University Of Minnesota

NIH Research Projects · FY 2026 · 2022-12

PROJECT SUMMARY/ABSTRACT Over 1 million Americans require mechanical ventilation each year and mortality estimates range from 30-35% with significant variability at the patient, hospital, and regional level. More recently, physicians were found to be associated with mortality in mechanically ventilated patients, adding yet another level of variation. There is little research as to what individual physicians do to cause this variation in outcomes and whether provider practice patterns can be modified to improve outcomes. To date, morbidity and mortality reduction interventions in this population involve ventilation strategies and harm reduction therapies. Despite these interventions being evidence-based and guideline-supported, their use remains highly variable. The potential link between provider-level variability in mortality and population-level variation in evidence-based practice represents a critical knowledge gap. Specifically, there is a need to understand how physicians’ adherence to evidence- based practices vary, the degree to which this results in harm, and what barriers are modifying practice patterns. The candidate's prior work developed a method, using electronic health record metadata, to assign a provider retrospectively and reliably to each patient for each intensive care day. Using these data, provider- level adherence to low tidal volume ventilation strategies significantly varied across a 12-hospital health system. This Career Development Award builds from that work and seeks to achieve three aims, that together, will promote the candidate's long-term goal of developing and testing strategies to increase adherence to evidence-based care and improve acute respiratory failure survivors' outcomes. Specifically, in this award, the candidate seeks to (1) quantify variation among physicians in adherence to evidence-based practices, (2) generate hypotheses about barriers and facilitators to evidence-based practice adherence, and (3) develop and pilot an intervention targeting barriers to evidence-based care. To complete these aims the candidate will perform a retrospective cohort study (Aim 1), perform a mixed-method study enrolling 40 ward-based physicians that care for mechanically ventilated patients (Aim 2), and use an intervention mapping framework to develop and pilot an intervention targeting barriers to low tidal volume ventilation. The hands-on experience he will acquire in completing these three studies using different methods will be complemented by carefully selected didactic coursework and structured mentoring by senior investigators from multiple disciplines. This work will lead to pilot grants and R01 to support a randomized clinical trial of this intervention. Completing this research will build upon the candidate’s past training and will provide him with the protected time and experience to achieve his career goal of becoming a leading, independently funded outcomes researcher focused on conducting studies within learning health systems to improve outcomes among survivors of ARF and other critical illnesses.

NIH Research Projects · FY 2026 · 2022-12

Program Summary/Abstract Recent summits and national reports have emphasized the need for more rigorous methodology when designing, evaluating, and disseminating/implementing dementia care interventions. The short-term career objective of this Academic Leadership Career Award is to further develop my expertise and leadership in dementia care intervention science by developing and successfully delivering the Advanced Behavioral Intervention Design in Dementia Care (ABIDDC) program to pre-doctoral and post-doctoral trainees (n = 12). By successfully building and delivering the ABIDDC, I will be better positioned to achieve my long-term career objective: the creation and leadership of sustained infrastructure at the University of Minnesota (UMN) that cultivates new/early stage investigators and serves as a national resource for dementia care intervention science. The Specific Aims of the K07 are as follows: 1) Create and deliver a graduate curricula in advanced dementia care intervention science; 2) Establish a robust mentoring program to support early career investigators in dementia care science; and 3) Leverage existing support at UMN to position trainees to launch successful, independent careers in dementia care science. If the Aims of the proposed K07 are achieved, I anticipate assuming a leadership role in providing the infrastructure, training, and support necessary to cultivate a cadre of early career investigators and other investigators across the U.S. who are prepared to conduct state-of-the-art dementia care science.

NIH Research Projects · FY 2026 · 2022-12

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and refractory malignancy, whose five-year survival rate remains only 9%. Less than 20% of the patients visiting clinics are candidates for surgery because most PDAC patients have advanced diseases at the time of diagnosis. The majority of PDAC patients therefore require systemic therapies. While there is promising advance in cancer therapeutics, their median survival is < 6 months. These PDAC patients need development of new approaches for systemic treatment. Oncolytic viruses are promising anti-cancer agents under development. Among them, oncolytic adenovirus (OAd) is one of the strong candidates. Despite needs of systemic treatments for PDAC, the vast majority of OAds are designed for local administration due to several obstacles, such as sequestration to normal organs, difficulty for selective delivery to the tumor, neutralizing antibodies, and hemagglutination. Aiming at development of an OAd enabling treatment of advanced PDAC patients by systemic injection, we will tackle these obstacles in this project. Adenoviruses have more than 50 serologically defined types, and this is a unique feature enabling escape from neutralizing Abs. However, simple switching the backbone has not realized cancer specificity because tropisms of adenoviruses are not cancer specific. We previously identified mesothelin (MSLN)-targeted OAd for PDAC treatment and reported the feasibility of knob switch. We will generate a new series of OAds based on a variety of Ad species other than Ad5, where the fiber-knob regions are replaced by the knob with pancreatic cancer-specific binding motif in the original binding domain (AB-loop). We hypothesize that these viruses will allow selective delivery to the tumor by systemic injection while avoiding the effect of nAbs and hemagglutination. This project is expected to overcome the current and potential issues of systemic therapy of PDAC with oncolytic virus by exploiting the advantages of the adenoviral vector system and our unique advantages in adenovirus targeting strategies. The potential impact of systemically injectable OAd for PDAC is significant.

