University Of Minnesota

NIH Research Projects · FY 2026 · 2004-09

Summary This proposal seeks continued funding to expand and enhance the IPUMS Health Surveys Project. IPUMS Health Surveys provides streamlined access to core U.S. survey data on population health through two integrated databases: the National Health Interview Survey (IPUMS NHIS) and the Medical Expenditure Panel Survey Household Component (IPUMS MEPS). The NHIS is the leading source of information on U.S. health, health disparities, and the social determinants of health; the MEPS is the primary source of information on national trends and correlates in health care spending and health systems change. The proposed project will further improve this crucial resource for pathbreaking research in four ways: (1) Expand the database. We will integrate data and documentation from five new years of NHIS (2024-2028) and MEPS (2023-2027), nearly doubling the number of MEPS variables we offer. (2) Lower the barriers to cutting-edge research. We will enable rigorous and reproducible research by creating several complex variables critical for answering urgent population health questions, including (a) the addition of MEPS family interrelationship variables to allow users to easily attach information across records (e.g., parent to child, spouse to spouse); (b) harmonization of NHIS occupation and industry information to support research on occupational health; (c) creating summary measures of health insurance coverage instability over the course of the full MEPS panel; (d) bridging the substantial break between ICD-9 and ICD-10 condition codes and creating simplified, policy-relevant categories to support analyses of condition-specific health care expenditures using MEPS; (e) creating simplified MEPS prescribed medicines variables so users can quickly identify broad categories of policy-relevant variables (e.g., generics, opioids); and (f) improving the prescription medication data. (3) Enhance data access. We will enhance data access tools in five ways: (a) enabling researchers to incorporate additional information (e.g., reason for visit, type of medical provider seen) in the variables created through the MEPS variable construction system; (b) developing the capability for users to easily create and download custom MEPS variables that summarize the complex prescribed medicines data; (c) allowing extracts through the data access system with person-level data attached to event- and condition-level records; (d) enabling analysis of customized datasets using our online data analysis system; and (e) further simplifying access to user-defined summary variables by making them accessible through our data extract Application Programming Interface (API). (4) Disseminate data to a broad, diverse spectrum of users. We will engage in user support, training, and outreach activities to attract new users and support current users. Activities will include conference exhibits, presentations, introductory workshops, virtual office hours, timely answers to user queries, and webinars. We will also offer a three-day, in-person MEPS training workshop geared towards early-career scholars and scholars from historically underrepresented backgrounds.

NIH Research Projects · FY 2024 · 2004-07

Abstract The primary objective of this T32 renewal proposal is to continue the University of Minnesota (UMN) Pediatric Endocrinology Program's tradition of guiding pediatric endocrinology fellows into academic careers, by providing intensive training in basic, translational, patient-oriented, or education science. Our secondary objective is to provide an environment that will facilitate the successful advancement of women into academic careers. The program has been highly successful in achieving its goals. From its inception in 2004 through the summer of 2019, we will have graduated 11 fellows from the 3 year training program, with an additional 3 in training. Nine of our 11 graduates are women, and 7 currently have University faculty appointments. Two are Associate Professors one is expected be promoted to Professor within the next couple years. Our goal at last renewal was to increase the diversity of our trainees, which we achieved by recruiting both an Hispanic and an Africa American fellow. Fellows are selected based on a demonstrated desire to pursue research training. They may follow a clinical/translational, a basic science, or a medical education path, and are expected to obtain a master's degree to formally and rigorously prepare them for a scholarly career. We work closely with incoming fellows to join their research interests with available opportunities and experienced mentors who can support their training and provide guidance for advancement to the next phase of their academic careers. The core group of senior faculty mentors are well established investigators, selected for their ability to impart a culture of responsible, rigorous, and robust science, as is the tradition of the UMN. Numerous and varied research opportunities are available. The program has particular research strengths in the critical public health domains of diabetes, obesity, and metabolism. Members of the Division of Pediatric Endocrinology enjoy a strong tradition of scientific collaboration with other divisions within the Department of Pediatrics, other departments within the UMN, and other institutions including the Mayo Clinic. This provides fellows with a rich environment for scientific collaboration. The program trains physician scientists in the spectrum of skills necessary to be well-grounded in the fundamental underpinnings of their research area by the completion of fellowship so they are ready to enter a junior faculty academic research position.

NIH Research Projects · FY 2025 · 2003-09

Project Summary/Abstract The Comparative Medicine and Pathology training program was initiated in Fall 2003 and over two decades has consistenUy provided state-of-the-art research training to veterinarians as a pathway to careers as veterinarian-scientists. Five years of continuing support are requested in the present application, including support for six postdoctoral trainees in each program year. It is anticipated that most of these individuals will have completed a residency in veterinary medicine, surgery, or pathology prior to entering the training program. Selection criteria will include 1) a strong interest in research and a desire for a career in academic veterinary medicine; 2) academic credentials and performance during clinical training/residency; and 3) desirable personal characteristics, including integrity, perseverance, and oral and written communication skills. The training program is located in the College of Veterinary Medicine at the University of Minnesota and is directed by Drs. Molly McCue, Cathy Carlson, and David Brown. Thirty-four faculty mentors, all members of the Comparative and Molecular Biosciences (CMB) and/or Veterinary Medicine (VMED) graduate programs, will participate in the training program. These individuals represent a diverse group of disciplines, including pharmacology, cell biology, infectious disease, neurobiology, kinesiology, genetics, molecular biology, and orthopedics. Trainees without a PhD degree will pursue a PhD degree in either the CMB or VMED graduate program; both are well-organized, multidisciplinary programs created to focus graduate education efforts by faculty interested in comparative biomedical sciences and the molecular mechanisms responsible for human and animal health and disease. The goals of our training program are to provide students with broad-based scientific knowledge, superb communication skills, and advanced research training essential for a career as an independent investigator.

