determine the effect of CBD on tobacco withdrawal-related changes in psychobiological mechanisms of the stress response in tobacco users; 4) Explore sex differences in the psychobiological mechanisms of the stress response and acute effects of CBD in dependent tobacco users. This research is the first to examine CBD's effect during exposure to acute stress and tobacco withdrawal using relevant measures that are known to be sensitive to acute stress and to tobacco withdrawal. The research builds on important preliminary results and uses rigorous, reproducible procedures.

NIH Research Projects · FY 2025 · 2010-07

7. Project Summary/Abstract This is a competitive renewal of the “Minnesota Training Program in Virology” following a highly productive funding period. Discoveries in virology research have led to many fundamental insights into molecular and cellular processes of cells, basic mechanisms of viral replication and pathogenesis, and strategies for how host cells respond to viral infection (i.e., virus-host interactions). Viruses and their capacity to cause serious diseases and death have had a profound impact on the history of humanity and continually threaten global health and economic stability. This was dramatically emphasized by the COVID-19 pandemic. This training program utilizes 44 accomplished preceptors, who are conducting research on a wide variety of important viruses. The Institute for Molecular Virology (IMV) serves as the focal point for virology research at University of Minnesota (UMN) and has championed virology research as a critically important university investment at a time of declining institutional resources. Such investments in the past decade have included a 80,000-square-foot, $63 million Microbiology Research Facility that opened in 2015 as well as $25 million for additional research infrastructure. Key highlight’s of the training activities of our program in the current funding segment include the creation of a virology-dedicated graduate course designator and the implementation of foundational coursework in virology as well as a wide-range of IMV-sponsored activities attended by both trainees and preceptors that provide important intellectual, technical, and career development opportunities (i.e., weekly Virology Journal Club, monthly IMV Research in Progress seminars, quarterly IMV Innovations in Virus Research Lecture Series, annual UMN-Mayo Distinguished Lectures in Virology & Gene Therapy, the IMV Educational and Career Development Series, the annual IMV Symposium, a collaborative ‘Wisc-e-sota’ T32 symposium, and annual sessions in Responsible Conduct in Research). Trainee participation in these training program activities have fostered the exchange of ideas and stimulated collaborative projects. Oversight of trainee progress is monitored on multiple levels, including yearly evaluations by the training program Executive Committee. Outstanding predoctoral trainees are attracted to the UMN. From this pool, outstanding predoctoral trainees are recruited to preceptor labs by the individual strength of each preceptor’s research program. Trainee recruitment is enhanced by the breadth of career development opportunities provided through the IMV that include the hosting of national and international virology meetings that brings students – including students from underrepresented populations – to our campus to develop long-lasting interactions with all members of our virology research community. The program has developed a strong record of training achievement. To fulfill our training mission with our available resources, we request support for 5 predoctoral positions per year for the next 5-year funding period.

NIH Research Projects · FY 2025 · 2010-03

PROJECT SUMMARY Facioscapulohumeral muscular dystrophy (FSHD) is a genetically dominant progressive muscular dystrophy associated with inappropriate expression of the DUX4 gene. FSHD afflicts over 25,000 individuals in the United States, is a very common genetic disease, and is currently without treatment. In the previous cycle of this renewal application, we discovered that DUX4 gene expression is self-limited to short bursts of activity, with the DUX4 target gene DUXA serving as a feedback inhibitor, and a degron in the C-terminus leading to protein instability. We also discovered that transient DUX4 expression in muscle fibers in our iDUX4pA doxycycline-inducible mouse model tips muscle into an injury-sensitive pro-fibrotic state mediated by long-term changes to the FAP compartment, and developed a p300-specific inhibitor, iP300w, for treating DUX4-induced disease, including finding that iP300w inhibits CIC-DUX4, a fusion oncoprotein that causes a very aggressive pediatric sarcoma. The renewal application builds on this work, with a series of studies aimed at continuing to explore the molecular mechanism of DUX4 activity by understanding the function of proteins that interact with DUX4 including those that degrade it, developing p300 inhibition as a therapeutic approach, and investigating pathological mechanisms underlying DUX4-mediated skeletal muscle disease using transient and cell type-restricted expression of DUX4 in the iDUX4pA mouse model.

