University Of Minnesota

NIH Research Projects · FY 2024 · 2020-01

Healthy adipose tissue function is essential for maintaining metabolic homeostasis and preventing metabolic diseases. While hypertrophic expansion of adipocytes can lead to adipose tissue dysfunction and contribute to obesity-related metabolic complications, expansion through hyperplasia, driven by adipogenesis, can serve as a protective mechanism. Impaired adipogensis is associated with obesity and aging, promoting the development of metabolic syndrome. Therefore, understanding the mechanisms behind impaired adipogenesis is crucial for designing therapeutic strategies to combat metabolic diseases. In both human and mouse obesity, defective adipogenesis has been linked to senescence in adipose progenitor cells. Recent evidence suggests that extracellular vehicles (EVs) play a role in intercellular communication within adipose tissue and regulate adipose tissue function. However, the specific EVs responsible for regulating adipoegnesis and the factors controlling the secretion and adipogenic function of EVs remains unexplored. Our preliminary studies indicate that Lipocalin 2 (Lcn2), as a novel phosphatidic acid (PA) binding protein, plays a regulatory role in senescence and adipogenesis of adipocyte progenitors through EV-mediated intercellular communication. Lcn2 deficiency impairs adipogenesis and results in hypertrophic obesity under high fat diet conditions. Stromal-vascular (SV) cells from brown and white adipose tissue of Lcn2 knockout (KO) mice exhibit increased senescence and decreased adipogenesis. Additionally, we have discovered that Lcn2 is present in a specific population of small EVs secreted by adipocytes. Lcn2 deficiency reduces the small EV population and the secretion of EVs from adipocytes, particularly under inflammatory conditions. Our recent investigations unveiled a pivotal role of Lcn2 as a PA binding protein in the recursive regulation of phospholipase 2 (PLD2)-PA loop and PA production, which is crucial for EV biosynthesis and secretion. Our hypothesis is that Lcn2 functions as an anti-senescence factor that maintains the health of adipose stem and progenitor cells (ASPCs) via regulating EV-mediated intercellular communication within adipose tissue. This one-year project proposes two Aims. Aim1 will establish the protective role of Lcn2 against senescence and adipogenic defects in ASPCs during diet-induced obesity, focusing on anti-senescence and adipogenic effects of Lcn2 overexpression in adipocytes. Aim2 will determine the role of Lcn2 in EV-mediated intercellular communication necessary for maintaining the adipogenic function of ASPCs. We will characterize the role of Lcn2 in the release and cargo loading of EVs from adipocytes in response to metabolic stress and inflammatory stimulation. The findings from this project will provide new insights into the pathogenesis of hypertrophic obesity and to pave the way for the development of novel therapeutic approaches.

NIH Research Projects · FY 2026 · 2019-12

PROJECT SUMMARY Huntington’s disease (HD) is a neurodegenerative disease caused by a CAG repeat expansion in the HTT gene that preferentially affects medium spiny neurons (MSNs) of the striatum. HD is primarily characterized as a motor disease, but it also manifests with cognitive and behavioral deficits that appear well before motor symptoms onset and are considered the most burdensome for patients and caregivers. Cognitive changes in HD are most highly associated with functional decline and can be predictive of nursing home placement. However, the etiology of cognitive decline in HD is significantly understudied. The goal of this proposal is to provide a mechanistic understanding for how cognitive decline arises in HD. The dorsomedial striatum (DMS), the most affected area in HD, has long been recognized as an important structure in the regulation of various cognitive functions and its degeneration has been observed in patients with various forms of dementia. The striatum’s function is regulated by two major excitatory glutamatergic inputs: thalamo-striatal (T-S) and cortico- striatal (C-S). T-S synapses contribute to the regulation of cognitive flexibility, working memory, and some forms of learning, and are preferentially lost in young HD mice. Studies in HD patients before-clinical motor diagnosis found a strong thalamus–striatum association that significantly co-varies with cognitive performance and is predictive of cognitive impairment and disease progression. During the prior research period, we established a connection between the stability of T-S synapses and Heat Shock transcription Factor 1 (HSF1), a protein known for its role in protein homeostasis and stress response, in both physiology and HD. In the renewal of this R01 we are seeking to understand how HSF1 participates in the early loss of T-S synapses in HD and whether T-S synapse loss leads to cognitive decline in HD. Our preliminary HSF1 ChIP-seq analyses in young zQ175 HD mice revealed a deficit in HSF1 DNA binding onto specific postsynaptic scaffolding genes involved in synapse maintenance and HSF1 RNAi injected in the striatum of WT mice mimicked decreased T-S synapses and impaired cognition as seen in HD mice. Our previous proteomic work also revealed HSF1 interacts with unique proteins in HD that negatively influence HSF1 activity. We hypothesize that HSF1 interacts with unique proteins in HD that impair HSF1 binding and regulation of genes involved in the formation and maintenance of T-S synapses, causing T-S synapse loss and cognitive decline. We will test this hypothesis by 1) investigating the mechanism responsible for the alteration of HSF1 DNA-binding in early HD, 2) assessing how HSF1 regulates the synaptoproteome of T-S synapses, and 3) evaluating the role of HSF1- mediated loss of T-S synapses in the dysregulation of striatal synaptic plasticity and cognitive deficits in HD. Successful completion of our work will shed light into the mechanisms responsible for cognitive decline in HD and perhaps other forms of dementia in which HSF1 and DMS dysregulation have been observed.

NIH Research Projects · FY 2025 · 2019-12

ABSTRACT Antifungal drug resistant Candida species pose an urgent antimicrobial threat worldwide. Patients with invasive Candida infections experience high mortality >40%, despite the use of modern antifungal therapies. Only three drug classes are frequently used to treat Candida infections: azoles, echinocandins, and polyenes. Resistance to all three classes is increasing. The acquisition of antifungal drug resistance is frequently associated with large genomic copy number changes in diverse fungal pathogens, including Candida species. We identified novel large accordion-like DNA amplifications in C. albicans that rapidly expand during adaptation to azoles in vitro, amplifying hundreds of genes to more than 10 copies. We also reported that 50% of azole resistant C. albicans clinical isolates are aneuploid, and that Candida auris aneuploids can evolve during on-patient antifungal therapy. Aneuploidy is also associated with antifungal tolerance, a poorly understood phenotype that enables Candida to grow slowly at high concentrations of all three drug classes, well above the minimum inhibitory concentration. We propose that aneuploidy-mediated antifungal tolerance is promoting the evolution of antifungal resistance. Despite the frequency of aneuploidy, the rate and dynamics of chromosome copy number changes during adaptation to antifungal drug are not known for any fungal pathogen. We developed several high throughput single-cell and population-level approaches to comprehensively quantify the emergence and spread of all genomic changes during the acquisition of antifungal resistance, in real time. Our multidisciplinary approach uniquely positions us to identify new mechanisms of acquired antifungal tolerance and resistance in a rigorous and reproducible way. For example, we identified the sterol biosynthesis pathway as a hotspot for acquired multidrug resistance and tolerance across diverse Candida species, creating a paradigm shift: Multidrug resistance can evolve during adaptation to a single antifungal drug class, due to acquisition of a single point mutation. The aims of this proposal take a new approach to identifying the mechanisms driving antifungal drug resistance: We will use a new single-cell flow cytometry assay to quantify the rate and dynamics of aneuploid events during adaptation to each drug class and determine the effect of drug class on the evolution of drug resistance (Aim 1). We will comprehensively identify genes that when amplified alter drug susceptibility in vitro and in vivo using a novel CRISPR-amplification approach (Aim 2). Finally, we will use comprehensive molecular approaches to determine the degree to which mutations in the sterol biosynthesis pathway cause multidrug resistance in diverse Candida species (Aim 3). This comparative analysis of acquired resistance will provide a strong foundation for work in other Candida species. Together the outcomes from these experiments will identify the mechanisms that underlie how Candida species acquire drug tolerance and resistance and can pave the way for developing therapeutics to reduce the significant mortality caused by diverse antifungal drug resistant Candida species.