NIH Research Projects · FY 2026 · 2022-12

Project Summary Tick and rodent surveillance for pathogens requires substantial technical expertise and laboratory infrastructure. Most surveillance activities focus on detection of one or two potential pathogens in the vector or reservoir population and non-target pathogens remain undetected. To overcome the current limitations associated with traditional tick surveillance methods, we are proposing a novel dual metagenomic and metatranscriptomic sequencing solution using cutting-edge nanopore adaptive sampling (NAS) protocols. The NAS method leverages Oxford Nanopore Technologies sequencing technology (a portable MinION sequencer) and a recently developed bioinformatic pipeline that facilitates the immediate mapping of individual nucleotide molecules (DNA, cDNA, or RNA) to a given reference as each molecule is sequenced. User-defined thresholds then specify the retention or rejection of specific molecules, informed by the real-time reference mapping results as they are physically passing through a given sequencing nanopore. Hundreds to thousands of individual sequencing pores are controlled in real-time using a powerful Graphics Processing Unit (GPU) and the NAS software with retain/reject decisions made in less than a second for each individual pore. This allows for sensitive detection of a very wide range of targeted pathogen and host species barcoding sequences without becoming swamped in the sea of non- target host and symbiotic bacterial nucleic acids. The system can be field deployed and requires minimal infrastructure. An internet connection is not required. In the course of this proposed study, we will test NAS for diagnostic accuracy (sensitivity, specificity, and threshold of detection), test for detection of a variety of in vitro grown DNA and RNA-based pathogens, differentiate closely related pathogen species and strains, develop and ground truth protocols for field testing on wild ticks and rodents from a well-characterized region (Minnesota), and comprehensively field test the methods and protocols in a region predicted to have the one of the highest densities of emerging rodent-associated zoonoses in the US (central Kansas). We expect NAS to become an important and affordable tool with a wide variety of surveillance applications.

NIH Research Projects · FY 2026 · 2022-12

Project Summary/Abstract The Minnesota Craniofacial and Oral health Research Experience (MnCORE) aims to introduce new generations of future independent investigators to questions in craniofacial, oral health, and dental research. Drawing on the research environment at the University of Minnesota, this training program brings together highly qualified research mentors in state-of-the-art research environments with undergraduates interested in investigating an oral biology research project. The research strengths of this training program include immunology/cancer, biomaterials, bone biology and microbiology. The foundation of the program is an integrated ten-week residential summer research and career development program at the University of Minnesota. MnCORE has four integrated components: 1) completion of a research project, 2) weekly group seminars, 3) introduction to oral biology and dental career paths, and 4) development of professional skills. To help recruit a talented and motivated applicant pool for MnCORE, we are working with North Hennepin Community College/ Bemidji State University, the University of Texas-San Antonio, and the University of Minnesota's Life Sciences Summer Undergraduate Research Program (LSSURP). We will also work with LSSURP to engage with other summer research programs at the University of Minnesota and provide enrichment activities and social support that complement MnCORE's goals. To fulfill our training mission with our available resources, we request support for 8 undergraduate students per year for the 5-year funding period. To ensure we are meeting the needs of MnCORE trainees, we will use a comprehensive and adaptive evaluation plan for rigorous programmatic assessment and continuous program improvement.

NIH Research Projects · FY 2026 · 2022-12

SUMMARY Sepsis is a life-threatening, systemic response to infection and is 13-times more likely to occur in individuals over 65, leading to hospitalization, increased mortality, and chronic repercussions. Why older persons are more susceptible to sepsis is poorly defined, although hyperactivation of the immune system is an underlying feature. Visceral white adipose tissue (vWAT) is the organ that ages first; changes include tissue expansion and increased immune cell activation. We demonstrated that a hyperinflammatory state in old organisms contributes to increased mortality in response to infection, whereas young mice remain healthy. We also discovered that there is an accumulation of aged adipose B cells (AABs) and inflammatory macrophages in vWAT of old mice. We showed that these immune cells inhibit lipolysis, a metabolic pathway essential for maintaining energy homeostasis. Lipolysis is also necessary to keep inflammation in check in mice challenged with lipopolysaccharide (LPS), a bacterial pathogen-associated molecular pattern from gram-negative bacteria. Together these studies support the premise that age-related inflammation mediated by the vWAT contributes to risk of sepsis. This proposal seeks to identify how signaling events from vWAT immune cells, which regulate lipolysis in adipocytes, are altered with age and sepsis. We recently described a role for the NLRP3 inflammasome activation and the expansion of AABs that increase inflammation, and reduce tissue function, including lipolysis and insulin sensitivity. These findings have led to our hypothesis that vWAT lipolysis is impaired in old organisms due to exacerbated inflammasome activation and altered signaling by AABs, and this negatively impacts responses to endotoxemia and sepsis. We will test this hypothesis in three aims that focus on a mouse model of endotoxemia. Aim 1: Define the lipolytic response of adipocytes from old vs. young mice. Aim 2: Determine if inflammasome activation and GDF3 mediate reduced lipolysis and increased inflammation in vWAT upon LPS challenge of old mice. Aim 3: Determine the role of adenosine signaling on lipolysis in old vWAT during LPS challenge. This information will contribute to the identification of new signaling pathways that can be targeted to treat sepsis in the elderly.

NIH Research Projects · FY 2026 · 2022-12

PROJECT SUMMARY/ABSTRACT Prostate cancer is the most common non-cutaneous cancer in males. Prostate cancer cells are dependent on a transcription factor called the androgen receptor (AR), which is activated by the androgens testosterone and dihydrotestosterone. Accordingly, an effective treatment for patients with advanced prostate cancer is androgen deprivation therapy, which blocks the effects of androgens, inhibits the AR, and halts the growth of prostate cancer cells. Although this form of treatment is very effective for advanced prostate cancer, the stress of this therapy will eventually lead to the prostate cancer cells developing resistance. In approximately 25-30% of cases, the stress of prostate cancer therapy will cause the prostate cancer cells to transform into cellular states where they no longer resemble the original disease. These prostate cancer cells take on features of alternative cell types through a process called lineage plasticity. These lineage plastic prostate cancers are very difficult to treat because they do not contain AR and there are no effective therapeutics available. Additionally, the processes by which standard prostate cancer therapies can cause prostate cancer lineage plasticity is poorly understood. This proposal seeks to understand the biology of prostate cancer lineage plasticity and develop new therapeutic strategies to treat, prevent, or reverse this disease stage. Our preliminary data demonstrates the stem cell transcription factor KLF5 is up-regulated by standard prostate cancer therapies that inhibit the AR. Up-regulation of KLF5 enhances androgen-independent growth of prostate cancer cells, as well as migration and colony formation phenotypes. Functionally, the transcriptional program initiated by up-regulated KLF5 clashes with the transcriptional program activated by the AR. Because the AR transcriptional program controls prostate cancer cell identity, KLF5 up-regulation breaks down this identity and promotes very early steps in lineage plasticity of prostate cancer cells. We hypothesize that targeting this early step in therapy-induced prostate cancer lineage plasticity will block later events that lead to very aggressive, treatment-resistant manifestations of the disease. We have identified ERBB2 as a focal point of this tug-of-war between AR and KLF5, and shown that ERBB2 inhibitors can block the oncogenic effects of KLF5. To advance these findings and identify additional therapeutic vulnerabilities in this pathway, we propose 2 Specific Aims. In Aim 1, we will study induction of KLF5 and lineage plasticity phenotypes in CRPC. In Aim 2, we will test therapeutic potential of blocking early steps in CRPC lineage plasticity. A successful outcome can lead to rapid development of clinical trials testing these therapeutic strategies for treatment or prevention of lineage plastic prostate cancer.

