Mayo Clinic Rochester

NIH Research Projects · FY 2025 · 1997-04

Mayo Clinic Comprehensive Cancer Center (MCCCC) is the only National Cancer Institute (NCI) Designated Comprehensive Cancer Center in the United States with three NCI Comprehensive Cancer Center sites, operating within the Mayo Clinic campuses in Rochester, MN; Jacksonville, FL; and Phoenix/Scottsdale, AZ. Our goals are to: provide exceptional, unparalleled cancer diagnosis, prevention, and treatment to patients within our regional catchment areas and from across the nation; conduct innovative transdisciplinary research to discover more effective means to prevent, treat, and cure cancer in its earliest and advanced stages; share our data, platforms, and knowledge to drive research and transform cancer care and clinical trials; engage patients and communities to assure optimal cancer outcomes for all; and educate, train, and mentor the cancer workforce of the future. Over the last four years, MCCCC underwent a full transformation with a new Executive Director, Senior Leadership Team, and Research Program and Disease Group leaders. Community Outreach & Engagement and Cancer Research Training & Education were rebuilt with new leaders and impactful programs. Membership was enhanced with 363 Full Members (46% new; 116 newly recruited) and >200 Associate and Trainee Members. Building upon innovative institutional strengths and scientific opportunities, the Center’s Research Programs were reorganized into six scientific discipline, platform-based programs: Cancer Prevention, Control & Survivorship; Risk Assessment, Early Detection & Interception; Cancer Genomics, Signaling & Metastasis; Cancer Immunology & Immunotherapeutics; Novel Therapeutics & Therapeutic Modalities; and Advanced Clinical Trials & Translational Sciences. As a result, in this 5-year period, MCCCC achieved the highest performance metrics in its 50-year history. Research funding increased 30% to $150M in annual direct costs, peer-reviewed cancer funding 26% to $74.2M, and NCI funding 8% to $46M, with 5 NCI SPOREs and 83 multi-investigator, programmatic grants. Compared to the prior 5-years, publications increased 72% (7,997; 28% high impact). Interventional clinical trial accrual increased 24-fold (191,761) and interventional treatment trial accrual increased 34% (8,520); 38% of patients accrued to therapeutic trials were from rural regions of the U.S. while 11% were racial/ethnic minorities. MCCCC led or participated significantly in 164 practice-changing clinical trials, leading to 50 new cancer drug approvals. Guided by the MCCCC 2030 Strategic Plan, we will drive and deepen innovative discovery science; detect and intercept cancer in its earliest stages; discover novel therapeutics and therapeutic modalities; transform cancer research, clinical practice, and community health with data science and artificial intelligence; and transform and decentralize cancer care delivery and clinical trials beyond our walls to home and community settings. We will share our platforms, knowledge, and expertise to assure that cancer care is accessible to all - at any place and any time - transcending geographic and physical barriers to meet patient and community needs.

