Mayo Clinic Rochester

NIH Research Projects · FY 2025 · 2019-09

PROJECT SUMMARY This renewal application continues to focus on older people with insulin resistance (IR) and aims to understand the mechanisms of exercise benefits. The original grant focused on the mechanisms of resistance exercise training (RT) related enhancement of peripheral (muscle) insulin sensitivity (IS) and muscle hypertrophy. The premise of the current proposal is built on substantial preliminary data obtained with a supplement to our current grant which was focused on the effect of RT on brain metabolism and cognition. We will address the neuronal benefits of six months of either high-intensity aerobic interval training (HIIT) or RT in 60–85-year-old people with IR compared to sedentary controls (n=24 per group). We hypothesize that enhancement of IS in response to six months of HIIT or RT will improve cognition, measured by NIH Toolbox, concurrent to enhanced brain regional connectivity, measured by resting-state functional MRI, and greater glucose uptake in brain regions rich in insulin receptors, measured by PET scanning (F-18 FDG). We also will determine whether HIIT and RT increase cortical and hippocampal volumes measured by volumetric MRI. Although exercise benefits in central neuronal regulation are postulated, based mostly on pre-clinical experimental data, the benefits of exercise training on brain metabolism and cognition remains incompletely defined in humans. Furthermore, in addition to our postulation that exercise training enhances neuronal connections within the brain, we also propose that exercise can enhance neuronal connection between the brain and skeletal muscle. We will utilize transcranial magnetic stimulation combined with electromyography (TMS-EMG) to test a hypothesis that RT and HIIT increase neuronal connections from the central nervous system to muscle, as indicated by lower threshold of cortical stimulation needed to activate muscle, prior to structural and morphological changes accompanying long-term exercise training. We will compare TMS-EMG data at baseline, 2 weeks, 3 months, and 6 months after the initiation of exercise training with changes in muscle mass, histology, and metabolites. The results from these studies will determine if there are central neural adaptations to exercise training that drive muscle mass and strength changes. To ensure the successful completion of the study, we have assembled a group of highly experienced investigators with strong collaborative track records. The results from the proposed studies are likely to substantially advance our understanding of exercise benefits to neuronal and cognitive function in people with IR, who are at 2- to 4-fold greater risk for developing dementia compared to people without IR. We submit that these results can potentially form the basis of targeted exercise therapies and lay the groundwork for developing novel therapeutic approaches benefitting people who are unable to perform exercise training.

NIH Research Projects · FY 2025 · 2019-09

ABSTRACT - OVERALL Total joint arthroplasty (TJA) is the most common and fastest growing surgery in the nation with more than 7 million Americans currently living with artificial joints. Despite the high surgery volume, the evidence base for TJA procedures, technologies and associated interventions are limited. Many surgical approaches, implants or surgical technologies (computer navigation, robotic surgery) are adopted based on theoretical grounds with limited clinical evidence of effectiveness and safety. The wider TJA research community needs access to large, high quality and rich data sources, state-of-the-art clinical research standards and information technologies to overcome methodological and practical challenges in studies of surgical and nonsurgical interventions in TJA. American Joint Replacement Research-Collaborative (AJRR-C) is a Core Center for Clinical Research exclusively focused on TJA. The overarching goal of AJRR-C is to facilitate innovative, methodologically rigorous and interdisciplinary clinical research that will directly improve TJA care and the outcomes. AJRR-C is a disease (TJA) and theme-focused Center providing shared methodological expertise, education, data and infrastructure resources. AJRR-C leverages big data resources for TJA research, provides customized methodology resources in epidemiology, biostatistics, health services research and medical informatics, and has established synergistic interactions around an integrated Resource Core (American Joint Replacement Registry – AJRR). The Specific Aims of AJRR-C are: (1) To provide administrative and scientific oversight of AJRR-C activities (Administrative Core), (2) To provide integrated and customized services, access to large databases and novel analytical methods for clinical research in TJA (Methodology Core); and (3) To meet the unique data and infrastructure needs of the TJA research community and to strengthen the national capacity for large-scale observational and interventional studies in TJA (Resource Core). AJRR-C is integrated within the long- standing and highly centralized clinical research environment of Mayo Clinic, thereby leveraging existing expertise and infrastructure resources. AJRR-C activities are evaluated using robust metrics to ensure continuous evaluation, flexibility and improvement in response to the most pressing needs of the TJA research community.

NIH Research Projects · FY 2025 · 2019-09

ABSTRACT The purpose of this study is to determine whether oral memantine daily for 6 months, when compared to placebo, is associated with reduction in decline of cognitive function at 12 months in children ages 4-18 receiving cranial radiotherapy (RT) for primary central nervous system tumors and to correlate protective effects of memantine with imaging biomarkers. Radiotherapy is a proven curative therapeutic tool in the treatment of primary brain tumors. However, cranial RT results in significant cognitive morbidity. The mechanisms of radiation-induced injury result in a picture that is a combination of the small vessel disease seen with vascular dementia as well as neurodegenerative diseases like Alzheimer’s dementia. Ischemia and injury can induce excessive NMDA stimulation and lead to excitotoxicity, and pre- clinical data suggests that selective blocking of the NMDA receptor can restore long-term potentiation and restore learning in both models of ischemia as well as models of radiation injury. Memantine is a non- competitive, low-affinity, open- channel NMDA blocker, which has been shown to be neuroprotective in pre- clinical models. In two placebo- controlled phase III trials, memantine proved to be effective treatment for Alzheimer’s and vascular dementia, especially for patients with small-vessel disease. Memantine has also proven effective in reducing cognitive dysfunction in adults receiving whole-brain radiotherapy for brain metastases. Memantine delayed time to cognitive decline and reduced the rate of decline in memory, executive function and processing speed. Importantly, cognitive function in patients receiving memantine remained stable even after memantine was discontinued; suggesting memantine had a protective effect rather than simply a therapeutic effect. In this study, we propose evaluating the efficacy of memantine in preventing cognitive dysfunction in pediatric patients receiving cranial radiation through the clinical trial mechanism of the Children’s Oncology Group. This study is novel in that children will undergo early cognitive evaluations (baseline prior to radiation, 3, 6, and 12 months post-radiation) with a brief computerized testing battery that we will correlate with formal cognitive testing as well with long-term cognitive function (24 and 48 months) assessed with both methods. If successful, this study will provide validated early cognitive assessment time points that correlate with late cognitive toxicity and result in an framework for accelerated study design that will allow for early assessment of efficacy for future neuro-protectant trials. Dose- and volume-dependent reduction in brain volume is seen after radiotherapy exposure and is associated with cognitive decline. We hypothesize that neuroprotection with memantine will also preserve relevant brain volume and this will correlate with domain-specific improvements in cognitive function. We will use quantitative volumetric MRI analysis to correlate protective effects of memantine with brain substructure (white matter, hippocampus, frontal lobes etc) volume changes over time and correlate with cognitive assessments. Radiographic analysis will provide proof-of-principle for the mechanism of action of memantine as well as a biomarker that can be utilized in future trials of radio-protectants, which is especially important for young patients or patients not neurologically capable of completing cognitive assessments but who may benefit the most from neuroprotective interventions.

