Mayo Clinic

PRECISION MEDICINE INITIATIVE COHORT PROGRAM BIOBANK

MAYO COMPREHENSIVE CANCER CENTER GRANT

STATISTICS AND DATA CENTER FOR THE ALLIANCE FOR CLINICAL TRIALS IN ONCOLOGY

ARTFL LEFFTDS LONGITUDINAL FRONTOTEMPORAL LOBAR DEGENERATION (ALLFTD)

MAYO CLINIC CENTER FOR CLINICAL AND TRANSLATIONAL SCIENCE (CCATS)

CREST-2 CLINICAL COORDINATING CENTER

MAYO CLINIC CENTER FOR CLINICAL AND TRANSLATIONAL RESEARCH

MAYO CLINIC CENTER FOR CLINICAL AND TRANSLATIONAL SCIENCE (CCATS)

MAYO CLINIC BREAST CANCER SPORE

NORTH CENTRAL CANCER TREATMENT GROUP

ALZHEIMER DISEASE PATIENT REGISTRY

BIOLOGY AND PATHOBIOLOGY OF APOE IN AGING AND ALZHEIMER'S DISEASE - PROJECT SUMMARY (APOE U19: OVERALL) THE OVERARCHING GOAL OF THIS U19 PROJECT IS TO COMPREHENSIVELY UNDERSTAND THE BIOLOGY AND PATHOBIOLOGY OF APOLIPOPROTEIN E (APOE) IN AGING AND ALZHEIMER’S DISEASE (AD) TO INFORM THERAPEUTIC STRATEGIES. THE E4 ALLELE OF THE APOE GENE (APOE4) IS THE STRONGEST GENETIC RISK FACTOR FOR AD IMPACTING 50-70% OF ALL AD PATIENTS, WHILE THE E2 ALLELE IS PROTECTIVE COMPARED TO THE COMMON E3 ALLELE. APOE4 IS ALSO A STRONG RISK FACTOR FOR AGE-RELATED COGNITIVE DECLINE AND VASCULAR COGNITIVE IMPAIRMENT. TO INTEGRATE EXISTING KNOWLEDGE AND ADDRESS CRITICAL GAPS, WE PROPOSE A UNIFIED APOE CASCADE HYPOTHESIS THAT THE STRUCTURAL DIFFERENCES AND RELATED BIOCHEMICAL PROPERTIES AMONG THE THREE APOE ISOFORMS INITIATE THEIR DIFFERENTIAL EFFECTS ON A CASCADE OF EVENTS AT THE CELLULAR AND SYSTEMS LEVELS ULTIMATELY IMPACTING AGING-RELATED PATHOGENIC CONDITIONS INCLUDING AD. TOWARDS THIS, WE HAVE ASSEMBLED A MULTI-DISCIPLINARY TEAM TO SYNERGIZE EXPERTISE AND RESOURCES ACROSS MULTIPLE INSTITUTIONS. BY INTEGRATING FIVE INTERACTIVE PROJECTS AND SEVEN ROBUST CORES, WE WILL CREATE A NEXUS FOR APOE-RELATED AGING RESEARCH, SHARING THE KNOWLEDGE, EXPERTISE AND RESOURCES WITH THE BROADER SCIENTIFIC COMMUNITY. PROJECT 1 WILL WORK CLOSELY WITH CORE B TO ADDRESS THE STRUCTURAL AND BIOCHEMICAL PROPERTIES OF THE THREE APOE ISOFORMS TO GENERATE INSIGHTS FOR FUNCTIONAL OUTCOMES. PROJECTS 2, 3 AND 4 WILL INTERACTIVELY STUDY HOW APOE ISOFORMS EXPRESSED IN ASTROCYTES, MICROGLIA, OR VASCULAR MURAL CELLS IMPACT LIPID METABOLISM, GLIAL AND VASCULAR FUNCTIONS, AD-RELATED PATHOLOGIES, AND CELLULAR AND MOLECULAR PATHWAYS USING CONDITIONAL MOUSE MODELS AND SYSTEMS- BASED APPROACHES. THESE STUDIES WILL GENERATE CELL TYPE-SPECIFIC APOE/LIPOPROTEIN PARTICLES THAT WILL BE COLLECTED THROUGH IN VIVO MICRODIALYSIS FOR STRUCTURAL AND BIOCHEMICAL STUDIES. PROJECT 5 WILL CARRY OUT GENOMIC AND GENETIC ANALYSES TO IDENTIFY MODIFIERS OF APOE-RELATED AGE AT ONSET OF AD. STUDIES IN PROJECTS 2-5 WILL BE INTERACTIVELY SUPPLEMENTED BY NEUROPATHOLOGICAL STUDIES USING POSTMORTEM BRAINS FROM HEALTHY AGING STUDIES OR WITH AD PATHOLOGIES (CORE C), BIOMARKER STUDIES USING BOTH HUMAN AND MOUSE BIOSPECIMENS (CORE D), AND FUNCTIONAL STUDIES USING HUMAN IPSC-DERIVED CELLULAR AND ORGANOID MODELS (CORE E). THIS U19 PROPOSAL IS SUPPORTED BY A COMPREHENSIVE MULTI-OMICS CORE (CORE F) FOR CENTRALIZED PROTEOMICS, LIPIDOMICS, AND METABOLOMICS STUDIES ON VARIOUS ANIMAL AND IPSC MODELS, AS WELL AS HUMAN POSTMORTEM BRAINS AND FLUID BIOSPECIMENS. THE BIOINFORMATICS, BIOSTATISTICS, AND DATA MANAGEMENT CORE (CORE G) WILL PROVIDE CRITICAL SUPPORTS FOR ANALYZING LARGE DATASETS INCLUDING THOSE FROM SINGLE-CELL RNA-SEQ AND BIOSTATISTICS SUPPORTS TO ENSURE SCIENTIFIC RIGOR. CORE G WILL ALSO WORK CLOSELY WITH THE ADMINISTRATIVE CORE (CORE A) TO MAINTAIN AN APOE WEB PORTAL DESIGNATED AS EPAAD WHERE KNOWLEDGE, RESOURCES, AND DATA WILL BE SHARED WITH THE SCIENTIFIC COMMUNITY. CORE A WILL ALSO ORGANIZE ANNUAL APOE SYMPOSIUM TO PROMOTE COLLABORATION AND ENGAGE THE APOE COMMUNITY. AS SUCH, THIS U19 WILL DRIVE A TEAM-BASED EFFORT TO GENERATE ESSENTIAL KNOWLEDGE TO GUIDE DISEASE- MODIFYING THERAPIES FOR AD AND OTHER AGING-RELATED CONDITIONS.

