Heart disease is the number one cause of death worldwide. Following a myocardial infarction (MI), adults irreversibly lose billions of cardiomyocytes, which are replaced by a fibrotic scar that compromises cardiac function. The decrease in cardiac function often leads to heart failure and death. However, our lab has demonstrated that neonatal mice can fully regenerate myocardial tissue during the first week of life following surgical amputation or myocardial infarction, providing an opportunity to understand the molecular basis of cardiac regeneration. The molecular cues that allow or promote myocardial regeneration are not well characterized. Moreover, how these pro- regenerative signals are silenced by the end of the first week of life is unknown. Thus, elucidating the cues that extend or maintain the myocardial regenerative potential is essential for designing new therapeutics for cardiac regeneration and repair. Neonatal myocardial regeneration is accompanied by organ-wide cardiomyocyte proliferation. The observation that adult mice lack a proliferative capacity following injury suggests there may be a block in cytokinesis in the adult mammalian heart, preventing myocardial regeneration. DNA methylation is well characterized for its role in gene silencing;therefore, we examined the possibility that cll cycle related genes are being silenced by DNA methylation shortly after birth, preventing the capability of cardiomyocytes to proliferate following injury. Our preliminary studies indicate an increase in the expression of DNA methyltransferase 3a (Dnmt3a) at birth, which is followed by the promoter methylation and a decrease in expression of Survivin, a component of the chromosomal passenger complex that promotes cytokinesis. Here, we propose that cardiomyocyte-specific loss of Dnmt3a or Survivin gain-of-function will promote the proliferation of cardiomyocytes and enhance the myocardial regenerative capacity. In addition, we will determine the molecular events that lead to Survivin silencing. The successful completion of this project will offer much needed insight into how the neonatal mammal regulates myocardial regeneration and will offer new approaches to promote adult heart regeneration and repair.
The goal of this project is to elucidate the mechanism of action of DNA methylation during mammalian, neonatal cardiac regeneration in an effort to uncover novel pathways and targets for designing new treatment paradigms for heart disease.
|Papizan, James B; Olson, Eric N (2014) Hippo in the path to heart repair. Circ Res 115:332-4|