NIH Research Projects · FY 2026 · 2002-09

Project Summary IPUMS is a family of nine integrated databases that comprise the largest and most intensively-used data resource for research on population dynamics and health. This competing continuation proposal has two main goals. First, the project will provide the primary support for expanding, improving, and maintaining IPUMS-USA, which consists of microdata from decennial censuses and American Community Surveys. Second, the project will provide central coordination across the nine IPUMS databases, exploiting synergies and eliminating redundant work. Over the past five years, IPUMS has seen 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. At the same time, however, there is unprecedented demand from researchers for expansion, improvement, and support of the infrastructure. This project will undertake four major activities to meet this demand: 1. Database Expansion. We will add data from the American Community Survey and the 1950 census, update variables to accommodate new standards, and evaluate new Census Bureau disclosure controls. 2. IPUMS-FSRDC. We will make IPUMS data housed in the Federal Statistical Research Data Centers more usable through comprehensive documentation, streamlined access, and improvement of the restricted microdata, including new harmonized small-area identifiers. 3. Data Access Redesign. We will redesign the IPUMS user interface and provide new tools for variable discovery and data sharing, including a new user interface conforming to modern accessibility standards, simplified data sharing for replication and collaboration, and enhancement of our online data analysis tool. 4. IPUMS Coordination. The project will synchronize technological development, user support and outreach, and long-run planning for preservation and sustainability across the nine IPUMS databases to avoid duplication of effort, increase the impact, and reduce the cost of IPUMS data infrastructure. IPUMS reduces costs for the population and health research community by minimizing redundant effort, simplifying data access, increasing the replicability of studies, and improving data reliability. The availability of large-scale integrated microdata has opened extraordinary new opportunities for fine-grained contextual analyses of population dynamics and health, resulting in transformational research across a diverse range of topics and disciplines.

NIH Research Projects · FY 2025 · 2002-02

Pitch plays a fundamental role in auditory and speech perception. In music it defines melody and harmony; in speech it carries prosodic and (in tone languages) lexical information; and in everyday complex acoustic environments it plays a critical role in helping us to segregate and hear out important sounds against a background of other sounds. Despite its importance, fundamental questions surrounding how pitch is perceived and neurally encoded remain unanswered. There is, for instance, no consensus on how and why pitch accuracy degrades with hearing loss and/or age. Similarly, despite cochlear implants’ many successes, pitch remains very poorly conveyed for reasons that remain a matter of debate. This project combines behavioral studies in normal- hearing and hearing-impaired adults across the lifespan (Aim 1), behavioral and EEG studies in infants (Aim 2), and high-resolution neuroimaging (fMRI) studies in adults (Aim 3) with computational modeling to answer a cohesive set of fundamental questions on how pitch is perceived and represented. These questions include whether peripheral or more central (experienced-based) factors lead to the dominance of low-numbered harmonics in everyday pitch perception (Aims 1 and 2), and whether the interactions between the perceptual dimensions of pitch (based on fundamental frequency) and brightness (based on spectral centroid) follow a developmental trajectory that is also reflected in their cortical representations (Aims 2 and 3). The first two experiments of Aim 1 (Exp. 1A/B) use individual differences to determine the effects of age and hearing loss on the accuracy of pitch perception. They test the hypotheses that the sharp transition between good and poor pitch discrimination as lower harmonics are progressively removed is due to the limits of auditory filtering, as influenced by cochlear hearing loss, and that overall pitch fidelity across all conditions is degraded by age, as expected from age-related cochlear synaptopathy. Aim 1’s third experiment (Exp. 1C) utilizes recent signal- processing developments to test the role of harmonicity of either the target or interfering speech in the perceptual segregation of competing talkers. Aim 2 uses a developmental approach to test whether properties that are currently believed to be innate, including interference between pitch and brightness (Exp. 2A/B), and poor accuracy at high harmonic numbers and/or frequencies (Exp. 2C/D), are in fact centrally mediated developmental traits that emerge after extensive exposure to natural sounds. Finally, Aim 3 uses ultra-high-field (7T) fMRI to determine whether the perceptual interference observed in adults between pitch and brightness is reflected by interdependence of cortical tuning (Exp. 3A); whether cortical mapping of pitch and frequency is affected by the context in which the tones are presented (Exp. 3B); and whether cortical correlates of pitch interval size and direction can be observed (Exp. 3C). By improving our fundamental understanding of the neural coding and perception of pitch, we will be better placed to improve its representation in people with hearing loss and cochlear implants.

NIH Research Projects · FY 2025 · 2001-09

PROJECT SUMMARY Relapse prevention post-allogeneic hematopoietic cell transplantation (alloHCT) remains a paramount challenge. This project aims to test a novel graft-versus-host disease (GVHD) prophylaxis regimen that could also prevent malignant relapse. Our novel regimen accomplishes this goal by eliminating mycophenolate mofetil (MMF) from a post-transplant cyclophosphamide (PTCy) and sirolimus (SIR)-based regimen, and instead adding a novel, oral Aurora kinase A inhibitor that not only constrains GVHD through CD28 signal transduction blockade but also provide direct anti-tumor effects. Elimination of both MMF and tacrolimus (TAC) from our proposed regimen enhances graft-versus-leukemia (GVL) effects, further contributing to relapse mitigation. We propose to compare our GVHD prophylaxis regimen of PTCy/SIR/VIC-1911 to the widely used PTCy/SIR/mycophenolate mofetil (MMF) regimen in a randomized, phase II clinical trial in adults with hematologic malignancies undergoing myeloablative alloHCT. We hypothesize that substitution of VIC-1911 for MMF will result in a significantly better 1-year graft-versus-host disease-free, relapse-free survival (GRFS), setting a new standard in the field. Preclinical and phase I human data from the University of Minnesota show significant promise in the combined PTCy/SIR/VIC regimen, with low rates of acute/chronic GVHD and relapse, while not adding significant patient burden or side effects to the GVHD prophylaxis regimen. Partnering with the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) will provide a robust platform for trial implementation, capitalizing on their expertise, multicenter collaborative infrastructure, and access to a large and diverse patient population, ensuring rigorous evaluation of our innovative regimen and its transformative potential in the field of alloHCT. The University of Minnesota unequivocally affirms its commitment to the BMT CTN, bringing its expertise and institutional resources to further enhance its mission and objectives through clinical trials such as the one we propose herein.