NIH Research Projects · FY 2026 · 2022-09

Neurological and psychiatric diseases are a major burden on society and new treatment options are strongly needed. One strategic goal of NIBIB is to develop innovative biomedical technologies that integrate engineering and life sciences to improve health. TMS is a non-invasive neuromodulation technique that can directly interfere with brain activity. TMS is FDA-approved for a range of brain disorders, however, shows mixed efficacy. Thus, improved stimulation protocols would have a major impact in providing better treatments for brain diseases associated with alterations in cortical excitability. Here, we propose to develop a multiscale network model of TMS that will combine electric field simulations with neuron models and molecular simulations of intracellular calcium.

NIH Research Projects · FY 2025 · 2022-09

Summary The UMASH Center continues to develop productive multidisciplinary collaborations. Our work implements a One Health approach. Evidence of this is through our communications, collaborations, and cooperation of the varying human, animal, and environmental systems that are integral to health and safety. Our innovative research projects build on past success and address important and timely health and safety problems relevant to the agricultural workforce in the Upper Midwest, the country, and the world. The outreach and engagement activities are active, relevant, and forward-looking, with widely accessed and available resources. Our Emerging issues program addresses timely topics relevant to today's issues encompassing input from our human, animal, and environmental experts and stakeholders. We recognize the ever-changing agricultural landscape and our need to be nimble to address those needs. Our robust evaluation program and personnel will ensure our work will be impactful. The UMASH team looks forward to continuing to address issues related to the health and well-being of agricultural workers and their families.

NIH Research Projects · FY 2026 · 2022-09

Hypoglycemia (HG) is common in the lives of people with type 1 diabetes (T1D) and may prevent them from achieving the benefits associated with optimal glycemic control. Recurrent HG over a few days to weeks may lead to the condition of impaired awareness of HG (IAH) where the first sign of a low blood sugar is confusion or unconsciousness. Avoiding HG is associated with a reduced risk of IAH and when strictly done, may restore HG in some but not all patients with IAH. The reason for this heterogeneity in response remains uncertain.The purpose of this application is to apply to become part of a consortium that will implement a protocol designed to restore awareness of HG in persons with T1D and IAH. As instructed by the FOA, we address the following objectives in our application: 1. Determine if diabetes care with use of the most up-to-date management strategies with T1D and IAH. 2. Determine the physiological factors that are associated with restoration of HG awareness, including but not limited to age, duration of diabetes and metrics of glycemia. 3. Determine the association of the current self-report questionnaires (or develop new questionnaires or metrics) for identification of IAH with measurement of CRR using "state of the art" metabolic assessments. To meet objective 1, we propose the consortium enroll 650 subjects with T1D and IAH into a randomized clinical trial where a 12-month intervention of HG avoidance education and use of a hybrid closed loop system for insulin infusion is compared to standard care (which includes HG avoidance education, insulin administration via regular pump or injections, and CGM usage). With epinephrine response during the hypoglycemic clamp at 12 months as our primary outcome variable, we will test the hypothesis that subjects in the closed loop intervention arm will have a greater epinephrine response during the hypoglycemic clamp at 12 months of follow- up than will subjects in the control arm. To meet objective 2, we will collect information about glycemic variability, food quality and quantity, physical activity, sleep, stress, mood, and feelings about HG as well as patient characteristics such as HG induced glucagon secretion, residual C-peptide secretion, and diabetes duration. This information will then be explored using machine learning techniques to see what exposures and experiences correlate with IAH restoration. To meet objective three, we will compare the concordance of the Clarke, Gold, and Hypo-AQ questionnaires at categorizing subjects into IAH and NAH groups. The scores on each of the questionnaires will also be correlated with objective measures of the counterregulatory response.

NIH Research Projects · FY 2025 · 2022-09

PROJECT SUMMARY Human milk confers numerous infant health benefits, yet the compositional elements responsible for these benefits and the fundamental molecular mechanisms shaping the unique milk “recipe” for each infant remains lacking. Genomic advances pioneered to probe the cellular and molecular biology of other human tissues provide powerful strategies to understand biological systems, but are underutilized in milk research.. It is time for a new era of human milk research focused on deep interrogation of maternal mammary cell genomics, in interaction with maternal clinical and behavioral factors, in shaping milk composition. Furthermore, the scope of normal variation in milk composition is yet to be established. Outlining the scope of normative variation in milk is key to next-generation human milk fortification techniques to support the nutritional needs of preterm infants and other clinical populations of interest. The primary objective of the proposed project is to generate a systems-level view of human milk in the context of healthy mothers and their term infants. As such, the proposed work is directly responsive to NIH/NICHD RFA-022-020, “Human Milk as a Biological System”. The study leverages existing data, milk, and fecal specimens from a richly phenotyped cohort of 400 mother-infant dyads, and is based on compelling preliminary data identifying novel genetic sequence variation shaping milk gene expression, and relationships of milk metabolomic, lipidomic, and microbiomic variation to infant growth and cognition. Specific Aim 1: to identify maternal genetic and clinical factors that shape human milk gene expression. We will identify novel genetic determinants of the milk transcriptome and assess potential modification of these genetic associations by gestational weight gain, diet, and other clinical factors. Single-cell RNA-sequencing will provide additional necessary information for characterization of the cell type composition within human milk. Specific Aim 2: to describe key features of the normative human milk biosystem and their interactions with one another. The project expands on existing milk omics data from the cohort, including milk microbiomes, oligosaccharides, metabolomics, and lipidomics, to be integrated with the genomic data produced under Aim 1. Established and novel machine learning techniques will be used to characterize interaction networks and correlational structures among these key features of human milk. Specific Aim 3: to establish how the milk biosystem is related to variation in infant gut microbiomes and health. Milk multi-‘omic networks will be aligned with infant growth, body composition, and gut microbiome variation from birth to 6 months in the 400 infant offspring from the above cohort. Statistical and machine learning techniques will define the scope of milk system variation consistent with normal infant growth and gut microbiome development. For a subset of 150 infants, we will also incorporate innovative early life cognitive assessments for exploratory analyses. Finally, we will develop an online portal for visualizing the resulting data, enabling other researchers to investigate specific features and relationships of interest.