NIH Research Projects · FY 2025 · 2019-09

PROJECT SUMMARY/ABSTRACT Disruptions in mechanosensation are commonly responsible for symptoms in diseases of gut-brain interaction (DGBI), like irritable bowel syndrome (IBS), which affect ~15% of the US population. Therefore, my laboratory’s long-term goal is to elucidate the cellular and molecular mechanisms of gastrointestinal (GI) mechanosensitivity in health and in DGBIs. There are several mechanosensory pathways in the GI tract. One such important mechanosensory pathway that is involved in DGBIs is initiated through the specialized sensory epithelial enteroendocrine cells (EECs). Upon stimulation, EECs release diverse signaling molecules that have a range of physiologic effects, and disruption in this signaling is involved in DGBIs. We discovered an EECs sub-population which is mechanosensitive. These EECs express Piezo2, a mechano-gated ion channel that connects forces to release of EEC signaling molecules and endows the intestine with an ability to sense small luminal forces to adjust GI motility and secretion. The objective of this proposal, based on strong rationale and extensive preliminary data, is to test the hypothesis that rectal Piezo2+ mechanosensitive EECs co-express select GPCRs sensitive to digestive metabolites, which modulate Piezo2 mechanosensitivity. These rectal mechanosensitive EECs connect chemo- and mechano- signaling in rectal EECs, and thereby regulate regional and proximal intestinal motility. We have established novel transgenic mouse models that allow us to lineage track, stimulate, and interrogate specific EEC sub- populations, and we will use these mouse models and validated EEC lines with a range of innovative and established gold-standard approaches from single cells to in vivo to study mechanosensitive EECs and their roles in GI physiology. Aim 1 will determine the cellular mechanisms of chemo- and mechano-signaling in EECs. Aim 2 will determine how the mechanosensitive EECs stimulated by forces and luminal digestive metabolite to modulate GI motility. The proposed experiments are foundationally linked to our previous work, but they represent a new and exciting direction and can be completed in the defined award period. The results from this study are important because they will allow us to deeply understand mechanosensitive EEC cellular physiology and their roles in GI motility, which will enable us to examine alterations in disease, and then potentially target these pharmacologically as novel and specific therapies for DGBIs.

NIH Research Projects · FY 2025 · 2019-09

ABSTRACT – ALLFTD2: OVERALL SECTION Frontotemporal lobar degeneration (FTLD) is an overarching term for a group of neurodegenerative disorders associated with the accumulation of toxic protein aggregates in the CNS, most commonly comprised of one of two major proteins—microtubule associated protein tau (i.e., FTLD-tau) and TAR DNA binding protein molecular weight 43 (i.e., FTLD-TDP). FTLD is approximately as common as Alzheimer’s disease in those who manifest symptoms prior to age 65. FTLD is uniformly fatal, and there are no effective therapies that can slow or halt disease progression. Approximately 30% of all FTLD patients have a dominantly inherited familial disorder (f- FTLD), with the three most commonly mutated genes being microtubule associated protein tau (MAPT), progranulin (GRN), and chromosome 9 open reading frame 72 (C9orf72). Most new therapies will target one of these gene products. While there are no current clinical or biomarker findings that confidently predict the underlying proteinopathy in those with s-FTLD, it is likely that some of these agents might also be useful in sporadic (s-) FTLD, particularly if FTLD-tau and/or FTLD-TDP specific biomarkers are developed. Over the prior two grant cycles, the Advancing Research and Treatment in Frontotemporal Lobar Degeneration (ARTFL; U54 NS092089) and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS; U01 AG045390) projects (abbreviated ARTFL/LEFFTDS; 2014-2019), and the current ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD; U19 AG063911, 2019-2025) have been successful in many regards, but numerous knowledge gaps remain. The current proposal represents our plan to continue and expand efforts in the renewal grant application: ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration, Cycle 2 (ALLFTD2). This program will expand the infrastructure and data collection methods by enrolling 1450 unique persons over 5 years (610 from f-FTLD kindreds and 840 with s-FTLD). Due to the lack of deep and frequent phenotypic data on key FTLD participants that is crucial for optimizing clinical trial design, a subset of participants in the late presymptomatic phase of f-FTLD, and early symptomatic phase of f- and s- FTLD, will undergo clinical, biofluid and imaging data/sample/scan collection every 3-6 months over a 12-month time span. The Cores will contribute data and expertise to the Projects, which will focus on asymptomatic/minimally symptomatic f-FTLD (Project 1) and mildly symptomatic s-FTLD (Project 2). If funded, the ALLFTD2 program will provide data/samples/scans/tissue to the greater scientific community while addressing several knowledge gaps relating to FTLD, with the ultimate goal of fostering development of effective treatments for those with FTLD.

NIH Research Projects · FY 2026 · 2019-09

PROJECT SUMMARY/ ABSTRACT Repetitive subconcussive head impacts (RHI) in contact sports are gaining attention, with prolonged exposure linked to chronic traumatic encephalopathy and cognitive decline. Since RHI is often asymptomatic in the early stages, there is an unmet need for early detection of RHI-induced impairments. In our previous grant cycle, we focused on the function of connected anatomic interfaces, particularly the skull-brain (SB) interface (which has evolved to isolate the brain from impact) and its early impairments due to RHI. We developed noninvasive harmonic MR elastography (MRE)-based imaging markers to quantify SB mechanical decoupling, providing the first evidence of early SB impairment in individuals with a history of asymptomatic RHI. We hypothesize that RHI exposure alters the viscoelastic properties of the pia-arachnoid complex through repeated injury and healing. This impairment increased with longer RHI exposure and decreased with longer intervals after exposure, suggesting individual variability in the progression and repair of SB impairments. Other research also indicates that brain injury severity varies significantly due to increased vulnerability from prior RHI exposure or inherent factors. These findings highlight the need for further research into individual SB mechanical vulnerabilities (SBMV) and the longitudinal effects of RHI, which is the focus of this renewal grant. While harmonic MRE metrics developed in the prior grant cycle can assess SB decoupling at equilibrium and track longitudinal changes from RHI, they may be less suitable for evaluating pre-existing individual SBMVs. The risk of SB interface impairments or injury is hypothesized to be linked to spatial and temporal variations in SB interface responses to real-life transient impacts, like existing research on brain injury risk predictions. However, as illustrated in our preliminary data, harmonic MRE, which focuses on equilibrium vibration states, fails to detect regional variations in cortical responses, which are revealed by transient MRE. Advancing from harmonic to transient MRE is thus crucial for identifying SBMV, as transient MRE provides critical in vivo measures of high-risk SB interface areas under low impact levels, with these regions likely remaining at risk or worsening under higher impacts, presumably linking to SB decoupling variability in RHI outcomes. In this renewal, Aim 1 addresses the technical challenge of implementing and validating a new transient MRE method to efficiently characterize impulse responses. In Aim 2, we will build individualized SBMV maps and study age/sex effects. In Aim 3, we will integrate harmonic and transient MRE in a longitudinal sports study, with two goals: 1) detect post-season equilibrium SB decoupling changes, and 2) link the likelihood of these changes to pre- season SBMV. Our hypotheses are: 1) post-impact mechanical alterations occur at the SB interface, and 2) these alterations are related to pre-existing SBMV. We will also correlate MRE metrics with diffusion and cognitive function for outcome predictions. Ultimately, this project aims to develop an imaging approach to identify individuals at high risk for SB decoupling impairment from RHI, enabling targeted mitigation and recovery monitoring.

