Hypertrophic cardiac disease affects millions of people in the United States with total health care costs estimated in the billions of dollars. Investigation of the mechanisms that drive cardiac hypertrophy and remodeling are necessary in order to prevent and treat this disease. The long term goals of this project are to identify molecular mechanisms that drive this pathologic process, and to suggest new targets for the treatment of cardiac hypertrophy. MicroRNAs (miRs) have beeri strongly implicated in both heart development and disease. MiRs are small RNA molecules that decrease the expression of target genes by inducing sequence specific mRNA translational silencing or degradation. Specifically, miR-21 was identified as the most upregulated miR after pressure overload hypertrophy. Overexpression of miR-21 induces cardiac hypertrophy. These data strongly suggest that miR-21 plays a role in stress-induced cardiac hypertrophy and remodeling. This project will study the role of miR-21 in cardiac hypertrophy. This will be performed by investigation of the stress-responsive enhancer of miR-21. Characterization of this enhancer will suggest mechanisms that regulate the expression of miR-21 and thus implicate possible mechanisms of pharmacologic miR-21 modulation. The role of miR-21 in cardiac hypertrophy will be examined in vivo by generation of a miR-21 conditional knockout mouse. Both global and cardiac-specific deletion of miR-21 will allow for dissection of the role of this miR in stress-induced hypertrophy and remodeling. The mechanism of miR-21 induced cardiac hypertrophy will be determined. Determination of miR-21 target genes will suggest novel molecular mechanisms driving cardiac hypertrophy. These studies will provide insight into the mechanisms regulating cardiac disease, and they will define potential therapeutic targets for the future treatment of cardiac hypertrophy.