NIH Research Projects · FY 2024 · 2022-09

OVERALL Abstract The vagus nerve is involved in normal physiology, and disturbances in vagal control have been implicated in several pathophysiological conditions. However, there is a lack of information on the physiology of this nerve in humans as well as multi-organ responses to vagal nerve stimulation (VNS), despite over 100,000 VNS implants worldwide to treat epilepsy, depression, anxiety, and gastrointestinal disorders. Likewise, very little is known about how to best optimize VNS settings for existing therapies or how to develop VNS for new therapies. The proposed Research Evaluating Vagal Excitation and Anatomical Linkages (REVEAL) center aims to conduct groundbreaking research on the effect of VNS on four key systems: the autonomic nervous system (ANS), the cardiovascular system, the immune system, and metabolic system. The ambitious scope of the research requires the participation of eight major academic and medical institutions with over 40 participating key personnel, over 140 patients, an External Advisory Board (which includes patient advocates), a Data and Safety Monitoring Board, and an NIH Steering Committee and other NIH personnel. REVEAL will have three aims corresponding to its Cores. The Clinical Core will manage over 140 patients and clinical staff from 8 different institutions to obtain consistent data on VNS effects on ANS, the cardiovascular system, the immune system, and metabolism. The Data and Analysis Core will gather, store, and analyze data from clinical sites to produce publicly available datasets for development of VNS-based therapeutics and other research. The Administration Core will coordinate the work of the REVEAL Cores and stakeholders to meet the goals of NIH SPARC’s VESPA program.

NIH Research Projects · FY 2025 · 2022-09

Project Summary In the 50 years since the genetic counseling profession began, a systematic study of genetic counseling (GC) processes and outcomes in real-life sessions across specialties has never been conducted. In order to optimize GC quality and improve efficiency of care, the field must first be able to accurately and comprehensively measure GC processes and determine which processes are most critical to achieve positive patient experiences and outcomes. The overarching objective of this study is to characterize GC processes using a novel and pragmatic measure and to link variations in processes and session time to patient-reported outcomes using a rigorous approach to define quality, efficient GC in practice. The central hypothesis is that GC processes impact patient outcomes in complex ways and that by evaluating and linking processes with outcomes we can identify ways to optimize GC quality and efficiency. To test the central hypothesis and attain the overall objective, a reliable, pragmatic checklist will be used to measure GC processes in audio recorded sessions and to characterize the extent and types of variability in GC processes across genetic counselors and specialties using actual patient sessions of varying lengths. Surveys will measure patient experience, empowerment, activation, decisional and informational needs and information overload. Coincidence analysis will be conducted to identify patterns of GC processes that consistently make a difference for high scores on each patient-reported measure. Comparison of the extent to which characteristics of GC sessions (including time) influence variability in the processes used and variability in patient outcomes will be accomplished through random effects multilevel models. We will then test the effectiveness of a GC efficiency intervention that tailors counseling to a patients’ informational preferences and values assessments and removes select processes found not to contribute to differences in patient outcomes using a stepped-wedge randomized controlled study. The study will integrate perspectives from four community advisory boards and a genetic counselor advisory board to provide vital input throughout the study process. This participatory approach was chosen to leverage diverse perspectives to create research that is feasible, acceptable, and usable beyond the research environment. The results of this study will be useful in considering which GC processes are essential for optimizing various patient outcomes in minimal time for a diversity of patients. This study is expected to improve measurement of GC processes, more clearly delineate differences in genetic counseling processes and patient reported outcomes, and increase genetic counseling efficiency by reducing in person visit times while maintaining or improving quality patient outcomes.

NIH Research Projects · FY 2025 · 2022-09

At present there are more than 25,000 patients waiting to receive liver transplants. The number is increasing due to an aging US population accompanied by an increasing incidence of chronic liver diseases associated with such disorders as alcoholic liver disease, hepatitis, MAFLD and NASH. In spite of efforts to persuade people to serve as organ donors, the demand increasingly outstrips the supply for organ transplantation. One solution to this problem is the ability to generate human livers in animals for liver as well as hepatocyte transplantation. Although there are numerous protocols to differentiate human embryonic stem cells (hESCs), and inducible pluripotent stem cells (iPSCs) ex vivo to a variety of cell types, they have encountered significant challenges in translation to the clinic. However, it is now possible to regenerate the replica of organs/cells from one species of animal within the body of a second species. This involves the knockout (KO) of specific developmental genes in the blastocyst of species two; and the intra-blastocyst injection of pluripotent stem cells from species one to generate offspring that carry organs/cell types derived from that donor. The translation of this approach requires an efficient gene-editing technology. In fact, novel TALEN/CRISPR/Cas9 technologies provide such a rapid, and cost-effective means to generate genetically modified animals. Accordingly, we propose to employ gene-editing technology to knockout specific genes associated with liver development in the mouse embryo. We hypothesize that rat liver can be generated in the mouse by the injection of rat ESCs or PSCs into CRISPR-genetically engineered murine blastocysts and transplanted back into syngeneic rats. The studies represent a first step of interspecies development of exogenic organs for transplantation without immunosuppression. We have designed three Specific Aims to test our central hypothesis. Specifically, we will characterize (1) intra- and interspecies exogenic liver and endothelium derived from HHEX KO embryos; (2) the immunology and function of interspecies exogenic liver and endothelial development derived from HHEX KO embryos; and (3) several approaches to enhance the generation of interspecies chimeras that include humanization of morphogen ligand- receptor interactions. The resulting exogenic rat liver and endothelium will be transplanted back into syngeneic rats to evaluate graft survival and functionality. The generation of whole livers that are comprised primarily of rat hepatic and endothelial cells derived from implanted rat ESCs or PSCs would represent a paradigm shift and provide the necessary preclinical evidence for ultimately creating human livers in animals. If successful, the proposed research would be a game-changer that could conceivably pave the way for an alternate source of human livers for organ and/or hepatocyte transplantation that is tailored to specific patients. In addition, this novel, albeit somewhat high-risk approach circumvents many of the problems associated with research on xenotransplantation. The potential impact on improved health care in the U.S. and worldwide for liver diseases is great and represents a major step towards the goal of individualized medicine.

