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).

抽象的： 在开发过程中，细胞分裂（增殖或增生）紧密耦合 细胞肿块（肥大），以确保肌细胞大小恒定；但是，在成人心肌细胞中 （ACM），相似的生长信号主要诱导肥厚性生长而没有增殖 同一信号通路被激活。在分子水平上，增生生长与 用E2F转录因子家族调节的细胞周期基因的表达，这些 基因在肥厚性肌细胞中没有上调。尽管有许多描述性研究表征 ACM因响应各种刺激而退出G1或分裂的能力有限，几乎没有数据 解释为什么大多数ACM在刺激时不会进入S阶段。我们已经确定了一本小说 在ACM中沉默G2M/细胞因子基因的机制；即，调节的RB-E2F的组蛋白甲基化 细胞周期基因。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中被上调，并针对E2F依赖性细胞周期基因。我们建议测试是否 这些表观遗传标记的重要性，如果它们针对E2F依赖性细胞周期基因 体内的家庭成员。转基因小鼠中遗传重新激活的细胞周期基因与 重新表达特定组蛋白脱甲基酶，通常仅在增殖胎儿心脏 心肌细胞不是肥大。有趣的是，这些表观遗传变化可能是可逆的事实 建议这可能是“重塑”或“重新编程” ACM的治疗途径 增殖潜力。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H3K9和H3K27组蛋白甲基化是否会将肥厚的回购转化为 成人心肌细胞的增生（AIM 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预防增殖（AIM2）中的作用（AIM2），并确定如何 组蛋白甲基化重塑发生在ACM中及其生理意义（AIM 3）。