NIH Research Projects · FY 2025 · 2010-02

Project Summary T cell immunity may be exploited through vaccination, immunomodulating therapies, and engineered adoptive cell therapies to immunize against or control infections and cancer. However repeated or prolonged stimulation can result in T cell dysfunction and senescence which impairs protective immunity or allows disease progression. Establishing numerically robust, durable, and functional T cell immunity and preventing or reversing T cell exhaustion remain substantial goals in immunology that have significant clinical ramifications. Our preliminary data demonstrates that repeated stimulation, even when punctuated by periods of rest, can result in senescence. However, we also show that this fate can be avoided, allowing indefinite boosting across multiple mouse lifetimes, while preserving function and durability. Additional preliminary data indicates that T cells can adapt to become inured to exhaustion. The goals of this proposal are to determine the underlying mechanisms that permit T cells to undergo indefinite clonal expansion while avoiding functional exhaustion or proliferative senescence. Successful execution of the proposal will inform our understanding of the regulation of immunological memory, vaccine development, and immune therapies for chronic diseases. .

NIH Research Projects · FY 2025 · 2009-12

ABSTRACT Lung cancer is the leading cause of cancer death in the U.S. This renewal application for years 11-15 of our Program Project Grant entitled “Mechanisms of Ethnic/Racial Differences in Lung Cancer Due to Cigarette Smoking” brings together our team of renowned experts in cancer molecular epidemiology, tobacco control, mechanisms and biochemistry of tobacco carcinogenesis, and biostatistics to continue our groundbreaking research on biochemical, molecular, and epigenetic mechanisms by which cigarette smoking causes lung cancer. We will build on our significant findings from ongoing studies which include important advances in the epigenetics of lung cancer, biochemistry of nicotine leading to addiction and cancer, DNA damage by tobacco smoke carcinogens including acrolein and 1,3-butadiene, and tobacco carcinogen biomarker studies which expand and explain the dramatic differences in lung cancer incidence among cigarette smokers from 5 ethnic groups – African Americans, Native Hawaiians, Whites, Latinos, and Japanese Americans. Project 1, “Genetic and epigenetic risk markers for lung cancer in former smokers” proposes to identify these markers of lung cancer risk in people who have quit smoking and improve our understanding of the ethnic/racial differences in lung cancer risk among former smokers. Project 2, “CYP2A6 genetic score, nicotine metabolism, and lung cancer” will focus on the primary catalyst of nicotine metabolism which is critical because people with low activity of this enzyme smoke fewer cigarettes and smoke those less intensely because they need less nicotine, which is proposed to lead to lower lung cancer risk. Project 3, “Untargeted adductomics to characterize ethnic differences in the exposome of smokers” hypothesizes that biological responses towards cigarette smoke exposure differ among individuals and ethnic groups due to genetic and/or epigenetic factors that lead to differences in metabolic and inflammatory responses to smoking. Project 4, “Carcinogenesis biomarkers in former smokers of the Multiethnic Cohort Study” will use a unique approach to determine the metabolic activation of polycyclic aromatic hydrocarbons as well as lipid peroxidation in the lungs of former smokers compared to never smokers. These 4 projects will be supported by 3 outstanding Cores: Administrative Core, Clinical and Biomarkers Core, and Biostatistics Core. Thus, our experienced investigators propose to continue their superb and unique teamwork to make significant progress in understanding lung cancer mechanisms among present and former cigarette smokers leading to new insights for prevention of fatal lung cancer.

NIH Research Projects · FY 2025 · 2009-07

ABSTRACT This T32 regional postdoctoral training grant in eating disorders research is a competitive renewal application for an Institutional Ruth L. Kirschstein NRSA that was initially awarded in 2009. This multisite postdoctoral training program aims to prepare the next generation of scientists to advance the field of eating disorders research. The mortality risks and disease burden associated with eating disorders necessitate highly innovative and impactful investigations conducted by well-trained scientists. Mechanistic studies of the neurobiological, psychological, and environmental causes and maintenance factors of eating disorders that can be targeted in novel treatment and prevention programs are especially critical and remain a focus of our training program. This multidisciplinary T32 program combines the long-standing strengths of eating disorders research programs at the University of Minnesota (Minneapolis, MN), the University of Chicago (Chicago, IL), and Sanford Center for Biobehavioral Research (Fargo, ND) to train emerging scientists in state-of-the-art research methods. Comprehensive training is provided in the context of mentored research and weekly T32 seminars as well as coursework. Trainees include 2 postdoctoral fellows at each site with training durations of 2-3 years. T32 faculty across the three sites include 23 experts in eating disorders and related conditions who represent multiple disciplines including psychology, psychiatry, epidemiology, dietetics, neuroscience, and biostatistics. Each postdoctoral fellow is paired with an on-site primary mentor as well as a multisite mentoring team to identify and pursue individualized training goals. Training progress is monitored with the use of Individual Development Plans that are regularly reviewed and updated. Through their mentored research experiences, seminars, coursework, and on-site learning opportunities, postdoctoral fellows develop advanced skills in conducting rigorous research, publishing manuscripts, and submitting grant applications. Multisite collaborations are strongly supported. Research ethics, scientific rigor, and reproducibility are emphasized throughout the training program. Currently in its 14th year, this T32 program continues to be successful with a competitive applicant pool and high levels of research productivity among current and previous trainees in both publications and grant awards.