MAYO CLINIC SPORE IN OVARIAN CANCER

CENTRALLY-LINKED LONGITUDINAL PERIPHERAL BIOMARKERS OF AD IN MULTI-ETHNIC POPULATIONS - SUMMARY ABSTRACT (30 LINES): EXISTING CEREBROSPINAL FLUID (CSF) AND NEUROIMAGING MEASURES OF AMYLOID SS, TAU AND NEURODEGENERATION (A,T,N) SERVE AS USEFUL DIAGNOSTIC BIOMARKERS FOR ALZHEIMER’S DISEASE (AD), HOWEVER THERE REMAINS AN URGENT, UNMET NEED FOR BLOOD BASED BIOMARKERS IN AD. FIRST, MULTI-OMIC STUDIES DISCOVERED MANY PERTURBED BIOLOGICAL PATHWAYS IN AD, HOWEVER, SYSTEMATIC STUDIES FOR BIOMARKERS THAT CAPTURE THESE DIVERSE BIOLOGICAL FACETS OF AD ARE LIMITED. SECOND, AD IS A HETEROGENEOUS DISORDER BUT BIOMARKERS THAT CAN DISTINGUISH THE BIOLOGICAL SUBTYPES OF AD ARE LACKING. THIRD, CORE AD NEUROPATHOLOGY OFTEN CO-EXISTS WITH OTHER NEUROPATHOLOGIES SUCH AS VASCULAR DISEASE (V). THESE CO-MORBIDITIES AND CO-PATHOLOGIES NEED TO BE CONSIDERED IN BIOMARKER DISCOVERY. FOURTH, EXISTING BIOMARKER STUDIES ARE HEAVILY FOCUSED ON NON-HISPANIC WHITES (NHW). SIMILAR STUDIES IN UNDERREPRESENTED POPULATIONS (URP) ARE NEEDED. THIS U19, BRINGING TOGETHER >40 EXPERTS ACROSS 13 INSTITUTIONS, AIMS TO BRIDGE THESE KNOWLEDGE GAPS FOR DISCOVERY AND VALIDATION OF CENTRALLY-LINKED LONGITUDINAL PERIPHERAL BIOMARKERS OF AD (CLEAR-AD) IN MULTI-ETHNIC POPULATIONS. CLEAR-AD U19 IS BASED ON THE PREMISE THAT AD IS A COMPLEX DISORDER IN WHICH MANY BIOLOGICAL PATHWAYS ARE DISRUPTED DUE TO MULTI-OMIC PERTURBATIONS, WHICH CAN BE DETECTED IN BRAIN AND REFLECTED IN BLOOD, I.E. CENTRALLY-LINKED PERIPHERAL MOLECULAR SIGNATURES (CLPMS). THE SPECIFIC AIMS OF CLEAR-AD U19 ARE: 1) TO DISCOVER CLPMS OF THE COMPLEX AND HETEROGENEOUS AD PATHOPHYSIOLOGY AND ITS CO-PATHOLOGIES. 2) TO IDENTIFY LONGITUDINAL CLPMS THAT DETECT AND PREDICT DYNAMIC NEUROIMAGING, FLUID BIOMARKER, AND CLINICAL CHANGES ACROSS AD SPECTRUM. 3) TO CHARACTERIZE DIFFERENCES AND SIMILARITIES IN CLPMS PROFILES ACROSS NHW, AFRICAN AMERICAN (AA) AND LATINO AMERICAN (LA) PARTICIPANTS TO UNCOVER BIOMARKER PATTERNS IN MULTI-ETHNIC GROUPS. 4) TO MAKE THESE VAST RESOURCES AVAILABLE TO THE SCIENTIFIC COMMUNITY TO AMPLIFY AND ACCELERATE ITS IMPACT. IN THIS U19 MANAGED BY THE ADMINISTRATIVE CORE, WE WILL LEVERAGE NIH-FUNDED ADNI, MCSA AND ADRC COHORTS OF >3,700 MULTI-ETHNIC PARTICIPANTS TO GENERATE >20,000 MULTI-OMICS MEASURES (OMICS CORE) THAT WILL BE PROCESSED AND INTEGRATED WITH >48,000 HARMONIZED AD COGNITIVE, NEUROIMAGING AND FLUID ENDOPHENOTYPES (ANALYTIC CORE). USING THESE DATA, WE WILL IDENTIFY BRAIN REGION AND CELL-TYPE SPECIFIC CLPMS, WHICH REFLECT BIOLOGICAL SUBTYPES OF AD AND DISEASE STAGE (PROJECT 1). WE WILL DISCOVER LONGITUDINAL CHANGES IN CLPMS THAT PREDICT COGNITIVE AND A/T/N/V PROGRESSION (PROJECT 2). WE WILL DEFINE LONGITUDINAL COGNITIVE AND A/T/N/V CHANGES AND CLPMS IN URP THAT ARE EITHER CONSERVED WITH NHW OR POPULATION-SPECIFIC (PROJECT 3). THIS U19 WILL A) IDENTIFY THE NEXT GENERATION OF AD BIOMARKERS WITH MECHANISTIC INSIGHTS; B) ESTABLISH A PRECISION MEDICINE APPROACH FOR RIGOROUS MULTI-OMICS BIOMARKER DISCOVERY AND VALIDATION IN AD; C) DISCOVER MOLECULES THAT CAN SERVE AS BIOMARKERS AND THERAPEUTIC TARGETS; D) ENHANCE BIOMARKER RESEARCH IN TRIAL-READY MULTI-ETHNIC POPULATIONS; AND E) GENERATE AND SHARE A VAST AND HARMONIZED RESOURCE OF ENDOPHENOTYPE AND MULTI-OMICS DATA IN NIH-FUNDED COHORTS.

