The molecular mechanisms that control cardiomyocyte proliferation and growth are fundamental to normal heart development, and dysregulation of these processes contributes to congenital and adult cardiac disease. During prenatal development, the heart grows mainly through hyperplastic growth of differentiated cardiomyocytes, 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 during development and that control perinatal cardiomyocyte cell cycle withdrawal are not completely known. In skeletal and smooth muscle, FoxO transcription factors antagonized by Akt phosphorylation directly regulate expression of genes that inhibit cell cycle progression and promote muscle atrophy. The functions of the Akt signaling 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. The hypothesis is that Akt-mediated inactivation of FoxO transcription factors promotes cardiomyocyte proliferation and regulates heart growth during development. Preliminary studies demonstrate that FoxO are expressed in the developing heart, and treatment of fetal cardiomyocytes with IGF-I leads to increased proliferation and FoxO1 phosphorylation through a PI3K-dependent mechanism.
Aim 1. Determine if FoxO1 or FoxOS regulate proliferation and maturation downstream PI3K/AKT signaling in cultured embryonic, fetal or neonatal cardiomyocytes.
Aim 2. Determine if FoxO1 regulates differential growth and hypertrophy of the developing myocardium in vivo. The immediate goal is to determine if FoxO transcription factors regulated by Akt phosphorylation control cardiomyocyte proliferation and cell size (hypertrophy) at specific stages of cardiomyocyte development and maturation. The long term goal is to define signal transduction mechanisms underlying growth, differentiation and maturation of the developing and adult myocardium. These studies are designed to reveal developmentally important growth control mechanisms of cardiac muscle that could be exploited in the treatment of congenital or adult heart disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL069779-10
Application #
8374758
Study Section
Special Emphasis Panel (ZHL1-PPG-D)
Project Start
Project End
2013-08-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
10
Fiscal Year
2012
Total Cost
$293,124
Indirect Cost
$97,708
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
Travers, Joshua G; Kamal, Fadia A; Robbins, Jeffrey et al. (2016) Cardiac Fibrosis: The Fibroblast Awakens. Circ Res 118:1021-40
Schwanekamp, Jennifer A; Lorts, Angela; Vagnozzi, Ronald J et al. (2016) Deletion of Periostin Protects Against Atherosclerosis in Mice by Altering Inflammation and Extracellular Matrix Remodeling. Arterioscler Thromb Vasc Biol 36:60-8
Bernardo, Bianca C; Blaxall, Burns C (2016) From Bench to Bedside: New Approaches to Therapeutic Discovery for Heart Failure. Heart Lung Circ 25:425-34
Valiente-Alandi, Iñigo; Schafer, Allison E; Blaxall, Burns C (2016) Extracellular matrix-mediated cellular communication in the heart. J Mol Cell Cardiol 91:228-37
Xiang, Fu-Li; Guo, Minzhe; Yutzey, Katherine E (2016) Overexpression of Tbx20 in Adult Cardiomyocytes Promotes Proliferation and Improves Cardiac Function After Myocardial Infarction. Circulation 133:1081-92
Fang, Ming; Xiang, Fu-Li; Braitsch, Caitlin M et al. (2016) Epicardium-derived fibroblasts in heart development and disease. J Mol Cell Cardiol 91:23-7
James, Jeanne; Robbins, Jeffrey (2016) Healing a Heart Through Genetic Intervention. Circ Res 118:920-2
Travers, Joshua G; Schafer, Allison E; Blaxall, Burns C (2016) GRK2 in Lymphocytes: Expanding the Arsenal of Heart Failure Prognostics. Circ Res 118:1049-51
Previs, Michael J; Mun, Ji Young; Michalek, Arthur J et al. (2016) Phosphorylation and calcium antagonistically tune myosin-binding protein C's structure and function. Proc Natl Acad Sci U S A 113:3239-44
Gupta, Manish K; McLendon, Patrick M; Gulick, James et al. (2016) UBC9-Mediated Sumoylation Favorably Impacts Cardiac Function in Compromised Hearts. Circ Res 118:1894-905

Showing the most recent 10 out of 108 publications