Genetic Analysis of Cardiac Growth

心脏生长的遗传分析

• 批准号: 8518180
• 负责人: William Robb MacLellan
• 金额: $ 36.77万
• 依托单位: UNIVERSITY OF WASHINGTON
• 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 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8518180
• 关键词: Address; Adult; Cardiac; Cardiac Myocytes; Cell Cycle; Cell Cycle Proteins; Cell division; Cells; Complex; Congestive Heart Failure; Coupled; Cytokinesis; Data; Development; Ensure; Epigenetic Process; Family; Family member; Figs - dietary; Funding; Gene Expression; Gene Silencing; Genes; Growth; Heart; Heterochromatin; Histones; Hyperplasia; Hypertrophy; In Vitro; Injury; Knowledge; Link; Mediating; Methylation; Mitosis; Modeling; Molecular; Muscle Cells; Myocardial; Myocardium; Natural regeneration; Pathway interactions; Physiological; Proliferating; Proteins; Public Health; Recruitment Activity; Retinoblastoma Genes; Role; S Phase; Secondary to; Serum; Signal Pathway; Signal Transduction; Stimulus; Testing; Therapeutic; Transcription factor genes; Transgenic Mice; Up-Regulation; abstracting; c-myc Genes; cdc Genes; constriction; fetal; genetic analysis; histone modification; in vivo; muscle form; novel; overexpression; physiologic model; pressure; prevent; promoter; response; restoration; transcription factor

Abstract: During development, cell division (proliferation or hyperplasia) is tightly coupled to the accumulation of cell mass (hypertrophy) to ensure that myocyte size is constant; however, in adult cardiac myocytes (ACMs), similar growth signals primarily induce hypertrophic growth without proliferation even though many of the same signaling pathways are activated. At a molecular level, while hyperplastic growth is associated with the expression of a panel of cell cycle genes regulated by the E2F family of transcription factors, these genes are not upregulated in hypertrophic myocytes. Despite numerous descriptive studies characterizing the limited ability of ACMs to exit G1 or divide in response to various stimuli, almost no data exists to explain why the majority of ACMs do not enter S phase when stimulated. We have identified a novel mechanism for silencing G2M/cytokinesis genes in ACMs; namely, histone methylation of Rb-E2F regulated cell cycle genes. We show that the two major histone modifications associated with stable gene silencing are upregulated in ACMs and targeted to E2F-dependent cell cycle genes. We propose to test if the importance of these epigenetic marks and if they are targeted to E2F-dependent cell cycle genes by Rb family members in vivo. Genetically reactivating cell cycle genes in transgenic mice is associated with the reexpression of specific histone demethylases, something normally seen only in proliferating fetal cardiac myocytes not hypertrophy. Interestingly, the fact that these epigenetic changes might be reversible suggests that this might be a therapeutic avenue to "remodel" or "reprogram" ACMs to restore their proliferative potential. We will explore the importance of histone methylation in limiting ACM proliferation by determining if reversing H3K9 and H3K27 histone methylation converts a hypertrophic reposnse to hyperplasia in adult cardiac myocytes (Aim 1), determining the factors that target histone methylations in ACMs and their role in silencing cell cycle genes and preventing proliferation (Aim2) and determining how histone methylation remodeling occurs in ACMs and its physiologic significance (Aim 3).

摘要： 在发育过程中，细胞分裂（增殖或增生）与细胞周期的积累紧密相关。 细胞质量（肥大），以确保肌细胞大小恒定;然而，在成人心肌细胞中， （ACM），类似的生长信号主要诱导肥大性生长而不增殖，尽管许多生长信号在细胞中的表达是不稳定的。 相同的信号通路被激活。在分子水平上，虽然增生性生长与 随着一组由E2 F家族转录因子调控的细胞周期基因的表达， 基因在肥大肌细胞中不上调。尽管有许多描述性研究 ACM退出G1或分裂的能力有限，几乎没有数据存在， 解释为什么大多数ACM在刺激时不进入S期。我们发现了一本小说 在ACM中沉默G2 M/胞质分裂基因的机制;即，Rb-E2 F的组蛋白甲基化调节 细胞周期基因我们发现两个主要的组蛋白修饰与稳定的基因沉默有关， 在ACM中上调并靶向E2 F依赖性细胞周期基因。我们建议测试 这些表观遗传标记的重要性以及它们是否被Rb靶向E2 F依赖性细胞周期基因 家人在体内。转基因小鼠中的遗传再激活细胞周期基因与 特异性组蛋白去甲基化酶的重新表达，这通常仅见于增殖的胎儿心脏， 肌细胞不肥大。有趣的是，这些表观遗传变化可能是可逆的， 表明，这可能是一种治疗途径，“改造”或“重新编程”ACM，以恢复其 增殖潜能我们将探讨组蛋白甲基化在限制ACM增殖中的重要性， 确定逆转H3 K9和H3 K27组蛋白甲基化是否将肥大性反应转化为 目的1：确定靶向组蛋白甲基化的因素， ACM及其在沉默细胞周期基因和防止增殖（Aim 2）中的作用，并确定如何 组蛋白甲基化重塑发生在ACM及其生理意义（目的3）。