BIOINFORMATICS APPROACH TO INFLUENZA A/H1N1 VACCINE IMMUNE PROFILING

CANCER AND LEUKEMIA GROUP B STATISTICAL CENTER

MAYO ALZHEIMER'S DISEASE RESEARCH CENTER

TARGETING CELLULAR SENESCENCE TO EXTEND HEALTHSPAN

A SYSTEM APPROACH TO TARGETING INNATE IMMUNITY IN AD

MAYO CLINIC MULTIPLE MYELOMA SPORE

MAYO CLINIC SPORE IN PANCREATIC CANCER

THE LYMPHOMA EPIDEMIOLOGY OF OUTCOMES (LEO) COHORT STUDY

MAYO ALZHEIMER'S DISEASE RESEARCH CENTER

MAYO CENTER FOR CELL SIGNALING IN GASTROENTEROLOGY

LONGITUDINAL IMAGING BIOMARKERS OF DISEASE PROGRESSION IN DLB

PATHOBIOLOGY OF THE ENTERIC SYSTEM

PHYSIOLOGY OF BONE METABOLISM IN AN AGING POPULATION

LIVING ORGAN DONATION REIMBURSEMENT PROGRAM (LODRP)

MAYO CLINIC HEPATOBILIARY SPORE

PATHOBIOLOGY OF NEURODEGENERATION IN C9ORF72 REPEAT EXPANSION

SCALABLE EXPANDED ACCESS WITH ANALYSIS OF NEUROFILAMENT AND OTHER BIOMARKERS FOR IBUDILAST IN ALS (SEA-NOBI-ALS) - PROJECT SUMMARY/ABSTRACT CURRENT TREATMENT OPTIONS FOR AMYOTROPHIC LATERAL SCLEROSIS (ALS) ARE INADEQUATE, AND MANY PATIENTS LIVING WITH ALS SEEK ACCESS TO EXPERIMENTAL THERAPIES WITH THE HOPE THAT THEY WILL BE EFFECTIVE. SINCE MOST PATIENTS ARE EXCLUDED FROM PARTICIPATION IN INTERVENTIONAL TRIALS BASED ON RESTRICTIVE INCLUSION AND EXCLUSION CRITERIA, EXPANDED ACCESS PROGRAMS (EAPS) CAN BRIDGE AN IMPORTANT GAP. AS SUCH, THROUGH AN EAP, WE ARE NOW PROPOSING TO OFFER A PROMISING DRUG – IBUDILAST – THAT IS PRESENTLY IN A PHASE 2/3 TRIAL FOR ALS. IBUDILAST HAS A WELL-ESTABLISHED FAVORABLE SAFETY RECORD AND HAS BEEN APPROVED FOR ASTHMA AND POST-STROKE SYMPTOMS IN JAPAN. MOST RELEVANT TO OUR APPLICATION IS THE FACT THAT IT IS ABLE TO PENETRATE THE CENTRAL NERVOUS SYSTEM AND HAS BENEFICIAL PHARMACOLOGICAL EFFECTS FOR ALS, SUCH AS PHOSPHODIESTERASE INHIBITION, INCREASED AUTOPHAGY, AND AMELIORATION OF TDP-43 PATHOLOGY. THIS EAP WILL OFFER IBUDILAST AS AN EXPERIMENTAL TREATMENT TO 200 ALS PATIENTS FOR 6 MONTHS. OUR PROJECT WILL DEVELOP A NETWORK OF ALS PHYSICIANS, TO BE MANAGED BY MAYO CLINIC AND WIDETRIAL, WHICH FEATURES SELF-ACTIVATION AND STREAMLINED WORKFLOWS WITH E-CONSENT AND ENROLLMENT, HOME-HEALTH VISIT ORDERING, DRUG SUPPLY ORDERING, AND OVERSIGHT OF SAFETY EVENTS AND OUTCOMES DATA CAPTURE. EVALUATIONS WILL BE DONE EITHER IN A PHYSICIAN’S OFFICE OR VIRTUALLY IN THE PATIENT’S HOME TO MINIMIZE THE BURDEN OF PARTICIPATION. SAFETY MONITORING WILL BE CONDUCTED BY THE TREATING PHYSICIAN AND THROUGH BLOOD DRAWN IN THE PATIENT’S HOME, PROCESSED IN A CENTRAL LABORATORY. WE WILL DETERMINE THE EFFECT OF IBUDILAST ON ALS PROGRESSION USING THE GOLD STANDARD PRIMARY CLINICAL TRIAL OUTCOME MEASURE – THE ALS FUNCTIONAL RATING SCALE REVISED (ALSFRS-R) – WITH THE EMERGING BIOMARKER NEUROFILAMENT LIGHT (NFL) AS CO-PRIMARY OUTCOME. GIVEN THE URGENT NEED FOR RELIABLE BIOMARKERS, WE WILL ALSO TEST OTHER CANDIDATES (E.G., TDP-43 MARKERS). FURTHERMORE, TO AID IN DIFFERENTIATING BETWEEN IBUDILAST RESPONDERS AND NON-RESPONDERS, WE WILL USE CUTTING-EDGE MULTI-OMIC SEQUENCING METHODS. OUR USAGE OF LONG-READ WHOLE- GENOME SEQUENCING ENABLES US TO SPAN THE FULL RANGE OF GENOMIC VARIATION, AND BY GENERATING COMPLEMENTARY TRANSCRIPTOMIC DATA, WE CAN CAPTURE RNA SIGNATURES AND DISEASE-RELEVANT CELL POPULATIONS. THUS, WE STRONGLY BELIEVE THAT OUR DATASETS WILL PROVIDE A VALUABLE RESOURCE AND CAN POSSIBLY ASSIST IN PATIENT STRATIFICATION. IN SUMMARY, OUR EAP WILL OFFER A PROMISING DRUG, BRING TOGETHER NOVEL WEB-BASED INFRASTRUCTURES, IMPLEMENT NOVEL BIOMARKERS, AND OBTAIN MULTI-OMIC PROFILES OF RESPONDERS, THEREBY ALLOWING TAILORED PERSONALIZED THERAPIES AND SETTING THE STAGE FOR FUTURE ALS CLINICAL TRIALS.

