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

描述(申请人提供)：心肌细胞表现出两种发育调节的生长形式，即增生性(细胞数量增加)和肥厚性生长(细胞大小增加)。在机制水平上，区分肥大生长和细胞周期进展的信号是未知的。然而，由于细胞周期进程与细胞质量密切相关，一定有一些因素在功能上将它们联系在一起。参与调控心肌肥大和增生性生长的内源性因子之一是即刻早期转录因子c-Myc。为了探索其在成人心肌中的作用，我们建立了一种新的可诱导的心脏限制性转基因模型，在该模型中，我们可以暂时调节心脏中Myc的活性(MycER)。我们已经证明，Myc本身足以诱导肥大生长和引起细胞周期重新进入，甚至在成年有丝分裂后的心肌细胞中也是如此。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，因为使Myc缺失的心肌承受血流动力学压力会导致细胞凋亡和替代性纤维化。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验证的假说。 我们假设Myc通过不同的转录程序调节肥大和增生性生长，并且它在正常生长中是必要的，以防止细胞凋亡。这项建议将试图通过使用MycER小鼠直接评估Myc在肥大生长中的重要性来从遗传学上剖析心肌生长控制，特别是Myc的作用，以确定Myc介导的成人心肌肥大生长的基础(目标1)，确定区分Myc诱导的肥大生长和肥大生长的分子机制(目标2)，并通过阐明Myc在调节心肌细胞凋亡中的作用来探索Myc需要正常血流动力学反应的机制(目标3)。

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).