NIH Research Projects · FY 2024 · 2019-09

Project Abstract – Bupropion for the Prevention of Postpartum Smoking Relapse Postpartum smoking relapse rates have remained stagnant for over a decade with approximately 50% of those who are able to achieve smoking abstinence during pregnancy relapsing within the first few months after childbirth. Maternal cigarette smoking results in a significant increase in a variety of negative health consequences for both mother and child. Of women who smoke three months prior to pregnancy, 55% quit during their pregnancy. The following postpartum period presents a unique and challenging time for women to maintain smoking abstinence. Several modifiable risk factors are predictive of postpartum smoking relapse including depression, weight concerns, and smoking related symptomatology. Bupropion is uniquely suited to address each of these relapse related risk factors in postpartum women. Treatments that address these multi- faceted barriers related to postpartum smoking relapse may lead to sustained abstinence. Bupropion has proven efficacy for smoking cessation in the general population, doubling quit rates at six months. Though less explored in the literature, bupropion treatment for smoking relapse prevention has demonstrated a delay to relapse in those receiving bupropion. Yet the use of bupropion for postpartum smoking relapse prevention has not been explored. Therefore, our central hypothesis is that bupropion will prevent postpartum smoking relapse among women who quit smoking during pregnancy. To explore this hypothesis, we will conduct a two-arm, double-blind, placebo-controlled randomized clinical trial using rigorous, validated and reproducible methods that will be implemented by a team of experienced investigators who are familiar with this population. We will enroll pregnant women (n=230) who quit smoking after learning they were pregnant and are motivated to stay abstinent postpartum. Participants will be randomized to receive extended release bupropion (active 300mg or placebo once daily beginning 4 to 10 days postpartum to 12 weeks post randomization). All participants will complete the same data collection procedures (e.g., biological sample collection for hormone and cotinine analysis and completion of validated questionnaires) at baseline (gestational week 36), weekly from 4 to 10 days postpartum through 12 weeks post randomization and at weeks 12, 24, 36 and 52 post randomization. Intervention adherence will be confirmed quantitatively via high performance liquid chromatography using biological samples. The implications of this novel study, pursued by a highly skilled and productive team, will directly advance the current state of the science by expanding on the role of a known pharmacotherapy within this highly vulnerable population. Further, should our central hypothesis be supported, the dissemination of this intervention is clinically applicable, relevant and may be immediately pursued.

NIH Research Projects · FY 2025 · 2019-09

PROJECT SUMMARY / ABSTRACT Bacteria are important to human health and therefore, effective control strategies are critical to mitigate the risks posed by microbial activities. The current paradigm of chemical (antibiotics) control is eroding with the escalating challenge from resistance, and new strategies are needed. Quorum sensing (QS), a communication system utilized by bacteria and based on signaling molecules is appealing because it controls several bacterial behaviors. However, our current understanding of QS and our ability to manipulate is rudimentary. Here we propose to comprehensively investigate QS using interference strategies, specifically enzymes such as lactonases that can degrade the signaling molecules N-acyl-homoserine lactones, to decode the microbial language. Our group demonstrated the efficacy of interference in QS using these enzymes across various contexts, including monocultures and complex communities. Yet, challenges remain in achieving the selectivity needed to specifically isolate the contribution of individual signals and infer their biological roles. We propose to address critical gaps in QS interference by elucidating its effects on bacterial behavior and interspecies competition. Additionally, we will continue to unravel the molecular determinants governing lactonase mechanisms and substrate selectivity. Lastly, we will characterize and enhance enzymes capable of degrading orthogonal signals, such as autoinducing peptides (AIPs) to considerably expanding the scope of QS manipulation. The expected impact from this proposal extends beyond the fundamental insights into bacterial communication. By unveiling novel regulatory mechanisms and advancing our enzymatic understanding, this work will enable the design of highly specific quorum quenchers. Ultimately, these findings will inform bacterial control strategies with implications for human health and beyond.

NIH Research Projects · FY 2024 · 2019-09

PROJECT SUMMARY The purpose of this study is to expand measurement-based psychiatric care across 6 early psychosis treatment teams in Minnesota, each providing coordinated specialty care and in total serving 200 individuals per year. Our first goal is to efficiently deploy valid longitudinal outcome measures across each team, implement state-of-the-art informatics tools, and aggregate pooled data to inform and support program evaluation activities as well as novel data-driven analytics. Our second goal is to perform a practice-based research project designed to answer two questions: 1) Does a structured personalized feedback session that includes an explicit focus on cognition and motivated behavior provide benefit to stakeholders--service users, family members, and primary clinicians? 2) Can cognition and motivated behavior be addressed as key treatment goals within real-world settings, using a 12-week mobile intervention program? Our central scientific premise is that cognitive dysfunction and impaired motivated behavior are critical unmet therapeutic needs in early psychosis. We have shown that auditory cognitive training can be successfully delivered on a mobile device to individuals with early schizophrenia, resulting in significant gains in global cognition that endure 6 months after the end of the intervention. We have also demonstrated that the addition of social cognition training drives improvements in measures of motivated behavior. More recently, we demonstrated that a 12-week mobile digital health coaching and social networking app designed to target motivated behavior in early psychosis resulted in significantly greater improvements in self-reported depression, defeatist beliefs, self-efficacy, and a trend towards improved motivation/pleasure and negative symptoms (compared to a wait-list control). These improvements were maintained when re- assessed 3 months after the end of the trial. Based on this work and on our experience running successful coordinated specialty care teams, our project will address the following two aims: Aim 1: Establish highly reliable measurement-based psychiatric care for 200 early psychosis individuals per year across 6 clinical teams; Harness clinical encounter data to perform novel data-driven trajectory analyses, predictive modeling, and causal discovery analyses. Aim 2: Investigate potential benefits of identifying cognitive functioning and motivated behavior as explicit treatment targets for individuals entering care; Study a well-defined 12-week mobile intervention program to address these targets.

