Oxidative DNA Damage Regulates Cardiomyocyte Proliferation

项目摘要 心力衰竭是一种昂贵而致命的疾病，影响着500多万美国人。水平为核心 心力衰竭的病理生理学是成年哺乳动物心脏在损伤后不能再生。在 与成人心脏形成鲜明对比，我们的研究小组证明，新生小鼠的心脏能够 在各种类型的损伤后显著再生，主要由先前存在的 心肌细胞这种再生能力在出生后第7天丧失，这与细胞周期停滞相一致。 大部分心肌细胞。我们的目标是确定上游信号介导的开关， 子宫内增生，肥大的出生后心肌细胞表型，并开发工具， 逆转这个过程。出生后环境的相对高氧血症导致 线粒体氧化代谢和相对于葡萄糖利用对脂肪酸的依赖增加， 能源生产。我们已经证明，这些代谢变化促进反应性增加， 氧自由基（ROS），氧化性DNA损伤，DNA损伤反应的激活，以及细胞周期阻滞。 心肌细胞有趣的是，以尿道为靶点的ROS清除剂延长了出生后的 心肌细胞增殖和DNA损伤减少，但细胞周期停滞最终随之而来。我们的中央 假设线粒体ROS介导的DNA氧化损伤调节心肌细胞周期， 产后心脏因此，在本建议中，我们的目的是研究 心肌细胞周期受DNA损伤和DNA损伤的反应及决定性变化的作用 在线粒体代谢中的作用此外，我们还首次开发了 ROS探测器阵列，针对各种核隔室。我们将使用这些新工具来确定 ROS在心肌细胞核内的空间分布，并据此设计靶向核 清除剂消除心肌细胞的DNA损伤和细胞周期停滞。其长期目标是 该项目是通过重新激活心脏的增殖能力来再生受伤后的成年心脏。 心肌细胞

Project summary Heart failure is a costly and deadly disease affecting over 5 million Americans. At the core of the pathophysiology of heart failure is the inability of the adult mammalian heart to regenerate following injury. In sharp contrast to the adult heart, our group demonstrated that the newborn mouse heart is capable of significant regeneration following various types of injury, mediated primarily by proliferation of preexisting cardiomyocytes. This regenerative capacity is lost by day 7 postnatally, which coincides with cell cycle arrest of the majority of cardiomyocytes. Our objective is to identify the upstream signals that mediate the switch from the hyperplastic intrauterine, to the hypertrophic postnatal cardiomyocyte phenotype, and to develop tools to reverse that process. The relative hyperoxemia of the postnatal environment results in upregulation of mitochondrial oxidative metabolism and an increased reliance on fatty acid relative to glucose utilization for energy production. We have demonstrated that these metabolic changes promote an increase in reactive oxygen species (ROS), oxidative DNA damage, activation of DNA damage response, and cell cycle arrest of cardiomyocytes. Interestingly, mitochondrial-targeted ROS scavengers prolonged the postnatal window of cardiomyocyte proliferation and decreased DNA damage, but cell cycle arrest eventually ensued. Our central hypothesis is that mitochondrial ROS-mediated oxidative DNA damage regulates cardiomyocyte cell cycle in the postnatal heart. Therefore, in this proposal we aim to examine the mechanism of regulation of cardiomyocyte cell cycle by DNA damage and the DNA damage response and determine the role of changes in mitochondrial metabolism in oxidative DNA damage. In addition, we have developed for the first time an array of ROS detectors that target various nuclear compartments. We will use these novel tools to determine the spatial distribution of ROS within cardiomyocytes nuclei, and accordingly design targeted nuclear scavengers to abrogate DNA damage and cell cycle arrest of cardiomyocytes. The long-term goal of this project is to regenerate the adult heart following injury by re-activating the proliferative capacity of cardiomyocytes.