NIH Research Projects · FY 2025 · 1996-05

ABSTRACT Premature birth necessitates interventions such as supplemental O2 (hyperoxia; typically <60% O2) with/without respiratory support primarily using non-invasive nasal CPAP. Studies from the previous cycle of this longstanding R01 have shown neonatal O2 is associated with development of airway hyperreactivity (AHR) and remodeling (cell proliferation, fibrosis): effects that contribute to a wheezing phenotype and predispose to asthma. While CPAP is initially beneficial, long-term effects on highly compliant bronchial airways are less known. We previously found static stretch of CPAP induces sustained AHR and airway thickening even after CPAP is stopped and involves airway smooth muscle (ASM). What we do not fully understand are upstream mechanosensitive transducers of stretch, and downstream pathways by which O2 and stretch interact to produce these effects, Based on preliminary data, we hypothesize that mechanosensitive Piezo (PZ) channels in developing ASM contribute to CPAP-induced AHR and remodeling. There are currently limited data on PZ channels in lung (which does express them) and none in airways. Preliminary data show PZ1 and PZ2 are expressed in human fetal ASM (fASM) and in neonatal mouse, and that PZs are functional in enhancing Ca2+ responses, proliferation and ECM formation. 50% O2 and stretch each increase fASM PZ: effects also noted in newborn mice where 7 days CPAP results in sustained AHR and remodeling at 3 wks, and inhibition of PZ blunts CPAP effects. Downstream of PZ, we find that canonical Wnt/β-catenin signaling is important, and can be increased by stretch/CPAP. Our overall hypothesis/model is that in developing airways, ASM PZ channels and downstream Wnt/β-catenin pathways are linked in the context of O2 and/or stretch effects, leading to AHR and remodeling. Our 3 Specific Aims to explore our model are: Aim 1: Determine the role of PZ channels in O2- and stretch-induced responses of human fASM; Aim 2: Determine mechanisms that mediate PZ effects in O2 and stretch-induced human fASM responses; Aim 3: In a neonatal mouse model of O2 and CPAP, determine role of PZ in AHR and remodeling. In Aims 1 and 2, 18-22 wk human fASM cells are exposed to normoxia vs. moderate hyperoxia with/without static stretch on a background of cyclic strain, mimicking clinical application of O2 +/- CPAP in spontaneously breathing premies. In Aim 1, complementary imaging and biochemical techniques are used with PZ modulators to assess roles of PZ in fASM [Ca2+]i (imaging), contractility (traction force microscopy), proliferation and fibrosis. In Aim 2, complementary biochemical and molecular tools are used to examine mechanisms that are involved in PZ effects on remodeling in particular with a focus on Wnt/β-catenin. In vitro results are integrated in Aim 3 using clinically- relevant neonatal mouse models of moderate hyperoxia (50% O2) with/without intermittent CPAP applied for the first 1 wk followed by 2 wks recovery in WT and inducible smooth muscle PZ1 KO (sm-PZ1 KO) mice. Effects of inhibiting PZ1 vs. PZ2 are tested towards establishing clinical significance of targeting these novel pathways to alleviate adverse long-term effects of hyperoxia and CPAP.