NIH Research Projects · FY 2024 · 2019-09

PROJECT ABSTRACT Major depressive disorder (MDD), anxiety disorders, and substance use disorders (SUDs) are common, complex psychiatric traits that frequently co-occur and are associated with significant functional impairment, increased healthcare utilization and cost, and higher mortality risk. Not only are these three conditions highly prevalent in the general population and generate a huge societal burden, but recent studies by our team and others have shown that shared covariance from common genetic variation significantly contributes to these psychiatric comorbidities. Large data sets are needed to understand how the multifaceted interplay of genetics, including polygenic risk scores (PRSs), and social determinants of health, such as employment and educational attainment, can impact the risk of these psychiatric disorders and clinical outcomes, such as multiple psychiatric hospitalizations. PRSs have shown potential for risk prediction, but the clinical utility of PRSs for psychiatric conditions is just starting to be explored. Research utilizing Electronic Health Records (EHRs) offers the promise of large data sets to examine these relationships in cohorts of patients seen in clinical practice. However, the use of EHRs is in its infancy in the study of psychiatric disorders and their treatment. This study will address critical knowledge gaps in “genotype-psychiatric phenotype” relationships in large, demographically and geographically diverse population-based samples derived from EHR-linked biobanks across four medical centers - Columbia, Cornell, Mayo Clinic and Mount Sinai. Our objectives are to (1) develop improved methods for EHR phenotyping of MDD, anxiety, and SUDs, and related outcomes based on a data-set of >30 million EHRs, (2) evaluate associations between PRSs and these conditions, and (3) assess the association between PRSs and outcomes including treatment resistance in MDD and healthcare utilization in patients with MDD, anxiety and SUD. The PRS analyses will utilize data from biobanks with >50,000 persons with both EHR and GWAS data. Successful completion of this study will substantially advance our understanding of the clinical utility of PRSs for commonly occurring psychiatric disorders.

NIH Research Projects · FY 2024 · 2019-08

PROJECT SUMMARY/ABSTRACT Pten is a prominent tumor suppressor whose tumor protective ability is exquisitely sensitive to alterations in level of expression or activity. This property has led to speculation that mechanisms controlling Pten expression, sta- bility, conformation, homo- and heterotypic protein interactions, localization, or catalytic activity, including post- translational modifications, are prominent targets for deregulation in human cancer. However, this concept has not been critically tested at the organismal level, mainly because of difficulty in manipulating Pten in mice due to its essential role in embryogenesis. Our long-term objective is to close this knowledge gap by the use of mouse models in which specific Pten domains or regulatory mechanisms are inactivated and to apply the information gained to develop innovative strategies for the treatment of human cancers with Pten alterations. As the next step in the pursuit of this goal, our objective here is to understand, at the physiological level, how the phosphor- ylation status of the C-tail region regulates Pten. Based on extensive preliminary studies, we hypothesize that individual C-tail serine/threonine residues differentially regulate the stability, localization, interactome and/or phosphatase activity of Pten in vivo, thereby impacting its tumor suppressive functions in both Akt-dependent and -independent fashions. We propose to test this hypothesis by pursuing two specific aims. In the first aim, we will comprehensively examine tissues and cultured cells from a core set of eight nonphosphorylatable and phos- phomimetic C-tail mutant mice for changes in Pten biological properties and functions. In the second aim, we will monitor these same mouse strains alongside cohorts of wildtype, Pten hypomorphic and Pten+/– mice for the development of spontaneous tumors, with emphasis on prostate and mammary gland lesions. Additionally, we will conduct a comparative analysis of pre-tumorous and tumorous tissues of these strains for alterations in Pten properties and functions. By completing these aims, we expect to gain insight into the properties of these C-tail mutants in physiologically relevant settings with regards to protein stability, localization, catalytic activity and binding partners, and to integrate these findings with information about the biological and tumor suppressive functions that these mutants have lost, preserved, or gained. The expected overall impact of this innovative proposal is that it will fundamentally advance our mechanistic understanding of the normal and neoplastic func- tions of the second most frequently mutated tumor suppressor gene in human cancer. This knowledge will con- ceptually advance the cancer biology field, improve our understanding of the Akt signaling pathway in normal physiology and cancer, and lay the foundation for the development of new therapeutic strategies that will improve the clinical outcome of cancer patients with alterations in Pten.

