Oxidative DNA Damage Regulates Cardiomyocyte Proliferation

DNA 氧化损伤调节心肌细胞增殖

基本信息

批准号：
9921473
负责人：
LUKE I. SZWEDA
金额：
$ 79.04万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9921473
关键词：
Address Adult Affect American Base Excision Repairs Birth Cardiac Myocytes Cell Cycle Cell Cycle Arrest Cell Cycle Progression Cell Cycle Regulation Cell Nucleus Cell Respiration DNA DNA Damage DNA Repair DNA lesion Data Detection Disease Environment Event Fatty Acids Fibrosis Free Radicals Fresh Tissue Functional disorder Genes Glucose Goals Heart Heart failure Hyperplasia Hypertrophy Imaging Techniques Injury Link Mediating Metabolic Mitochondria Mitosis Mus Natural regeneration Neonatal Newborn Infant Nuclear Oxidative Phosphorylation Oxygen Pathway interactions Phenotype Process Production Proliferating Pyruvate Reactive Oxygen Species Regulation Respiration Role Signal Transduction Spatial Distribution Testing Therapeutic Time Up-Regulation anaerobic glycolysis base cardiac regeneration cost design detector mitochondrial metabolism novel overexpression oxidation oxidative DNA damage postnatal postnatal development prevent regenerative repair enzyme repaired response tool

项目摘要

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.

项目概要心力衰竭是一种昂贵且致命的疾病，影响着超过 500 万美国人。其核心是心力衰竭的病理生理学是成年哺乳动物心脏受伤后无法再生。在与成年小鼠的心脏形成鲜明对比，我们的研究小组证明，新生小鼠的心脏能够各种类型损伤后的显着再生，主要由先前存在的增殖介导心肌细胞。这种再生能力在出生后第 7 天丧失，这与细胞周期停滞一致大多数心肌细胞。我们的目标是识别调解从子宫内增生、出生后心肌细胞肥厚表型，并开发工具扭转这个过程。产后环境的相对高氧血症导致线粒体氧化代谢以及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会促进反应性的增加氧 (ROS)、氧化性 DNA 损伤、DNA 损伤反应的激活以及细胞周期停滞心肌细胞。有趣的是，针对线粒体的 ROS 清除剂延长了产后窗口心肌细胞增殖并减少了 DNA 损伤，但最终出现了细胞周期停滞。我们的中央假设线粒体 ROS 介导的氧化 DNA 损伤调节心肌细胞周期产后心脏。因此，在本提案中，我们旨在研究监管机制心肌细胞的细胞周期由DNA损伤和DNA损伤反应的变化而决定作用线粒体代谢中DNA氧化损伤。此外，我们还首次开发了针对各种核区室的 ROS 探测器阵列。我们将使用这些新颖的工具来确定心肌细胞核内ROS的空间分布，并相应地设计靶向核清除剂可消除心肌细胞的 DNA 损伤和细胞周期停滞。本次活动的长远目标该项目的目的是通过重新激活心脏的增殖能力来再生受伤后的成人心脏心肌细胞。