COMMUNITY CLINICAL ONCOLOGY PROGRAM

LONGITUDINAL EVALUATION OF FAMILIAL FRONTOTEMPORAL DEMENTIA SUBJECTS (LEFFTDS)

EMR PHENOTYPE AND COMMUNITY ENGAGED GENOMIC ASSOCIATIONS

PROSTATE CANCER SUSCEPTIBILITY: THE ICPCG STUDY

PATIENT-CENTRIC ELECTRONIC ENVIRONMENT FOR IMPROVING ACUTE CARE PERFORMANCE

PHARMACOGENETICS OF PHASE II DRUG METABOLIZING ENZYMES

INVESTIGATING REGIONAL AND CELLULAR VULNERABILITIES TO TAU PATHOLOGY IN YOUNG-ONSET ALZHEIMER'S DISEASE - PROJECT SUMMARY/ABSTRACT DEVELOPMENT OF COGNITIVE PROBLEMS AT ANY AGE IS DEVASTATING, BUT DEVELOPMENT OF COGNITIVE PROBLEMS IN WORKING-AGE PEOPLE WITH DEPENDENTS REPRESENTS A MAJOR PUBLIC HEALTH CONCERN. YOUNG-ONSET ALZHEIMER'S DISEASE (YOAD) IS DEFINED AS INDIVIDUALS WHO PRESENT BEFORE AGE 65 AND LACK MUTATIONS KNOWN TO CAUSE ALZHEIMER'S DISEASE (AD) PATHOLOGY. NEUROPATHOLOGY AND NEUROIMAGING STUDIES DEMONSTRATE GREATER TAU ACCUMULATION IN YOAD WHO OFTEN PRESENT WITH ATYPICAL, NON-AMNESTIC SYNDROMES. OUR PRELIMINARY DATA DEMONSTRATES THAT TAU ACCUMULATION OCCURS THROUGH PROGRESSIVE MATURITY LEVELS IN TANGLE-BEARING NEURONS, WHICH DISPROPORTIONATELY AFFECTS CORTICAL MORE THAN LIMBIC STRUCTURES IN YOAD. MOREOVER, WE SHOW YOUNGER AGE ONSET IS ASSOCIATED WITH GREATER TANGLE ACCUMULATION AND NEURONAL LOSS IN NUCLEUS BASALIS OF MEYNERT (CHOLINERGIC HUB) AND LOCUS COERULEUS (NORADRENERGIC HUB) – TWO NEUROMODULATORY HUBS IMPLICATED IN EARLY STAGE OF DISEASE. AS STEREOTYPIC AMYLOID-SS PLAQUE PATTERNS ARE ROBUSTLY OBSERVED REGARDLESS OF AGE, AND COMORBID NEUROPATHOLOGIES ARE LESS FREQUENT IN YOAD, THIS COHORT IS IDEALLY SUITED FOR A TARGETED INVESTIGATION OF SELECTIVE VULNERABILITIES TO TANGLE PATHOLOGY IN AD. REGIONAL VULNERABILITIES TO ADVANCED TANGLE MATURITY LEVELS IN CORTICOLIMBIC STRUCTURES AND NEUROMODULATORY HUBS ARE HYPOTHESIZED TO UNDERLIE THE SYNDROMIC HETEROGENEITY OBSERVED IN YOAD. THE OVERALL GOAL OF THIS GRANT IS TO UNCOVER SIGNATURES OF REGIONAL AND CELLULAR VULNERABILITIES UNDERLYING SYNDROMIC HETEROGENEITY IN YOAD BY INVESTIGATING WHAT MODIFIES PATTERNS OF TANGLE ACCUMULATION AND MICROGLIAL ACTIVATION. OUR PRELIMINARY DATA FROM SINGLE-CELL RNA SEQUENCING UNDERSCORES THE IMPORTANCE OF CONSIDERING DISEASE HETEROGENEITY AND THE UTILITY OF QUANTITATIVE NEUROPATHOLOGY FOR VALIDATING GENE EXPRESSION CHANGES. THIS PROPOSAL SEEKS TO SHIFT CURRENT RESEARCH IN AD BY FOCUSING ON YOUNGER-AGED INDIVIDUALS AND DEMONSTRATING HOW REGIONAL VARIABILITY CAN INFORM CELLULAR BIOLOGY EVEN IN THE CONTEXT OF END-STAGE DISEASE. TO ACCOMPLISH OUR GOALS AND FACILITATE STRATIFICATION BY ATYPICAL AND TYPICAL (AMNESTIC) CLINICAL SYNDROMES, THE MPI TEAM HAS COMBINED EXPERTISE AND RESOURCES TO AMASS ONE OF THE LARGEST DOCUMENTED YOAD COHORTS TOTALING 558 BRAINS WITH AVAILABLE TISSUE FOR STUDY. THE GOAL OF THE GRANT IS TO TEST THE FOLLOWING HYPOTHESES: 1) MODIFIERS OF THE NEUROPATHOLOGIC PATTERNS OF TAU PATHOLOGY IN YOAD BRAINS DIFFER BETWEEN CASES STRATIFIED BY ATYPICAL VS. TYPICAL (AMNESTIC) CLINICAL SYNDROMES, 2) THE MOST VULNERABLE NEURONAL POPULATIONS TO AD-TAU SHARE A SIMILAR MOLECULAR SIGNATURE ACROSS CORTICOLIMBIC REGIONS REFLECTIVE OF SYNDROMIC HETEROGENEITY IN YOAD, AND 3) CORTICOLIMBIC MICROGLIAL ACTIVATION PATTERNS DIFFER IN THE BRAINS OF YOAD CASES STRATIFIED BY ATYPICAL VS. TYPICAL (AMNESTIC) CLINICAL SYNDROME. COMPLETION OF THIS PROJECT WILL IDENTIFY SPECIFIC CELL POPULATIONS VULNERABLE TO REGIONAL AD-TAU PATHOLOGY AND IDENTIFY MODIFIERS OF MICROGLIAL ACTIVATION PATTERNS CORRESPONDING TO AGGRESSIVE TAU ACCUMULATION IN YOAD.