NIH Research Projects · FY 2025 · 2022-09

Project summary/abstract Amyotrophic lateral sclerosis (ALS) is a universally disabling and fatal neurological condition. Current treatments have only modest benefit. Development of effective therapeutics is hampered in part by inadequate knowledge of ALS natural history. Though valuable, existing ALS registries have either large samples sizes but limited clinical information, focus on relatively small subsets of the ALS population, or provide information from a relatively brief period. However, as a part of routine clinical care, ALS multidisciplinary clinics (MDCs) develop a rich natural history dataset from all ALS patients, and most people living with ALS are seen at MDCs. We have built a combined, de-identified natural history dataset from over 1,700 ALS patients from 9 MDCs, with racial representation that is reflective of the ALS population at large and broad geographic representation as well. We offer enrollment to all patients at our clinics. We will build on our multicenter, longitudinal, prospective MDC dataset in collaboration with industry and the ALS patient community to provide information critical for clinical trial development and post-marketing evaluation. Specifically, we will do the following: record clinically relevant baseline characteristics and serum neurofilament light (NfL) measurements at enrollment as well as validated longitudinal measures of disease progression including ALSFRS-R and disease staging, respiratory vital capacity, speaking rate and 10 meter walk test (Aim 1), record disease milestones based upon patient-reported outcomes, durable medical equipment orders in the electronic health record, and other events such as dates of gastrostomy, hospitalizations, and death (Aim 2), and model time to events using baseline characteristics as well as retrospective and prospective longitudinal data (Aim 3). We have demonstrated the ability to enroll the vast majority of patients seeking care in our clinics so as to best represent the ALS population. Baseline characteristics will include ALS phenotype and results of genetic testing. Datasets will be made available to academic and industry investigators to advance ALS care, drug development, and outcomes research. We will expand existing engagement from industry and other stakeholders to include an advisory panel of people living with ALS and will encourage opportunities for data dissemination through these existing relationships and publications.

NIH Research Projects · FY 2025 · 2022-09

Project Summary/Abstract The aim of this proposal is to improve the treatment of neonatal seizures. Neonatal seizures affect 1 in 300 infants. Survivors have high rates (40-60%) of permanent disabilities such as cerebral palsy, global developmental delay and epilepsy. There is mounting evidence that seizures contribute to brain injury and neurodevelopmental disability; better treatment may improve long-term neurodevelopmental outcomes. Despite the randomized NEOLEV2 clinical trial showing greater seizure control with phenobarbital (PHB), PHB produced increased acute side effects in comparison to standard dose Levetiracetam (LEV). These side effects included respiratory suppression, hypotension, and sedation. Furthermore, there has been concern regarding long-term neurocognitive side effects of PHB. This proposed project will refine the standard clinical paradigm for neonatal seizure treatment by demonstrating a stratified approach; using an anti-seizure treatment with a significantly improved effect profile, LEV, targeted at reducing mild to moderate seizure burden, reserving PHB with its associated side effects for neonates with high seizure burden. Research Objectives are to (1) optimize the use of a newer, safer, non-toxic anticonvulsant medication for neonates with seizures and (2) develop technologies that will allow for accurate immediate automated diagnosis of seizures. A dose escalation and safety study will be performed to determine the maximum tolerated dose of LEV. Infants who continue to have seizures following standard dose LEV will receive either higher dose LEV or the control drug PHB, randomized in a 3:1 allocation ratio. Dose escalation will proceed in 3 phases to the maximal loading dose of 150mg/kg. A minimum of 10 subjects will be studied at each dosing level and safety data will determine if dose limiting toxicity has been demonstrated before further dose escalation. The primary endpoint will be the maximum tolerated dose. A secondary endpoint will be the additional efficacy of higher doses of LEV compared with standard dose LEV. The pharmacokinetics of high dose LEV in neonates will be studied. Facilitating early detection and rapid treatment of neonatal seizures is of equal importance to developing better drugs in improving outcomes. The usefulness of current seizure detection algorithms is limited by their low accuracy. Within the proposed study the accuracy of the new and improved Persyst neonatal seizure detection algorithm will be evaluated.

NIH Research Projects · FY 2025 · 2022-09

Ethyl alcohol (henceforth ethanol) is a human carcinogen.1,2 Its consumption has been associated with cancers at various sites, including the oral cavity. Despite strong epidemiological evidence, the mechanisms of ethanol carcinogenicity remain unclear, hampering the ability to develop efficacious preventive strategies, identify individual susceptibility, and effectively face the challenges deriving from the projected increase in consumption. Ethanol major metabolite, acetaldehyde (AA), is suggested to play a crucial role in head and neck cancers by reacting with DNA. These reactions generate chemical modifications (DNA adducts) that, if not repaired, may result in mutations and ultimately lead to cancer. Individuals with genetic deficiencies in ALDH2, the enzyme responsible for AA detoxification, were shown to have a 15% increased risk of developing oral cancer when drinking.5 Additionally, Fanconi Anemia (FA) patients, who have impaired mechanisms to repair AA-related DNA damage, have an average 500-fold higher chance of developing oral cancer.6 Previous studies have shown a direct and dose-dependent connection between ethanol consumed and AA-derived DNA damage, in the oral cavity of healthy volunteers.7 This effect was not as evident in blood DNA from the same individuals, indicating a distinct contribution of AA exposure coming from oral ethanol metabolism by the mucosa and oral microbiome. Our hypothesis is that AA resulting from oral metabolism of ethanol is playing a crucial role in oral cancer through the formation of DNA adducts, and that levels and persistence of driver adducts will increase in individuals with increasing oral cancer risk. Using cutting-edge analytical approaches, our objective is to characterize ethanol's oral metabolism and its corresponding DNA damage and mutational profiles, to develop a systematic assembly of biomarkers for identifying oral cancer risk and for developing strategies for early detection and prevention. This will be done by completing 3 aims. The first one will characterize DNA damage profiles in oral cells, collected after exposure to a controlled alcohol dose from participants from 3 groups at increasing risk of AA-related oral cancer (active ALDH2*1/1* homozygotes, inactive ALDH2*1/2* heterozygotes and FA patients). Driver adducts will be identified as those increasing in the groups following the increased cancer risk and persisting over time in FA patients. The second aim will focus on investigating the role of the oral microbiome in ethanol metabolism, by characterizing the oral microflora and measuring the aldehyde profile resulting from the ethanol dose in the saliva of study participants. Additionally, the oral microbiome will be characterized in samples from non-drinkers, included to investigate if ethanol consumption results in a specific profile. Finally, the third aim will analyze genome-scale mutational signatures in oral cell lines exposed to AA, for which DNA adducts will be profiled, and in oral tumor tissues from rats chronically exposed to AA or ethanol. This will yield mechanistic evidence on ethanol-related oral mutagenesis and cancer formation and identify DNA adducts bearing mutagenic potential.