NIH Research Projects · FY 2024 · 2009-07

The lysosomal disorders (LD) are a group of approximately 70 inherited metabolic conditions resulting from defects in lysosomal function; usually deficiency of a single enzyme required for the metabolism of lipids, glycoproteins, or mucopolysaccharides. Collectively, LD are not especially rare; estimates suggest that approximately 1:5,000 newborns will be affected with one identified LD. Individually however, each disorder occurs with a much lower frequency. Assuming that 180 individuals per 1 million live births will be affected with an LD, extrapolation incidences range from Gaucher at 25 per 1 million births to 7 per 1 million births for GM1- gangliosidosis; other LD are much rarer still. Most LD are monogenetic disorders caused by a mutation in a single gene and follow an autosomal recessive inheritance pattern, although a few are X-linked recessive. Although each LD results from a unique gene mutation, at the biochemical level they share a common characteristic—the inability to clear metabolic substrate from the lysosome. Presenting symptoms vary widely among the disorders and are modified by age of onset and severity (most LD present as either a severe or attenuated phenotype); beyond categorization as severe or attenuated, a more specific genotype/phenotype correlation has not been feasible. To date, about a dozen or so LD have therapeutic options, but apart from MPS I, which has been shown amenable to stem cell transplant, LD drug therapies are not particularly effective in those conditions with neurologic dysfunction. And while new treatments, be it next generation drug therapy, gene therapy, or other gene editing techniques, are essential to improve outcomes for those affected with LD, early detection is critical in order for a person with an LD to hope for a normal life. In the past three decades, lysosomal diseases have been a test bed for some of the most innovative therapeutic modalities. In the past 9 years of NIH funding, the LDN has accelerated knowledge acquisition in the field—with 95 NCBI cited publications—and furthered the development of therapeutic options. For the next 5 years, the overarching thematic goals of the LDN are: clinical trial readiness, newborn screening, long-term outcomes, and global reach. We will advance these goals through clinical investigation via 5 longitudinal studies focused on elucidation of disease pathology by (a) CRIM status and immune tolerance induction in Pompe disease, (b) cardiac and kidney pathology in Fabry disease, (c) multi-system survey (cardiac, developmental, skeletal, QOL) in the mucopolysaccharidoses, and (d) MRI and biomarker development as outcome measures for the gangliosidoses. The fifth project is a survey study designed to catalog both the odyssey individuals go through before reaching a proper diagnosis and the effectiveness of therapeutics at allowing individuals with lysosomal disease (specifically treated MPS) to live an independent life. Every participant who enrolls in an LDN project is expected to complete the survey studies. Biostatistical analysis assures relevant statistical models for each project.

NIH Research Projects · FY 2025 · 2009-02

Strength loss occurs with age affecting quality of life and impinges upon healthspan. 17β-estradiol (E2) deficiency in females also causes strength loss. The overall goal of this project is to determine the cellular and molecular mechanisms through which E2 deficiency perturbs skeletal muscle and contractile functions with age. The sole focus of our research has been on aging females and in this competitive renewal submission, we also seek to determine mechanisms of E2 in male muscle as the impact of estrogens in male non- reproductive physiology is becoming increasingly recognized. Results from the previous funding periods have led to novel hypotheses outlined in this proposal. Specifically, Aim 1 tests the hypothesis that E2 signals through estrogen receptor α (ERα) and the G protein-coupled ER (GPER) in skeletal muscle to enhance dynamic strength in male as well as female mice. We use genetic, surgical, and pharmacologic approaches to probe both the ligand and receptor sides of E2-ER signaling. We pair this approach with comprehensive in vivo and in vitro measures of muscle contractile functions to elucidate mechanisms and determine the long- term consequence of E2-ER disruption in muscle. While the particular muscle proteins to be analyzed in the first aim are guided by specific contractile outcomes that are affected by E2-ER signaling, Aim 2 takes an unbiased approach to quantitate phosphoproteins that are critical for strength yet altered in aged and E2- deficient muscle. This will be accomplished through the development of a novel parallel reaction monitoring (PRM) assay with computational modeling, which is based on our global phosphoproteomic work that identified differentially expressed phospho-peptides related to calcium signaling and contractile proteins in several E2-replete vs E2-deficient muscle conditions. Our customized PRM assay will further predict candidate E2-sensitive kinases that will be validated in high-throughput assays to yield potential gerotherapeutic targets for preserving muscle strength with age. It has been shown that 17alpha-E2, the minor and weak epimer of E2, extends lifespan and improves several characteristics of healthspan in male mice. Aim 3 is designed to test the hypothesis that skeletal muscle will be enhanced by 17alpha-E2 in both aged males and females through activation of ERα and downstream signaling. This aim brings forth the intriguing prospect that 17alpha-E2 is a non-feminizing geroprotector that extends healthspan by supporting muscle strength and thus physical activity, movement, and quality of life. Accomplishing these three aims will solidify that change in sex hormones and their receptors is one of the pleiotropic mechanisms underlying muscle weakness with age and addresses the long-term goal of our research program, which is to determine estrogenic mechanisms that preserve strength with aging, regardless of sex.