PAUL CALABRESI PROGRAM IN CLINICAL-TRANSLATIONAL RESEARCH AT MAYO CLINIC

SHARP AREA 4: SECONDARY USE OF EHR DATA

INSTITUTIONAL CAREER DEVELOPMENT CORE

SYNERGISTIC INTERACTION OF AMYLOID-BETA AND ALPHA-SYNUCLEIN IN LEWY BODY DEMENTIA

MAYO SPORE IN BRAIN CANCER

BIOLOGY AND THERAPEUTICS OF CARDIOVASCULAR PEPTIDES

HEREDITARY CAUSES OF NEPHROLITHAISIS AND KIDNEY FAILURE

SOUTHEAST MINNESOTA COUNTY HEALTHCARE INFORMATION TECHNOLOGY COLLABORATION

BETA1-SELECTIVE BLOCKADE FOR PREVENTION OF POSTMENOPAUSAL BONE LOSS: A RANDOMIZED CONTROLLED TRIAL - OSTEOPOROSIS IS A DISEASE OF AGING THAT LEADS TO ~2 MILLION FRACTURES AND ~$17 BILLION IN HEALTHCARE COSTS ANNUALLY. ALTHOUGH SEVERAL DRUGS ARE FDA-APPROVED FOR THE TREATMENT OF OSTEOPOROSIS, THE POTENTIAL FOR SERIOUS SIDE EFFECTS (E.G., OSTEONECROSIS OF THE JAW, ATYPICAL FEMUR FRACTURES) HAS LED MOST PHYSICIANS TO USE THESE DRUGS ONLY FOR THE TREATMENT, BUT NOT THE PREVENTION, OF OSTEOPOROSIS. THIS HAS LED TO THE CURRENT SITUATION WHERE MOST POSTMENOPAUSAL WOMEN MUST WAIT UNTIL THEY DEVELOP FRANK OSTEOPOROSIS (I.E., FRACTURES, OR SUFFICIENTLY HIGH FRACTURE RISK) TO BEGIN DRUG THERAPY. AS SUCH, THERE IS A COMPELLING NEED FOR NOVEL, RELATIVELY LOW-RISK AND LOW-COST PHARMACOLOGICAL APPROACHES TO PREVENT OSTEOPOROSIS. THE CURRENT PROPOSAL AIMS TO TRANSLATE EVIDENCE FROM RODENT STUDIES SHOWING THAT THE SYMPATHETIC NERVOUS SYSTEM (SNS) IS AN IMPORTANT REGULATOR OF BONE METABOLISM TO A SIMPLE, COST-EFFECTIVE, AND SAFE APPROACH FOR OSTEOPOROSIS PREVENTION. IN KEY PRELIMINARY DATA, WE OBTAINED MULTIPLE LINES OF EVIDENCE TO ESTABLISH CLEARLY THE ROLE OF THE SNS IN REGULATING HUMAN BONE METABOLISM. A CRITICAL COMPONENT OF THESE DATA WAS A “PROOF-OF- CONCEPT” INTERVENTIONAL STUDY DEMONSTRATING THAT SS1-SELECTIVE BLOCKERS (ATENOLOL, NEBIVOLOL), BUT NOT A NON- SELECTIVE SS-AR BLOCKER (PROPRANOLOL), HAVE FAVORABLE EFFECTS ON BONE TURNOVER AND BONE MINERAL DENSITY (BMD) IN POSTMENOPAUSAL WOMEN. BASED ON THESE DATA, WE WILL PERFORM A RANDOMIZED, DOUBLE-BLIND, PLACEBO- CONTROLLED 2 YEAR