NIH Research Projects · FY 2024 · 2022-09

Back pain (BP), including low back and neck pain, is one of the most prevalent and disabling pain disorders. Most cases remain poorly managed and known socio-ecological factors that pose barriers to care have been especially under-addressed resulting in critical gaps in BP management. Importantly, BP, like other chronic conditions, requires ongoing self-management. Unfortunately, most care offered through health systems fails to support sufferers’ self-care and instead focuses on costly and provider-dependent therapies with little supporting research evidence. The persistent use of these practices contradicts evidence-based BP guideline recommendations for less invasive complementary and integrative health (CIH) approaches which can support self-care. Importantly, our team has demonstrated CIH approaches can be safely and effectively delivered in non-clinical settings in both in person and video-conferencing formats which can overcome access barriers. The long-term objective is to bolster the widespread implementation of evidence-based CIH approaches that support whole person oriented, self-care for individuals with BP. We will use a two-phase project that applies established models and frameworks for facilitating long term sustainability to develop, feasibility test, and evaluate the effectiveness of a community supported CIH self- management program, Partners4Pain compared to an active control, Keys to Wellbeing. This project builds upon our team’s extensive background in BP and CIH self-management research and established partnerships with community and health organizations with broad reach including the YMCA, YWCA, and others. Phase I (R61) will involve planning and preparations leading to a randomized feasibility study (n=40) including co-development and assessment of Partners4Pain, a self-management program comprised of evidence based CIH approaches (e.g. pain education, mindfulness, cognitive behavioral/pain coping strategies, exercise). Phase II (R33) includes a full-scale multi-level randomized hybrid effectiveness implementation trial (n=376) of the community supported self-management program, Partners4Pain compared to the active control, Keys to Wellbeing, both of which will have been optimized and feasibility tested in Phase I. By co-developing scalable evidence based CIH interventions with community stakeholders that can be delivered in an accessible manner by community partner organizations with extensive reach, we will remove an important barrier that currently exists within the costly and burdensome health care systems. This approach has the potential for larger scale implementation across a range of community-based organizations and settings, improving access to resources that will support BP sufferers’ ability to gain greater agency in their own pain care, leading to better health and wellbeing.

NIH Research Projects · FY 2025 · 2022-09

Project Summary/Abstract The COVID-19 pandemic has had an alarming impact on already unacceptably high childhood obesity rates, and emerging evidence shows that traditional approaches to pediatric weight management have been markedly less effective since the onset of the pandemic. As obesity during childhood is much more likely to be sustained during adulthood, and children with obesity and other chronic conditions are more likely to have severe forms of COVID-19 requiring hospitalization, this alarming increase in childhood obesity rates is poised to have a broad and long-term impact on population health unless effective interventions are implemented. Yet, we know very little about the unique drivers of this dramatic increase in childhood obesity and whether BMI increases will persist and become lifelong. We know even less about the protective factors that mitigate this risk, as some youth will not develop obesity/worsening cardiometabolic health or may recover quickly despite risk exposures. Our goals are to uncover the biobehavioral pathways through which pandemic-related stressors drive childhood obesity and cardiometabolic risk, and to identify protective factors and intervention targets to mitigate the long-term impact of the pandemic on children’s health. The proposed research offers a unique, time-sensitive opportunity to prospectively examine the impact of multilevel stressors brought on by the pandemic to identify factors influencing BMI and cardiometabolic health trajectories. We will leverage an established longitudinal cohort of racially/ethnically diverse children (60% Latino) from predominantly low- income households, who were enrolled at 2-4 years of age (U01HD068890) and followed annually through ages 7-11 (R01HD090059). Underscoring the timeliness, uniqueness, and significance of this cohort, body composition, cardiovascular and metabolic functioning, neuroendocrine, oxidative stress, and inflammatory biomarkers, and health behaviors were obtained just prior to the onset of the pandemic (n=338). Drawing on a rich history of longitudinal data over 5 previous timepoints including immediately prior to the pandemic, we propose to add two new waves of data collection (7- and 8-years after inception of the cohort, 2-3 years post- onset of the pandemic) when children will be 10-14 years of age, an important developmental window of obesity and cardiometabolic imprinting. Multiple levels of pandemic-related stressors will be measured, alongside gold standard biological measures of stress activation, adiposity and cardiometabolic health, objective health behavior measures, and parent-child surveys. Our specific aims focus on identifying the pathways, parent-child factors, and neighborhood/community contexts needed to guide effective childhood obesity interventions in the aftermath of the pandemic and reduce adverse health consequences among vulnerable and understudied populations.

