"Cardiovascular disease is the primary cause of morbidity and mortality worldwide. Despite numerous treatment options the prevalence of cardiovascular indications continues to increase, underscoring the need for new therapeutic strategies.In recent years, prominent roles of microRNAs (miRNAs) have been uncovered in a variety of cardiovascular disorders. miRNAs are short, single stranded RNAs that regulate gene expression by suppressing multiple, often related, mRNAs.Our studies have focussed on the cardiac specific miRNA, miR-208. We showed that, in the setting of heart failure, genetic deletion as well as therapeutic inhibition of miR-208 resulted in reduced cardiac remodeling (less hypertrophy and fibrosis), the inability to upregulate beta-MHC (a sensitive marker of pathological cardiac stress) and improved survival.Unexpectedly, mice treated with antimiR-208 displayed resistance to obesity and enhanced glucose metabolism in a mouse model of type II diabetes. These effects suggest that the heart plays a previously unrecognized role in systemic metabolic control via a miR-208 dependent mechanism.Although these studies indicate a crucial role for miR-208 in cardiac remodeling and systemic metabolism, the mechanism of action still remains to be defined. Our preliminary gene expression data indicate a cohort of miR-208 targets to be regulated in our stress models, many of which so far have unknown or ill-studied cardiac functions.The aim of the present proposal is to use genetics, gene expression analyses, stress models and antimiR approaches to study the relevance of downstream miR-208 targets for cardiac remodeling and total body metabolism and explore whether additional miRNAs besides miR-208 are relevant for cardiometabolic disease. Together these projects will increase our mechanistic understanding of miRNA function in cardiac and metabolic disease which will advance the clinical application of miRNA therapeutics."