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

心脏生长的基因剖析：c-Myc 的作用

• 批准号: 6776638
• 负责人: William Robb MacLellan
• 金额: $ 41.48万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-05 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6776638
• 关键词: apoptosis; biological signal transduction; cardiac myocytes; cardiogenesis; cell cycle; cell growth regulation; developmental genetics; gene expression; hemodynamics; histology; hyperplasia; hypertrophic myocardiopathy; hypertrophy; laboratory mouse; laboratory rat; protooncogene

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).

描述（由申请人提供）：心肌细胞表现出两种受发展调节的生长形式，即增生（细胞数增加）和肥厚性生长（细胞大小增加）。在机械水平上，区分肥厚性生长与细胞周期进程的信号尚不清楚。但是，由于细胞周期的进程与细胞量密切相关，因此必须有一个因素，在功能上将其联系起来。与心脏肌肉增生和肥厚性生长的调节有关的一个内源性因子是早期转录因子C-Myc。为了探索其在成人心肌中的作用，我们创建了一种新型的诱导性心脏限制性转基因模型，从而可以在心脏（mycer）中暂时调节MYC活性。我们已经证明，即使在成年有丝分裂后心肌细胞中，仅MYC就足以诱导肥厚的生长并引起细胞周期再入。我们的初步数据表明，MYC对于体内心脏肥大的发展也是必要的，因为使Myc-Null心肌受到血液动力学应激会导致细胞凋亡和替代纤维化。这些数据提出了关于MYC在调节心脏增长和生存中的作用的一些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厚性和增生性生长，并且在正常生长中必须进行预防凋亡。该提议将尝试通过直接评估MYC在肥大性生长中的重要性，通过使用Mycer小鼠来确定MYC介导的成年心肌中肥大性生长的基础（AIM 1），并确定MyC诱导的多型和肥大症的机制（AIL 2），并确定Myc介导的肥大性生长（AIL 2），并试图通过直接评估MYC在肥大性生长中的重要性，从而试图在遗传上剖析心脏生长的控制，并确定MyC介导的肥大性生长（AIL 2），并探索了多余的AID 2）血流动力学反应通过阐明MYC在调节心肌细胞凋亡中的作用（AIM 3）。