Renewing the heart: cardiomyocyte cell cycle regulation

项目总结 心力衰竭仍然是全球发病率和死亡率的主要原因。心脏定位中的一个主要问题 失败是心肌细胞的丧失，以及成年哺乳动物心肌细胞不能自我替代 通过细胞周期重新进入和细胞分裂。与之形成对比的是，蝾螈、斑马鱼和新生哺乳动物心肌细胞 可以通过有丝分裂细胞分裂来再生心脏。先前的研究旨在刺激细胞周期重新启动 成年哺乳动物心肌细胞的进入和增殖已取得部分成功。顽固不化 成年心肌细胞有效进行增殖细胞分裂反映了表观遗传和转录 程序规定了成年心肌细胞状态的多种属性，这些属性为其提供了障碍 增殖能力。这些障碍包括：激活细胞周期抑制物；抑制细胞周期激活物； 一种代谢状态，有利于获得相对较高的氧气水平和大量的线粒体， 丰富和高度组织化的肌原纤维结构，以及高水平的双核。因此，更改 信号通路或单一细胞周期调节因子的过度表达可能不能有效地克服ALL 这些障碍。相反，促进成年心肌细胞的有效增殖可能需要多个- 三管齐下，克服所有这些障碍。尽管我们对表观遗传学和 调控心肌细胞发育的转录程序，我们关于表观遗传和 调控从胎儿到成人心肌细胞状态的复杂转变的转录程序 是有限的。对这些计划的全面深入了解将通过以下方式深入了解机制 我们可以克服成年心肌细胞内的多种障碍，促进细胞周期的重新进入。在 在拟议的研究中，我们将研究关键的表观遗传调节因子DOT1L对心肌细胞周期的调节。 确定驱动心肌细胞周期不同状态的转录因子编码，检查关键字的作用 代谢转录因子HIFs对成人心肌细胞增殖的影响 非典型E2F因子对心肌细胞双核和增殖的影响这些研究的结果将是 开创性和未来的影响，因为我们希望提供特定节点的路线图， 可以靶向地允许成年心肌细胞进行生产性和受控的增殖，从而铺平 心脏再生疗法的方法。 。

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. .