NIH Research Projects · FY 2025 · 2019-07

PROJECT SUMMARY - OVERALL The Mayo Clinic Alzheimer’s Disease Research Center (ADRC) has been operating at the Mayo Clinic Rochester (MCR) and Mayo Clinic Florida (MCF) since 1990. The theme of the current cycle of the ADRC is Multiple Etiology Dementias. We recruit and follow participants on the Alzheimer’s disease (AD), frontotemporal lobar degeneration (FTLD), Lewy body disorders (LBD) and vascular cognitive impairment dementia (VCID) spectra to study the roles of multiple pathologic processes functioning to impact cognition in aging. We will be evaluating the social and structural determinants of health in African American/Black and Hispanic/Latino communities at MCF and rural residents at MCR to determine the manner in which the multiple pathologic processes evolve in these communities. Our team has secured several grants in AD, FTLD, LBD and VCID to allow us to leverage the resources of the ADRC against these projects to advance our knowledge. New cores in this ADRC application include the Genomics Core that will study the role of multi-omic aspects of various neurodegenerative and cerebrovascular disease (CVD) disorders, and a Digital Innovation Core that will combine aspects of artificial intelligence neuroimaging, gait, speech/language and remote cognitive assessments to help diagnose and evaluate the longitudinal outcome of neurodegenerative and CVD disorders. The Biomarker Core will evaluate several plasma assays and platforms to determine the utility of these plasma markers in predicting the underlying pathologies, assisting in the biological aspects of the diagnosis and following treatments of these disorders. The Neuroimaging Core will continue to unify imaging protocols across modalities between MCR and MCF as well as move the field forward with defacing MRI and PET images to maximize research participant privacy. Our Neuropathology Core has been at the forefront of developing neuropathology criteria and serves the vital function of confirming the multiple etiological nature of most degenerative/CVD conditions. The Data Management and Statistical Core will continue to lead the field in electronic data capture for our Center enabling the robust sharing of data. The Research Education Component has been successful at training the next generation of investigators from underserved populations and will expand these efforts. The Mayo Clinic ADRC will continue to be a leader in sharing images, data and biospecimens with the other ADRC’s and the broader research community. The unique focus of the Mayo Clinic ADRC involving the combinations of most of the major neurodegenerative and CVD disorders will advance the field for refining diagnoses leading to the development of therapies.

NIH Research Projects · FY 2026 · 2019-06

OVERALL: Targeting Cellular Senescence to Extend Healthspan – SUMMARY This proposal is for the renewal of P01 AG62413, Targeting Cellular Senescence to Extend Healthspan. In the initial funding cycle, we made major conceptual and technical advances in the understanding of cellular senescence, its mechanistic role in the aging of three distinct tissues, and its modifiability by pharmacological intervention. The influence and impact of this highly collaborative PPG are highlighted by over 130 publications, complementary grants, career development awards, and significant engagement in the Common Fund Cellular Senescence Network. Moreover, several clinical trials have been initiated, consistent with the overall goal to build a firm foundation of multidisciplinary discovery science in cellular senescence that leads to a pipeline of therapeutic strategies that slow or prevent age-associated diseases.to drive translational geroscience forward. Our progress has also yielded several exciting and critical questions centered on the molecular underpinnings of the senescence program, including the unique and overlapping roles of p16Ink4a and p21Cip1, the role of specific senescent cell sub-types in tissue and systemic aging, and the tractability of these cell populations by next-generation small molecules engineered to promote their elimination (senolytics) or alter their behavior (senomorphics). We have assembled a uniquely qualified, highly collaborative, and multidisciplinary team to pursue these new and important scientific directions in the renewal through three tissue-centered projects and four highly complementary cores. The projects are Cellular Senescence and Bone Aging (Project 1), Cellular Senescence and Skeletal Muscle Aging (Project 2), and Cellular Senescence and Brain Aging (Project 3). The multidisciplinary cores consist of an Administrative and Systems Biology Core (Core A), a Common Mouse Models Core (Core B), a Drug Discovery and Development Core (Core C), and a Senescence Molecular Phenotyping Core (Core D), each armed with innovative technologies and the appropriate expertise. Collectively, through the coordination, integration, and analysis of research activities and results across the three projects and four cores detailed in this application, this PPG will yield fundamental insights into the governing roles of p16Ink4a and p21Cip1 in cellular senescence and aging, critical data on the therapeutic potential of senotherapeutic compounds for age-related tissue dysfunction, and an advanced understanding and new hypotheses regarding cellular senescence as a mediator of inter-organ communication between bone, skeletal muscle, and brain.

NIH Research Projects · FY 2026 · 2019-04

PROJECT SUMMARY Mayo Clinic has a longstanding tradition of clinical research and remains a dedicated supporter of the National Clinical Trials Network (NCTN). This commitment dates to its role in founding the North Central Cancer Treatment Group, now part of the Alliance for Clinical Trials in Oncology. Mayo Clinic continues to provide sustained leadership within the NCTN, with multiple staff holding key roles in NCTN and NCI-sponsored initiatives. Notably, Dr. Evanthia Galanis assumed the role of Group Chair of the Alliance for Clinical Trials in Oncology in 2023. NCTN trials remain a priority within Mayo Clinic’s clinical research portfolio, reflected in high accrual rates, supplemental funding, and refined activation and monitoring strategies. Mayo Clinic physicians actively lead and develop NCTN trials while contributing to national and international scientific discourse through presentations and high-impact publications. Researchers also conduct secondary analyses and leverage biospecimens to advance cancer science. Additionally, Mayo Clinic is committed to fostering the next generation of NCTN investigators, ensuring continued leadership and innovation in clinical research. Our primary goal is to meet the needs of our patients by advancing care through clinical trials.

NIH Research Projects · FY 2026 · 2019-02

PROJECT SUMMARY / ABSTRACT Cholestatic fibrogenesis is a pathobiological process of the bile ducts, characterized by biliary strictures, cholestasis, and progressive peri-portal fibrosis. During biliary fibrosis, diseased cholangiocytes become highly secretory, releasing a variety of paracrine signaling molecules that subsequently activate hepatic stellate cells (HSC). Progression toward end stage disease is characterized by an exaggerated fibrogenic response to chronic injury, culminating in peri-portal deposition of matrix molecules that progresses to biliary cirrhosis. We have also shown that the cholangiocyte secretome, which mediates the crosstalk, depends heavily on regulatory mechanisms involving epigenetic enzymes and long non-coding RNAs (lncRNAs) to modify chromatin. The ensuing histone modifications in cholangiocytes drive transcription of pathological gene networks that perpetuate fibrosis. The novel direction described here supports the concept that TGF-β induced lncRNAs in cholangiocytes can serve either as decoy lncRNAs to prevent engagement of chromatin silencers (e.g., enhancer of zeste homologue 2, EZH2) or as guide lncRNAs to engage chromatin activators (e.g., lysine acetyl transferase 2A, KAT2A). We have generated the following novel preliminary data: i) Pathologic TGF-β signaling induces upregulation of 267 lncRNAs in cholangiocytes, including TILC and TGFB2-AS1; ii) A network of cholangiocyte-derived paracrine activators of HSCs are regulated by histone modifiers and lncRNAs as demonstrated by chromatin immunoprecipitation sequencing (ChIP-seq), RNA-sequencing (RNA-seq) and RNA immunoprecipitation (RIP); iii) Biliary organoids derived from MDR2 knockout (KO) mice demonstrate distinct upregulation of lncRNAs; and iv) Biliary fibrosis is exacerbated in EZH2 KO mice and blunted in KAT2A KO mice. Based on this preliminary data, we propose the central hypothesis that dysregulated cholangiocyte lncRNAs orchestrate the cholangiocyte epigenome to amplify production of a fibrogenic secretome. In Aim I, we will test the subhypothesis that a decoy lncRNA prevents gene silencing by excluding EZH2 from chromatin. In Aim II, we will evaluate the subhypothesis that a guide lncRNA recruits KAT2A to chromatin to promote a fibrogenic secretome. In Aim III, we will investigate the subhypothesis that targeting specific lncRNAs will prevent fibrogenesis in mouse models and human organoids. In summary, we propose the novel concept that lncRNA dysregulation influences key epigenetic regulators in cholangiocytes to modify chromatin and drive transcription of a fibrogenic gene network. Interventions targeting these newly discovered pathways with RNA therapeutics may have the capability to prevent or reverse specific molecular events that underlie biliary fibrosis.

