The molecular mechanisms that control cardiomyocyte proliferation and growth are fundamental to normalheart development, and dysregulation of these processes contributes to congenital and adult cardiacdisease. During prenatal development, the heart grows mainly through hyperplastic growth of differentiatedcardiomyocytes, and increased sarcomeric architecture is apparent as development proceeds. Postnatally,cardiomyocytes withdraw from the cell cycle, and heart growth is due largely to cardiomyocyte hypertrophy.The regulatory mechanisms that control differential regulation of proliferation and hypertrophy duringdevelopment and that control perinatal cardiomyocyte cell cycle withdrawal are not completely known. Inskeletal and smooth muscle, FoxO transcription factors antagonized by Akt phosphorylation directly regulateexpression of genes that inhibit cell cycle progression and promote muscle atrophy. The functions of the Aktsignaling pathway and FoxO transcription factors in the developing heart will be examined in embryonic,fetal, neonatal and adult cardiomyocytes in cell culture and in genetically manipulated mouse models. Thehypothesis is that Akt-mediated inactivation of FoxO transcription factors promotes cardiomyocyteproliferation and regulates heart growth during development. Preliminary studies demonstrate that FoxO areexpressed in the developing heart, and treatment of fetal cardiomyocytes with IGF-I leads to increasedproliferation and FoxO1 phosphorylation through a PI3K-dependent mechanism.
Aim 1. Determine if FoxO1or FoxOS regulate proliferation and maturation downstream PI3K/AKT signaling in cultured embryonic, fetalor neonatal cardiomyocytes.
Aim 2. Determine if FoxO1 regulates differential growth and hypertrophy of thedeveloping myocardium in vivo. The immediate goal is to determine if FoxO transcription factors regulated byAkt phosphorylation control cardiomyocyte proliferation and cell size (hypertrophy) at specific stages ofcardiomyocyte development and maturation. The long term goal is to define signal transductionmechanisms underlying growth, differentiation and maturation of the developing and adult myocardium.These studies are designed to reveal developmentally important growth control mechanisms of cardiacmuscle that could be exploited in the treatment of congenital or adult heart disease.
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