NIH Research Projects · FY 2024 · 2008-09

Advancements in computational psychiatry allow us to isolate multiple, specific cognitive mechanisms that determine human behavior. This formal modeling framework generates quantitative parameter estimates that can serve as bridges between pathophysiology and psychopathology. A major goal of computational psychiatry is to translate these laboratory tools so that they can be used in the clinic. Two critical hurdles need to be overcome. First, the enhanced validity and sensitivity of computational metrics needs to be established relative to standard behavioral performance metrics in key psychiatric and nonpsychiatric populations. We propose to do that by addressing a range of cognitive and motivational domains that have been strongly implicated in psychopathology, including working and episodic memory, visual perception, reinforcement learning, and effort based decision making. Second, we need to establish and optimize the psychometrics of these computational metrics so that they can be used as tools in treatment development, treatment evaluation, longitudinal, and genetic studies. These powerful metrics must have adequate test-retest reliability, and not be limited by ceiling and floor effects. We propose to develop these methods using an open, flexible, and scalable framework and demonstrate that they provide valid data both in the laboratory and in large-scale Internet-based data collection, facilitating “big data” studies of cognitive processes. To this end, the current project will leverage the expertise of Cognitive Neuroscience Task Reliability and Clinical applications in Serious mental illness (CNTRACS) consortium, a multi-site research group with an established record of rapid cognitive tool development and dissemination. Aim 1 is to establish that model based parameters for the measurement of cognitive function are more sensitive than standard behavioral methods in assessing deficits across a range of common mental disorders, and have an enhanced capacity to predict clinical symptoms and real-world functioning, with a sample of 180 patients with psychotic and affective disorders (both medicated and unmedicated) and 100 healthy controls. Aim 2 is to measure and optimize the psychometric properties (test re-test reliability, internal validity, floor and absence of ceiling and practice effects) of computational parameters described in Aim 1, in a new sample of 180 psychiatric patients and 100 healthy controls. Aim 3 is to establish the feasibility and replicability of model-based analytic approaches outside the laboratory for assessing RDoC dimensions of interest, and to assess their relationships to variation in psychotic-like experience, depression and anhedonia, as well as real- world functioning in a community sample of 10,000 recruited over the Internet. Aim 4 is to validate key model based parameters against well-characterized neurophysiological measures acquired using EEG recordings during task performance. Successful completion of these Aims will significantly advance the field by providing easily administered and scalable web-based tools for estimating the integrity of key neural systems that underlie normal cognition and motivation and form the basis of common forms of cognitive and affective psychopathology.