NIH Research Projects · FY 2026 · 1993-07

ABSTRACT: Pneumocystis jirovecii pneumonia (PJP) remains a significant cause of morbidity and mortality in AIDS1. During AIDS and other immunosuppressive states, the absence of CD4 lymphocytic immunity results in serious PJP 2,3. In addition to CD4 cells, organism clearance requires a balanced macrophage response since excessive inflammation promotes lung injury and respiratory failure4. We have shown that polarization of AMs toward M1 versus M2 type phenotype, leads to detrimental lung inflammation during Pneumocystis pneumonia5. Corticosteroids given in addition to antibiotics significantly improves outcome during PJP 6. However, concerns exist that corticosteroids further suppress immunity and increase co-infections 7,8. New strategies to promote killing and clearance of Pneumocystis while balancing lung inflammation are required for patients with PJP, particularly for those who are refractory to antibiotic therapy alone. Our prior studies have shown that host innate immunity to Pneumocystis is mediated by C-Type Lectin Receptors (CLRs) on macrophages and involves downstream CARD9 activation 9. We have further shown that the CARD9 can be targeted by a novel specific small molecule inhibitor (BRD5529) that significantly reduces inflammatory signaling in macrophages stimulated with Pneumocystis 10. CARD9 serves as the central intracellular molecule through which Dectin-1, Dectin-2, Mincle, and other CLRs signal 11. Dectin-1 CLR is activated through its own intracytoplasmic ITAM domain12, while other innate CLRs (e.g. Dectin-2 and Mincle) require interactions with a common Fc-gamma receptor (FcγR) accessory chain to mediate responses to Pneumocystis 13,14. Strikingly, we observed that mice double deficient in both Dectin-1 and Fcer1g (which lack the FcγR gamma chain) demonstrated markedly reduced organism clearance compared to Card9-/- infected animals. These mice also possess deficiencies in immunoglobulin (Ig) Fc receptors directly mediating antibody uptake responses, further implicating altered humoral responses in Pneumocystis opsonization and killing. Thus, we hypothesize that innate immune responses through the CLR-CARD9 axis, humoral activity, and macrophage polarization act together to mediate effective responses resulting in optimal organism uptake, killing and generation of host inflammatory responses. This hypothesis will be addressed through three independent but interrelated Aims. In Aim #1. We will determine the relative roles of CLRs, CARD9, and FcRγ- mediated mechanisms in Pneumocystis organism clearance and inflammatory responses in vitro. We will study alveolar macrophages (AMs) and bone marrow-derived myeloid cells from wild-type, CARD9, and Dectin-1/FcRγ deficient animals. In addition, we will also now include mice deficient in all activating (FcγRI, FcγRIII, and FcγRIV, termed FcγRI/ FcγRIII/FcγRIV-/- mice) Fc receptors but retaining the functioning FcRγ chain signal transduction subunit. We will further study uptake and killing of Pneumocystis and subsequent cytokine release after organism challenge with and without PCP convalescent serum. Additionally, we will study polarization kinetics of AMs toward M1 or M2 type phenotypes after stimulation with Pneumocystis. Under Aim #2, we will determine the relative roles of CLRs, CARD9 and antibody-mediated mechanisms in Pneumocystis clearance and inflammation in mouse models of PCP. Studies will be performed in wild-type, CARD9, Dectin-1/FcRγ, and FcγRI/FcγRIII/FcγRIV-deficient mice. We will evaluate Pneumocystis clearance and inflammatory responses in both immune competent and CD4-depleted immunocompromised mice with PCP. Strikingly, our preliminary studies show that while CD4-depleted Clec7a-/- Fcer1g-/- (Dectin-1/FcRγ deficient) mice show significantly greater organism burdens compared to Card9-/- animals, and both deficient mouse lines showed dramatic decreases in proinflammatory cytokines compared to wild-types, but similar to one another. Accordingly, we will examine the kinetics of CARD9 driven innate immunity and the additional role of antibody-mediated responses during PCP in both CD4-depleted and immunocompetent mice. Finally, in Aim 3, we will exploit the differences in the CLR innate and antibody-mediated response pathways to test novel therapeutic strategies for adjuvant treatment of refractory PCP. While current anti-PJP strategies are usually beneficial, patients with severe refractory PCP (~30% cases) still experience high mortality (80%)15,16. We will employ combinations of adjuvant antibody interventions to promote Pneumocystis clearance, along with CARD9 inhibition strategies to blunt excessive inflammation during infection. These strategies will be investigated in CD4-depleted mice, which mimic the immune deficiencies present during AIDS. Better understanding of these responses and the ability to target them alone or in combination will be used to test novel adjuvant treatment strategies in mouse models of severe PCP.

