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: 7215589
• 负责人: William Robb MacLellan
• 金额: $ 42.29万
• 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/7215589
• 关键词: Adult; Apoptosis; Apoptotic; Binding; Birth; Cardiac; Cardiac Myocytes; Cell Count; Cell Cycle; Cell Cycle Progression; Cell Size; Cells; Complement; Complex; Consensus; DNA-Directed RNA Polymerase; Data; Development; Dissection; Endogenous Factors; Family; Family member; Fetal Development; Fibrosis; G1 Phase; Gene Family; Genetic; Genetic Transcription; Growth; Heart; Heart Hypertrophy; Helix (Snails); Hyperplasia; Hypertrophy; Injury; Knock-out; Lead; Leucine Zippers; Ligands; Link; Mediating; Mitochondria; Mitotic; Molecular; Mus; Muscle Cells; Myocardium; Numbers; Pathway interactions; Pattern; Phosphotransferases; Proliferating; Protein Family; Protein Overexpression; Proteins; RNA Polymerase I; RNA chemical synthesis; Regulation; Respiration; Ribosomal RNA; Role; Sequence-Specific DNA Binding Protein; Signal Transduction; Stress; Tissues; Transgenic Model; Transgenic Organisms; base; c-myc Genes; ear helix; hemodynamics; in vivo; inhibitor/antagonist; interest; member; novel; prevent; programs; response; transcription factor

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（由申请方提供）：心肌细胞显示出两种发育调节的生长形式，即增生性（细胞数量增加）和肥大性生长（细胞大小增加）。在机制水平上，区分肥大性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，因此必须存在功能上将它们联系起来的因素。一种参与调节心肌中增生性和肥大性生长的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作用，我们建立了一种新的诱导型心脏限制性转基因模型，从而我们可以暂时调节Myc在心脏中的活性（MycER）。我们已经证明，Myc单独足以诱导肥大生长和导致细胞周期折返，即使在成年有丝分裂后的心肌细胞。我们的初步数据表明，Myc也是必要的心肌肥大在体内的发展，因为受到Myc空心肌血流动力学应激的结果在细胞凋亡和替代纤维化。这些数据提出了一些有趣的和可验证的假设，Myc在调节心脏生长和生存的作用。 我们假设Myc通过不同的转录程序调节肥大和增生性生长，并且在正常生长中必须防止凋亡。该提案将尝试通过使用MycER小鼠直接评估Myc在肥大性生长中的重要性来从遗传上剖析心脏生长控制，特别是Myc的作用，以确定Myc介导的成年心肌肥大性生长的基础（Aim 1），确定区分Myc诱导的增生性和肥大性生长的分子机制（目的2）通过阐明Myc在调节心肌细胞凋亡中的作用，探讨Myc对正常血流动力学反应的作用机制（目的3）。