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
Robbins, Jeffrey (2017) Oliver Smithies, DPhil: 1925-2017. Circ Res 120:1535-1536
Travers, Joshua G; Kamal, Fadia A; Valiente-Alandi, Iñigo et al. (2017) Pharmacological and Activated Fibroblast Targeting of G??-GRK2 After Myocardial Ischemia Attenuates Heart Failure Progression. J Am Coll Cardiol 70:958-971
Schafer, Allison E; Blaxall, Burns C (2017) G Protein Coupled Receptor-mediated Transactivation of Extracellular Proteases. J Cardiovasc Pharmacol 70:10-15
Xiang, Fu-Li; Fang, Ming; Yutzey, Katherine E (2017) Loss of ?-catenin in resident cardiac fibroblasts attenuates fibrosis induced by pressure overload in mice. Nat Commun 8:712
Singh, Sonia R; Zech, Antonia T L; Geertz, Birgit et al. (2017) Activation of Autophagy Ameliorates Cardiomyopathy in Mybpc3-Targeted Knockin Mice. Circ Heart Fail 10:
Khalil, Hadi; Maillet, Marjorie; Molkentin, Jeffery D (2017) Spatial Gene Profiling in the Ischemic Heart: Fibroblasts Put on Their SOX. Circulation 136:1410-1411
Tallquist, Michelle D; Molkentin, Jeffery D (2017) Redefining the identity of cardiac fibroblasts. Nat Rev Cardiol 14:484-491
Rudomanova, Valeria; Blaxall, Burns C (2017) Targeting GPCR-G??-GRK2 signaling as a novel strategy for treating cardiorenal pathologies. Biochim Biophys Acta 1863:1883-1892
Kamal, Fadia A; Travers, Joshua G; Schafer, Allison E et al. (2017) G Protein-Coupled Receptor-G-Protein ??-Subunit Signaling Mediates Renal Dysfunction and Fibrosis in Heart Failure. J Am Soc Nephrol 28:197-208
McLendon, Patrick M; Davis, Gregory; Gulick, James et al. (2017) An Unbiased High-Throughput Screen to Identify Novel Effectors That Impact on Cardiomyocyte Aggregate Levels. Circ Res 121:604-616

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