NIH Research Projects · FY 2025 · 2001-07

OVERALL: SUMMARY The Minnesota Population Center (MPC) is a University-wide interdisciplinary cooperative for demographic research at the University of Minnesota. MPC develops and supports innovative, high-quality, and transformative interdisciplinary population dynamics research projects by (1) creating, sustaining, and expanding an intellectual community of interdisciplinary population researchers; (2) helping researchers to develop, fund, and execute cutting-edge population research projects; (3) formally and informally training the next generation of interdisciplinary population researchers; (4) providing outstanding administrative and technical support for population research and training; (5) effectively and efficiently disseminating and communicating research findings and their implications to diverse stakeholders and audiences; and (6) responding to and engaging with local, state, national, and international research partners and communities. MPC’s Administrative, Development, and Scientific/Technical Core services and resources allow MPC members—especially new and early stage investigators—to make efficient use of their funding for population dynamics research from NICHD, NIH more broadly, and other funders. Our members include 65 faculty and research scientists from seven colleges/schools and 13 departments at the University of Minnesota. In addition, we serve many population dynamics researchers at institutions across the country and globally. Their work is concentrated in MPC’s five primary research areas: (1) Population Health and Health Systems; (2) Spatial and Environmental Demography; (3) Reproductive Health; (4) Work, Family, and Time; and (5) Structural Racism and Health Inequities. This application for continued support has three Specific Aims: (1) Enhance and expand MPC’s vibrant and productive intellectual environment; (2) Provide efficient end-to-end support for population dynamics research projects; and (3) Invest in the next generation of population dynamics researchers. MPC has become one of the largest and most influential population research centers in the world. The Center currently has the largest portfolio of NICHD/PDB research grants among P2C-supported centers. Between 2015 and 2019, MPC was among the top P2C centers with respect to publications appearing in Demography, the leading journal of the field. MPC members’ data infrastructure projects provide the global research community with free access to the world’s largest sources of population data. At the same time, MPC members’ substantive research is leading and transforming the fields of population dynamics and health research, providing the scientific foundations for best practices in public health and public policy in the U.S. and around the world.

NIH Research Projects · FY 2026 · 2001-05

A group of investigators seeks to renew support for the Minnesota Muscle Training Program (MMTP), the NIH T32 interdisciplinary training program in muscle research at the University of Minnesota, for both predoctoral and postdoctoral scientists. This program began in 2001 with a primary focus on basic muscle research. Since that time, UMN has placed a high priority on the expansion of muscle research at all levels, particularly translational research, aimed at the development of new therapeutic approaches. The institution has recruited internationally prominent researchers in muscle disease and therapy and has established new facilities that support this research. In the previous funding period, further developments have led us to improve the quality of an already outstanding training program (which received a perfect score of 10 in 2011 and 2016), as measured by the funding and training records of the faculty; and by the number of qualified trainees, their publication record during training, and their research career success after training. Program faculty are drawn from several departments, but their graduate students are enrolled in the interdepartmental graduate programs in Biochemistry, Molecular Biology, and Biophysics (BMBB) or Molecular, Cellular, Developmental Biology and Genetics (MCDBG), which share a common admissions program (Molecular Cellular and Structural Biology, MCSB) and first-year curriculum. The intellectual center of the training program is an intensive one-semester course entitled “Muscle,” directed by the MMTP Director and taught by the MMTP faculty, which emphasizes both basic and translational research. This course has been expanded to accommodate an increasing emphasis on muscle disease and therapy. This is augmented by a weekly Muscle Journal Club, a biweekly internal seminar program, a monthly external seminar including international leaders in muscle research, and an annual MMTP Symposium in which all members of the training faculty’s research groups actively present and discuss their research, featuring a keynote speaker who is an internationally prominent muscle researcher. A significant strength of MMTP is its leadership. The Director (Thomas), who founded the program in 2001, is a world leader in the molecular biophysics of muscle, has had NIH funding on muscle since 1980 (including two MERIT Awards), and has mentored more than 100 predoctoral and postdoctoral trainees, most of whom have gone on to productive independent careers in muscle research. This program will now be strengthened by MPI structure, with Thomas joined by Ervasti and Lowe. Ervasti is a world leader in the biochemistry of muscle disease, and is Research Director for the Muscular Dystrophy Center, which is closely associated with MMTP. Lowe is a world expert on muscle physiology in areas of aging, disease, and gender differences. The University provides strong institutional support for MMTP, including a generous offer of matching funds. The primary goal of MMTP is to help these exceptional predoctoral and postdoctoral trainees to develop the intellectual and technical tools needed for productive careers as independent investigators and educators in muscle research.

NIH Research Projects · FY 2026 · 1999-08

Project Summary The grant “TR2 nuclear receptor in vitamin A signaling” (since 08/01/99) was initiated from studying retinoic acid (RA) signaling using an embryonic stem cell-specific orphan receptor TR2’s (NR2C1) as a model to understand RA’s action in developmental regulation. The long-term goal is to comprehensively understand RA signaling pathways in health and diseases. Results first established RA’s activity in chromatin-remodeling via RA receptors (RARs), Retinoid X receptors (RXRs) and TR2. In 2008, we reported a then-mysterious effect of RA that did not involve RAR/RXR - it occurred rapidly in the cytoplasm to modulate ERK signaling, and thus was proposed as “non-canonical”. Previous proposal (05/1/2017-04/30/2022) aimed to i) identify the mediator of this non-canonical activity of RA in modulating ERK signaling and synthetic RA-like ligands specific to this pathway, and ii) determine the physiological relevance. Results (published in 14 papers) have established Cellular Retinoic Acid Binding Protein 1 (CRABP1) as the mediator, characterized RA-CRABP1-RAF-MEK- ERK signaling pathway and CRABP1 ligands specific to this pathway, and revealed physiological relevance in maintaining neuron stem cell pool, adiposity and inflammation, all involving CRABP1-ERK regulation. Recently, a second signaling pathway also directly modulated by CRABP1 was uncovered, calcium/calmodulin- dependent protein kinase II (CaMKII), but in a different physiological context - excitable cells requiring tight regulation of CaMKII such as motor neurons (MNs) and cardiomyocytes. The principal hypothesis is, RA- CRABP1 signalosomes form in specific cellular environments to provide timely (rapid) modulatory mechanisms ensuring homeostatic propagation of intracellular signals that are critical to the survival/function of the cells. Pertinent to CRABP1-CaMKII, our recent data show that CRABP1 is highly expressed in MNs, and CRABP1 knockout (CKO) mice spontaneously develop age-dependent motor deficit resembling motor symptoms of MN degenerative disease Amyotrophic Lateral Sclerosis (ALS), preceded by morphological, structural, and functional deterioration of MNs and neuromuscular junctions (NMJs). We thus engineered a sequenced MN-muscle co-differentiation system on custom-fabricated Hydrogel to generate an in vitro, functional 3D NMJ model for molecular studies. Two aims are to i) dissect molecular mechanisms of RA-CRABP1-CaMKII signalsome action in NMJ and identify CRABP1 ligands specific to this pathway, and ii) determine the physiological action of RA-CRABP1-CaMKII signaling and its disease relevance/therapeutic applications. Aim 1 will employ engineered 3D NMJ model to dissect physiologically relevant signaling pathways and molecular mechanisms. Aim 2 will distinguish “non-canonical” from “canonical” activity of RA by comparing CRABP1 ligands and RA in maintaining healthy NMJs, and determine the therapeutic potential of targeting CRABP1 to improve motor function.