NIH Research Projects · FY 2025 · 2019-08

Project Summary/Abstract The extraordinarily rapid aging of the developing world represents one of the most significant demographic transformations in history, with profound consequences for disease and disability, intergenerational relations, work and retirement, geographic mobility, and other economic and demographic processes. The United Nations projects that the population aged 60 and older will grow by over 50% over the next 15 years. Most of the growth of the older population will take place in the Global South, which will include 80% of the older population by 2050. The growth of the older population in Latin America, Africa, and South Asia is occurring far more rapidly than it did in the developed countries of Europe and North America. Despite its manifest significance, population aging in the Global South is understudied, partly because of a dearth of suitable data. To grapple with processes of population aging across the Global South over multiple decades, researchers must have access to big microdata. Over the past two decades, the Integrated Public Use Microdata Series (IPUMS) has created a vast database of census and survey microdata covering most of the globe from the 1960s to the present. These data include detailed information about each person's geographic location, demographic characteristics, and economic activities. The data also cover education and literacy, fertility history, migration and place of former residence, marital status and consensual unions, disabilities, water supply, sewage, housing features (e.g., floor and roof material), and a host of other characteristics. This competing continuation proposal requests funding to expand and adapt the world’s most comprehensive collection of census microdata to meet the needs of research on aging in the Global South. We have four specific aims: (1) Data acquisition and long-run preservation. We will obtain and preserve census and survey microdata from the Global South, including the newest microdata from household surveys and older data at risk of destruction. (2) Data processing. We plan to expand the IPUMS database by adding data for approximately 100 million individuals included in 40 censuses and surveys, focusing on recent data from Africa and Latin America. This expansion will require data cleaning, development of comprehensive machine-processable metadata, spatial data ingest and harmonization, and variable harmonization. (3) Innovations in data, metadata, and technical infrastructure. We will make major improvements to IPUMS data and metadata while adding new capabilities to IPUMS data processing and dissemination systems. (4) Dissemination and outreach. We will provide user support, training, and outreach and will develop new online training capabilities. We will harness the expertise of the user community and promote collaboration and scientific discovery through surveys of users, workshops, and online interaction. Most critically, we will maintain our network of collaboration with the national statistical agencies that provide the source data.

NIH Research Projects · FY 2025 · 2019-08

PROJECT SUMMARY Glioblastoma (GBM) is the most aggressive form of human cancers with very high fatality rate and short survival time, and the cancer cells aggressively infiltrate the brain and are intrinsically resistant to chemotherapy and radiation therapy. Intra-tumoral heterogeneity is a major challenge in therapeutic development for GBM patients because surgical acquisition of clinical specimens cannot be used to monitor the tumor progression and/or the underlying metabolic changes. Various neuroimaging methods have been used to study the morphology of the brain tumors. However, the need for noninvasively characterizing the brain tumors and their metabolic features has not been met, which should be critical for prognosis or for monitoring the tumor progression and response to treatment. It is well known that a common hallmark of the cancer cells is disrupted glucose metabolism, in which upregulated glycolysis is accompanied by inhibited mitochondrial oxidation, i.e., the “Warburg effect”. Imaging the “Warburg effect” and its spatial variability in brain tumors is a new attempt that can have a major impact on cancer research, particularly in the treatment of GBM, because therapies aimed at reversing the Warburg effect have shown promise in GBM ; however, great efforts are needed to develop novel metabolic imaging techniques to achieve the capabilities sought by clinicians. We have recently initiated a project aiming to develop a neuroimaging technique based on deuterium (2H) MRS (DMRS) detection of 2H-labeled brain metabolites following an administration of D-Glucose-6,6-d2 (d66). Our preliminary results indicate that the dynamic DMRS imaging can determine the cerebral metabolic rates of glucose (CMRGlc) and TCA cycle (VTCA), thus, the lactate production rate (CMRLac) in addition to the concentrations of deuterium-labeled glucose (Glc), mixed glutamate/glutamine (Glx) and lactate (Lac) in living brains. Furthermore, we demonstrated for the first time that the uncoupling between the glycolysis and oxidation in brain tumor can be quantitatively imaged via mapping the [Lac]/[Glx] ratio defined as an index of Warburg effect (IWE); and it has been shown that IWE is highly sensitive for distinguishing brain tumor from surrounding normal tissues. In this application, we are seeking NIH funding support to move forward with the DMRS imaging development through: i) integrated hardware and software development and the ultrahigh field MR technology to further boost signal-to-noise ratio (SNR), spectral resolution and spatiotemporal resolution; ii) testing the ultrahigh resolution DMRS imaging in healthy subject, and tumor patients and establishing a quantification model and imaging processing pipeline for future application; and iii) comparing the DMRS imaging results with the neuropathological and immunohistochemical findings of the biospecimens to understand the correlation between the DMRSI measurements and biological features of brain tumor. Our interdisciplinary research team with unique expertise is ready for a full-scale development of this highly innovative and cost-effective neuroimaging essential for basic research and clinic application in neuro-oncology.

NIH Research Projects · FY 2026 · 2019-08

PROJECT SUMMARY / ABSTRACT Since the discovery of penicillin in the 1920s, bioactive peptide natural products have been used as antibiotic, antiviral, immunosuppressive, and anti-cancer agents. Many of these bioactive peptides harbor backbone α-N-methylations and/or macrocyclizations, since these tailorings significantly improve peptide pharmacokinetics. As seen in the blockbuster immunosuppressant cyclosporin A, α-N-methylated peptides have increased structural rigidity, proteolytic resistance, and membrane permeability. Despite these advantages, inefficient synthetic and in vitro processes hinder the production, screening, and optimization of α-N-methylated peptides. In addition, natural sources of amide backbone-methylated peptides were thought to be completely limited to inflexible nonribosomal peptide biosynthetic pathways. The goal of this work is to identify new α-N- methylated metabolites and tease out the mechanistic and structural constraints of biocatalysts from our newly discovered ribosomally encoded peptide natural product family named the borosins. Our first objective aims to uncover rules of iterative catalysis, inhibition, and cooperativity in our model borosin system. Our second objective targets the discovery and study of structurally complex borosin metabolites from cystic fibrosis pathogens. Our last objective focuses on the mechanism and structure of α-N-methylation–dependent proteases and macrocyclases. This research will create a diverse toolbox of flexible and efficient catalysts for the biological production, screening, and optimization of genetically templated bioactive α-N-methylated peptides.