NIH Research Projects · FY 2025 · 2022-09

ABSTRACT The study of the human temporal bone has proven to be incredibly powerful and is responsible for much of what we know about the anatomy and pathology of the ear. However, propagation of otopathology research has been hampered by barriers that affect every step of the research chain (procurement, processing, distribution, and dissemination). The major goals of this project are to propagate the use of human temporal bones for research and training through the establishment of our lab as national resource for temporal bone expertise and to become part of the collaborative network to be established by the NIDCD to serve the auditory and vestibular research communities. These goals will be achieved through 4 specific aims. In Specific Aim 1, we will establish a core service for processing and distribution of high-quality temporal bone tissue. We will leverage our high procurement capacity, digitization of our collection, and technical experience to implement a structured approach for prioritizing and processing human temporal bones that are of special scientific interest to meet research needs of the scientific community. In Specific Aim 2, we will optimize human temporal bone preparation techniques to reduce processing costs and time and improve the capacity to retain, preserve, and extract proteins and DNA/RNA. We will investigate technologies for improving the speed and quality achieved during fixation, embedding, decalcification, sectioning, and visualization. In Specific Aim 3, we will provide technical instruction on the processing and use of human temporal bones for the scientific and clinical communities. Innovative hybrid educational modules will be employed, and all materials, training, and protocols will be freely disseminated to increase the number of well-trained technicians and researchers. In Specific Aim 4, we will provide outreach to the scientific and clinical communities to disseminate and promote the use of human temporal bones in research. This will be achieved in-person at major scientific meetings and virtually using multiple multimedia resources. Our multidisciplinary team of experienced investigators has the necessary knowledge and skills aligned with ample resources (large archival collection, high procurement capacity of high-quality temporal bones, highly skilled team of technicians, internal distribution services to send biological specimens), collaborations with centers of excellence for imaging and tissue processing, and innovative educational and audiovisual services to provide the necessary means to propagate and take temporal bone research to the next level.

NIH Research Projects · FY 2025 · 2022-09

Project Summary Adolescence is one of the most critical periods of neurodevelopment. The brain undergoes a profound reorganization during this stage, including the formation and stabilization of neural circuits that control decision- making. We, and others, hypothesize that age-related improvements in decision-making are driven by changes in brain circuits that encode specific decision-making mechanisms. Direct evidence supporting this hypothesis, however, has been limited. The prefrontal cortex in particular undergoes an intense restructuring during adolescence and brain imaging studies have observed robust changes in the orbitofrontal cortex (OFC) and anterior cingulate cortex (ACC). The OFC and ACC are altered in individuals with mental illness, which is thought to be the mechanism underlying decision-making deficits that emerge in these clinical populations. When and how these alterations occur is not known, but emerging evidence suggests developmental changes in subcortical projections to the OFC and ACC may be involved. Here, we propose to use in vivo calcium imaging and optogenetic techniques coupled with computational modeling, to longitudinally assess circuit and neuronal activity in behaving rats at multiple adolescent ages to determine how developmental changes in OFC and ACC networks mediate improvements in decision-making. In Aim 1 we will determine how encoding of attention and reward-prediction errors in amygdala and ventral tegmental area (VTA) projections to the OFC improves across adolescence in rats using a reversal-learning task. We will then use a new transsynaptic tracing approach in Aim 2 to demonstrate that attention and reward prediction errors controlled by amygdala and VTA projections are integrated into OFC neurons to determine the degree to which action values are updated and strengthened during adolescence. Finally, Aim 3 studies will investigate the role of OFC projections to the ACC in integrating value updating with current action value estimates that guide adaptive decision making. Together, these studies will provide key insights into the developmental mechanisms that guide complex decision making. Our normative data will provide a framework for identifying and understanding the neurodevelopmental mechanisms of mental illness, and inspire future translational studies.

NIH Research Projects · FY 2024 · 2022-09

Project Summary Adolescence is one of the most critical periods of neurodevelopment. The brain undergoes a profound reorganization during this stage, including the formation and stabilization of neural circuits that control decision- making. We, and others, hypothesize that age-related improvements in decision-making are driven by changes in brain circuits that encode specific decision-making mechanisms. Direct evidence supporting this hypothesis, however, has been limited. The prefrontal cortex in particular undergoes an intense restructuring during adolescence and brain imaging studies have observed robust changes in the orbitofrontal cortex (OFC) and anterior cingulate cortex (ACC). The OFC and ACC are altered in individuals with mental illness, which is thought to be the mechanism underlying decision-making deficits that emerge in these clinical populations. When and how these alterations occur is not known, but emerging evidence suggests developmental changes in subcortical projections to the OFC and ACC may be involved. Here, we propose to use in vivo calcium imaging and optogenetic techniques coupled with computational modeling, to longitudinally assess circuit and neuronal activity in behaving rats at multiple adolescent ages to determine how developmental changes in OFC and ACC networks mediate improvements in decision-making. In Aim 1 we will determine how encoding of attention and reward-prediction errors in amygdala and ventral tegmental area (VTA) projections to the OFC improves across adolescence in rats using a reversal-learning task. We will then use a new transsynaptic tracing approach in Aim 2 to demonstrate that attention and reward prediction errors controlled by amygdala and VTA projections are integrated into OFC neurons to determine the degree to which action values are updated and strengthened during adolescence. Finally, Aim 3 studies will investigate the role of OFC projections to the ACC in integrating value updating with current action value estimates that guide adaptive decision making. Together, these studies will provide key insights into the developmental mechanisms that guide complex decision making. Our normative data will provide a framework for identifying and understanding the neurodevelopmental mechanisms of mental illness, and inspire future translational studies.

