Oxidative DNA Damage Regulates Cardiomyocyte Proliferation

项目总结 心力衰竭是一种代价高昂且致命的疾病，影响着500多万美国人。在这个问题的核心 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……里面 与成人心脏形成鲜明对比的是，我们的团队证明了新生的老鼠心脏有能力 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吻合 大多数心肌细胞。我们的目标是确定传递切换的上行信号 子宫内增生性疾病，到肥大的出生后心肌细胞表型，并开发工具来 扭转这一过程。出生后环境的相对高氧血症导致血管紧张素转换酶 线粒体氧化代谢和对脂肪酸的依赖增加相对于葡萄糖的利用 能源生产。我们已经证明，这些代谢变化促进了反应性的增加。 氧物种(ROS)、DNA氧化损伤、DNA损伤反应的激活和细胞周期停滞 心肌细胞。有趣的是，线粒体靶向的ROS清道夫延长了出生后窗口 心肌细胞增殖，DNA损伤减少，但细胞周期最终停止。我们的中央 假说线粒体ROS介导的DNA氧化损伤调节心肌细胞周期 出生后的心脏。因此，在这项建议中，我们的目标是研究监管机制 DNA损伤对心肌细胞周期和DNA损伤反应的影响及决定作用 线粒体代谢中的氧化DNA损伤。此外，我们还首次开发了一种 ROS探测器阵列瞄准不同的核隔间。我们将使用这些新颖的工具来确定 ROS在心肌细胞核内的空间分布，并据此设计靶向细胞核 清除心肌细胞DNA损伤和细胞周期停滞的清道夫。这样做的长期目标是 该项目是通过重新激活心肌细胞的增殖能力来再生损伤后的成人心脏 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.