NIH Research Projects · FY 2026 · 1993-06

PROJECT SUMMARY / ABSTRACT In 2010 we proposed, and in 2013 revised, a hypothetical model of the temporal evolution of biomarkers and clinical symptoms for individuals in the Alzheimer’s disease (AD) pathway. The biomarker model is based on a hypothesized cause and effect sequence which can be summarized as: amyloidosis (A), promotes tauopathy (T), which promotes neurodegeneration (N), which is the proximate cause of clinical symptoms (C). For simplicity, we use this ATNC notation: A T  N  C. The current cycle of AG011378 was designed to test aspects of this model that were testable using imaging; however, a major missing element when the current cycle AG011378 began in 2013 was a method to measure fibrillar tau deposits with imaging. Tau PET has recently become available and, consequently for the first time, imaging biomarkers exist to ascertain three of the most important pathologic features of AD: amyloid, tau and neurodegeneration. An important insight gained from the current cycle of AG011378 was that modeling AD biomarkers on the assumption that AD is the only pathological process present in the general aging population is conceptually flawed. We argue that biomarker modeling within the general aging population should accommodate at least three broad groups based on currently available biomarkers: (1) individuals with no biomarker abnormalities whose future biomarker profiles are unknown; (2) individuals along the Alzheimer’s continuum; and (3) a heterogeneous group with primarily suspected non-AD pathologies (SNAP). Our aims in this renewal are based on modeling longitudinal amyloid PET (A), tau PET (T), and MRI (N) biomarkers. The overarching goals of the renewal are to empirically evaluate our hypothetical model of AD biomarkers and to create complementary imaging biomarker models for individuals who are not in the Alzheimer’s continuum. Our specific aims are: Aim 1. To model the sequence of biomarker and clinical transitions over time across multiple pathways. Aim 1 employs hidden Markov models. 1a) To model the sequence of biomarker and clinical transitions in the Alzheimer’s continuum, 1b) To model the sequence of biomarker and clinical transitions in SNAP pathways. Aim 2. To model continuous biomarker and clinical trajectories over time across multiple pathways. Aim 2 analyses employ non-linear latent class mixed models. 2a) To model biomarker and clinical trajectories in the Alzheimer’s continuum, 2b) To model biomarker and clinical trajectories in SNAP pathways. Aim 3. To formulate mechanistic inferences about biomarker and clinical changes over time across multiple pathways. 3a) inferences in the Alzheimer’s continuum, 3b) inferences in SNAP pathways. Aim 4: To establish temporal ordering of topographic spread of A, T, and N within each modality, across imaging modalities, and establish how these temporal orderings relate to cognitive impairment within (4a) the Alzheimer’s continuum and (4b) the SNAP pathways. Aim 4 uses a conditional probability approach.

NIH Research Projects · FY 2026 · 1992-09

Project Summary/Abstract Our goal is to understand the why obesity, and specifically upper body/visceral obesity (UBO), causes insulin resistance, Type 2 Diabetes and the other health problems. We study what regulates the storage of fat in adipose tissue and release of free fatty acids (FFA) from adipose tissue (lipolysis) in humans. For this application we propose to complete five Specific Aims. We will determine whether, in response to an energy deficit intervention that results in an 8 kg loss of body fat in adults with Class I obesity: 1) preferential upper body/visceral fat loss will be associated with greater improvements in metabolic health; 2); basal/meal suppressed lipolysis in UBSQ and LBSQ adipose tissue under baseline and/or active weight-loss conditions is related to preferential loss of fat from those depots; 3) meal fat storage in UBSQ and LBSQ adipose tissue under baseline and/or active weight-loss conditions is related to preferential loss of fat from those depots; 4) the functional (enzyme) and gene regulation responses in UBSQ and LBSQ adipose tissue predicts changes in fat storage/release; 5) the depot-specific fat loss will be similar in pre- and postmenopausal women. These studies will offer insights as to whether inter-individual differences in adipose tissue lipolysis or meal fatty acid storage in adipose tissue are responsible for differential fat loss from lower body and upper body fat. The responses of different adipose tissue depots to weight loss interventions will provide mechanistic information as part of our goals of identifying obesity phenotypes that can inform future therapeutic strategies to maximize the health benefits of weight loss.