NIH Research Projects · FY 2025 · 2022-09

PROJECT SUMMARY Chronic kidney disease (CKD) is an important health problem associated with high morbidity and mortality. Unraveling the mechanisms associated with risk of or protection from CKD will significantly advance a precision- medicine approach to CKD prevention, diagnosis, and treatment. The Minnesota-KPMP (Minn-KPMP) will ethically and safely obtain research kidney biopsies, biosamples, and data from well phenotyped participants with CKD due to diabetes or hypertension and from patients with no clinical manifestations of CKD despite decades of type 1 diabetes (T1D). In a highly diverse metropolitan area actively confronting racism and disparities, Minn-KPMP will engage a diverse patient population to evaluate and address barriers to enrollment in KPMP and to elicit the perspectives of our local participants on ethical issues posed by the KPMP, such as return of results and biobank governance. This will add significantly to KPMP community engagement and ethics. Leveraging the Biomedical Informatics and Data Access service of the University of Minnesota Clinical and Translational Science Institute (CTSI) Best Practices Integrated Informatics Core (BPIC), we will interrogate the large MHealth Fairview (MHealth) database to identify, recruit, enroll, and obtain clinical data, biosamples, and kidney biopsies from patients with CKD-Diabetes and CKD-Hypertension and resilient-T1D. We will work closely with KPMP and help to refine and follow common study protocols while following maximum safety precautions. The long-standing successful track record of our group in recruiting patients into clinical trials of CKD, and our ethically rigorous approach to consenting for kidney biopsy and strict adherence to KPMP safety measures will ensure our meaningful contribution to the KPMP mission and goals. Minn-KPMP has assembled an outstanding team of investigators and consultants to recruit and follow participants with CKD and with resilient T1D (Res-T1D). Directly relevant to this application, the Minn-KPMP study team has a long-standing track record of successfully recruiting, following-up, and safely and ethically performing research kidney biopsies, including sequential kidney biopsies, in a wide range of participants, including participants with diabetes and with no clinical manifestations of CKD, siblings with diabetes, kidney donors, kidney transplant recipients, and pancreas transplant recipients. Obtaining high quality biosamples, including kidney biopsy samples, from well phenotyped study participants is key to KPMP success, so that these tissues can be used for transcriptomic, proteomic, and metabolomic analyses. The Minn-KPMP is eager and fully prepared to collaborate with the other KPMP recruiting sites, tissue interrogation sites, central hub, steering committee, DSMB, external expert panel, and the almost 300 members of the KPMP.

NIH Research Projects · FY 2025 · 2022-09

PROJECT SUMMARY Sudden cardiac arrest (SCA), a sudden catastrophic loss of the pulse, continues to be a major public health issue. A proportion of SCA events occur in persons engaging in drug use and given that drug overdose deaths are at unprecedented levels in the United States, the epidemiology of drug related SCA is changing rapidly. Recognition and characterization of drug related SCA events is critical for accurate estimates of mortality associated with drug use, and to inform public health measures, especially in the context of the ongoing opioid epidemic. This proposed study will address several of the major knowledge gaps. This K01 Career Development Award leverages the existing infrastructure and clinical data archive of two ongoing prospective community-based studies of SCA. Dr. Norby will use this data to examine the epidemiology of SCA associated with drug use, with the overall goal of improving community-based approaches to SCA prevention. This proposal aims to 1) identify opportunities that will improve survival from SCA in the setting of drug use, and 2) identify substrate-trigger factors that initiate SCA in the presence of drug use. Taken together, these aims will interface community-based surveillance and comprehensive investigative reports to fill in the epidemiology and research gaps in SCA events related to substance use. To address these research aims, Dr. Norby will assemble records and reports in these two communities for SCA cases that have previously been excluded due to evidence of drug use. The overall goal of this K01 is to inform a sequence of R series grants to further investigate the prediction and prevention of SCA, and to improve survival after an SCA event related to drug use. With the support of this K01 award, Dr. Norby will be able to pursue this goal and transition to independent investigator status through essential training and mentorship. She will gain advanced training in 1) combining multimodal health records across systems and extracting pertinent information; 2) pharmacoepi drug use research and analysis of drug-drug combination; and 3) SCA mechanisms, SCA response and care, and additionally gain familiarity with toxicology and autopsy reports. Cedars-Sinai Smidt Heart Institute provides the ideal infrastructure to complete the research and training activities. Through the proposed research, training, and career development Dr. Norby will gain the scientific and professional skills necessary to become a successful independent investigator and lead a research program that advances the field of SCA associated with drug use.

NIH Research Projects · FY 2024 · 2022-09

Speech understanding is a key function of human audition with important roles in learning, professional, and social functions. Ageing is associated with increased difficulties with speech recognition, particularly in noisy backgrounds, even in the absence of clinical hearing loss. A growing body of work has identified increased compensatory use of cognitive resources, collectively known as listening effort (LE), as a key change within the ageing and hearing-impaired populations. Additionally, individuals with mild cognitive impairment (MCI) and Alzheimer’s Disease (AD), whose cognitive deficits compromise their ability to efficiently utilize LE mechanisms for coping with distracting information, exhibit substantial deficits in perception of speech in the presence of competing talkers. However, the neural underpinnings of these behavioral deficits in MCI remain poorly understood, including the relative extent to which neurobiological changes in the brain due to AD affect lower- level processing of speech acoustics versus higher-level mechanisms involved in linguistic processing. Moreover, because cortical processing of continuous speech in people with MCI due to AD has been virtually unexplored, it is unknown whether such measures could have utility as a neural biomarker for early, affordable diagnostics of AD, as well as for tracking of AD progression. The present proposal aims to address both of these key goals by collecting the first data set of continuous speech processing under varying listening effort demands in people with MCI due to AD and matched controls. In Aim 1, we will address the question of how neurobiological changes due to AD influence cortical processing of acoustic and linguistic features of speech in MCI. In a sample of participants with MCI due to AD with AD biomarkers, as well as matched controls, we will measure non- invasive electroencephalographic (EEG) responses to continuous narrative audiobooks presented either in isolation (Low LE condition) or dichotically in the presence of a distracting secondary audiobook (High LE condition). Model-based temporal response function (TRF) analyses will subsequently be used to derive responses to a range of acoustic and linguistic features of speech to assess how MCI status and LE demands interact in cortical processing of speech. In Aim 2, we will test whether cortical responses to speech can be reliably used to, 1), classify the MCI (vs. control) status of individual participants, and 2), predict speech comprehension performance and scores on cognitive battery tests (e.g., working memory capacity, attentional inhibition scores). These goals will be achieved by building cross-validated classification and regression models to identify which features (acoustics vs. linguistic), conditions (clean vs dichotic speech), and types of neural measures (e.g., feature tracking strength vs. response latencies) are most reliable for classifying MCI status and predicting behavioral scores. This work will provide a foundation for future grant proposals aimed at elucidating perceptual and neural consequences of AD, and identification of novel and affordable biomarkers of AD useful for early detection of AD, tracking of disease progression, and evaluation of novel clinical interventions.