NIH Research Projects · FY 2026 · 2008-09

Project Summary/Abstract With 494 billion data points and 62 million map polygons, IPUMS National Historical Geographic Information System (NHGIS) is the world’s largest publicly accessible population database and is an essential component of the shared data infrastructure for population and health research. NHGIS gathers area-level U.S. census data from diverse sources, formats them consistently, develops comprehensive standardized machine-processable metadata, and creates high-precision GIS boundary files describing the spatial units. To eliminate major obstacles for studies of small-area population change, NHGIS distributes geographic time series that link comparable data across multiple census years. The data are broadly accessible to health researchers through powerful dissemination tools that make it easy to navigate the intricacies of the U.S. statistical system, enabling rigorous and reproducible population health research. NHGIS reduces costs for population and health researchers by minimizing redundant effort, simplifying data access, and improving data reliability. NHGIS currently disseminates 12 terabytes of data per year to 81,900 investigators, with a new citation of NHGIS appearing in Google Scholar once every 14 hours. To meet the demands of a rapidly increasing user base and ever-expanding requests for more and improved data, this project has five major goals: 1. Add to core census datasets. The proposed project will incorporate new releases of American Community Survey (ACS) summary data with corresponding boundary files and broaden the coverage of existing NHGIS datasets with 1980 block boundary data for all metropolitan areas, Puerto Rico data from the 1980–2000 censuses, and ACS tables for detailed race/ethnicity/tribe/ancestry groups. 2. Add resources to support analysis of noisy 2020 census data. To protect privacy, the Census Bureau is adding noise to 2020 census data, causing some data to be unreliable in ways that are difficult to predict. This project will add three key resources to NHGIS to help researchers understand and account for the added noise: confidence intervals, Noisy Measurement Files, and data for optimized block groups. 3. Extend integrated spatiotemporal datasets. To broaden research opportunities, this project will extend NHGIS geographic crosswalks to cover more levels and years, extend time series tables to cover more years and subjects, and extend annual estimates of tract-level populations through 2027. 4. Improve data access. The project will give data users new options for code-based access to NHGIS data and metadata via our Application Programming Interface (API) and a Python package. 5. Expand and support the research community. The project will invest in extensive user support, training, and outreach, leveraging two new data user networks built with recent NSF and NIA funding to reach new, underrepresented, and early-career scholars. The project team will also develop new guides to key concepts in U.S. census data.

NIH Research Projects · FY 2025 · 2008-05

Project Summary / Abstract A group of principal investigators at the University of Minnesota seeks to renew our Training Program under the new title “Functional Multi-omics of Aging” to support predoctoral and postdoctoral trainees. The goal of the Training Program is to assist exceptional young scientists develop the intellectual and technical skills needed for productive careers as biomedical researchers and educators in aging biology with a focus on training in -omics technologies. The Training Program is in its 14th year of funding and has trained 23 pre- and 15 post-doctoral trainees. Didactic training occurs through four T32-led courses covering fundamental biology that drives aging, the Geroscience Hypothesis of Aging, emerging -omics technologies in aging research, and professional development to prepare trainees for the next step in their scientific careers. Novel to this funding period, the Training Program will interface with the newly established and continually expanding Institute on the Biology of Aging and Metabolism (iBAM) at the University of Minnesota to further provide trainees experiential training in the biology of aging and multi-omics through workshops, conferences, seminars, symposia, journal clubs, and a visitorship program. Through iBAM, our institution has recruited internationally prominent researchers in aging biology and with this explosion of energy and ideas, our training faculty has grown from 19 to 23, diversifying rank, background, and departmental homes. Training faculty research focuses on the use of -omics technologies to reveal the molecular details behind aging and they draw trainees from five graduate programs: Biochemistry, Molecular Biology and Biophysics, Chemistry, Integrative Biology & Physiology, Neuroscience, and Rehabilitation Science. New leadership of this T32 takes on an MPI structure to capture the breadth of needs with Drs. Arriaga, Lowe, and Niedernhofer synergizing their expertise in graduate education, -omics technology, aging research, and professional development. Our aging research is supported by outstanding genomics, proteomics, and imaging cores at UMN equipped with state-of-the-art single cell and spatial transcriptomics and proteomics platforms. These new developments have led to an even stronger Training Program as measured by the publication records and research career success of past trainees as well as the funding and training records of Training Program faculty. Together, the team of distinguished mentors, the extensive interdisciplinary collaborations among faculty and trainees from multiple departments, the technological resources, and the didactic and experiential training helps our trainees to shape successful careers in aging research.