NIH Research Projects · FY 2026 · 1999-07

PROJECT SUMMARY/ABSTRACT The role of synchronized oscillations and changes in coherence and connectivity within the basal ganglia thalamocortical (BGTC) network in the development of motor signs in Parkinson’s disease (PD) remain under debate. While deep brain stimulation (DBS) has been an effective therapy for many PD patients, the mechanism(s) that underlie its therapeutic effect or how these compare to those that result from administration of L-dopa are not known. To advance DBS therapy we must improve our knowledge of the pathophysiological changes that underlie the development of PD and how DBS and L-dopa therapies that improve motor signs affect synchronized oscillations and connectivity in the “broader” BGTC (bBGTC) circuit (STN, GPi, motor thalamus, motor cortex (MC), supplementary motor area (SMA), premotor and prefrontal cortices (PMC and DLPFC respectively)). To address these questions, we will record neuronal and local field potential (LFP) activity simultaneously from 4 cortical (MC, PMC, SMA and DLPFC) and 3 subcortical sites (STN, GPi, and motor thalamus) in the nonhuman primate MPTP (1methyl-4-phenyl-1,2,3,6-tetrahydropyridine) model of parkinsonism. We will test the hypothesis that synchronized oscillations form across cortical and subcortical structures, alter the timing of synchronization and desynchronization of neuronal populations in specific frequency bands during movement and change connectivity patterns found in the normal state. We will characterize the relative change in synchronized coupling and connectivity in the bBGTC network and parkinsonian motor signs during DBS (STN, GPi, and STN + GPi) and compare that to the effect of L-dopa, and L-dopa + DBS (SA1). We will use directional leads to define the relative change in synchronized coupling and connectivity in the bBGTC network on parkinsonian motor signs and the degree of activation of motor, associative and limbic circuits during dDBS that steers current into motor versus associative regions of the STN and GPi (SA2). We will also determine the effect of a closed loop DBS approach on bBGTC connectivity and motor signs where stimulation is time locked to specific phases of the oscillatory biomarker determined through each animal’s resonant oscillatory frequency, i.e., phase-locked DBS (plDBS) (SA3). This study will provide a greater understanding of the pathophysiological changes that occur in bBGTC circuitry in PD, further delineate the mechanisms underlying the therapeutic effects of DBS and L-dopa, and characterize the relative effect of dDBS and a novel closed loop DBS approach on network connectivity and motor signs. These data will provide the rationale upon which current DBS therapies can be improved and future DBS therapies developed not only for PD but for other neurological and psychiatric disorders.

NIH Research Projects · FY 2026 · 1998-06

Overall Summary The Masonic Cancer Center (MCC) is an NCI-designated Comprehensive Cancer Center dedicated to cancer research, education, and patient care for the citizens of Minnesota. Since the time of the first award in 1997, there has been growth of the membership and research base. In our original application, there were 89 members; this has increased to 245 members from 49 departments and 11 colleges and schools of the University of Minnesota. Since our last renewal, there has been growth in cancer-related direct funding from $71.8M to $88.1M, a 23% increase. The MCC is organized into 6 Programs that focus on specific scientific themes: Screening, Prevention, Etiology and Cancer Survivorship; Carcinogenesis and Chemoprevention; Genetic Mechanisms; Cell Mechanisms; Immunology; and Transplant and Cellular Therapy. These programs are supported by 10 Shared Resources. The past funding period has seen increased emphasis on developing our translational pipeline. The resources available to members for effective translation have been reorganized under the leadership of a single Associate Director (AD) with oversight of both the fiscal resources and “idea generating” Translational Working Groups. Close collaboration between the AD for Translational Research and our AD for Clinical Research has led to the emergence of multiple new interventional trials from the science of MCC. MCC is a successful matrix organization in a large public research university that engages its faculty to focus on the problem of cancer. As such, MCC has engaged the community within our entire catchment area, established a longitudinal training pathway for learners, and is developing a plan for enhancing diversity within our workforce and patient population. Our current period of support has been characterized by growth in NCI- funded research; stability in our leadership; enhanced engagement of our community; and creation of several new cancer-focused initiatives including a statewide cancer clinical trials network, a global cancer prevention institute, and a developmental therapeutics initiative. Together, these activities fulfill our aims to 1) conduct high-impact population, basic, translational, and clinical research focused on eliminating the burden of cancer, especially in underrepresented populations; 2) provide the administrative and research structure at the University of Minnesota to engage our partners in the conduct of cancer research; 3) build multi- and transdisciplinary teams to address complex cancer problems; 4) educate the next generation of cancer researchers with special emphasis on enhancing diversity within the workforce; and 5) engage local, state, national, and international partners in helping MCC solve the problem of cancer.

