Renewing the heart: cardiomyocyte cell cycle regulation

更新心脏：心肌细胞细胞周期调节

• 批准号: 10350617
• 负责人: SYLVIA M EVANS
• 金额: $ 86.9万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-15 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10350617
• 关键词: Adult; Automobile Driving; Cardiac Myocytes; Cause of Death; Cell Cycle; Cell Cycle Regulation; Cell Proliferation; Cell division; Code; Complex; Development; Epigenetic Process; Future; Genetic; Genetic Transcription; Goals; Heart; Heart failure; Knowledge; Metabolic; Mitochondria; Mitotic; Morbidity - disease rate; Natural regeneration; Neonatal; Newts; Nodal; Oxygen; Pathway interactions; Proliferating; Property; Repression; Role; Signal Pathway; Structure; Zebrafish; fetal; inhibitor; insight; mortality; overexpression; prevent; programs; regenerative therapy; success; transcription factor

PROJECT SUMMARY Heart failure remains a leading cause of morbidity and mortality worldwide. A major issue in the setting of heart failure is loss of cardiomyocytes, and the inability of adult mammalian cardiomyocytes to replace themselves by cell cycle re-entry and cell division. In contrast, newts, zebrafish and neonatal mammalian cardiomyocytes can undergo mitotic cell division to regenerate the heart. Previous studies aimed at provoking cell cycle re- entry and proliferation of adult mammalian cardiomyocytes have met with partial success. Recalcitrance of adult cardiomyocytes to efficiently undergo proliferative cell division reflects epigenetic and transcriptional programs that dictate multiple properties of the adult cardiomyocyte state that provide barriers to their proliferative ability. These barriers include: activation of cell cycle inhibitors; repression of cell cycle activators; a metabolic state geared toward availability of relatively high oxygen levels with high numbers of mitochondria, abundant and highly organized myofibrillar structure, and high levels of binucleation. Thus, alteration of a signaling pathway or overexpression of a single cell cycle regulator may not be able to efficiently overcome all these obstacles. Instead, promoting efficient proliferation of adult cardiomyocytes is likely to require a multi- pronged approach, where each of these obstacles is overcome. Although we know much about epigenetic and transcriptional programs regulating cardiomyocyte development, our knowledge concerning epigenetic and transcriptional programs regulating the complex transitions from the fetal to adult cardiomyocyte state is limited. A comprehensive in depth understanding of these programs will give insight into mechanisms by which we can overcome multiple barriers within adult cardiomyocytes to promote cell cycle re-entry. In the proposed studies, we will examine cardiomyocyte cell cycle regulation by a key epigenetic regulator, Dot1L, identify transcription factor codes driving distinct states of cardiomyocyte cell cycle, examine effects of key metabolic transcription factors, HIFs, on adult cardiomyocyte proliferation, and investigate the potential role of atypical E2F factors on cardiomyocyte binucleation and proliferation. Results of these studies will be groundbreaking and be of future impact in that we hope to provide a roadmap of specific nodal points that can be targeted to allow the adult cardiomyocyte to undergo productive and regulated proliferation, thus paving the way for regenerative therapies for the heart. .

项目摘要 心力衰竭仍然是全球发病率和死亡率的主要原因。心脏环境中的主要问题 失败是心肌细胞的丧失，而成年哺乳动物心肌细胞的无力取代 通过细胞周期再进入和细胞分裂。相比之下，NEWT，斑马鱼和新生儿哺乳动物心肌细胞 可以进行有丝分裂细胞分裂以再生心脏。先前的研究旨在引起细胞周期的重新启动 成年哺乳动物心肌细胞的进入和扩散已经取得了部分成功。重新稳定 成年心肌细胞有效地经历增生性细胞分裂反映表观遗传和转录 决定成人心肌细胞状态多种特性的程序，该状态为其提供障碍 增殖能力。这些障碍包括：细胞周期抑制剂的激活；抑制细胞周期激活剂； 一种代谢状态，旨在供应相对较高的氧气水平，线粒体数量较高， 丰富且高度有条理的肌原纤维结构和高水平的双核结构。因此，改变 单个细胞周期调节器的信号通路或过表达可能无法有效克服所有 这些障碍。相反，促进成人心肌细胞的有效增殖可能需要多种多样 克服这些障碍中的每一个。尽管我们对表观遗传学了解很多 调节心肌细胞发展的转录计划，我们关于表观遗传和的知识 转录程序调节从胎儿到成人心肌细胞状态的复杂过渡 有限。深入了解这些程序的深入了解将使您深入了解机制 我们可以克服成人心肌细胞内的多个障碍，以促进细胞周期重新进入。在 拟议的研究，我们将通过关键的表观遗传调节剂DOT1L检查心肌细胞周期调节 确定转录因子代码驱动驱动心肌细胞细胞周期不同状态，检查钥匙的效果 代谢转录因子，HIF，成人心肌细胞增殖，并研究 心肌细胞双核和增殖的非典型E2F因子。这些研究的结果将是 开创性和未来影响，我们希望提供特定的节点的路线图 可以针对目标，使成人心肌细胞进行生产和调节的增殖，从而铺路 心脏再生疗法的方式。 。