NIH Research Projects · FY 2025 · 1988-08

Project Summary/Abstract Our goal is to understand the mechanisms by which obesity, and specifically upper body/visceral obesity (UBO), causes insulin resistance, Type 2 Diabetes and the other health problems. We study what regulates the release of free fatty acids (FFA) from adipose tissue (lipolysis) in humans. For this application we propose to complete the following Specific Aims: 1. We will determine whether impaired insulin-induced suppression of regional lipolysis (measured by IC50) in UBO compared with insulin-sensitive control groups is related to differences in adipocyte lipolysis protein responses. 2. We will determine whether the suppression of regional lipolysis induced by niacin, acting independently of the insulin signaling pathway, is impaired in UBO compared with insulin-sensitive control groups and, if so, if this is related to local differences in adipocyte lipolysis-regulating proteins. 3. We will determine whether stimulated adipose tissue lipolysis resulting from the combination of somatostatin infusion (to suppress insulin secretion) and intravenous epinephrine, is impaired in UBO compared with insulin-sensitive control groups and, if so, if this is related to regional differences in lipolysis and adipocyte lipolysis-regulating proteins. 4. We will determine whether the regional release of FFA relative to glycerol as a measure of intracellular reesterification accounts for the differences in systemic FFA delivery between UBO and non-UBO adults. Combined, we believe these studies will offer insights as to whether adipose tissue lipolysis is abnormal in UBO specifically in response to insulin, or if there are more fundamental issue with metabolic flexibility that relate to adipocyte size. By understanding what is different in the process of lipolysis in UBO we hope to provide guidance as to what therapeutic strategies might be employed to treat adipose dysfunction.

NIH Research Projects · FY 2025 · 1979-07

Project Abstract In 1988 the Mayo Clinic training programs in Endocrinology (DK07147 funded in 1968) and Diabetes and Metabolism (DK07352 funded in 1979) were merged to create this Training Program in Diabetes and Metabolism (DK07352). This program supports postdoctoral research training in Endocrinology, Diabetes and Metabolism for individuals with MD, MD,Phd, or PhD degrees. Our goal is to prepare trainees for academic careers with the ability to conduct research as independent investigators. The Program supports up to three years of laboratory research training. The faculty consist of 20 investigators funded with NIH R01 grants and/or other funds, 4 of whom are junior faculty members in the process of developing independent programs and mentoring skills. We work with adjunct faculty in both basic science and clinical departments. The Program is provides trainees with: (i) intense, in-depth education regarding all components of the scientific method, (ii) a specific project to gain a focused approach to scientific investigation, (iii) experience with state-of-the-art analytical tools and methodologies, (iv) grant writing abilities, and (v) the skills needed to become independent biomedical research scientists. We provide access to formal didactic course work (including classes on grant writing and participation in mock study sections), the opportunity to attend intra- and extra-mural seminars, conferences and scientific presentations related to their area of study. These opportunities are in the context of a focused research experience in the laboratories of established investigators. The Program is administered by the Steering Committee and chaired by the Program Director, with advice from an External Advisory Committee. The Steering Committee is responsible for interviewing and selecting trainees, as well as assuring they have an appropriate laboratory assignment and didactic curricula. They review the trainees' initial project, and assist with the annual review of the trainees' progress. We are committed to maintaining a focused approach to well-defined training goals for each laboratory-based trainee with sufficient dedicated research time to assure an optimal educational experience. Our full facutly are very successful in obtaining extramural funding as we would expect of independent investigators that serve as primary faculty. We believe our training record is exceptional and that it has been enhanced by our enthusiastic and knowledgeable junior training faculty. We can also point to support from adjunct faculty whose primary areas of basic science and/or clinical investigation are intimately tied to those of metabolism, diabetes and endocrinology. The breadth of the faculty's research programs is notable; ranging from molecular endocrinology to clinical research. Because our program continues to be highly sought after, because of the success of our trainees, and because the large amount of research funds awarded to our highly qualified faculty, we propose to continue our program at the current level of 6 fellowship slots.