NIH Research Projects · FY 2025 · 1997-09

PROJECT SUMMARY/ABSTRACT Immune effector cells (IECs) targeting tumor associated antigens, such as with chimeric antigen receptors (CARs) and bi- and tri- specific antibodies, offer unprecedented results in patients previously considered incurable. The number of cellular immunotherapies for solid tumors and hematological malignancies has dramatically increased. CAR T cells are now being considered early in the patient’s treatment plan as in children with CD19+ acute lymphocytic leukemia (ALL), no longer reserved for salvage therapy. However, as experience grows, a number of issues need to be addressed urgently. The grand challenges of adoptive IEC therapy include: on-target/off-tumor toxicities, T cell exhaustion, tumor escape by antigen loss, immunosuppressive tumor microenvironment, variable persistence, and time and cost of individualized product manufacture, limiting global access. To this end, there are 5 important research themes woven throughout the 3 Projects and 4 Cores, specifically, 1) the need for safe and effective allogeneic off-the-shelf IECs, 2) IECs that can target multiple tumor antigens to minimize tumor escape, 3) development of drug regulatable CARs for greater control, limiting on- target/off-tumor adverse effects and T cell exhaustion, 4) more selective cytokine stimulation to enhance IEC persistence and potency with minimal systemic side effects, and 5) translation of new engineering methods for industrial-scale manufacturing. During the current funding period, there have been key discoveries that will drive the next 5 years of this grant, specifically: the finding that (a) Tregs are effective cancer IECs which can be engineered to effectively target and kill cancer comparable to conventional T cells, (b) ability to generate iPSC- derived CD8 iTregs as a renewable starting cell source, readily amenable to genetic engineering and ex vivo expansion, (c) iPSC-derived NK cells engineered to express a high-affinity, non-cleavable CD16a (hnCD16) and membrane-bound IL-15/IL-15R without expression of CD38 enhances in vivo persistence and NK fitness and permits use of anti-CD38 antibody for in vivo depletion of regulatory cells, (d) the construction of antibodies that engage multiple targets, i.e. NK cells and tumor cells, with a stimulatory cytokine increase anti-tumor efficacy, and, (e) large scale IEC manufacturing, providing 100s to 1000s of cell doses, is possible. These discoveries will be further optimized and tested in relevant model systems in support of clinical translation. Project 1 will test the hypothesis that engineered allogeneic CD4 Tregs can be engineered to express synthetic stimulatory receptors and drug inducible CARs for maximum safety and reduced risk of exhaustion. Project 2 we will test the hypothesis that off-the-shelf CD83 CAR iPSC CD8 iTregs can be engineered to avoid rejection and exhaustion but retain potent tumoricidal activity against AML. And, Project 3 will test the hypothesis that the combination of iNK genetic engineering and antigen specific targeting with TriKEs and CARs will enhance specificity, potency, persistence for maximal AML killing.

NIH Research Projects · FY 2026 · 1996-07

Summary The durability of diverse forms of T cell memory is critical for effective immunity against various pathogens, and can be harnessed for cancer immunotherapy. Yet the signals that maintain T cell memory, and preserves the identity of distinct memory subsets, are incompletely understood. In particular, while there is considerable data suggesting that the cytokines IL-7 and IL-15 are important for preservation of memory CD8+ T cells, there are discrepancies in the literature that suggest this does not apply to all subpopulations of memory cells, or to all infectious systems. We believe some of these discrepancies arise from experimental procedures that do not accurately evaluate established memory T cell homeostasis (but which are conditioned by effects on memory generation). To test this, in Aim 1, we will use temporally inducible gene knockout strategies to eliminate sensitivity of T cells to IL-7 and/or IL-15, after the memory populations have been generated. We will examine these models in both steady-state T cell homeostasis and in the response to “bystander” infections. In Aim 2, we investigate the stability of two major classes of memory T cells – recirculating memory cells (“TMM”) and tissue-resident (“TRM”) cells. Each has different functional roles and distinct trafficking patterns. Based on published and preliminary studies, we will explore the role of the transcription factor KLF2 in controlling the “identity” of TMM vs TRM (and whether changes in KLF2 expression – by genetic manipulation or in response to statin drugs - will cause interconversion of TRM and TMM). We also investigate novel findings which indicate that expression of the egress factor S1PR1 (which is a gene regulated by KLF2) is critical for recirculation of TMM produced following some infections but not others, with consequences for therapeutic strategies to restain pathogenic T cell responses by targeting S1PR1. Again, these models will harness inducible gene knockout/expression models, as well as pharmacological treatments. Together, these studies represent a novel and highly significant investigation into the basis for durability in the diverse subpopulations of memory CD8+ T cells, with implications for how this can be manipulated for therapeutic goals.

NIH Research Projects · FY 2025 · 1994-07

PROJECT SUMMARY/ABSTRACT The long-term objective of this project is to fully define the functions of dystrophin in striated muscle to understand how its absence or abnormality leads to the pathologies observed in Duchenne and Becker muscular dystrophies, and to inform on the potential for miniaturized dystrophins or utrophin to substitute for dystrophin in a therapeutic context. In the current project period, we generated a new line of transgenic mdx mice that expresses dystrophin lacking in vitro microtubule binding activity, but which surprisingly presented with a fully rescued cortical microtubule lattice. We also analyzed microtubule organization in existing lines of transgenic mdx mice expressing different truncated dystrophin constructs and found that two different micro- dystrophins were less effective than two mini-dystrophins in restoring microtubule organization in mdx muscles. Exciting new preliminary data identified a second region required for microtubule organization and showed that the microtubule lattice of transgenic mdx mice expressing mini- or micro-dystrophins is rapidly disrupted by eccentric contraction through a mechanism involving reactive oxygen species. Thus, the first goal of aim 1 is to generate and characterize two new lines of transgenic mdx mice that will more definitively confirm the regions of dystrophin necessary for stable microtubule lattice organization. Aim 1 will then elucidate the relationship between eccentric contraction and reactive oxygen species in disrupting the microtubule lattice in mdx muscles expressing mini- or micro-dystrophins. Finally, aim 1 will delineate the interplay between the dystrophin-glycoprotein complex and cytoplasmic actins in effecting stable cortical microtubule organization in mature skeletal muscle. We have also recently published atomic force microscopy data suggesting that utrophin may be much stiffer than dystrophin and functionally less equivalent than previously thought. We have acquired exciting preliminary data showing that the cellular system used to express a model utrophin fragment significantly impacts its mechanical properties. In aim 2, we will extend our preliminary studies in bacteria and insect cells to measure the mechanical properties of dystrophin and utrophin constructs expressed in mammalian myoblasts. We will then carry out the first mechanical characterization of single, full-length dystrophin molecules for comparison with our published utrophin data. And finally, in aim 2 we will investigate how internal truncations affect the mechanical behavior of the most therapeutically-relevant miniaturized dystrophins. Our proposed studies will provide new understanding into the functions of dystrophin and utrophin in healthy muscle and will inform on the potential for miniaturized dystrophins and utrophin to functionally replace dystrophin as therapeutic approaches for Duchenne muscular dystrophy.