NIH Research Projects · FY 2026 · 2007-09

UNIVERSITY OF MINNESOTA’S (UMN) BUILDING INTERDISCIPLINARY RESEARCH CAREERS IN WOMEN’S HEALTH (BIRCWH) PROGRAM ABSTRACT This UMN BIRCWH application is a competitive renewal. We have been continuously funded for 14 years. The UMN BIRCWH is a three-year competency-based and interdisciplinary team-mentored research career development program for junior faculty, or “Scholars” built on the Office of Research on Women’s Health (ORWH) strategic goals. The main objective and vision of the UMN BIRCWH program is to improve the health of all women across the lifespan and, by extension, to improve the health of their families and communities in Minnesota, the nation, and the world. Our short-term objective to achieve the UMN BIRCWH vision is to facilitate the research careers and independence of our Scholars by expanding their research skills, their experience in team science, their research networks and leadership abilities, and increasing their scholarly productivity. We will accomplish this objective by having each Scholar go through our career development program or “pathway” which includes the following components: (1) an independent research project; (2) interdisciplinary mentoring teams; (3) competency-based core curriculum delivered through seminars, trainings, workshops, and conferences and (4) optional additional networking and training opportunities. Our long-term objectives to achieve the UMN BIRCWH vision, are to: 1. Increase scholarly publications and funding on women’s health and sex/gender differences research. 2. Increase the number of interdisciplinary research leaders who advance scientific knowledge in women’s health across the lifespan and in sex/gender differences in health and disease. 3. Foster new cross-disciplinary collaborations within the University and broader community to increase the impact of women’s health research. 4. Transform the academic environment by increasing the visibility of interdisciplinary women’s health and sex/gender differences research. 5. Effect the timely translation of women’s health and sex/gender differences research findings to clinical practice, public health, and policy. Over the last 14 years, our 16 Scholars have successfully published a total of 1,017 (367 first author) manuscripts and received 22 NIH grants as PI (total funding $48,239,932). Additionally, 13 alumni (81%) have been promoted to associate professor or higher and 10 are in leadership positions. In the current application, we will build on this strong track record of developing successful and highly productive Scholars and add new innovative and timely elements including a focus on: (1) health equity and antiracism; (2) community-engaged scholarship; and (3) academic leadership. These innovations, in addition to the strong multiple-PI team, rigorous evaluation plan, and highly interdisciplinary mentors will allow for the UMN BIRCWH to continue to set the standard for training Scholars in women’s health and sex/gender differences that meet and exceed the ORWH strategic goals.

NIH Research Projects · FY 2025 · 2007-05

PROJECT SUMMARY The University of Minnesota's R25 Short-Term Training Research Education Program has demonstrated remarkable success in advancing diversity in the nation's biomedical workforce over the course of 15 years. With a commitment to fostering inclusivity and empowering underrepresented students, the program has provided vital support to 294 talented undergraduate individuals from diverse backgrounds, propelling them towards successful baccalaureate degrees. 70% of former students embarked on advanced biomedical degrees, including MD, PhD, and MD/PhD degrees. These outcomes firmly establish our R25 program as a potent catalyst for nurturing diverse and skilled researchers. Building on its achievements, our program is steadfast in its vision to sustain and strengthen its commitment to diversity and educational excellence in the biomedical field. We request continued funding support to focus on sustaining participant diversity by actively recruiting a diverse and academically qualified group of 12 R25 grant-eligible students from local community colleges and nationwide each year (Aim 1). These promising trainees will be offered an enriching ten-week independent research experience mentored by distinguished faculty, while also benefiting from a wide array of enrichment activities. Workshops on responsible research conduct, scientific communication, graduate school applications, career mentoring, and addressing issues like implicit bias and imposter syndrome will serve as empowering tools for these aspiring researchers, helping them overcome barriers and succeed in their biomedical careers. In Aim 2, the R25 program centers around strengthening its Pre-Medical Scientist Training Program (Pre-MSTP) module, which has already achieved significant success with a remarkable 33% of alumni enrolled in or having graduated from MD/PhD programs. In Aim 3, the R25 program aspires to forge new frontiers of inclusivity by developing an innovative research training module tailored explicitly to the unique needs of community college transfer students, known as Bio-LEAP (Biomedical Life Science Enrichment for Academic Progress). With a keen recognition of the vast population of underrepresented students transferring from community colleges to the University of Minnesota, the Bio-LEAP module will prioritize engaging and nurturing this dynamic group. By providing tailored research training experience, the Bio-LEAP module seeks to facilitate a smoother transition to UMN, positively impacting academic progress toward a bachelor's degree, fostering a passion for research, and ultimately increasing their success in matriculating into competitive advanced biomedical degree programs. In summary, our proposed aims will enhance diversity in the biomedical research workforce, nurture a diverse generation of well-prepared researchers, and make a lasting positive impact on the mission of the National Heart, Lung, and Blood Institute, fostering excellence and inclusivity in the biomedical research community.