NIH Research Projects · FY 2026 · 2019-01

ABSTRACT/SUMMARY Background: Increased arterial stiffness has been associated with indicators of damage to the brain including presence of white matter hyperintensity, infarctions, and brain atrophy as assessed with magnetic resonance imaging (MRI). When vessels lose their ability to mechanically absorb the effects of pulsatile flow, that pulsatility is transmitted to the vasculature in the brain leading to deleterious changes in the brain tissue. Understanding the effect of ultrasound measured viscoelastic mechanical properties of central conduit (e.g., carotid) arteries relative to MRI measured brain health indicators could result in a very important tool for predicting and managing changes in brain function. This research project aims to address these unmet and critical needs to develop techniques for the accurate and translatable ultrasound measurement of viscoelastic arterial mechanical properties and evaluate associations with structural changes in the brain. Methods: Ultrasound is a first-line imaging modality for vascular evaluation, but most clinical scanners do not have the ability to evaluate the elastic or viscoelastic mechanical properties of vessels in an accurate, quantitative manner with high temporal resolution. In the first cycle of this grant, we developed an ultrasound- based method called arterial dispersion ultrasound vibrometry (ADUV) that utilizes acoustic radiation force to stimulate high-frequency (200-1500 Hz) waves in the arterial wall, followed by high frame rate ultrasound to measure the wave motion, which is used to characterize arterial viscoelastic mechanical properties. However, our research revealed that several aspects of ADUV could be further improved before being used on a daily basis in the clinic. Among these improvements are increasing the wave motion signal-to-noise ratio, making precise measurements of the vessel geometry with ultrasound, and improving our inversion and classification frameworks. With these improved ADUV methods, we will evaluate how the viscoelastic properties of the carotid artery are associated with the health of the brain as judged using MRI brain morphology data. With the strong collaborative team including expertise in cardiovascular medicine, radiology, ultrasound engineering, waveguide modeling, inverse problems, data reduction and classification, we will bring ADUV closer to widespread translation with the following Specific Aims: Aim 1) Optimize ADUV to enhance motion measurement quality for more accurate and precise mechanical property estimation. Aim 2) Develop advanced mathematical models for estimation of arterial mechanical properties and classification of disease state. Aim 3) Correlate ADUV measurements of carotid artery viscoelasticity with MRI indicators of brain health in patients.

NIH Research Projects · FY 2026 · 2019-01

ABSTRACT The proposed studies focus on the role of BDNF/TrkB signaling in promoting phrenic motor neuron (PhMN) survival and pre- and postsynaptic neuroplasticity to enhance functional recovery after cervical spinal cord injury (cSCI). We will leverage our extensive experience using two well-established models of incomplete cSCI, i.e., C2 hemisection - C2SH and C4 contusion injury - C4CI to explore neuroplasticity at PhMNs. We will also bring years of experience examining diaphragm muscle (DIAm) motor unit physiology, recognizing the importance of PhMN size in the recruitment of DIAm motor units. Stratifying the effects of BDNF/TrkB signaling on pre- and postsynaptic neuroplasticity in PhMNs of varying size is conceptually innovative and provides valuable mechanistic insight. The “Size Principle” is a key concept in neuromotor control physiology, but until now it has been difficult to directly include motor neuron size as a critical variable. We hypothesize that there are size- dependent differences in BDNF/TrkB signaling effects on pre- and postsynaptic neuroplasticity after cSCI. The proposed studies will provide novel information about PhMN neuroplasticity underlying functional recovery of inspiratory and post-inspiratory DIAm activity that will inform development of novel therapeutic approaches to enhance recovery of DIAm function in patients with incomplete cSCI. The proposed studies will utilize a comprehensive array of innovative techniques, many developed in our lab. In all 3 specific aims, we will examine the effects of modulating BDNF/TrkB signaling using a gain/loss of function approach utilizing intrathecal BDNF or TrkB-Fc treatment and a novel TrkBF616A rat with a 1NMPP1 sensitive knock-in allele that rapidly and selectively inhibits TrkB kinase activity. In Aim 1, we will use high resolution confocal imaging to explore the role of BDNF/TrkB signaling on the recovery of Glu and Gly/GABA presynaptic terminals on retrogradely labeled PhMNs of varying size following C2SH. In Aim 2, we will employ a novel RNAscope in situ hybridization technique to simultaneously explore changes in NMDA, Gly and GABAA receptor mRNA expression in PhMNs of varying size. In Aim 3, we will examine the neuroprotective effects (PhMN survival) of BDNF/TrkB signaling following C4CI. In addition, we will examine the effect of BDNF/TrkB signaling on Glu and Gly/GABA synaptic input and NMDA, Gly and GABAA receptor mRNA expression (pre- and postsynaptic neuroplasticity) in surviving PhMNs above (i.e., C3) and below (i.e., C5) the C4CI injury.

