Genetic Analysis of Cardiac Growth

心脏生长的遗传分析

• 批准号: 8048232
• 负责人: William Robb MacLellan
• 金额: $ 38.5万
• 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 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8048232
• 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; Recruitment Activity; Retinoblastoma Genes; Role; S Phase; Secondary to; Serum; Signal Pathway; Signal Transduction; Stimulus; Testing; Therapeutic; Transcription factor genes; Transgenic Mice; Up-Regulation; 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

DESCRIPTION (provided by applicant): 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 response 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). PUBLIC HEALTH RELEVANCE: Myocardial regeneration to restore cardiac muscle mass after injury has been proposed as a means to prevent the development of congestive heart failure for decades. Developing strategies that promote dedifferentiation and proliferation of the endogenous cardiac myocytes holds great promise as a therapeutic strategy. The studies in this application will address critical deficiencies in our current knowledge of cardiac growth and will identify specific molecular pathways amenable to directed therapies.

描述（由申请人提供）：在发育过程中，细胞分裂（增殖或增生）紧密耦合到细胞质量（肥大）的积累，以确保肌细胞大小是恒定的；但是，在成年心脏肌细胞（ACM）中，即使许多相同的信号通路被激活，相似的生长信号主要诱导肥厚性生长而无需增殖。在分子水平上，虽然增生生长与由E2F转录因子家族调节的一组细胞周期基因的表达有关，但这些基因在肥厚性心肌细胞中并未上调。尽管许多描述性研究表征了ACM退出G1或响应各种刺激的有限能力，但几乎没有数据来解释为什么大多数ACM在刺激时不会进入S相。我们已经确定了一种使ACM中的G2M/细胞因子基因沉默的新机制。即，RB-E2F调节细胞周期基因的组蛋白甲基化。我们表明，与稳定基因沉默相关的两个主要组蛋白修饰在ACM中上调，并针对E2F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针对体内RB家族成员靶向E2F依赖性细胞周期基因。转基因小鼠中遗传重新激活的细胞周期基因与特定组蛋白脱甲基酶的重新表达有关，通常仅在增殖的胎儿心肌细胞而不是肥大中看到。有趣的是，这些表观遗传变化可能是可逆的事实表明，这可能是“重塑”或“重编程” ACM的治疗途径，以恢复其增殖潜力。我们将通过确定逆转H3K9和H3K27组蛋白是否会转化成人心肌心肌增生的肥厚型反应（目标1），从而探索组蛋白甲基化在限制ACM增殖中的重要性（AIM 1），从而确定了ACMS中靶向甲基甲基甲基甲基甲基甲基甲基甲基化的作用（探测甲基甲基甲基甲基化的作用）发生在ACM中及其生理意义（AIM 3）。 公共卫生相关性：提议在受伤后恢复心脏肌肉质量的心肌再生，以防止数十年来发展充血性心力衰竭的一种手段。开发促进内源性心肌细胞的去分化和扩散的策略具有巨大的希望作为治疗策略。该应用程序中的研究将解决我们目前对心脏增长知识的关键缺陷，并将确定可符合定向疗法的特定分子途径。