Project Grant K01AG088232

FIBRO/ADIPOGENIC PROGENITOR METABOLIC REPROGRAMMING FOR AGE-RELATED MUSCLE FIBROSIS - ABSTRACT THIS APPLICATION IS FOR A K01 MENTORED RESEARCH SCIENTIST DEVELOPMENT AWARD TO PROVIDE DEDICATED CAREER DEVELOPMENT TRAINING FOR DR. DAVID LEE TO LAUNCH HIS OWN INDEPENDENT RESEARCH PROGRAM. DR. LEE HAS CONDUCTED BASIC SCIENCE RESEARCH IN THE AREAS OF MUSCLE CELL BIOLOGY, AGING AND METABOLISM. THIS K01 WILL ENHANCE DR. LEE'S ABILITY TO 1) BECOME AN EXPERT IN BIOLOGY OF FIBRO/ADIPOGENIC PROGENITOR CELLS (FAPS) AND MUSCLE FIBROSIS, 2) CONDUCT MASS SPECTROMETRY-BASED SCIENCE WITH STATE-OF-THE-ART EQUIPMENT, 3) USE NOVEL COMPUTATIONAL APPROACHES TO PERFORM INFORMATICS ANALYSIS ON LARGE SCALE METABOLOMICS DATA (TO GO FORM SPECTRAL PEAKS TO SPECIFIC PATHWAYS), 4) DEVELOP AND IMPLEMENT STRATEGIES TO MANIPULATE WNT DRIVEN GLYCOLYSIS IN FAPS TO COUNTERACT MUSCLE FIBROSIS AND 5) DEVELOP HIGH-QUALITY INDEPENDENT RESEARCH PROGRAM THAT WILL ALLOW COLLABORATIVE AND INCLUSIVE OPPORTUNITIES FOR SCIENCE. TO ACHIEVE THE GOALS, DR. LEE HAS DEVISED A CLEAR AND FOCUSED TRAINING PLAN WITH CLEARLY ASSIGNED INDIVIDUALS WHO WILL EACH CONTRIBUTE UNIQUE EXPERTISE TO THE AFOREMENTIONED AREAS OF TRAINING. DR. LEE'S PRIMARY MENTOR IS DR. CHRISTOPHER NEWGARD (CAREER DEVELOPMENT, METABOLOMICS INTERPRETATION). DR. LEE'S CO-MENTOR IS DR. JAMES BAIN (MASS SPECTROMETRY, METABOLOMICS). DR. LEE HAS ALSO ENLISTED THREE RESEARCH ADVISORS: DR. JIANHONG OU (BIOINFORMATICS, -OMICS DATA REDUCTION/INTERPRETATION), DR. MATT HILTON (CAREER DEVELOPMENT, FAPS BIOLOGY), DR. JAMES WHITE (MUSCLE, AGING, SARCOPENIA). THERE EXISTS A HEAVY SOCIAL AND ECONOMIC COST ASSOCIATED WITH LOST INDEPENDENCE AND MOBILITY DUE TO MUSCLE WEAKNESS AND INJURY. THERE ARE CURRENTLY NO EFFECTIVE STRATEGIES TO FULLY COUNTERACT SARCOPENIA TO RESTORE MOBILITY AND STRENGTH. NO RIGOROUS RESEARCH HAS INVESTIGATED THE FIBROGENIC DEVELOPMENT OF FAPS IN AGE-RELATED MUSCLE FIBROSIS, AND I HYPOTHESIZE THAT FAPS COULD BE A CELLULAR TARGET FOR ANTI-FIBROSIS THERAPIES TO DELAY OR PREVENT THE LOSS OF MUSCULAR STRENGTH IN THE CONTEXT OF SARCOPENIA. THE FIRST OBJECTIVES (AIM 1) OF THE PROPOSED STUDIES ARE TO DETERMINE THE ONSET OF FAP FIBROGENESIS THROUGH A TIME COURSE STUDY OF SARCOPENIA DEVELOPMENT TO INFORM THERAPEUTIC STRATEGY. SECOND (AIM 2), I WILL DETERMINE IF GREATER FAP GLYCOLYSIS IS A DRIVER OF FAP FIBROGENESIS USING ORTHOGONAL METABOLOMICS AND GLYCOLYTIC FLUX ANALYSIS. FINALLY (AIM 3), INFORMED BY MY PRELIMINARY DATA, I WILL MECHANISTICALLY DETERMINE IF WNT SIGNALING DRIVES FAP GLYCOLYSIS AND FIBROGENESIS MAKING IT A TARGET FOR ANTI- FIBROSIS THERAPY TO DELAY MUSCLE WEAKNESS IN SARCOPENIA. TOGETHER, THE K01 TRAINING AND MENTORSHIP WILL ENABLE DR. LEE TO TRANSITION INTO AN INDEPENDENT RESEARCH CAREER AND BECOME A LEADER IN DEVELOPING THERAPEUTIC STRATEGIES TO COMBAT AGE-RELATED MUSCLE WEAKNESS AND FIBROSIS FOR TRANSLATION THERAPEUTICS.