NIH Research Projects · FY 2025 · 2018-09

OVERALL – PROJECT SUMMARY This is a renewal of the NCI-supported Mayo Clinic SPORE in Hepatobiliary Cancers (HBC), with a foundation built upon innovative translational science and utilizing state-of-the-art approaches to understand and treat liver cancers; these are the second leading cause of cancer deaths in the country. The breadth of the projects spans hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), and pediatric/young adult fibrolamellar (FLC). Three unique translational projects promise significant steps forward, supported by three well-constructed and responsive cores. Additionally, robust Developmental Research and Career Enhancement Programs continue to identify and support talented HBC-investigators Ongoing support from the Mayo Foundation and Mayo Clinic Comprehensive Cancer Center benefit these components by enabling integrated resources, skilled staff, and leadership guidance to ensure success. The approach remains comprehensive, milestone focused, and patient centered. For example, the completion of former Project 3 has led to a novel first-in- class compound that has advanced to clinical trial. Three projects have developed successfully into innovative renewal pro- jects that utilize novel approaches of immunotherapeutics, computational biology, and chemical genomics. The translational projects in this renewal proposal investigate HBC biology to enhance therapeutic response, building on recent, promising clinical and preclinical advances, summarized below. Diagnostics and drug repurposing for FLC: Project 1 demonstrates 1) differential therapeutic sensitivity of FLC but with 2) variability in patient responsiveness, and now extends into a novel functional approach to precision medicine by 3) defining therapeutics that affect FLC cell viability, while also 4) developing blood- and urine-based biomarkers for tumor burden. Targeting yes- associated protein (YAP), transcriptional enhanced associate domain (TEAD) oncogenic signaling, and therapeutic resistance in CCA: developed from studies defining alternative mechanisms activating this “undruggable” target (YAP) in CCA, Project 2 will 1) leverage a novel inhibitor in preclinical models and 2) test clinical efficacy in a clinical trial. Reversal of the immune suppressive HCC microenvironment through appropriately timed and optimally delivered combination viroimmunotherapies: advancing the use of oncolytic viruses to augment the killing of tumor cells for HCC, new Project 3 now will 1) test the clinical efficacy of a novel virotherapy combined with standard of care immunotherapy, 2) develop new combination viroimmunotherapies with increased potency in pre-clinical Sleeping Beauty models, and 3) develop a novel standard of care, virotherapy, CAR T-cell therapy combination. Collectively, this innovative, interactive, and highly collaborative translational research program is expected to advance prevention, early detection, diagnosis, treatment, and prognosis of patients with cancers of the liver and biliary tree.

NIH Research Projects · FY 2025 · 2018-09

Monoclonal B-cell lymphocytosis (MBL) is one of the most common malignant precursor conditions, affecting 8-10 million adults >40 years of age in the United States. MBL is defined by the presence of a clonal B-cell population in the blood with sub-classification based on the immunophenotype of the cell surface markers and the size of the B-cell clone: low-count MBL (LCMBL) is defined as clonal B-cell count <0.5 x109 cells/L and high-count MBL (HCMBL) as clonal B-cell count between 0.5 and 5x109/L. Of clinical and

NIH Research Projects · FY 2025 · 2018-08

Project Summary Unifying scientific principles in the life sciences continue to be discovered in viral systems. Gene therapy and oncolytic virotherapy depend on viral vectors. Awareness that a deep understanding of fundamental virology is necessary for the development of gene therapy led to the foundation of the Virology and Gene Therapy (VGT) track of Mayo Clinic Graduate School of Biomedical Sciences (MCGSBS) in 2004; since 2018 the NIH supports three of its best pre-doctoral students. Ph.D. training leverages the strength of basic research and the robust translational infrastructure at Mayo Clinic. Training is performed in the laboratories of 22 VGT faculty members. Eight are from the Department of Molecular Medicine, three from Medical Oncology, two each from Infectious Diseases, Hematology, and Biochemistry/Molecular Biology. The others are from five different departments. The faculty is united by leadership in research on viruses, vectors, mechanisms of human disease, cancer treatment, and gene therapy. VGT popularity is based in part on its unique training opportunities in both virology and the translation of viral and gene therapeutics. During the entire time of their thesis the students engage in a full array of programmatic activities including journal clubs, seminar series, an annual retreat and national scientific meetings. Requirements for the VGT track conform to the general requirements of MCGSBS. Continued NIH support of three trainees would allow further development of this successful and innovative program.

NIH Research Projects · FY 2025 · 2018-08

Alcohol-associated liver disease (ALD) is a leading cause of liver-related mortality/morbidity, and there is no FDA-approved therapy for any stage of ALD. Advanced ALD conditions, including severe alcohol-associated hepatitis (sAH) have especially poor outcomes. Indeed, the 90-day mortality for sAH is ~30%. Return to drinking impacts quality of life, morbidity and mortality in these patients. There are limited drug therapies or well-studied behavior therapies in this patient population. An optimal approach would be the integration of AUD and ASLD care givers and therapies, but there are no guidelines for this approach. Our proposed AUD/ALD team approach seeks to overcome the perceived stigma of alcohol misuse which can adversely affect treatment seeking, quality of care and patient outcomes. The AlcHepNet RCT was stopped at the interim analysis because of the unexpected 90% 90-day survival in sAH patients treated with prednisone using the Lille stopping rule. These dramatic results need to be confirmed, and novel therapies such as IL-22 need to be studied in sAH. Acamprosate appears to be the safest FDA-approved therapy for AUD in patients with ALD, but safety and efficacy in severe ALD need to be evaluated. Motivational interviewing/enhancement therapy is well-suited behavioral therapy for patients with ALD. Based on preliminary data and knowledge gaps, our overall hypothesis is that integrated management of ALD and AUD will improve clinical outcomes in patients with sAH and decompensated ALD. We will utilize the following AIMS: Aim 1. Perform a randomized controlled trial of treatment for steroid-eligible patients with severe AH. A SMART trial design will be used to compare daily prednisone for 28 days (with the 7-day Lille score-based stopping rule) vs IL-22 fusion protein (F-652) followed by randomization of each of these groups to receive motivational Interviewing/enhancement therapy combined with acamprosate vs usual care including referral to 12-step programs before discharge from the hospital. The primary endpoint of the trial will be a composite measure of mortality, liver, and alcohol use related outcomes at 6 months. AIM 2. Build a platform for biosamples, data repositories, and patient registries to support site-specific and network-wide ancillary studies. In summary, these proposed studies will leverage the existing resources of the AlcHepNet to evaluate the clinical impact of integrated ALD/AUD treatment in a cohort of patients for whom there are limited treatment options.

