Genetic Dissection of Cardiac Growth: The Role of c-Myc

描述（由申请人提供）：心肌细胞显示两种发育调节的生长形式，即增生（细胞数量增加）和肥厚生长（细胞大小增加）。在机制水平上，区分肥厚生长和细胞周期进程的信号是未知的。然而，由于细胞周期进程与细胞质量密切相关，因此一定有一些因素在功能上将它们联系起来。心肌增生性和肥厚性生长调控的一个内源性因子是直接早期转录因子c-Myc。为了探索其在成人心肌中的具体作用，我们创建了一种新的可诱导的心脏限制性转基因模型，通过该模型我们可以暂时调节Myc在心脏中的活性（MycER）。我们已经证明，即使在成年有丝分裂后心肌细胞中，Myc本身也足以诱导肥厚性生长和引起细胞周期再进入。我们的初步数据表明，Myc对于体内心肌肥厚的发展也是必要的，因为Myc缺失的心肌受到血流动力学应激会导致细胞凋亡和替代纤维化。这些数据提出了一些关于Myc在调节心脏生长和存活中的作用的有趣和可测试的假设。

DESCRIPTION (provided by applicant): 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).