NIH Research Projects · FY 2025 · 1994-07

Acute respiratory distress syndrome (ARDS) is characterized by increased vascular permeability, decreased lung compliance, massive atelectasis and loss of aerated tissue, which often leads to respiratory failure and 40% mortality. Effective treatments for ARDS have become even more necessary as ARDS in non-survivors of Covid- 19 may be as high as 90%. LS plays two key roles in healthy respiration: (1) it establishes a minimum surface tension 𝛾!"#~15 mN/m, and (2) it prevents the lung from collapsing due to the Laplace Instability, by ensuring 2𝐸∗(𝜔) > 𝛾, where 𝐸∗(𝜔) = 𝐴(𝜔)(𝜕𝛾⁄𝜕𝐴) is the dilatational modulus, which describes the change in 𝛾 with interfacial area, 𝐴 at a breathing frequency 𝜔. Lung lavage of ARDS patients shows decreased concentrations of lung surfactant and increased concentrations of phospholipase A2 (PLA2), fatty acids and lysolipids (LPC). PLA2 catalyzes the hydrolysis of double-chain phospholipids in pathogen membranes into insoluble fatty acid and soluble single-chain LPC that accumulates in the alveolar fluids. Notably, LPC forms micelles at exceedingly low micromolar (𝜇𝑀) critical micelle concentrations (CMC). By incorporating otherwise insoluble LS molecules, LPC micelles can effectively “scrub” lung surfactant (LS) from the alveolar interface. By replacing LS at the interface with LPC, 𝛾!"# increases from ~ 15 to ~ 40 mN/m; moreover, the dilatational modulus decreases so that 2𝐸∗(𝜔) < 𝛾, triggering the Laplace instability. Injured or inflamed areas with LPC concentration above CMC are thus susceptible to lung instability, decreased compliance and alveolar flooding as observed in ARDS. Moreover, replacement surfactants would suffer the same fate so long as LPC concentrations are above the CMC. In Aim 1, we will characterize how lysolipid micelles solubilize LS using dynamic light scattering as well as by adsorption to alveolar sized bubbles in the capillary pressure microtensiometer (CPM) built for this project. We will examine shorter and longer chain lysolipids with choline, ethanolamine or anionic glycerol headgroups to correlate lysolipid CMC with 𝛾 and 𝐸∗(𝜔). This hypothesis suggests that decreasing the LPC concentration in the alveolar fluids below the CMC may be key to successful ARDS therapeutics. Adsorption of LPC into protein- free liposomes that do not adsorb to the air-water interface can reduce the LPC below the CMC. Co-administered synthetic lung surfactants containing the LS protein SP-B or peptide mimics of SP-B we developed, adsorb rapidly to the air-water interface to replace LPC at the interface. In Aim 2, we will examine the coupling between monolayer domain morphology and interfacial curvature. Monolayer collapse determines the minimum surface tension and is fundamentally different on curved surfaces compared to the flat surface of the Langmuir trough. We will use new experimental and theoretical techniques to measure line tension, dipole density difference, and the Young’s modulus of LS monolayers to quantify how monolayers bend or fold at collapse and describe the effects of interfacial curvature. These first of their kind experiments and theory should determine an optimal lung surfactant composition resistant to LPC adsorption and provide a new way of stabilizing the ARDS lung.

NIH Research Projects · FY 2025 · 1994-07

Health workforce projections for the United States consistently indicate a shortage of well-trained researchers in the fields of epidemiology and prevention. Importantly, the U.S. Bureau of Labor Statistics reports that the employment of epidemiologists is projected to grow 26 percent from 2021 to 2031, much faster than the average for all occupations. Meeting this surge in demand will require sustained support for training programs across the U.S. This five-year proposal is for renewal of a longstanding training grant in the epidemiology and prevention of cardiovascular disease administered by the Division of Epidemiology & Community Health, School of Public Health, University of Minnesota. The program is highly successful, having graduated 75 postdoctoral and predoctoral fellows since 1977. Among graduates in the past 15 years, 93% are currently in research positions, and 67% have obtained research funding, mostly from NIH. The training program’s excellent facilities, large and diverse faculty, and broad research opportunities offer an outstanding training environment. Our training program has continued to evolve and improve, to offer a cutting-edge training experience in cardiovascular disease epidemiology and prevention. In the most recent period (2019-2024), the program was awarded four predoctoral and three postdoctoral fellowship positions. Positions have been filled throughout and we continue to have outstanding applicants. A total of 14 different faculty have served as a formal mentor for at least one trainee during this same time period, demonstrating the breadth of expertise available to the trainees and the extent of involvement of participating faculty in the delivery of training. Fellows have been highly productive, generating impactful publications and presenting at national and international meetings. Our proposal for renewal (2024-2029) is to maintain seven fellowship positions per year – three postdoctoral and four predoctoral. The University of Minnesota T32 fellowship program offers outstanding training opportunities in direct research experience combined with a strong curriculum of formal coursework, seminars and expert mentorship. The uniqueness of the training is the commitment of its faculty and the breadth of existing research, from the laboratory to the community. The continued need for qualified cardiovascular epidemiologists and the program’s documented success justify its renewal.