NIH Research Projects · FY 2026 · 1979-01

In this renewal application of an established (47 years), successful multidisciplinary training program in Digestive Diseases, we will continue to train qualified postdoctoral individuals (M.D., and/or Ph.D.) for academic careers in digestive diseases. Our interdisciplinary, full time faculty of 40 scientists supports two tracks for potential trainees: i) basic/disease-oriented research; and ii) patient-oriented research. The basic/disease-oriented track remains one of long-standing excellence with training opportunities in mucosal immunology, cell biology, enteric neurosciences, liver pathobiology, and new opportunities organized around regenerative medicine/stem cells, transcription/epigenetics, microbiome and artificial intelligence and informatics. Training in this track is strongly supported through interactions with the NIH funded Mayo Comprehensive Cancer Center, Basic Science Departments at Mayo Clinic, and the NIH P30 Digestive Disease Center grant. The patient-oriented track, which is educationally buttressed through the Mayo Clinic Center for Clinical and Translational Science (CCaTS), maintains training opportunities in biomedical ethics, clinical innovation and entrepreneurship, clinical trials, individualized medicine, and quantitative research methods. Additional concentrations in artificial intelligence, geroscience, health disparities and community engagement and health policy are forthcoming, as new areas of institutional focus. We continue to request support for 5 postdoctoral trainees/year that are selected through objective and consensus-driven mechanisms from a talented annual pool of approximately 100 M.D., PhD, or M.D./PhD candidates derived from a variety of clinical and basic disciplines. The overall success of the program continues to be outstanding with 88% of trainees from the most recently completed 10-year cohort (n=26) entering into a research intensive/related positions and a funding portfolio from this cohort that includes 15 new federal grants (8 K series, 2 R series, 5 P30 pilots). Our trainees are representative of the communities and populations served by the institution which has a broad national reach. Institutional support also continues to be strong and well documented. Thus, this highly established training program remains creative, innovative, and dynamic, thereby continuing to be highly successful in achieving its goal of training individuals for academic careers in gastroenterology and hepatology.

NIH Research Projects · FY 2025 · 1975-07

The mission of the “Cardiovasology” Training Program at Mayo Clinic is to address national needs in developing and sustaining the next generation workforce in cardiovascular science and medicine, and from whom new leaders in this multidisciplinary field will emerge. The renewal, for years 46 to 50, builds on a legacy of excellence with demonstrated track-records in scientific proficiency and productivity, extramural support and academic placement, contributing to the nation’s best practices for the betterment of health. Drawing from the highest educational standards and cutting-edge technological platforms, “Cardiovasology” is customized to match the background and career path of each trainee providing opportunities to widen interests and expand capabilities in pursuit of evolving scientific advances. Heart failure is the central theme, informed by morbidity and mortality trends. The interactive faculty of 31 funded subject matter experts from 9 departments, with robust mentoring records, enables team-science training across basic, translational, clinical and population science tracks. Spanning tracks, curricula are practical, relevant and timely, and focus on application of research methods to address patient needs optimizing the trainee's ability to challenge, refine or create paradigms. Newly established local/regional/national transdisciplinary synergies expedite high-throughput discovery and data mining, disease model interrogation, clinical trial execution, and outcomes research. Program strength rests in leveraging Mayo Clinic investments in state-of-the-art infrastructures and institutional priorities in individualized medicine, regenerative medicine, and science of health care delivery, expanding the means for novel diagnostics, prognostics and therapeutics. Content in disruptive innovation and deep learning (including artificial intelligence, augmented reality, advanced biotherapies), and prominence in product development, regulatory science, and bio-business, further equip trainees with the readiness to apply new know-how to combat heart failure burden and actuate the NHLBI Strategic Plan. The renewal capitalizes on degree-granting programs, and attracts highly competitive MD, MD/PhD, and PhD candidates from across the nation. A history of strong recruitment and retention, supplemented with a fellow-to-faculty career development program, has fostered the stepwise launch of competitive independent careers. Accordingly, “Cardiovasology” requests the continuous support for six postdoctoral trainees. Committed to attracting the highest quality candidates, this program will provide trainees with essential skillsets and new competencies, the Program actively builds the workforce of the future supplying the pipeline to meet a 2030 trajectory. The renewal underscores the creative, innovative and dynamic vision of the “Cardiovasology” Training Program empowering the emerging academic cadre to lead the way in turning science into cardiovascular health.