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(申请人提供)：在发育过程中，细胞分裂(增殖或增殖)与细胞团(肥大)的积累紧密相连，以确保心肌细胞大小恒定；然而，在成人心肌细胞(ACM)中，相似的生长信号主要诱导肥大生长而不增殖，即使许多相同的信号通路被激活。在分子水平上，虽然增生性生长与一组受E2F家族转录因子调控的细胞周期基因的表达有关，但这些基因在肥大的心肌细胞中并没有上调。尽管许多描述性研究描述了ACM对各种刺激反应退出G1或分裂的能力有限，但几乎没有数据可以解释为什么大多数ACM在受到刺激时没有进入S阶段。我们已经确定了一种新的机制来沉默ACM中的G2M/胞质分裂基因，即Rb-E2F调节的细胞周期基因的组蛋白甲基化。我们发现，与稳定的基因沉默相关的两个主要组蛋白修饰在ACM中上调，并针对依赖E2F的细胞周期基因。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家族成员依赖于E2F的细胞周期基因。在转基因小鼠中，基因重新激活细胞周期基因与特异组蛋白去甲基酶的重新表达有关，这种情况通常只在增殖的胎儿心肌细胞中出现，而不是肥大。有趣的是，这些表观遗传学改变可能是可逆的，这表明这可能是一种治疗途径，可以“重塑”或“重新编程”急性髓细胞，以恢复其增殖潜力。我们将通过确定逆转H3K9和H3K27组蛋白甲基化是否将成人心肌细胞肥大反应转化为增殖(目标1)、确定针对ACM中组蛋白甲基化的因素及其在沉默细胞周期基因和防止增殖中的作用(AIM2)以及确定组蛋白甲基化重塑如何在ACM中发生及其生理学意义(AIM2)来探讨组蛋白甲基化在限制ACM增殖中的重要性(AIM2)。 公共卫生相关性：几十年来，心肌再生以恢复损伤后的心肌质量被认为是防止充血性心力衰竭发展的一种手段。开发促进内源性心肌细胞去分化和增殖的策略有望成为一种治疗策略。这项应用中的研究将解决我们目前对心脏生长知识的严重不足，并将确定适合定向治疗的特定分子途径。