Regulation of Cardiomyocyte Turnover in the Adult Mammalian Heart

 描述（由申请人提供）：哺乳动物心肌细胞细胞周期的调节几十年来一直是心血管生物学的中心问题，仅次于心力衰竭的负担。虽然成人心脏不具有显著的再生潜力，但最近已经清楚的是，可测量的心肌细胞周转实际上确实发生在成人心脏中，由预先存在的心肌细胞的增殖介导。事实上，成年人心脏中心肌细胞更新的速率在20至40岁之间为每年约2%，此后为每年0.5 - 1%。虽然这种肌细胞更新率不足以在损伤后进行心脏再生，但它对于死亡或受损肌细胞的不断替换至关重要。因此，人类心脏中近45%的心肌细胞在其整个生命周期中被替换。我们最近发现，大多数心肌细胞的细胞周期停滞的一个重要机制是线粒体活性氧（ROS）介导的氧化DNA损伤，并激活DNA损伤反应（DDR）。此外，我们开发了第一个小鼠模型来命运映射出生后心脏中罕见的循环心肌细胞群体，我们发现这些循环心肌细胞的特征在于缺氧应激反应的上调，并受到保护免受氧化DNA损伤。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。我们将首先描述新生儿、成人和老年心脏中缺氧心肌细胞周转的动力学特征。我们还将研究DNA损伤在缺氧心肌细胞更新调控中的作用。最后，我们将探讨维持缺氧信号在循环心肌细胞的内源性机制。实现这一目标的建议将提供新的见解，在成年哺乳动物心脏心肌细胞周转的机制。我们希望利用这些结果来开发新的策略来增强衰竭心脏中的心肌细胞更新。

 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.