Role of Meis1 in Regulation of Cardiomyocyte Proliferation

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DESCRIPTION (provided by applicant): Heart failure is a costly and deadly disease, affecting over 23 million patients worldwide, 5.8 million patients in America, half of which die within 5 years of diagnosis. In addition, heart failure costs the US government over 39 billion Dollars in health care costs annually. Systolic heart failure, resulting from cardiomyocyte loss, is the leading cause of heart failure. At the core of the pathophysiology of heart failure is the inabilit of the adult heart to regenerate. Instead, lost myocytes are replaced by fibrous tissue, which results in progressive remodeling, dilatation, and further contractile dysfunction. We recently discovered that the newborn mouse heart is able completely regenerate following injury, primarily through proliferation of pre-existing cardiomyocytes. Moreover, we identified Meis1 as a key regulator of mammalian cardiomyocyte proliferation post-natally. Our preliminary results using targeted Meis1 deletion in cardiomyocytes indicate that loss of Meis1 results in robust cardiomyocyte proliferation in the adult heart. Finally, we identified the cell cycle inhibitors p1 and p21 as potential targets for Meis1 in cardiomyocytes. Therefore, we hypothesize that Meis1 regulates cardiomyocyte proliferation through transcriptional activation of p16 and p21. We will utilize Meis1 loss of function and gain of function mouse models, as well as an array of in vivo and in vitro techniques to address this hypothesis. Ultimately, we hope to exploit our understanding of the role of Meis1 in cardiomyocyte proliferation to uncover new disease mechanisms and therapeutic approaches for cardiovascular diseases.