NIH Research Projects · FY 2025 · 2005-07

Recent high-profile advances have reinvigorated enthusiasm for immunologic and cell-based therapies for cancer. While the first 15 years of this Program focused on related donor sourced products and defining the immunogenetics of NK cell contributions to allotransplantation, the adoptive transfer of single donor products is limited to specialty centers because of high cost, difficulty in exporting, and inability to test multi-dosing strategies. We have formed new strategic partnerships to shift from single donor products to off-the-shelf approaches. This approach is simpler for protein-based NK cell immune engagers, as they are readily druggable, but more challenging for cell products. Therefore, our overall goal is to develop off-the-shelf NK cell products to be used alone or in combination with novel immune engagers. We have assembled a team of Minnesota and international experts to lead the Projects and Cores. In Project 1, we discovered that NKG2C+ adaptive NK cells induced by CMV have properties of immune memory, exhibit a unique methylation signature similar to CD8+ T cells, and are primed for anti-tumor activity. Our group also published the 1st clinical link between adaptive NK cells and reduced rates of leukemia relapse in 2016. We will now conduct a multi-institutional phase I/II trial of allogeneic KIR-HLA mismatched adaptive NK cell infusions to treat patients with AML/MDS. We will also perform preclinical testing of off-the-shelf NK cell products and novel immune engagers called tri-specific killer engagers (TriKEs). TriKEs contain 3 arms: an arm that engages the CD16 activating receptor on NK cells; an arm that specifically engages a tumor antigen on cancer cells; and an IL-15 linker. In the current funding, we discovered that IL-15 is superior to IL-2 in promoting in vivo NK persistence and expansion; however, it also stimulates host CD8+ T cells in many subjects, and we will test whether IL-15’s targeted delivery via TriKE minimizes bystander T cell activation. Project 2 will focus on NHL and clinically test a dual-targeted strategy using an off-the-shelf, iPSC- derived NK (iNK) cell product containing a CAR against CD19, a CD16 receptor, and membrane bound IL-15. Preclinically, we will test whether targeting NK cell metabolism can improve in vivo NK cell performance. Project 3 will extend off-the-shelf iNK cell therapies into a solid tumor setting. Initial testing of adaptive NK cells in ovarian cancer showed that the intraperitoneal ( IP) space is immune privileged and allows for NK cell persistence. We will conduct a phase I clinical trial to determine whether IP delivery of off-the-shelf iNK cells expressing a non- cleavable CD16 (FT516) improves outcomes among patients with ovarian cancer. Preclinically, we will test novel immune engagers (TriKEs) in combination with FT516 and a new iNK cell product expressing a chimeric CD64/16A receptor capable of multi-antibody targeting. Projects will be supported by the Administration & Clinical Research Support (Core A), Biostatistics (Core B), and Immune Monitoring & Tissue Analysis (Core C) resources. This Program will build upon our success in establishing a signal of clinical efficacy with single-donor NK cells by moving from individually sourced related donor products to multi-dosed, off-the-shelf strategies.

NIH Research Projects · FY 2025 · 2005-02

PROJECT SUMMARY/ABSTRACT While abundant skeletal (ask-actin) and cardiac (aca-actin) actin isoforms are famous for their essential role in striated muscle contraction, low abundance non-muscle “cytoplasmic” actin isoforms (bcyto- and gcyto-actin) are also emerging as important in the maintenance of specialized structures (and functions) in normal and diseased skeletal muscle. During this project, we generated and characterized muscle-specific mouse lines either lacking or overexpressing bcyto-actin or gcyto-actin to understand their endogenous functions and role(s) in dystrophin-deficient muscular dystrophy. Interestingly, each bcyto-actin or gcyto-actin single knockout develops a qualitatively similar phenotype characterized by a progressive myopathy with significant myofiber degeneration/regeneration and muscle weakness. We have shown that skeletal muscle-specific overexpression of bcyto-actin or gcyto-actin in dystrophin-deficient mdx mice affords significant protection from eccentric contraction-induced force drop while overexpression of a C272A mutant of gcyto-actin affords no protection. These and other data suggest that eccentric contraction drives a rapidly-reversible, reactive oxygen species (ROS)-mediated inhibition of sarcomeric contractility that may function to protect dystrophic muscles from damage caused by repeated, high force contractions. Our new preliminary data show that muscle-specific ablation of bcyto-actin or gcyto-actin from wildtype muscle results in eccentric contraction-induced force drop that is reversed by the nonspecific antioxidant N-acetylcysteine. Finally, we have obtained new data suggesting that gcyto-actin is important for repair of membrane damage. Going forward, we will make use of our unique animal models, isoform-specific reagents, and biochemical and physiological methodologies to address new fundamental questions about cytoplasmic actins in normal skeletal muscle function and in dystrophin-deficient muscular dystrophy. In aim 1, we will identify the sources of ROS contributing to eccentric contraction-induced force drop in dystrophic mdx skeletal muscle as well as the downstream targets of ROS that ultimately inhibit force production. In aim 2, we will investigate the role of oxidative stress in driving the myopathy and eccentric contraction-induced force drop associated with genetic ablation of bcyto- or gcyto-actin in skeletal muscle. In aim 3, the interplay between cytoplasmic actin isoforms and ROS in membrane repair will be investigated using state-of-the-art imaging approaches to analyze muscles from the same mouse lines used in aims 1 and 2. The results of the proposed studies will further delineate the unique and important contributions of cytoplasmic actin isoforms to the function of normal and dystrophic skeletal muscle.