CLINICAL TRIAL ADDRESSING THE FOLLOWING SPECIFIC AIMS: (1) TEST THE HYPOTHESIS THAT TREATMENT WITH A WIDELY USED, INEXPENSIVE, AND RELATIVELY SS1-SELECTIVE BLOCKER (ATENOLOL) WILL PREVENT BONE LOSS AT THE LUMBAR SPINE AND FEMUR NECK AS ASSESSED BY DUAL-ENERGY X-RAY ABSORPTIOMETRY IN 420 POSTMENOPAUSAL WOMEN WITHOUT PRE-EXISTING OSTEOPOROSIS (AIM 1A); AND EVALUATE THE TOLERABILITY AND SAFETY OF ATENOLOL WHEN USED FOR THE PREVENTION OF BONE LOSS (AIM 1B). (2) EVALUATE THE EFFECTS OF ATENOLOL ON TRABECULAR AND CORTICAL BONE MICROARCHITECTURE USING HIGH RESOLUTION-PERIPHERAL QUANTITATIVE COMPUTED TOMOGRAPHY (AIM 2A), ON BONE TURNOVER MARKERS (AIM 2B), AND TEST WHETHER BASELINE MEASURES OF BONE TURNOVER OR OF SYMPATHETIC ACTIVITY (RESTING HEART RATE, PLASMA CATECHOLAMINE LEVELS) ARE PREDICTIVE OF THE BMD RESPONSE TO ATENOLOL OVER 2 YEARS (AIM 2C). (3) IN A SUBSET OF PATIENTS, EXPLORE THE UNDERLYING MOLECULAR AND CELLULAR MECHANISMS FOR THE EFFECTS OF SS1-SELECTIVE BLOCKADE ON BONE IN HUMANS USING ANALYSES OF OSTEOBLAST POPULATIONS ISOLATED FROM BONE BIOPSIES AS WELL AS TISSUE-LEVEL BONE FORMATION RATES ON QUADRUPLE-LABELLED BONE BIOPSIES (AIM 3). THE PROPOSED STUDIES WILL RIGOROUSLY TEST WHETHER ATENOLOL IS EFFICACIOUS AND SAFE FOR THE PREVENTION OF OSTEOPOROSIS IN POSTMENOPAUSAL WOMEN AND ALSO FURTHER DEFINE THE MECHANISMS OF SNS EFFECTS ON BONE IN HUMANS. IF OUR PROPOSED CLINICAL TRIAL DEMONSTRATES PROTECTION FROM BONE LOSS IN POSTMENOPAUSAL WOMEN BY ATENOLOL, THIS WOULD FILL A CRUCIAL CLINICAL NEED, AS THESE WOMEN CURRENTLY HAVE VIRTUALLY NO PHARMACOLOGICAL OPTIONS FOR OSTEOPOROSIS PREVENTION.

MAYO TRANSLATIONAL PKD CENTER (MTPC)

MAYO CLINIC CENTER FOR CLINICAL AND TRANSLATIONAL RESEARCH

THE ROLE OF HYPOXIA IN VENOUS NEOINTIMAL HYPERPLASIA IN HEMODIALYSIS GRAFTS

MOLECULAR DIAGNOSIS, PROGNOSIS, AND THERAPEUTIC TARGETS IN LYMPHOMA

A MULTIDISCIPLINARY TRANSLATIONAL APPROACH TO INVESTIGATE THE MECHANISMS, PREDICTORS, AND PREVENTION OF PERSISTENT POST-TRAUMATIC HEADACHE

FECAL INCONTINENCE TREATMENT STUDY (FIT STUDY)

