Renewing the heart: cardiomyocyte cell cycle regulation

项目摘要 心力衰竭仍然是世界范围内发病率和死亡率的主要原因。一个主要的问题，在设置的心 衰竭是心肌细胞的丧失，成年哺乳动物心肌细胞不能自我替代， 通过细胞周期的重新进入和细胞分裂。相反，蝾螈、斑马鱼和新生哺乳动物的心肌细胞 可以通过有丝分裂来再生心脏以前的研究旨在激发细胞周期的重新- 成年哺乳动物心肌细胞的进入和增殖已经取得了部分成功。不顺应性 成年心肌细胞有效地进行增殖细胞分裂反映了表观遗传和转录 这些程序决定了成年心肌细胞状态的多种特性，这些特性为它们的生长提供了障碍。 增殖能力这些障碍包括：细胞周期抑制剂的激活;细胞周期激活剂的抑制; 一种代谢状态，适合于相对高的氧气水平和大量线粒体的可用性， 丰富和高度组织化的肌原纤维结构，以及高水平的双核化。因此，A 单个细胞周期调节因子的信号传导途径或过表达可能不能有效地克服所有 这些障碍。相反，促进成年心肌细胞的有效增殖可能需要多方面的治疗。 这些障碍中的每一个都被克服了。虽然我们对表观遗传学了解很多， 调节心肌细胞发育的转录程序，我们关于表观遗传和 调节从胎儿到成人心肌细胞状态复杂转变的转录程序 是有限的。对这些程序的全面深入理解将使我们深入了解以下机制： 我们可以克服成年心肌细胞内的多种障碍，促进细胞周期重新进入。在 提出的研究，我们将研究心肌细胞细胞周期调控的一个关键表观遗传调节，Dot 1 L， 识别驱动心肌细胞细胞周期不同状态的转录因子编码，检测关键的 代谢转录因子HIF对成年心肌细胞增殖的影响，并研究HIF的潜在作用。 非典型E2 F因子对心肌细胞双核化和增殖的影响。这些研究的结果将 我们希望提供一个具体节点的路线图， 可以靶向使成年心肌细胞进行生产性和调节性增殖， 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. .