Regulation of Cardiomyocyte Turnover in the Adult Mammalian Heart

成年哺乳动物心脏心肌细胞周转的调节

• 批准号: 9463489
• 负责人: Hesham Sadek
• 金额: $ 40.5万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9463489
• 关键词: Acute; Adult; Age-Years; Aging; Biology; Birth; Cardiac; Cardiac Myocytes; Cardiovascular system; Cell Cycle; Cell Cycle Arrest; Cell Size; Characteristics; Chest; Chimeric Proteins; Competence; DNA Damage; Data; Exposure to; Genetic; Goals; Heart; Heart failure; Homeostasis; Human; Hypoxia; Injury; Ionizing radiation; Lasers; Longevity; Maintenance; Maps; Measurable; Mediating; Mediator of activation protein; Messenger RNA; Microdissection; Mitochondria; Modeling; Muscle Cells; Names; Nature; Neonatal; Oxygen; Pathology; Population; Procollagen-Proline Dioxygenase; Proteins; Radiation Induced DNA Damage; Reactive Oxygen Species; Regulation; Role; Secondary to; Signal Transduction; Tamoxifen; Therapeutic; Time; Transforming Growth Factor beta; Transgenic Mice; Up-Regulation; biological adaptation to stress; cardiac regeneration; insight; mouse model; oxidative DNA damage; postnatal; promoter; public health relevance; regenerative; response; tool; transcriptome sequencing; treatment strategy

 DESCRIPTION (provided by applicant): Regulation of mammalian cardiomyocyte cell cycle has been a central question in cardiovascular biology for decades, secondary to the burden of heart failure. Although the adult heart does not have a significant regenerative potential, it has recently become clear that measurable cardiomyocyte turnover does in fact occur in the adult heart, mediated by proliferation of pre-existing cardiomyocytes. In fact, the rate of cardiomyocyte turnover in the adult human heart is about 2% per year between 20 and 40 years of age, and 0.5 -1% per year thereafter. While this rate of myocyte turnover is insufficient for heart regeneration following injury, it is critical for constant replacement of dead or damaged myocytes. As a result, close to 45% of cardiomyocytes in a human heart are replaced throughout its lifespan. We recently showed that an important mechanism of cell cycle arrest of the majority of cardiomyocytes postnatally is mitochondrial reactive oxygen species (ROS)-mediated oxidative DNA damage, and activation of DNA damage response (DDR). Moreover, we developed the first mouse model to fate map the rare population of cycling cardiomyocytes in the postnatal heart, and we found that these cycling cardiomyocytes are characterized by upregulation of hypoxic stress response and are protected from the oxidative DNA damage. Therefore, we propose to examine the mechanism of cardiomyocyte turnover in the adult mammalian heart using the fate-mapping model that we developed. We will first characterize the dynamics of hypoxic cardiomyocyte turnover in the neonatal, adult and ageing heart. We will also examine the role of DNA damage in regulation of hypoxic cardiomyocyte turnover. Finally, we will investigate the endogenous mechanism of maintenance of hypoxia signaling in cycling cardiomyocytes. Achieving the goals of this proposal will provide new insights into the mechanism of cardiomyocyte turnover in the adult mammalian heart. We hope to exploit these results to develop new strategies to enhance cardiomyocyte renewal in the failing heart.

 描述（由适用提供）：数十年来，哺乳动物心肌细胞周期的调节一直是心血管生物学的核心问题，其次是心力衰竭的燃烧。尽管成人心脏没有显着的再生潜力，但最近很明显，实际上可测量的心肌细胞周转确实发生在成人心脏中，这是由成人人类心脏中既有的心肌细胞周转率的扩散介导的，每年约20至40岁，年龄为0.5 -1％，每年为0.5 -1％。虽然这种肌细胞更新的速率不足以在受伤后心脏再生，但对于持续替换死亡或受损的肌细胞至关重要。结果，在整个生命周期中，人心脏中近45％的心肌细胞被替换。最近，我们表明，大多数心肌细胞的细胞周期停滞在产后大多数是线粒体活性氧（ROS）介导的氧化物DNA损伤和DNA损伤反应（DDR）的激活。此外，我们开发了第一个小鼠模型来绘制产后心脏中罕见的循环心肌细胞的群体，我们发现这些循环心肌细胞的特征是低氧应激反应的上调，并受到了氧化性DNA损害的保护。因此，我们建议使用我们开发的命运模型来检查成人哺乳动物心脏中心肌周转的机制。我们将首先表征新生儿，成人和衰老心脏中低氧心肌细胞更新的动力学。我们还将检查DNA损伤在调节低氧心肌细胞更新中的作用。最后，我们将研究循环心肌细胞中缺氧信号传导的内源性机理。实现该提案的目标将为成人哺乳动物心脏中心肌细胞的机制提供新的见解。我们希望探索这些结果，以制定新的策略，以增强心脏衰竭的心肌细胞更新。