NIH Research Projects · FY 2025 · 2019-07

Summary Cardiovascular disease in the American population is continuously a major source of debilitation and death despite increased prevention, diagnostic, and treatment options. This calls for increased scientific understanding and innovative application of these findings to the care of patients to prevent or cure heart disease. This training program in cardiovascular innovation is designed to teach the scientific and technical skills necessary to develop a novel idea and carry this idea through to proof-of-concept in humans. The training program takes unique advantage of the strengths of the Lillehei Heart Institute, the University of Minnesota Cardiovascular Division, the wider community of translational medicine and entrepreneurship at the University of Minnesota, and the Twin Cities biotech, pharma, and device industries. This application will train basic and clinical scientists in an interdisciplinary environment to give them the insight and tools to be able to successfully carry an idea from conception to implementation in humans. Therefore, the goal of this Training Program is to provide an interdisciplinary research and training environment wherein trainees will be exposed to the continuum of technological development from conceptual idea to testing at the basic, small animal, large animal, and human levels. Trainees will be advantaged by community strengths in basic, translational, and clinical science, training in cardiovascular innovation and entrepreneurship, and industry interactions and mentorship. There are several unique features of this training program: 1) the focus on cardiovascular sciences, 2) the scientific qualification of its Trainers, 3) the curriculum focused on innovation, 4) the presence of industry mentors, and 5) the opportunity for meaningful industry interactions. The program will consist of a basic cardiovascular curriculum augmented by specific training in cardiovascular innovation. Each trainee has the opportunity to participate in the Bakken Innovation Fellows Program. The goal of this program is to train the next leaders in MedTech by fostering leadership and teaching risk management for medical innovations. Trainees will also partake of the Carlson School of Management Medical Industry Leadership Institute (MILI) program offerings. MILI offers students innovative experiences through industry-specific courses and unique, hands-on evaluations of emerging technologies from around the globe. Trainees will take at least 2 relevant half-day courses offered by the Technological Leadership Institute: 1) Innovation, Leadership & Communication, 2) How to Create and Stimulate a Culture of Innovation, 3) Communication in a Technical Environment: Developing Writing and Presenting Skills, and 4) the yearly Innovation Workshop "Becoming a Medical Technology Innovator." Trainees will engage in a minimum of 3 years of research training. The first two years of training will be for innovation and other didactics and for carrying out the research. Year 3 will be dedicated predominantly to developing a business plan related to the project and writing an appropriate grant application for career advancement. For PhDs, this would consist of a K99/R00 award application, and for MD trainees, the application would be for the K08 or K23 programs.

NIH Research Projects · FY 2025 · 2019-07

The University of Minnesota Chemistry-Biology Interface training grant’s mission is to provide rigorous and interdisciplinary training to biomedical scientists. We provide trainees with the skills to cross traditional boundaries, think critically, and understand and conduct research at the chemistry and biology interface, with the training grant appointment typically occurring in program years 2 and 3. Trainees will develop as professional scientists in career awareness, knowledge of chemical biology, rigor and reproducibility, ethical conduct of research, and appreciate contributions of scientists from all scientific backgrounds. Success in achieving these programmatic goals will be evaluated through quantitative metrics collected with a validated instrument. Outcomes include communicating high-impact cross-disciplinary research, increased professional soft skills, transitioning to careers in the biomedical workforce, and increased self-efficacy. This mission will be accomplished through the following objectives: 1) Provide trainees with interdisciplinary training at the interface of chemistry and biology. Training is accomplished by a combination of coursework from three departments and by a cross-training experience involving a co-mentor and a research experience of at least three months in the co-mentor’s laboratory. 2) Promote rigor and reproducibility in research using a combination of an online introduction, classroom instruction, interactive workshops, and discussion panels. 3) Expose students to cutting-edge science at the interface of chemistry and biology through seminars focused on this type of interfacial science (Chemical Biology Colloquium, CBC), empowering them to organize a symposium focused on the chemical biology interface, and travel to attend conferences. 4) Enhance communication skills of trainees by providing opportunities to present their research in different formats at the CBC, national or international conferences, in flash talks, and at company/academic site visits. 5) Educate and train students about the range of career opportunities available for scientists with backgrounds at the chemistry and biology interface via workshops, panels, site visits and UMN career services. 6) Stimulate interest and promote our training program by involving students, faculty, and industrial scientists from local high schools, four-year colleges, and companies in training activities. 7) Recruit and retain scientists carrying out research at the chemistry and biology interface in our program through targeted and validated training activities, including on-campus recruiting efforts at MNext. Research in this program spans a range of topics from developing chemical technologies and discovering new biology, to the study and treatment of diseases including cancer, aging, and infection. The 31 training faculty members are a highly collaborative group with a rich history of joint publications and are committed to devoting the effort it takes to effectively mentor our ten trainees with a breadth of skills and scientific backgrounds.

NIH Research Projects · FY 2026 · 2019-06

PROJECT SUMMARY/ABSTRACT The Minnesota Population Center (MPC) at the University of Minnesota (U of MN) requests five more years of support for its interdisciplinary training program in Population Health Science. Rationale: Effectively addressing complex public health problems requires training a new generation of scientists who view biological, social, economic, spatial, and policy factors as interacting over multiple time scales to shape population health. Unfortunately, training programs usually prioritize etiologic research over investigations of effective solutions, and most new scientists are trained only in the biological, social, or health care system influences on disease; few are trained to integrate all three. Objectives: We seek continued support for a pre- and postdoc training program in population health science that produces scientists who understand complex health problems and health disparities as resulting from multiple and interacting layers of influence that unfold over chronological, biological, and historical time. Design: The program features cross-training in (a) the biology and etiology of disease and (b) social sciences and policy contexts that shape disease. The program includes required coursework (for predocs only) in population health science, population modeling, and the responsible conduct of research; independent and collaborative research supervised by interdisciplinary teams of faculty mentors; required Scholar Development Meetings, workshops, and participation in interdisciplinary population health conferences; and intensive professional socialization designed to integrate trainees from diverse disciplinary backgrounds and prepare them to have outstanding careers as population health scientists. Trainee Outcomes: We train population health scientists to integrate knowledge, theory, and tools from multiple disciplines to conduct cutting edge research on the intersecting biological and social factors that shape health and to produce novel solutions to the nation’s most pressing public health issues. Appointments: We request five predoc (3-year) and three postdoc (2-year) training slots; this represents an increase in training slots from the previous project period (from four predoc and two postdoc slots). Our request for more training slots is based on the extraordinary success of our program in the first project period. Leadership: The program is co-directed by population health scholars John Robert Warren (Sociology) and Theresa Osypuk (Epidemiology & Community Health). They are supported by an internal Executive Committee, an external Advisory Board of nationally recognized population health scientists, and an outstanding team of 49 faculty mentors from five colleges and twelve disciplinary departments. Progress: In the first five years of the program, we successfully placed all alumni trainees in population health research positions; our trainees were extremely successful in publishing, competing for research funds; and developing identities as interdisciplinary population health researchers.

