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

描述（由申请人提供）：心肌细胞表现出两种发育调节的生长形式，即增生性生长（细胞数量增加）和肥大性生长（细胞大小增加）。在机制层面上，区分肥大性生长和细胞周期进展的信号尚不清楚。然而，由于细胞周期进程与细胞质量密切相关，因此必须存在将它们在功能上联系起来的因素。参与心肌增生和肥大生长调节的一种内源性因子是立即早期转录因子 c-Myc。为了探索其在成人心肌中的具体作用，我们创建了一种新型诱导型心脏限制性转基因模型，通过该模型我们可以暂时调节心脏中的 Myc 活性 (MycER)。我们已经证明，即使在成年有丝分裂后心肌细胞中，单独的 Myc 也足以诱导肥大性生长并导致细胞周期重入。我们的初步数据表明，Myc 对于体内心脏肥大的发展也是必需的，因为使 Myc 缺失的心肌承受血流动力学应激会导致细胞凋亡和替代性纤维化。这些数据提出了许多关于 Myc 在调节心脏生长和存活中的作用的有趣且可检验的假设。 我们假设 Myc 通过不同的转录程序调节肥大性和增生性生长，并且在正常生长中它对于防止细胞凋亡是必要的。该提案将尝试通过使用 MycER 小鼠直接评估 Myc 在肥厚性生长中的重要性来从基因角度剖析心脏生长控制，特别是 Myc 的作用，以确定 Myc 介导的成人心肌肥厚性生长的基础（目标 1），确定区分 Myc 诱导的肥大性生长和肥大性生长的分子机制（目标 2），并通过阐明 Myc 在调节心脏中的作用来探索 Myc 正常血流动力学反应所需的机制。 myocyte apoptosis (Aim 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).