NIH Research Projects · FY 2025 · 2018-06

Project Summary Giant Cell Arteritis (GCA) is a granulomatous vasculitis of the aorta and its major branch vessels that causes blindness, stroke and aortic aneurysm and serves as an informative model system of immune-mediated vaso-occlusive disease. Previous work supported by this award has implicated the spontaneous failure of the PD1/PD-L1 immune checkpoint in driving excessive T cell immunity that manifests as autoimmune disease of the three-layered large elastic arteries. Recent work has extended the immune checkpoint deficiencies in GCA patients to the inhibitory CD155/CD96 checkpoint, raising the intriguing possibility that a common abnormality in inhibitory signaling unleashes autoimmunity in blood vessels. We found that macrophages (Mφ) from GCA patients lacked surface expression of the inhibitory checkpoint ligands CD155 and PD-L1, enabling the unopposed expansion of pathogenic CD4+ T cells. Lack of negative signals delivered by CD155low Mφ licensed CD4+CD96+ T cells to become tissue invasive and differentiate into IL-9 producing effector cells. Gain-of function and loss-of-function experiments identified IL9 as a key regulator in vessel wall inflammation, linking the breach of self-tolerance to the CD155- CD96-IL9 pathway. In subcellular mapping studies of GCA Mφ, the CD155 and PD-L1 protein were retained on the membranes of the endoplasmic reticulum (ER) and ER stress induced retention of the ligands, providing important clues towards the underlying molecular abnormalities. These data strongly support a “lost inhibition model” as the core abnormality in GCA. Here, we propose that GCA is a syndrome of immune checkpoint failure, and that vascular inflammation is a result of insufficient containment of antigen-reactive immune responses. Our data assign the primary defect to antigen-presenting cells which retain inhibitory checkpoint ligands in the ER. Unrestrained CD4+ T cells invade the vessel wall and misdifferentiate into vasculitogenic effector cells. To pursue this hypothesis, we will define molecular and functional abnormalities in CD155low PD-L1low Mφ; investigate the impact of ER stress on the Mφ transcriptome and proteome and map the molecular defects causing disruption of CD155 intracellular trafficking (Aim 1). Aim 2 will examine the impact of CD155low PD- L1low Mφ on T cell differentiation and functional commitment. Specifically, we will identify CD4+ T cell populations that escape from containment in the absence of CD155 and PD-L1 signaling, define their phenotypic and functional specification through CITE-Seq and examine their disease relevance in the human artery-NSG model system of GCA. This proposal aims to leverage understanding of inhibitory immune checkpoints to build new paradigms for the diagnosis and therapy of autoimmune vascular inflammation.

NIH Research Projects · FY 2026 · 2018-04

PROJECT SUMMARY/ABSTRACT Cancer is a leading cause of mortality in the U.S. Screening reduces mortality from several of the most common (colorectal, breast, uterine cervix, and lung) cancers but most cancer types, accounting for 70% of cancer deaths, are not screened due to limitations in technology and low positive predictive value, driven by low incidence of each individual cancer type. It has been argued that multi-cancer detection tests might address this critical long-term gap in population health. To avoid false-positive results, commercial multi-cancer test developers train performance on high specificity goals at the penalty of low sensitivity for early-stage cancers, and current tests may more or less accurate depending on the organ/type of cancer. This application proposes to use unique sample archives to address key scientific questions. Specifically, there are relatively limited assessments of 1) how well and at what interval multi-cancer test predict the development of clinical cancer (indolent vs lethal) among asymptomatic individuals (prediagnostic performance study); 2) how to evaluate or validate promising liquid biopsy-based biomarkers in various risk populations; and, 3) how to facilitate the development of high-throughput, sensitive assay methods to validate biomarkers that are useful in early detection of early-stage cancers or their lethal precursors. This application is in direct response to NOSI (NOT-CA-23-004) “Utilization of Cohorts and Prospective Study Designs for Liquid Biopsy Assay Validation for Early Detection of Cancers,” in which NCI has encouraged partnerships between technology developers and population-based cohort/biorepository researchers to facilitate multi-cancer detection test investigations in the appropriate populations, and encouraged applications that investigate the use of existing cohort samples and samples from ongoing prospective collections for analytical and clinical validation of assays for earlier detection of cancer. With our biomarker candidate marker library, extensive sample archive, and unique access to a state-of-the-art assay and analytical platforms, accelerated implementation of multi-cancer detection testing in clinical practice is anticipated by addressing impactful scientific questions beyond the tactical focus of the commercial lens.

NIH Research Projects · FY 2025 · 2017-09

PROJECT SUMMARY / ABSTRACT Mild Cognitive Impairment (MCI) with core clinical features of dementia with Lewy bodies (DLB) is recognized as the prodromal stage of DLB (MCI-LB). Patients with MCI-LB frequently progress to DLB, but a subset may have a range of additional AD pathology. Rapid advances in the development of protein-specific disease- modifying therapies highlight a critical need for biomarkers in MCI-LB, because clinical trials will need to be sufficiently powered to detect changes in disease progression during the prodromal phase, when the disease- modifying therapies would be most effective. During the initial cycle of this project, we determined the cross- sectional and longitudinal imaging biomarkers of DLB with pathologic confirmation. The current cycle of the U01 project is designed to identify cross-sectional and longitudinal multi-modal biomarkers of prodromal DLB in MCI-LB, and prepare for protein-specific disease-modifying clinical trials that will need these biomarkers for selection of participants and to track outcomes in MCI-LB. The rationale for a multi-modal biomarker approach stems from the multi-factorial and co-existing LBD and AD pathology in DLB and similarly in MCI-LB. We will determine the cross-sectional and longitudinal PET, SPECT, MRI, and polysomnogram (PSG) biomarkers of MCI-LB compared to cognitively unimpaired controls. We will also determine whether age, sex as a biological variable, APOE ε4 status, and cerebrovascular disease lesions on MRI modulate these differences. In a pilot analysis, we will compare protein misfolding cyclic amplification (PMCA) and real-time quaking-induced conversion (RT-QuIC) assays for α-synuclein in CSF for differentiating MCI-LB from controls. Finally, we will correlate our findings with pathologic outcomes. Inclusion of MCI-LB patients in the current cycle will be based on the presence of one or more core clinical features of DLB and not on biomarker findings. This will provide the opportunity to validate the use of proposed and novel biomarkers in the diagnosis of MCI-LB and to determine which biomarkers predict progression from MCI-LB to DLB. All samples, clinical, imaging, and autopsy data from MCI-LB cases and controls will be collected and shared according to the Parkinson's Disease Biomarkers Program guidelines.

NIH Research Projects · FY 2025 · 2017-09

The overall aim of this application is to better understand the heterogeneity in glucagon secretion and action that we have observed in nondiabetic subjects. Abnormal glucagon secretion in the post-prandial period is recognized to play a key role in the pathogenesis of type 2 diabetes. While glucagon’s actions on glucose metabolism are reasonably well characterized, there is little understanding as to why individuals differ in their hepatic responses to this hormone. More importantly, it appears that the actions of glucagon to enhance hepatic clearance of amino acids is impaired in people with hepatic steatosis. Although there is some evidence that glucagon stimulates lipolysis and fatty acid oxidation, a review of the literature suggests that these aspects of glucagon’s actions have been ignored. In addition, there is no understanding as to whether the ability to stimulate endogenous glucose production and gluconeogenesis is independent of actions on amino acid and lipid metabolism. In rodents, α-cells mass is, in part, regulated by circulating amino acid concentrations which, in turn stimulate glucagon secretion (increasing hepatic clearance of amino acids). Whether this liver-α-cell axis is extant in humans is uncertain. However, our preliminary data shows that with caloric restriction fasting glucagon decreases in concert with fasting concentrations of several amino acids. Since caloric restriction is known to ameliorate hepatic steatosis and improve insulin action, this provides an opportunity to assess how changes in hepatic fat content alter the response to glucagon – specifically as it applies to carbohydrate, protein, and fat metabolism. As part of our prior work we have developed new methods to quantify glucagon secretion in vivo so that our proposed experiments will also examine how acute changes in circulating amino acid concentrations alter α-cell function. The experiments we propose will provide novel new information about glucagon secretion and action in humans.