NIH Research Projects · FY 2024 · 2019-06

PROJECT SUMMARY American Indians (AI) in Minnesota have 5-6x the opioid overdose death rate of other groups, and this figure continues to rise. Medication-assisted treatment (MAT) is the standard of care for opioid use disorder (OUD) treatment, but implementation and uptake has been slow nationally, especially for AI communities. Thus, there is an urgent need to understand multi-level barriers and facilitators of OUD treatment, including how AI cultural knowledge and practices can be interwoven within OUD treatment and how engagement can be improved along all points of the OUD “Cascade of Care” (CoC). This project will involve a partnership between the University of Minnesota Medical School, Duluth Campus, and a rural Minnesota tribal Nation. The overall objective of this application is to characterize the OUD CoC in a reservation-based, tribal treatment context. Our central hypothesis is that AIs benefit from MAT programs and OUD treatment, but there are multi-level barriers and facilitators that affect implementation of the CoC, some unique to tribal communities. The rationale for this project is that careful assessment of factors influencing the OUD CoC with AIs will optimize treatment implementation and ultimately reduce opioid-related heath inequities. The preparatory R61 aims include (1) characterizing the OUD CoC in a tribal context and delineating its components and transition points using community-based participatory research (CBPR) methods and data from existing sources; (2) identifying barriers and facilitators to engagement with the OUD CoC at key transition points via interviews with clinical stakeholders and individuals with OUD and their families, and (3) preparing and confirming feasibility of observational longitudinal data collection (R33 Aim 1) by developing and piloting study protocols and measures. The R33 aims include: (1) prospectively examining barriers and facilitators to treatment engagement and clinical outcomes defined within the CoC among 200 AIs with OUD after initial MAT clinic intake assessment, and (2) identifying a set of culturally-centered, evidence-based implementation strategies to address barriers and optimize treatment engagement across the CoC. The proposed project will leverage and complement the tribe’s SAMHSA Tribal Opioid Response and MAT Prescription Drug and Opioid Addiction funding. It is innovative because it considers barriers and facilitators across the entire OUD CoC in a tribal context, and is one of the first studies to apply a dissemination and implementation lens to opioid research with AI communities. The expected outcomes of the research include a culturally-centered description of the OUD Cascade of Care with identified implementation strategies to address barriers to engagement. Findings would provide generalizable scientific knowledge to optimize OUD services to reduce opioid-related health inequities for American Indians.

NIH Research Projects · FY 2024 · 2019-05

Project Summary Original 5-year Project: The effectiveness of social buffering in regulating stress appears to wane for a period with puberty at the same time that stress-reactivity increases and young adolescents become more vulnerable to stress-related affective pathology. There is a dearth of knowledge regarding the neural underpinnings of social buffering in children and the changes with puberty. Two of the proposed experiments address this gap in knowledge. In addition, the loss of social buffering effectiveness with puberty has been examined using cortisol as the stress measure. All three proposed experiments will examine the pervasiveness of the effect by examining autonomic, in addition to cortisol measures. Finally, the effectiveness of social buffers during the peripubertal period has only been examined for social evaluative stressors. The proposed experiments will also examine whether the loss of social buffering also extends to threat stimuli and to situations in which two friends are both experiencing the stressful event together. Participants will be 11-14 years old and Tanner staging by parent- and self-report will index pubertal status. Our prior research uncovered the waning of the effectiveness of parents to serve as social buffers of the HPA axis over the pubertal transition and the concomitant failure of friends to “step in” as stress buffers. The proposed experiments are the logical extension of this work. The results will have the potential to drive significant attention to the role of developmental disruptions in social stress buffering as possible contributing factors in the rise of affective problems in the early teen years. Administrative Supplement: Two of the studies have been completed, a third study not proposed in the original application [administratively approved] was conducted during the COVID-19 lockdown to create an on-line version of the social evaluative stressor task to allow continued data collection for the non-imaging study. The two imaging studies were shutdown and then severely hampered during the pandemic. We are, thus, delayed in completing data collection and pre-processing for the 2nd imaging study. The supplement will allow us to complete the work initially proposed.

NIH Research Projects · FY 2025 · 2019-05

Project Summary The long-term goal of our research is to understand fundamental principles of cell communications mediated by heparan sulfate proteoglycans (HSPGs). HSPGs are a special type of carbohydrate-modified proteins that serve as co-receptors for various growth factors, including bone morphogenetic proteins, Wnt/Wingless, and Hedgehog. These HSPG co-receptors play critical roles in quantitative and robust control of signaling output. We study in vivo functions of HSPGs using the Drosophila model. Our earlier research has established critical roles of HSPGs in development, namely in morphogen signaling/gradient formation and stem cell control. Although proteoglycan biology has made significant progress, several major questions remain to be elucidated. For example, the molecular mechanisms of co-receptor activities of HSPGs are poorly understood. It is also unknown how distinct HS structures regulate specific signaling and patterning events. Furthermore, despite extensive studies of HS functions in paracrine signaling, the involvement of HS in inter-organ communications remains to be determined. Our previous studies suggested that HSPGs cooperate with other factors to exert co-receptor activity on the cell surface. Using proteomic and genetic approaches, we recently identified candidate molecules of the HSPG regulators that can be classified into three groups: (1) secreted glypican-binding proteins, (2) transmembrane proteins, and (3) a different class of proteoglycans—chondroitin sulfate proteoglycans (CSPGs). We will study their roles in morphogen signaling and stem cell control. To understand how HS structures affect signaling and morphogenesis, we have developed an "in vitro" model using Drosophila cells. Using these cell lines, we will establish a direct link between detailed structural information of Drosophila HS and a wealth of knowledge on biological phenotypic information obtained over the last two decades using this animal model. Several lines of evidence suggest that Drosophila activins are novel HS-dependent factors. Three activins, Actß, Dawdle, and Myoglianin, regulate body size, sugar homeostasis, metabolism, and pH balance through inter-organ signaling. We will study the functions of HS in trapping the source tissue, systemic transport, recruiting to the target tissue, release from latency, and signal reception of activins. Together, this application will advance our field by: (1) defining fundamental molecular mechanisms of co-receptor function, (2) developing a comprehensive understanding of the structure-function relationship of HS, and (3) identifying novel functions of HSPGs in development and physiology.

NIH Research Projects · FY 2025 · 2019-03

The protein kinase mTOR (mechanistic target of rapamycin) pathways play crucial roles in regulating cell growth, survival, and metabolism in response to changes in cellular energy and nutrient status. Despite significant efforts, our understanding of mTOR pathways still has many gaps that need to be filled. To address the knowledge gaps, our research will focus on three directions. Firstly, we will investigate the mechanisms by which mTOR controls the initiation and termination of autophagy. Although our knowledge in this area has significantly improved, we still do not clearly understand how post-translational modifications, interactions, and translocations of autophagy regulators are coordinated to drive autophagy initiation. Furthermore, while mTOR regulates autophagy termination, the underlying mechanisms remain elusive. Secondly, we will investigate how cells decide between autophagy, mitophagy, and apoptosis during energy crisis caused by mitochondrial dysfunction. Our recent study has challenged the long-held notion that autophagy is responsible for supplying energy to energy-deprived cells for survival. Contrary to the prevailing concept, we found that energy-deprived cells restrain autophagy and mitophagy via activating AMPK, the major energy sensor kinase in mammalian cells. Our research has revealed previously unrecognized roles of ULK1, the central kinase that regulates autophagy downstream of mTOR, in the crosstalk between autophagy, mitochondria, and apoptosis. This finding highlights the critical importance of maintaining functional mitochondria for autophagy. Investigating the coordination mechanism underlying the crosstalk between autophagy, mitophagy, and apoptosis during energy stress is crucial for a comprehensive understanding of cellular energetics for cell survival. Thirdly, we will investigate the functions of mTOR in different cellular compartments. The majority of previous studies have focused on lysosomal mTOR, with limited explanation of how lysosomal mTOR controls protein synthesis and autophagy initiation that primarily occur in the endoplasmic reticulum. While non-lysosomal functions of mTOR have recently emerged, their roles in different cellular compartments remain largely unexplored. Through our single-molecule analysis, we have learned that the majority of mTOR exists in non-lysosomal compartments and that some forms of non-lysosomal mTOR are responsive to amino acids, providing unprecedented insights into mTOR distribution and regulation in various cellular locations. Addressing this critical knowledge gap is essential for elucidating previously unrecognized functions of mTOR. Through these three directions of research, our study aims to advance fundamental knowledge on mTOR functions in coordinating nutrient, growth, and energy status with autophagy, mitophagy, and cell survival. Additionally, the outcomes of this study are expected to provide crucial insights into the cellular pathways for energy sensing and response, as well as the mechanisms by which cells cope with energy stress and mitochondrial dysfunction.