NIH Research Projects · FY 2026 · 1992-09

PROJECT SUMMARY/ABSTRACT The Midwest Consortium for Hazardous Waste Worker Training (MWC) provides model training programs to workers and residents who may be exposed to hazardous substances. This programming is delivered by 13 training centers in 9 states: Illinois, Indiana, Kentucky, Michigan, Minnesota, North Dakota, Ohio, Tennessee, and Wisconsin. Eight of the centers are equipment-based centers that focus most strongly on HAZWOPER and related training for workers at designated hazardous waste sites; treatment, storage, and disposal facilities; and in a broad range of emergency response roles. The five remaining centers are community-based centers that focus on helping workers and residents, particularly those from disadvantaged populations, to recognize and react to hazardous materials in their communities. From 2020 to 2024, MWC training centers provided 3,333 programs to 50,850 trainees for 422,347 contact hours, demonstrating the impressive reach of the Consortium, even through the challenges posed by the COVID-19 pandemic. The long-term goal of the MWC is to improve occupational and environmental health and safety practices throughout the region it serves. In the shorter-term, the MWC's objective is to build capacity for workers to improve health and safety practices at their workplaces and for communities of workers and residents to recognize, prepare for, and recover from environmental exposures. To achieve this objective, the overall aims for the MWC are to facilitate delivery of model training programs at MWC training centers, enable training of participants who are underserved by workplace and community hazard programming, and modernize and simplify training program evaluation, providing greater insight into impacts of training. Achieving these aims will allow the MWC to continue to incorporate innovative training strategies and tactics into programming and to meet emerging needs such as to develop and deliver training on individual, workplace, and community resilience. The experienced, creative, and dedicated trainers at MWC centers have successfully trained hundreds of thousands of workers since 1987, increasing the collective training output over time and demonstrating impressive impacts. The centers provide training to workers at industrial sites, government agencies, tribal nations, healthcare systems, and elsewhere and to residents affiliated with faith-based groups, non-profit and community organizations, and neighborhood associations. Reported impacts of training demonstrate significant benefits to public health, particularly in the prevention and control of hazardous substances. Participants indicate that they learn how to act more safely and return to their workplaces and communities after training with a motivation to implement new procedures so that fundamental change will occur. From 2025 to 2030, MWC training centers will collectively provide 5,055 programs to 93,602 trainees during 841,366 contact hours.

NIH Research Projects · FY 2025 · 1991-09

This institutional training program at the University of Minnesota focuses on the preparation of neuroscience graduate students and postdoctoral fellows for research and study in the field of drug addiction. Research programs across the 26 participating investigators span cellular and molecular, systems, computational, and behavioral neuroscience-based approaches to studying addiction. The program aligns basic researchers, technology engineers, and translational scientists to provide an exceptional breadth of scientific scope and training capacity. The scientific environment is highly cooperative, with robust extramural research support that benefits from multiple active collaborations. Rigorous and effective training is supported through tailoring individual developmental plans, the addition of new courses in quantitative analyses and computational neuroscience methods, a highly comprehensive program for mentoring the mentors, thorough evaluation of training outcomes, and expanding outreach across the state of Minnesota. The commitment of the University of Minnesota to this training program is readily apparent; over 30 million dollars was recently invested in the hiring of faculty studying the neuroscience underlying drug addiction. This has resulted in the addition of numerous new exceptional mentoring faculty to the program. This proposal requests six predoctoral and three postdoctoral positions, the same number as previously supported. Robust institutional support will provide an additional three training slots, with the remaining matching funds providing resources for an annual retreat, on-going seminar series, and additional program expenditures. By providing training essential to the next generation of drug addiction researchers, this T32 program facilitates progress in the understanding of drug addiction.

NIH Research Projects · FY 2025 · 1989-09

Project Summary/Abstract This application requests support for years 35-40 of a predoctoral training program in Immunology at the University of Minnesota. During its long history, this training grant has served as a solid and consistent base of support for the highest quality graduate students in Immunology at the University of Minnesota. In doing so, it has played a key role in the development of the first University of Minnesota graduate program to feature Immunology, the recruitment of over 32 new immunology faculty, and the establishment of the multi-departmental Center for Immunology that now coordinates all University of Minnesota research and educational activities in this field. Most predoctoral students who seek training in Immunology enroll in the Microbiology, Immunology, and Cancer Biology (MICaB) Graduate Program. They take graduate level courses in cell and molecular biology and a rigorous semester-long foundational course designated "Immunity and Immunopathology" and an in-depth and intensive course called "Current Topics in Immunology". Predoctoral students are chosen for this training grant usually in their second or third year of training, through a competitive selection process based on research productivity and potential. All T32 preceptors vote to choose the new trainees. Once elected, students are supported for 2 years to conduct research in the laboratory of one of 28 preceptors whose interests broadly cover the field of Immunology. Supported students participate in research-in-progress meetings, journal clubs, and seminars featuring outside speakers. Trainees typically complete their research after 2-3 years, often publishing their work in high-impact journals, and then move on to postdoctoral training at top research institutions. The quality of the research produced by students supported by this training grant reflects an outstanding research environment, where faculty are highly invested in the success of trainees. This training grant is the only vehicle available at the University of Minnesota to enhance predoctoral-training in Immunology.

NIH Research Projects · FY 2025 · 1982-07

PROJECT SUMMARY/ABSTRACT The American Society of Hematology and National Heart, Lung, and Blood Institute have highlighted the need for the training of physicians and scientists in hematology. The Hematology Research Training Program at the University of Minnesota addresses this concern by providing: 1) inter- and multi-disciplinary research training in five major realms of hematology; 2) programs that enhance recruitment and retention of diverse trainees and promote a culture of equity and inclusion; 3) senior and junior faculty members of both genders as mentors; 4) an environment offering outstanding resources; 5) a fusion of research and clinical training for physician and PhD trainees; and 6) skill development for trainees to both survive and thrive in academic medicine. The overarching objective of the training program is to train physicians and scientists for careers in hematology- related research and academic medicine. Our program philosophy is to achieve trainee success by carefully balancing sufficient structure to ensure rigor in the training experience and programmatic flexibility to accommodate the different needs of trainees. Our Training Program provides the fundamental knowledge and skills enabling trainees to adapt to new paradigms of disease, employ new technologies, and embrace the highest ethical standards. This post-doctoral training program will allow six trainees a minimum of two years of research experience. Our Training Program boasts a long history of successfully recruiting outstanding, highly motivated individuals who work with exceptional mentors in achieving their career and research goals. Approximately 90% of our graduates from the past 15 years are engaged in research. Our faculty mentors are international and national leaders in hematology research, including sickle anemia, vascular biology, natural killer cell therapies, CAR T cell therapies, hematopoietic stem cell transplant, and gene therapies. In carrying on the tradition of the last 45 years, we are confident our mentors and research environment at the University of Minnesota will continue to cultivate future leaders in hematology.

