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: 9240660
• 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/9240660
• 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(由申请人提供)：几十年来，哺乳动物心肌细胞周期的调节一直是心血管生物学的中心问题，仅次于心力衰竭的负担。尽管成人心脏没有明显的再生潜力，但最近发现，在成人心脏中确实发生了可测量的心肌细胞周转，这是由先前存在的心肌细胞的增殖介导的。事实上，成人心脏的心肌细胞周转率在20-40岁之间每年约为2%，此后每年约为0.5%-1%。虽然这种心肌细胞周转率不足以使损伤后的心脏再生，但对于死亡或受损的心肌细胞的持续更新是至关重要的。结果，人类心脏中近45%的心肌细胞在整个生命周期内被替换。我们最近发现，线粒体活性氧(ROS)介导的DNA氧化损伤和DNA损伤反应(DDR)的激活是大多数生后心肌细胞细胞周期停滞的重要机制。此外，我们建立了第一个小鼠模型来定位出生后心脏中罕见的循环心肌细胞群，我们发现这些循环心肌细胞的特征是低氧应激反应上调，并受到氧化DNA损伤的保护。因此，我们建议使用我们开发的命运映射模型来研究成年哺乳动物心脏中心肌细胞周转的机制。我们将首先描述缺氧心肌细胞在新生儿、成人和衰老心脏中的周转动力学。我们还将研究DNA损伤在低氧心肌细胞周转调节中的作用。最后，我们将探讨循环心肌细胞维持低氧信号的内源性机制。实现这一建议的目标将为成年哺乳动物心脏中心肌细胞周转的机制提供新的见解。我们希望利用这些结果来开发新的策略来加强衰竭心脏的心肌细胞更新。