NIH Research Projects · FY 2025 · 2004-09

The University of Minnesota Department of Pediatrics and Masonic Cancer Center propose to continue a highly successful training program in translational and genomic pediatric cancer epidemiology research. Our program is sought nationally by scholars, and provides opportunities for 2 postdoctoral and 2 predoctoral trainees to enhance their research and experience across a spectrum of pediatric cancer research, with a goal of interdisciplinary cross-training. With 16 outstanding mentoring faculty, trainees work in a variety of research settings including classical epidemiology, genomic epidemiology, and clinical investigations; laboratory studies may complement trainee work in the other areas. Along with seminars specific to pediatric cancer, strong graduate school degree programs at the University of Minnesota in Epidemiology (PhD), Bioinformatics and Computational Biology (Ph.D., M.S.) and in Clinical Research (MS) offer opportunities for courses in epidemiology, cancer epidemiology, biostatistics, bioinformatics, cancer biology, genetic epidemiology, bioinformatics, computational biology, immunology, clinical trials/methods, and field research. Further, students have several unparalleled opportunities for supervised translational and genomic research projects in human, in vitro data, study design and development, statistical analysis, and individual and team grant writing. Predoctoral students are formally admitted to the graduate school PhD program in Epidemiology or Bioinformatics and Computational Biology. The postdoctoral trainees are drawn from the medical, basic and applied sciences through national advertising and our Masonic Cancer Center members, and from the cohort of medical fellows in the Department of Pediatrics who have completed advanced clinical training in pediatric oncology and are embarking on the research component of their training. We anticipate that two of our postdoctoral trainees will choose to obtain an MS in clinical research or bioinformatics and computational biology. Criteria for selection of both pre- and postdoctoral trainees include a strong academic performance and a career orientation toward independent research in an academic, clinical, or public health setting. Each trainee is guided by at least two senior mentors from complementary disciplines in their research projects. All trainees participate in courses in pediatric cancer topics and readings in pediatric cancer epidemiology, weekly pediatric cancer seminar meetings and pediatric tumor conferences, monthly seminars, annual retreats, and presenters of their own research at national meetings. Postdoctoral students receive additional training in grant writing/preparation. All receive instruction in the responsible conduct of research. Trainees who graduate from this program will have the capacity to undertake high impact pediatric cancer research across a spectrum of disciplines.

NIH Research Projects · FY 2025 · 2004-09

Project Summary/Abstract IPUMS is a key component of the world’s population health data infrastructure, and it is urgently needed. The extraordinary growth and redistribution of the human population is reshaping the planet with profound consequences for population health and health behaviors. Unless we understand the processes of change, we cannot hope to plan adequately. To meet the challenges created by rapid demographic, economic, and environmental change, researchers must have open access to the best possible information. Over the past two decades, IPUMS has created a vast archive of census and survey microdata covering 100 countries over multiple decades. There has been explosive growth in the number of researchers using the database, the amount of data they request, and the number of high-impact publications they produce. The massive growth of the database has created new challenges, however, for data discovery, processing, and management that will require creative new technical solutions. There is also high demand to further expand, improve, and support the database. The proposed continuation project will expand the database, enhance the data and metadata, improve key elements of the infrastructure, and support the research community. Aims 1 and 2 focus on acquiring, preserving, and processing microdata from Asia and Europe. Aims 3 and 4 will provide infrastructure and outreach that will benefit all IPUMS microdata efforts. Aim 1: Data acquisition and long-run preservation. The IPUMS International team will obtain and preserve census and survey microdata from Asia and Europe, including the newest microdata from household surveys and older data at risk of destruction. Aim 2: Data processing. The project will expand the IPUMS database by adding data for at least 120 million individuals included in at least 60 censuses and surveys, focusing on recent data from Asia and Europe. This will require data cleaning, development of comprehensive machine-processable metadata, spatial data ingest and harmonization, and variable harmonization. Aim 3: Data, metadata, and infrastructural improvements. This project includes dozens of improvements to IPUMS data and metadata while adding new capabilities to IPUMS data processing and dissemination systems. Aim 4: Dissemination and outreach. The project will continue to provide user support, training, and outreach and will develop new online training capabilities as well as promoting scientific discovery through surveys, workshops, and online interaction. Most critically, IPUMS will maintain collaborations with the national statistical agencies who provide the source data. The improved and expanded IPUMS database will allow investigators to make comparisons across the world over multiple decades of social and economic upheaval, creating a resource of unprecedented power for understanding ongoing transformations of demographic behavior and population health.