NIH Research Projects · FY 2026 · 2019-03

Title: Control of Chromosome Segregation by DNA Topoisomerase II. Abstract Chromosome segregation errors result in aneuploidy, which causes birth defects and cancer. We have defined a new mitotic Topo II-responsive control (TRC) that delays the cell cycle when Topo II activity is insufficient for accurate chromosome segregation. This TRC mechanism is conserved from yeast to human cells but has not been extensively studied. Activation of the TRC is triggered by stalling of the strand passage reaction of Topo II, when the enzyme becomes trapped on DNA in the Closed Clamp structural conformation. TRC activation requires two distinct modules within the catalytically inert C-terminal domain of TopoII: (i) A cluster of SUMOylation sites, and (ii) The Chromatin Tether domain of Topo II, which interacts with methylated nucleosomes. The central molecular model is that stalled strand passage leads to C-terminal domain SUMOylation that functions as a signal-generating scaffold to halt the cell cycle. The conservation between the human and yeast TRC responses provided unique opportunities to identify TRC components, but gaps remain in our understanding of the mechanism of TRC activation. We aim to determine how the TRC activates Mad2 to inhibit anaphase initiation, which will require determining the identity of the E3 ligase that SUMOylates TopoII as well as the relevant substrates of Aurora B kinase. We will determine how trapped Closed Clamps trigger TopoII SUMOylation and how they are repaired. The role of the ChT domain will be determined and whether interaction with nucleosomes is required for TRC activation. The results of these studies will impact opportunities for translational research because we will identify new potential therapeutic targets. Our findings will also impact the use of widely prescribed therapeutic drugs that target Topo II because we will gain mechanistic insight into cellular responses to Topo II inhibition. The preliminary data and newly developed experimental tools place us in a unique position to determine the conserved mechanism of this scarcely studied mitotic control.

NIH Research Projects · FY 2026 · 2019-02

ABSTRACT (OVERALL) The long-term goal of this NCBIB is to establish a national resource for enabling UHF (7T and above) magnetic resonance imaging (MRI) technologies to advance biomedical research and discovery. We propose to build on our successes in this renewal with four new closely linked technical research and development (TRD) projects. These projects will work synergistically to realize the potential of our unique imaging resources which include our 10.5 Tesla (currently the highest magnetic field available for human and large non-human primate (NHP) imagining above 10T), and 16.4 Tesla for small to medium size animal models (one of two such high fields systems in the world). TRD1 will undertake the development of a multimodal imaging with simultaneous MR and novel electrodes and augment its current effort on large NHPs with a small NHP model, namely the marmosets, for use in 16.4T MR and multiphoton optical imaging studies. The combination of non-invasive MR and an invasive technology will provide access to neuronal activity from single neuron and synapse level over the entire brain but at a coarser spatiotemporal resolution. This platform will provide opportunities for detailed studies of brain function in NHP models and inform future human studies using MRI alone. TRD2 will develop new MR contrasts and novel technologies for ultrahigh field applications, with a specific focus on selected technologies that will have the greatest impact on associated collaborative and service projects. The effort will provide unparalleled sensitivity to probe molecular and physiological parameters to characterize tissue, support biomedical research and impact our understanding of the living system in health and disease. TRD3 has been at the forefront of image reconstruction technologies, introducing multiple new methods for improved Deep Learning (DL) reconstruction and training, interpretable image denoising, and fast iterative algorithms. TRD3 will continue to tackle inverse problems through the lens of intelligent physics-driven technologies that synergistically utilize imaging physics and advances in DL methods targeting target higher resolutions and acceleration rates at lower signal-to-noise ratios (SNR), as well as to combine information across multiple nuclei or even modalities. TRD4 provides critical engineering solutions addressing both radiofrequency (RF) coil (i.e. antennae) designs and safety, towards capturing the significantly higher ultimate intrinsic SNR (uiSNR) provided by UHF. The effort will employ novel RF electronics concepts including miniaturized integrated circuit low noise amplifiers and coil clusters and explore new receiver concepts both for multinuclear and 1H imaging and spectroscopy studies at the high magnetic fields of 10.5T, 7T and 16.4T. While the focus is on uniquely high magnetic fields, the impact of this Center on biomedical research will extend to lower magnetic fields, as it has done so already, as well as to fields beyond MRI (cognitive science, neuroscience, senescence, musculoskeletal disorders, neurological disorder, cancer among others).

NIH Research Projects · FY 2025 · 2018-09

ABSTRACT The proposed project will build and evaluate the safety and design needs of a new type of intracranial auditory prosthesis that targets the auditory nerve between the cochlea and the brainstem (auditory nerve implant, ANI) in order to substantially improve hearing performance over the current standard of care, the cochlear implant (CI). Current CIs provide crucial speech information to many recipients, but do not restore normal hearing, and are particularly challenged in noisy or complex acoustic environments. Despite concerted efforts over the past 25 years, little overall improvement in CI performance has been obtained, primarily due to the poor electrode- neural interface in which the CI electrodes are immersed in cochlear fluids and separated from the auditory nerve by the cochlea's bony wall. The new approach will build upon encouraging data from animal studies, well-established human surgical techniques to access the auditory nerve, and high-density electrode and safe stimulation technologies currently available for human use in order to test the safety and efficacy of the ANI that enables direct contact between the electrodes and the auditory nerve. The ANI provides great promise of improved speech and music perception for its prospective recipients, by overcoming the challenge that has limited improvements in CIs for the past quarter century. The first aim is to design and build a full ANI system in accordance with regulatory requirements, including necessary reliability, safety, functional, biocompatibility, and sterilization testing for human use. The ANI system will be built by combining a well-established CI device in the auditory implant field with a novel electrode and cabling technology already being evaluated in human patients for other clinical applications. The second aim is to refine the ANI surgery in human cadaver experiments and acutely during other relevant in vivo operations to consistently position and anchor the electrode array and cabling into the target region. The third aim is to develop and validate critical psychophysical tests to properly evaluate the performance of the ANI during the pilot human study, which can then inform the design of a future clinical ANI device. The fourth aim is to seek regulatory approvals and set up the clinical trial infrastructure and monitoring entities. The fifth and final aim is to perform a pilot ANI study in up to three deaf patients to obtain safety, reliability and functionality data that can properly guide the design of a proceeding clinical device and a feasibility study.

