Cardiac myocytes display two developmentally regulated forms of growth, namely hyperplastic (increased cell number) and hypertrophic growth (increased cell size). At a mechanistic level, the signals that distinguish hypertrophic growth from cell cycle progression are unknown. However, since cell cycle progression is intimately linked to cell mass, there must be factors, which functionally link them. One endogenous factor implicated in the regulation of both hyperplastic and hypertrophic growth in cardiac muscle is the immediate early transcription factor, c-Myc. To explore its role specifically in adult myocardium, we created a novel inducible cardiac-restricted transgenic model whereby we can temporally regulate Myc activity in the heart (MycER). We have demonstrated that Myc alone is sufficient to induce both hypertrophic growth and cause cell cycle reentry, even in adult post-mitotic cardiac myocytes. Our preliminary data suggest that Myc is also necessary for the development of cardiac hypertrophy in vivo since subjecting Myc-null myocardium to hemodynamic stress results in apoptosis and replacement fibrosis. These data raise a number of interesting and testable hypotheses regarding the role of Myc in regulating cardiac growth and survival. We hypothesize that Myc regulates hypertrophic and hyperplastic growth by distinct transcriptional programs and that it is necessary in normal growth to prevent apoptosis. This proposal will attempt to genetically dissect cardiac growth control and specifically Myc's role by directly assessing the importance of Myc in hypertrophic growth by using MycER mice to determine the basis for Myc-mediated hypertrophic growth in adult myocardium (Aim 1), determine the molecular mechanisms that differentiate Myc-induced hyperplastic and hypertrophic growth (Aim 2) and explore the mechanisms underlying the requirement of Myc for a normal hemodynamic response by clarifying the role of Myc in regulating cardiac myocyte apoptosis (Aim 3).

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL070748-02
Application #
6881161
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Program Officer
Evans, Frank
Project Start
2004-04-05
Project End
2008-03-31
Budget Start
2005-04-01
Budget End
2006-03-31
Support Year
2
Fiscal Year
2005
Total Cost
$419,682
Indirect Cost
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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El-Nachef, Danny; Oyama, Kyohei; Wu, Yun-Yu et al. (2018) Repressive histone methylation regulates cardiac myocyte cell cycle exit. J Mol Cell Cardiol 121:1-12
Zhang, Yiqiang; Mignone, John; MacLellan, W Robb (2015) Cardiac Regeneration and Stem Cells. Physiol Rev 95:1189-204
Oyama, Kyohei; El-Nachef, Danny; Zhang, Yiqiang et al. (2014) Epigenetic regulation of cardiac myocyte differentiation. Front Genet 5:375
Gago-Lopez, Nuria; Awaji, Obinna; Zhang, Yiqiang et al. (2014) THY-1 receptor expression differentiates cardiosphere-derived cells with divergent cardiogenic differentiation potential. Stem Cell Reports 2:576-91
Sdek, Patima; Oyama, Kyohei; Angelis, Ekaterini et al. (2013) Epigenetic regulation of myogenic gene expression by heterochromatin protein 1 alpha. PLoS One 8:e58319
Ahuja, Preeti; Wanagat, Jonathan; Wang, Zhihua et al. (2013) Divergent mitochondrial biogenesis responses in human cardiomyopathy. Circulation 127:1957-67
Oyama, Kyohei; El-Nachef, Danny; MacLellan, W Robb (2013) Regeneration potential of adult cardiac myocytes. Cell Res 23:978-9
MacLellan, W Robb; Wang, Yibin; Lusis, Aldons J (2012) Systems-based approaches to cardiovascular disease. Nat Rev Cardiol 9:172-84
Weiss, James N; Karma, Alain; MacLellan, W Robb et al. (2012) ""Good enough solutions"" and the genetics of complex diseases. Circ Res 111:493-504

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