NIH Research Projects · FY 2025 · 2017-09

The overall objective of the CCaTS KL2 Institutional Career Development Core is to provide superb training to investigators who can assume leadership roles within multidisciplinary collaborative research teams that conduct outstanding clinical and translational science. The KL2 Program is open to individuals with a doctoral degree in a discipline applicable to clinical and translational research and an existing appointment as Mayo Clinic faculty or under consideration for a Mayo Clinic faculty appointment. After a rigorous selection process, successful applicants and their mentoring team formulate a career development plan based on defined core competencies for clinical and translational science. The plan includes appropriate didactic training; experiential and extramural learning opportunities; and a structured, mentored translational research project. The Specific Aims of this renewal application are to 1) recruit and support Scholars with outstanding potential to lead multidisciplinary, collaborative team science; 2) provide tailored educational experiences based on individual career development needs that include appropriate didactics, experiential activities, and a mentored research experience; and 3) foster a community of Scholars, including partnerships with other career development programs, both within Mayo Clinic and nationally. Key strengths of the KL2 Program include a long history of Program graduates having success as translational scientists, a multidisciplinary pool of faculty mentors with strong extramurally funded research programs and a record of mentoring prior Scholars, a large candidate pool subject to a rigorous selection process, a wide range of curricular options offered without charge, novel strategies to create a positive learning environment for all Scholars, multiple networking and community-building opportunities, options for experiential learning, strong institutional support for the transition to independence after Program completion, and a rigorous evaluation program. Although the KL2 Core has a long history of success, we have identified several opportunities for improvement and innovation, both by crafting new initiatives and by modifying existing program elements as guided by the results of our ongoing rigorous evaluation program. Planned enhancements include new required learning experiences in team science, social media, mentoring (including near-peer cascading mentorship), the hidden curriculum, and developing a positive working environment for staff, and acting as a visiting scholar. Equipping Scholars with skills addressing these key emerging competencies will prepare them for success as CTS investigators.

NIH Research Projects · FY 2025 · 2017-09

Mayo Clinic is one of the largest not‐for‐profit, academic health systems, top-ranked for quality more often than any other health care organization. It has integrated operations in 5 U.S. states, and more than 1 million people came to Mayo Clinic for care last year. Clinical and translational science (CTS) is a fundamental and highly valued element of Mayo Clinic; indeed, all research at Mayo Clinic is directed towards translation of scientific knowledge to improve patient care, with almost 60% of our NIH funding base classified as clinical research or trials. In recognition of the importance of continued advances in CTS to the Mayo Clinic mission, our institutional leadership has entrusted the Mayo Clinic Center for Clinical and Translational Sciences (CCaTS) to be the engine of translational innovation and the institutional advocate for CTS and translational research. CCaTS has served as a CTS innovation incubator for numerous efforts that were created with CCaTS funding and are now supported by the institution. The overall vision of CCaTS is to enable high-quality, team-based multidisciplinary research that accelerates clinical trial innovation, facilitates digital health transformation, and partners with our stakeholders and communities to improve patient care and health for all people. Our team-based culture has been described as one of “boundarylessness,” wherein organizational barriers are removed to enable talent, innovation, and knowledge to converge where needed. In this context and that of our longstanding commitment to patient-focused research, we are uniquely positioned to accomplish the following Specific Aims. In Aim 1, we will simplify and accelerate the work of translation to improve health for all by advancing clinical trial innovations and digital health transformations, streamlining methods and processes, and developing novel informatics solutions that increase efficiency and drive implementation of discoveries that improve health and promote health for all. In Aim 2, we will enhance our education programs through the expanded reach of competency-based, learner-focused solutions, training a multidisciplinary CTS workforce to be prepared to address the urgent health care needs of all communities in a rapidly changing environment. In Aim 3, we will engage local community members and patients to be active partners in translational teams, expanding research capabilities of communities, including rural populations. Our goal is to improve health by helping communities realize the benefits of CTS. In Aim 4, we will expand national and regional partnerships and strengthen collaborative CTS networks in all aspects of CTS and education, focusing on sharing innovative approaches, with the goal of improving human health and advancing health for all. In summary, sustained investment in CCaTS will enable us to continue to meet ongoing and emergent challenges in health care.

NIH Research Projects · FY 2025 · 2017-09

The long-term objective of the TL1 Program within Mayo Clinic CCaTS is to train tomorrow’s workforce of team-based, translational biomedical researchers at predoctoral levels using the R4 approach to learning (the Right content for the Right learner at the Right time using the Right educational modality). This will create a new generation of researchers who will lead multidisciplinary teams across the translational spectrum to improve health for all communities. The TL1 Program has 3 Specific Aims: 1) Transform the preparation of trainees for success in the workforce of the future, including uncovering the hidden curriculum for research and further developing our supportive scholar community in partnership with the KL2 Program. 2) Expand and integrate training opportunities in translational science, including foci in patient and community engagement and data immersion to promote health for all people, using novel approaches including rotations in community engagement and data immersion; new curricula in artificial intelligence, bioinformatics, and clinical trials; and newly required curricula. 3) Launch trainees toward a successful translational science career of their choice by providing opportunities to learn about a variety of career opportunities and to develop a network that can provide immersive experiential learning with shadowing and externships within community-engaged research, industry, regulatory agencies, start-ups, and organizations that succeed through teamwork. We will rigorously evaluate outcomes and disseminate successful models, so that these novel programs can be continuously improved and the CTSA Consortium and others can benefit from these experiences. Although our overall predoctoral program includes several degree and pathway programs, this application focuses on the PhD Program in Clinical and Translational Science, an innovative PhD track developed de novo to train leaders of translational research teams within an extensive and successful framework. We will build upon our considerable experience, retaining those elements of proven benefit and introducing new elements. Enhancements to the Program include expanded training opportunities; expanded opportunities for experiential learning on the Mayo Clinic campus and in partner institutions and novel extramural environments; enhanced ability to tailor the didactic curriculum to individual needs; and leveraging institutional and programmatic strengths to help individual trainees develop a career trajectory in translational science. We will increase our established collaboration with partner CTSA institutions at the University of Minnesota and in the Upper Midwest Consortium and further develop rigorous evaluation systems to track individual and Program outcomes using innovative and comprehensive metrics. We will disseminate successful practices through CTSA networks and national leadership.