NIH Research Projects · FY 2025 · 2018-09

PROJECT SUMMARY: Training of health professionals in sexual health care is critical to address a broad array of a nation’s sexual and reproductive health concerns. Research evaluating the effects of sexual health curricula on provider behavior is rare. In sub-Saharan Africa, an environment with the world’s highest rates of HIV, STIs, and multiple sexual and reproductive health challenges, training of health students in sexual health care is almost non-existent. Consequently, a rigorous study of its effects is needed if such education is to be widely adopted. In our “Training for Health Professionals” (THP-1) study, at Muhimbili University of Health and Allied Sciences (MUHAS) in Tanzania, we conducted formative research to identify the most common sexual health concerns. We then tailored a sexual health curriculum training for healthcare providers to the African context and conducted the world’s first single-blind, randomized controlled trial of its effects. Participants were 412 nursing, midwifery, and medical students at MUHAS. Post-test evaluations with the intervention arm showed the curriculum to be highly acceptable, culturally appropriate, needed, and feasible. At 3-month follow-up, as compared to controls, intervention arm students had moderate-to-large increases in sexual health knowledge, improved attitudes, and improved clinical skills. As required in a renewal application (THP-2), our long-term objective remains “to improve the sexual health outcomes for individuals in Tanzania by building the sexual and reproductive healthcare delivery skills of the health workforce.” We have three new specific aims. Aim 1 will assess the medium and long-term effectiveness of an African-centric, sexual health curriculum. We will conduct a single-blinded RCT of the curriculum against a waitlist control arm, to assess the effects on sexual health knowledge, attitudes, and counseling skills at 6-, 12- and 24-month follow-up (n=155 students per arm; 310 in total). In Aim 2, we will develop a train-the-trainer curriculum. We will conduct a training needs assessment of faculty at the ten other health universities in Tanzania, develop training materials, and pilot the training to faculty at two other health universities: University of Dodoma (UDOM) and Kilimanjaro Christian Medical College (KCMC). In Aim 3, we will conduct a Phase IV trial. This will be an observational study of the curriculum being taught by their faculty at the two new sites with 3- 6- and 12-month follow-up. MUHAS, KCMC, and UDOM are the largest health universities in Tanzania. This curriculum has high potential to be widely adopted as a new standard of training across Tanzania. These results also have high potential to inform the adaptation of sexual health curricula across Africa and beyond the continent, to other LMICs.

NIH Research Projects · FY 2025 · 2018-09

Project Summary This proposal seeks continued support to expand a powerful new health equity resource, the National Couples’ Health and Time Use Study (NCHAT). NCHAT is the only population-representative study (N = 3,642 ages 20- 60) with large subsamples of sexual and gender diverse (SGD; 45%) and racially and ethnically diverse (RED; 38%) coupled adults fielded during the pandemic with comprehensive measurement including groundbreaking state and county structural racism, sexism, and cis heterosexism measures. The COVID-19 pandemic and the co-occurring period of intense racial trauma exacerbated and laid bare the health inequities experienced by RED and SGD populations in the US. Attacks on the SGD and RED populations are ongoing with alarming numbers of targeted harmful policies. Health disparities for RED and SGD populations are preventable, and identifying their social determinants and underlying mechanisms is urgent. Aim 1. Reinterview and refresh the NCHAT sample. We propose to collect four additional waves of survey data and two waves of time diary and experience sampling method data. These short and frequent surveys allow flexibility with the inclusion of new content tracking the impacts of period shocks, such as COVID-19 or the aftermath of racial trauma, and the factors that exacerbate or mitigate these impacts during an era of growing mental health crises. As nearly 30% of individuals in their twenties identify as SGD, a refresher and oversample to include 300 new respondents will be added. Aim 2. Open the NCHAT panel so a diverse body of health equity scholars drive question content. Current population data infrastructure on health disparities is outmoded because 1) only select researchers decide on survey content and 2) a focus on repeated measurement can stymie innovation. Working with our inclusive advisory board, we seek to upend this system and ignite cutting-edge research with the inclusion of items contributed by health equity scholars across disciplines and institutions. These data will be rapidly released. Aim 3. Assess SGD trajectories of mental health in an era of escalating threats to SGD families. We will test vulnerabilities (structural and interpersonal discrimination and SES); strengths (social support, SGD socialization, identity centrality); and family functioning as mechanistic predictors during a period of growing anti- LGBTQ+ bills. Aim 4. Examine RED trajectories of mental health with a focus on recovery and deterioration. We will evaluate how couple stability and relationship functioning, social and community support, and structural and interpersonal experiences of discrimination act as mediators and moderators of trajectories of mental health in the wake of the pandemic and continuing racial trauma. Without longitudinal data and flexible measurement, scientific knowledge about the mechanisms underlying RED and SGD disparities will be stymied. This multi-disciplinary team is deeply invested and committed to ameliorating health disparities for RED and SGD populations. It is crucial that we expeditiously follow-up on these vulnerable populations and give voice to a broad range of scholars seeking health equity for all.

NIH Research Projects · FY 2026 · 2018-09

Our research program aims to understand the relationship between macromolecular structure, dynamics, and function, with a particular focus on large nucleic acid binding proteins. To this end, we use sensitive methyl-based solution-state nuclear magnetic resonance (NMR) spectroscopy, which is capable of probing the structure and dynamics of proteins and their complexes with masses >1 MDa. We couple NMR spectroscopy with other powerful biophysical techniques to probe structure and dynamics and then employ biochemical and in vivo activity assays to better understand function. Our strategy relies on rationally designing mutations to disrupt specific interactions within the protein/protein complex as well as naturally occurring mutations found in disease states to ‘break’ the structure/dynamics/function relationship in order to piece together how the protein complex works. Currently, our primary focus is the MRE11-RAD50- NBS1/Xrs2 (MRN/X) protein complex, which plays a central role in the DNA double strand break (DSB) repair response. The MRN/X complex is essential for detecting and repairing DNA DSB breaks, as well as for signaling their presence to the rest of the DNA DSB response. Additionally, the MRN/X complex has roles in DNA replication and telomere maintenance. Not surprisingly then, mutations in MRN/X have been found in many types of cancer and in diseases characterized by immunodeficiency, neuronal and cerebral degeneration, a sensitivity to ionizing radiation, and oncogenesis. To fully understand how the MRN/X complex performs all of its functions, it is necessary to determine structural models in the absence and presence of its various substrates. Indeed, structural biology techniques, including NMR spectroscopy, have been used to study the MRN/X complex and have revealed a diverse set of structures. Though insightful, these models have raised more questions about how the structures are specifically involved in MRN/X function, the relative populations of these heterogeneous structures in solution, the kinetics for the interconversion between these structures, and short and long-range allosteric communication within them. In the next five years, our goal is to bring clarity to each of these questions by applying our comprehensive biophysical and biochemical research strategy. In general, we strive to better understand how protein complexes use a diverse set of structures and biochemical activities to perform and coordinate complex biological functions. These proposed studies will provide an unparalleled view into MRN/X function in DNA DSB repair.