THE MACRO- AND MICRO- ANATOMY AND PATHOLOGY OF THE AGING KIDNEY

INTEGRATIVE TRANSLATIONAL DISCOVERY OF VASCULAR RISK FACTORS IN AGING AND DEMENTIA

CELLULAR SENESCENCE AND AGING

TRANSFORMING CLINICAL PRACTICES INITIATIVE - PTN

REGIONAL FATTY ACID METABOLISM IN HUMANS

EXPANDING INSIGHTS INTO FTD DISEASE MECHANISMS

ROCHESTER EPIDEMIOLOGY PROJECT

OPTIMIZING THE DIAGNOSTIC APPROACH TO CEPHALOSPORIN ALLERGY TESTING (DACAT TRIAL) - PROJECT SUMMARY IN THE UNITED STATES, BETA-LACTAM ANTIBIOTICS ARE THE LEADING CAUSE OF ALLERGIC REACTIONS. CEPHALOSPORIN ANTIBIOTICS, IN PARTICULAR, ARE THE MOST COMMON CAUSE OF DRUG-INDUCED ANAPHYLAXIS AND PERIOPERATIVE ALLERGY. FOR PENICILLIN ALLERGY, THE MECHANISM OF ALLERGY AND THE ANTIGENIC DETERMINANTS ARE KNOWN; VALIDATED PENICILLIN SKIN TESTING FOLLOWED BY DRUG CHALLENGE HAS A 100% NEGATIVE PREDICTIVE VALUE TO EXCLUDE AN IMMUNOGLOBULIN (IG)E-MEDIATED REACTION. FOR CEPHALOSPORIN ALLERGY, THE ANTIGENIC DETERMINANTS AND MECHANISM ARE NOT KNOWN, AND SKIN TESTING IS NOT VALIDATED. THE DIAGNOSTIC TEST CHARACTERISTICS OF SKIN TESTING WITH NATIVE CEPHALOSPORINS REMAIN UNCLEAR WITH NO SENSITIVITY NOR SPECIFICITY REPORTED. ALTHOUGH BETA-LACTAM CROSS-REACTIVITY HAS BEEN HYPOTHESIZED TO BE FROM THE SIMILARITY OF THE R1 SIDE CHAINS, RATHER THAN THE BETA-LACTAM RING, CROSS-REACTIVITY ESTIMATES AMONG BETA-LACTAMS VARY. FURTHERMORE, IT IS NOT KNOWN WHETHER THE VARIANCE IN CROSS-REACTIVITY IS DUE TO TRUE ALLERGY VERSUS SENSITIZATION BASED ON POSITIVE SKIN TESTING, GIVEN THAT DRUG CHALLENGES WERE NOT PERFORMED ON SKIN-TEST-POSITIVE PATIENTS. WHILE AN IGE MECHANISM IS ASSUMED FOR CEPHALOSPORIN ALLERGY AND SUPPORTED BY SKIN TESTING THAT HAS BEEN POSITIVE, THE BIOLOGY HAS YET TO BE CHARACTERIZED, AND SOME CEPHALOSPORIN ANAPHYLAXIS CAN OCCUR ON THE FIRST EXPOSURE, WHICH IS INCONSISTENT WITH AN IGE MECHANISM. GIVEN THE COMPLEXITY OF CEPHALOSPORIN STRUCTURES AND POTENTIAL EPITOPES, THERE MAY BE SEVERAL DISTINCT BIOLOGIC PATHWAYS INVOLVED IN CEPHALOSPORIN ALLERGY. FUTURE DIAGNOSTICS IN CEPHALOSPORIN ALLERGY ARE RELIANT ON DETERMINATION OF THESE BIOLOGICAL PATHWAYS AND FINDING KEY HAPTENS. CURRENT NATIONAL PRACTICE GUIDELINES RELATED TO CEPHALOSPORIN ALLERGY ASSESSMENT ARE CONSIDERED CONDITIONAL AND BASED ON LOW-QUALITY EVIDENCE. OUR OVERALL GOAL IS TO IDENTIFY THE OPTIMAL DIAGNOSTIC APPROACH TO CEPHALOSPORIN ALLERGY AND DETERMINE BETA-LACTAM CROSS-REACTIVITY, WHILE DISCOVERING THE MECHANISM AND ANTIGENIC DETERMINANTS OF CEPHALOSPORIN ALLERGY TO ADVANCE FUTURE DIAGNOSTICS. WE WILL DO THIS THROUGH A CLINICAL TRIAL THAT WILL GENERATE EMPIRICAL EVIDENCE THROUGH NOVEL TRIAL PROCEDURES, DOUBLE-BLIND SKIN TESTING, AND DOUBLE- BLIND PLACEBO-CONTROLLED DRUG CHALLENGES. OUR SPECIFIC AIMS ARE: 1) TO DETERMINE THE OPTIMAL APPROACH TO CEPHALOSPORIN ALLERGY EVALUATION; 2) TO ASSESS BETA-LACTAM CROSS-REACTIVITY IN CEPHALOSPORIN-ALLERGIC INDIVIDUALS; AND 3) TO INVESTIGATE THE ANTIGENIC DETERMINANTS AND MECHANISM OF CEPHALOSPORIN ALLERGY. WE WILL ACHIEVE THESE AIMS THROUGH COLLABORATION WITH AN ESTABLISHED NETWORK OF DRUG ALLERGY SPECIALISTS. OUR STUDY IS THE FIRST CLINICAL TRIAL IN DRUG ALLERGY THAT INVESTIGATES DIAGNOSTIC STRATEGIES AND MECHANISMS FOR A COMMON AND IMPORTANT ANTIBIOTIC CLASS. THIS PROJECT ALIGNS WITH NIH/NIAID GOALS TO ADVANCE DRUG ALLERGY RESEARCH AND PAR-21-083 TO SUPPORT HIGH-RISK CLINICAL TRIALS WITH MECHANISTIC STUDIES.

ADPKD: DISEASE SPECTRUM & GENOTYPE-PHENOTYPE CORRELATIONS

MAYO CLINIC PROSPECTIVE RESOURCE FOR BIOMARKER VALIDATION AND EARLY DETECTION OF PANCREATIC CANCER

PANCREATIC CANCER GENETIC EPIDEMIOLOGY CONSORTIUM (PACGENE)

