Project Grant F32HL188873

MECHANISM OF MYC TRANSCRIPTION FACTORS IN CARDIOMYOCYTE PROLIFERATION AND METABOLISM - PROJECT SUMMARY CARDIOVASCULAR DISEASE IS COMMON AND DEADLY. WHILE LOWER ORGANISMS HAVE A TREMENDOUS CAPACITY FOR REGENERATION, THE ADULT MAMMALIAN HEART IS MORE LIMITED IN ITS CAPACITY FOR REGENERATION AND REMUSCULARIZATION OF THE DAMAGED TISSUE FOLLOWING AN INJURY SUCH AS A MYOCARDIAL INFARCTION. RECENTLY, WE DEFINED AN EVOLUTIONARY CONSERVED SHH SIGNALING PATHWAY IN NEWT AND MOUSE THAT PROMOTES CARDIOMYOCYTE PROLIFERATION IN VITRO AND CARDIAC REPAIR. OUR NEW AND PRELIMINARY STUDIES UNCOVERED A CRITICAL ROLE FOR MYCN, AS A DOWNSTREAM EFFECTOR OF THE SHH SIGNALING PATHWAY, AND REGULATOR OF CARDIOMYOCYTE PROLIFERATION. WHILE THE ROLE OF MYCN IN THE CONTEXT OF CANCER HAS DEMONSTRATED THAT THIS FACTOR REGULATES METABOLISM CELL PROLIFERATION, TRANSCRIPTIONAL AND EPIGENETIC LANDSCAPE, ITS ROLE IN THE CARDIOMYOCYTE IS UNDEFINED AND WARRANTS INVESTIGATION. OUR RECENT PUBLICATIONS AND OUR PRELIMINARY DATA SUPPORT THE OVERALL HYPOTHESIS THAT THE SHH DOWNSTREAM EFFECTOR, MYCN, REGULATES CARDIOMYOCYTE METABOLISM, PROLIFERATION AND THE EPIGENETIC LANDSCAPE AND IS AN ESSENTIAL FACTOR THAT PROMOTES CARDIAC REGENERATION. IN THESE PROPOSED STUDIES, WE WILL USE A NUMBER OF UNIQUE GENETIC TOOLS THAT WE HAVE ENGINEERED, GENETIC MOUSE MODELS AVAILABLE IN OUR LAB AND WE TAKE AN INNOVATIVE STRATEGY TO DEFINE THE ROLE FOR MYC TRANSCRIPTION FACTORS AS KEY REGULATORS OF THE CARDIOMYOCYTE LINEAGE AND ESSENTIAL PROMOTERS OF CARDIAC REGENERATION AND REPAIR. TO TEST OUR HYPOTHESES, THIS F32 PROPOSAL WILL ADDRESS THE FOLLOWING AIMS: SPECIFIC AIM #1: TO DEFINE THE MECHANISM OF MYCN-MEDIATED REGULATION OF CM ENERGY METABOLISM; SPECIFIC AIM #2: TO DETERMINE THE FUNCTIONAL ROLE OF MYCN AND CMYC IN CM PROLIFERATION. THE IMPACT OF THESE AIMS AND THE RESULTS THAT WILL BE GENERATED ARE HIGHLY INNOVATIVE AND SIGNIFICANT FOR THE FIELD OF CARDIAC REGENERATION. THEY WILL UTILIZE OUR RECENTLY ENGINEERED GENETIC MOUSE MODELS, INDUCIBLE VIRAL VECTORS, MODIFIED MRNA-GFP CONSTRUCTS, GENETIC MOUSE MODELS, MOLECULAR ANALYSES AND BIOINFORMATICS ALGORITHMS. COLLECTIVELY, THESE STUDIES WILL COMPREHENSIVELY DEFINE THE ROLE OF MYC FACTORS AS AN ESSENTIAL FACTOR THAT GOVERNS CARDIAC REPAIR AND REGENERATION BY PROMOTING CARDIOMYOCYTE METABOLISM, PROLIFERATION AND GENE EXPRESSION FOLLOWING INJURY. GIVEN THE TREMENDOUS MORBIDITY AND MORTALITY OF CARDIOVASCULAR DISEASE IN OUR SOCIETY, THE POTENTIAL IMPACT OF THIS F32 FELLOWSHIP PROPOSAL IS TREMENDOUS.