NIH Research Projects · FY 2026 · 2018-09

Summary/Abstract This project will expand and improve the IPUMS Multigenerational Longitudinal Panel (MLP), the world’s largest longitudinal population data system. MLP currently includes linked censuses from 1850 through 1940, administrative records from Social Security, selected vital records, and links between several surveys of aging and the 1940 census. We propose to multiply the analytic power of MLP by expanding it and making it easily interoperable with other sources of linked data. Under our proposed Aims, MLP will be expanded to include all available records from the 1950 decennial census, new death certificate data, additional linkages to surveys of aging, and rich data on health outcomes. To make this massive infrastructure sustainable and accessible, we also propose refinement of software and methods for automatic record linkage, maintenance of the system of linked records, and dissemination of linked data. The expanded and improved MLP will provide the most comprehensive view of long-run changes in life-course dynamics available for any place in the world and will transform our understanding of processes of population aging. MLP is a highly cost-effective use of scarce resources to develop shared infrastructure for research, education, and policy-making on health and aging. The longitudinal panel will reduce redundant effort by researchers, increase data quality, and improve replicability and comparability. The proposed work is directly relevant to the core mission of the Population and Social Processes branch of NIA: The new data will advance fundamental knowledge about the causes and consequences of changes in social, demographic, economic, and health characteristics of the older population in the U.S. and will support research on the effects of public policies, social institutions, and environmental conditions on the health, cognition, well-being, and functioning of people, both over the life course and in their later years.

NIH Research Projects · FY 2026 · 2018-08

Project Summary The Upper Midwest Regional Coordinating Center (RCC), previously the University of Minnesota (UMN) RCC, is an established, high-performance RCC within Stroke Net. The pillars of the Upper Midwest Stroke Net RCC are: 1) unparalleled expertise in clinical trial conduct with a track record of high enrollment, most notably in complex time-sensitive acute stroke trials, 2) close collaboration with robust stroke care systems in the upper Midwest led by our colleagues and former trainees, and 3) direct integration with physician-scientist training programs. The Upper Midwest RCC comprises 12 sites with large urban and rural catchment areas throughout Minnesota and neighboring states. Our leadership is uniquely qualified, complementary, and aligned with Stroke Net aims. Dr. Streib (PI), the Cerebrovascular Director at M Health-Fairview (MHFV), developed a centralized internal stroke research network across MHFV hospitals. Within this network we are driving clinical research innovation: ~50% of our acute stroke trial participants are enrolled utilizing “remote research” in which the subject is not physically in the same location as the clinical and research teams. Remote research expands access to clinical trials more equitably thereby reaching diverse, underrepresented populations in clinical trials. Dr. Lakshminarayan (PI, Career Enhancement Director) directs the Clinical Research Training Program in the nationally-ranked UMN School of Public Health. She is an NIH-funded investigator whose research deliberately involves low-resource health systems, including federally qualified health centers, in order to ensure recruitment of under-represented minorities. Ms. Staugaitis' accumulated experience as project manager for Stroke Net, Strategies to Innovate Emergency Care Clinical Trials Network (SIREN), and essential multicenter COVID trials has been critical to operationalizing practical, efficient, and effective clinical research workflows. M-Health Fairview sites are top enrollers in multiple StrokeNet (MOST, ARCADIA, and CAPTIVA), NIH (PRECISE), and industry stroke trials (TIMELESS). Study aims are: 1) Continue as a leading RCC within StrokeNet through sustained high-volume recruitment and support and mentorship of our satellite sites. 2) Further study, develop, and implement standardized remote research capability throughout MHFV and StrokeNet in order to increase equitable access to clinical trials, promote diversity, and improve the generalizability of StrokeNet clinical trial results. 3) Leverage the resources of the UMN CTSI and School of Public Health and the StrokeNet to mentor exceptional physician scientists who will develop and conduct future stroke trials. In the next grant cycle, our RCC will remain a vital contributor to StrokeNet through continued high-volume recruitment, the further development, modernization and dissemination of best-practice clinical trial workflows, and strong commitment to educating the next generation of talented stroke physician-scientists.

NIH Research Projects · FY 2026 · 2018-08

ABSTRACT: Early-life iron deficiency (ID) is prevalent throughout the world, affecting 40-50% of pregnant women, fetuses, and children. ID impairs cognition in children, causes persistent cognitive impairments and increases risk of neuropsychiatric disorders despite postnatal iron treatment. The long-term effects of early-life ID are the real cost to society because of lost education and job potential and their association with transgenerational racial health disparities. In mice, hippocampal neuron-specific ID causes long-term learning/memory neurocircuit dysfunction despite postnatal iron repletion, demonstrating the long-term effects are due to neuronal iron loss during development. Thus, dysregulation of early-life neuronal iron-requiring activities set neuronal functional capacity across the lifespan. The fetal/neonatal brain is highly metabolic, accounting for 60% of total body oxygen consumption. The hippocampus has one of the highest regional metabolic rates in the neonatal brain. Iron provides the catalytic component for enzymes required for mitochondrial electron transport and energy production. Mitochondrial quality control mechanisms (e.g., redox balance, fusion/fission, and mitophagy) maintain mitochondrial structure and energetic homeostasis and prevent long-term mitochondrial damage and dysfunction. Early-life ID acutely disrupts these processes, impairing dendrite and synapse formation. Postnatal iron repletion does not rescue ID-induced mitochondrial energetic impairments in the adult brain, suggesting a permanent reprogramming. The cellular mechanisms of how developmental ID causes long-term neuronal structural and functional deficits and whether these can be prevented with iron treatment alone are unclear. We will test the overall hypothesis that permanently impaired hippocampal mitochondrial energetic capacity and quality control is programmed during early life, directly contributes to the compromised neurocircuitry that persists after recovery from early-life ID and that prenatal maternal iron repletion is required to prevent this. In Aim 1, we will utilize a unique in vitro model of chronic fetal-neonatal hippocampal neuronal ID to test the timing and dose of iron repletion during development in order to prevent programming of long-term mitochondrial neuronal structural deficits. We will treat iron-deficient hippocampal neuron cultures with moderate or high dose iron at neuron developmental stages equivalent to human 2nd trimester, birth, and 6-12 months. Recovery of mitochondrial quality control mechanisms and synapse formation will be assessed as outcome measures. Aim 2 uses an in vivo rat model of dietary fetal-neonatal ID to test whether fetal iron treatment is necessary and sufficient to prevent permanent abnormalities in hippocampal mitochondrial structure/function, epigenetics, neuron structure and neurocognitive behavior in adulthood. This proposal is highly significant because it will provide neurobiologically-based mechanistic evidence to delineate accurate timing and dosing of iron repletion and inform adjunct therapy strategies to reduce the lifelong consequences of fetal-neonatal ID.