TARGETING CYCLIC AMP AND PROTEIN KINASE A SIGNALING TO TREAT ADPKD: AN EFFICACIOUS STRATEGY WITH FURTHER POTENTIAL

MAYO CLINIC METABOLOMICS RESOURCE CORE

EPIDEMIOLOGY OF AGE-RELATED BONE LOSS AND FRACTURES

MAYO CLINIC PHYSICAL ACTIVITY RESEARCH CENTER: METABOLOMICS AND PROTEOMICS ANALYSIS SITE

ENHANCED, EHR-FACILITATED CANCER SYMPTOM CONTROL (E2C2) PRAGMATIC CLINICAL TRIAL

PREVENTION OF ALZHEIMER'S DISEASE IN WOMEN: RISKS AND BENEFITS OF HORMONE THERAPY

NEONATAL MODULATION OF AIRWAY CONTRACTILITY

GENETICS AND MOLECULAR BIOLOGY PARKINSONISM

FOLATE RECEPTOR ALPHA VACCINES FOR PREVENTING PROGRESSION OF TNBC FOLLOWING FIRST-LINE CONVENTIONAL THERAPY

NCI, NATIONAL CLINICAL TRIALS NETWORK LEAD ACADEMIC PARTICIPATING SITE (LAPS) UG1

THE EFFECT OF TCF7L2 ON GLUCOSE METABOLISM

IRREVERSIBLE KIDNEY INJURY IN RENOVASCULAR HYPERTENSION

HEART DISEASE IN RHEUMATOID ARTHRITIS

MECHANOBIOLOGY OF LUNG FIBROSIS

IDENTIFYING MECHANISMS OF DEMENTIA: ROLE FOR MRI IN THE ERA OF MOLECULAR IMAGING

DISSECTING THE PATHOGENESIS AND OUTCOMES OF PSC USING MULTI-OMICS BY STUDYING THE EXPOSOME AND GENOME

CHARACTERIZING THE FUNTION OF FIBBROCYSTIN AND FIBBROCYSTIN-L

SEX-SPECIFIC EFFECTS OF ENDOCRINE DISRUPTION ON AGING AND ALZHEIMER'S DISEASE

CENTER OF INNOVATION FOR BRAIN TUMOR THERAPEUTICS - PROJECT DESCRIPTION/ABSTRACT – OVERALL THE DEVELOPMENT OF EFFECTIVE THERAPIES FOR GLIOBLASTOMA (GBM) HAS BEEN INCREDIBLY VEXING WITH NO NEW DRUG APPROVALS IN OVER A DECADE. THERAPEUTIC RESISTANCE IN ANY ONE PATIENT WITH GBM CAN BE RELATED TO MULTIPLE FACTORS INCLUDING EXTENSIVE TUMOR CELL INFILTRATION INTO ADJACENT BRAIN, MOLECULAR HETEROGENEITY OF TUMOR CELL POPULATIONS, AND HETEROGENEITY OF DRUG DISTRIBUTION. IN ORDER TO UNDERSTAND AND OVERCOME THESE CHALLENGES, WE HAVE BUILT A HIGHLY PRODUCTIVE, MULTI-DISCIPLINARY SCIENTIFIC TEAM OVER THE PAST DECADE WITH EXPERTISE SPANNING SYSTEMS BIOLOGY, PHARMACOLOGY, TUMOR BIOLOGY, AND ANIMAL MODELS OF GBM. IN THE PROPOSED U19 CENTER APPLICATION, WE WILL INTEGRATE THIS ESTABLISHED CROSS-DISCIPLINARY TRANSLATIONAL SCIENCE TEAM WITH PHYSICIAN SCIENTISTS IN RADIATION AND MEDICAL ONCOLOGY, NEUROSURGERY AND NEURORADIOLOGY WITH A COLLECTIVE FOCUS OF TRANSLATING NOVEL THERAPEUTIC STRATEGIES INTO HIGHLY EFFECTIVE THERAPIES FOR PATIENTS WITH GBM. IMPAIRED DDR ENABLES THE GENOMIC INSTABILITY REQUIRED FOR TUMORIGENESIS, AND DIFFERENCES IN DDR FUNCTIONALITY BETWEEN TUMOR AND NORMAL TISSUE PROVIDES THE FUNDAMENTAL RATIONALE FOR USING RADIATION THERAPY OR GENOTOXIC DRUGS AS ANTI-CANCER THERAPIES. ADDITIONAL TARGETED PHARMACOLOGIC DISRUPTION OF DDR IN TUMORS CAN MARKEDLY ENHANCE THE EFFICACY OF THESE CYTOTOXIC THERAPIES AND WIDEN THE THERAPEUTIC WINDOW. IN THIS CONTEXT, WE HAVE COLLABORATED EXTENSIVELY WITH MULTIPLE PHARMACEUTICAL COMPANIES TO EVALUATE VARIOUS SMALL MOLECULE DDR INHIBITORS AND HAVE DEVELOPED SIGNIFICANT PRELIMINARY DATA DEMONSTRATING PROFOUND COMBINATORIAL EFFICACY FOR THESE DRUGS WHEN COMBINED WITH RADIATION OR ALKYLATING CHEMOTHERAPY ROUTINELY USED FOR GBM. THUS, THE INITIAL FOCUS FOR OUR CENTER IS TO OPTIMIZE THE CLINICAL DEPLOYMENT OF DDR INHIBITORS IN COMBINATION WITH CYTOTOXIC THERAPIES FOR GBM. A PHARMACOLOGY CORE WILL SUPPORT BOTH PHARMACOKINETIC (PK) AND PHARMACODYNAMIC (PD) EVALUATIONS IN ANIMAL MODELS AND HUMAN SAMPLES, AND OUR THERAPY EVALUATION CORE WILL SUPPORT BOTH PRE-CLINICAL AND CLINICAL TESTING OF NOVEL THERAPEUTIC STRATEGIES. THE PROJECT AND CORE TEAMS WILL WORK IN CLOSE COLLABORATION TO ACCOMPLISH THE GOALS OF THE CENTER, AND THIS COLLABORATIVE EFFORT WITHIN THE CENTER AND ACROSS THE BROADER GLIOMA THERAPEUTICS NETWORK (GTN) WILL BE COORDINATED BY THE ADMINISTRATIVE CORE.

FFA METABOLISM IN DIFFERENT TYPES OF HUMAN OBESITY

COMPUTATIONAL AND BIOLOGICAL APPROACH TO FLOW DIVERSION

LONGITUDINAL MULTI-MODALITY IMAGING IN PROGRESSIVE APRAXIA OF SPEECH