NIH Research Projects · FY 2025 · 1980-07

The Molecular, Genetic, and Cellular Targets of Cancer Training Program (TCTP) at the University of Minnesota (UMN) provides comprehensive laboratory-based training for predoctoral and postdoctoral trainees, preparing them to become research leaders in the therapeutic targeting of the molecular, genetic, and cellular mechanisms of cancer. With 35 faculty preceptors and 3 advisors, the TCTP emphasizes cutting-edge cancer research areas, including molecular targeted therapies, cancer genetics/epigenetics/genomics, cancer immunology, and tumor microenvironment studies, aligning with the UMN Masonic Cancer Center (MCC) mission to advance cancer prevention and treatment strategies. For the next funding period, several new initiatives are planned. These include a leadership transition, with Dr. Scott Dehm succeeding Dr. Carol Lange as Program Director, as well as the addition of administrative support from the MCC Education and Training Office. This will be coupled with enhanced trainee orientation and a new flexible training framework for postdoctoral trainees, allowing customization of coursework based on individual backgrounds and research needs. The program will also introduce modular training electives in advanced topics such as bioinformatics, genomics, and cancer immunology, reflecting emerging priorities in cancer research. Additional innovations include near-peer mentoring, individualized fellowship writing workshops, expanded mentor training for faculty, and a new monthly networking event designed to foster informal interactions among trainees, faculty, and TCTP alumni. The TCTP supports trainees’ participation in national conferences, MCC symposia, and professional development workshops. Career development initiatives, such as leadership training, team management, and professional seminar coaching, ensure that trainees are well-prepared for competitive roles in academia, industry, and other scientific venues. With the continued support of the MCC and the UMN Medical School, along with these new initiatives, TCTP remains a premier training program for laboratory-based cancer researchers and will continue contributing to the discovery of innovative cancer therapies.

NIH Research Projects · FY 2025 · 1979-07

Project Summary The purpose of the proposed program is to train the next generation of scholars in developmental psychopathology who will conduct multiple levels of analysis research addressing one or more of NIMH’s 2020 strategic objectives. The proposal requests continuation of a training program at the Institute of Child Development, University of Minnesota, continuously supported by the National Institute of Mental Health since 1959. In 1981 this training program added postdoctoral students and now consists of 3 predoctoral and 2 postdoctoral positions. The award-winning faculty on the training grant reflect various sub- disciplines of developmental science, including child clinical psychology, developmental behavioral neuroscience/developmental psychobiology, stress neurobiology, socioemotional development, pediatrics, and intervention science. External training faculty from other departments across the University of Minnesota (e.g., Family Social Science, Pediatrics, Psychiatry, Psychology, Pharmacology, Public Health) also will serve as co-mentors of the pre- and –post doctoral trainees. This allows our trainees to take advantage of the full richness of research in developmental psychopathology available at the University of Minnesota. In any given year, the predoctoral trainees represent approximately 10% of all Ph.D. students in the Institute of Child Development; thus, being placed on the training grant is highly competitive. Students enter the training grant as 2nd, 3rd or 4th year Ph.D. students (preferentially 3rd or 4th year) so that we can be more confident of their talent and of their commitment to research areas pertinent to NIMH’s strategic goals. Postdoctoral trainees are selected based on evidence of research potential, strong recommendations, and fit with the program. Predoctoral trainees complete one of two Ph.D. tracks, the Developmental Science track or the Developmental Psychopathology Clinical Science track; the latter involves a one-year clinical internship. All predoctoral trainees receive training in professional development, ethics in research, statistics, and cognitive and social development as part of the larger Ph.D. program. T32 trainees in addition take a course in developmental psychopathology, attend the annual research ethnic UMN conference, present at the annual clinical research day and complete grant-writing training. Postdoctoral students complete the grant writing training and, in consultation with their faculty mentor and the training grant director, any areas of developmental science that are critical to their research program and in which they lacked sufficient prior training.

NIH Research Projects · FY 2026 · 1977-08

ABSTRACT In the setting of the burgeoning obesity epidemic, metabolic health involving diabetes, diabetes-related risk factors and diabetes-related complications increasingly burden the US health care system. Yet, even as the disease burden increases, the number of investigators committed to finding ways to prevent and treat metabolic diseases has lagged persistently behind. The University of Minnesota (UMN) has held a T32 training grant since 1977 with demonstrated success. Within the last 10 years (n=13 trainees), 10 (77%) are in research related fields, 5 (38.4%) are Assistant Professors, and 7 (54%) are associated with NIH grants (either PI or Co-I). To drive the success of the T32 training program moving forward, we have assembled an outstanding, complementary leadership team (MPI between Drs Chow and Bernlohr) and sharpened the current proposal’s focus to leverage the recent flourishing success of UMN investigators in metabolic healthspan, the preservation of metabolic health. The proposed T32 program will provide advanced training in state-of-the-art research focused on the mechanisms affecting metabolic healthspan and enhancing metabolic health. To achieve this goal, we will employ a multifaceted approach inspired by our past history to train four postdoctoral students (MD, PhD or MD/PhD) per year for up to 2 years per trainee. The training approach includes the following: #1 Provide trainees with the skill sets necessary to perform multidisciplinary research regarding metabolic healthspan, #2 Provide high quality mentorship, now involving Senior/Associate Mentors (mentor dyads) to support trainee and Associate Mentor development, #3 Provide an outstanding environment fusing research and clinical training for physician and PhD trainees, #4 Provide skill development, including the experience of writing a F32 or alternative career development grant during the second year, for trainees to thrive in academic medicine and #5 Establish programs that enhance recruitment and retention of diverse trainees. The overarching objective of the proposed UMN T32 program is to train physicians and scientists for research careers focused on enhancing metabolic healthspan while providing a thoughtfully-designed training environment focused on meeting the unique development needs of postdoctoral fellows as they define their career and research goals.

Other NSERC · FY 2024

Decision making, Predator-prey interactions, Electrophysiology, Hippocampus, Neuroeconomics