Project 3 - Role of Proline Metabolism in Regulation of Mammalian Cardiomyocyte Proliferation

摘要 (项目3) 脯氨酸代谢在哺乳动物心肌细胞增殖调控中的作用 心力衰竭进展是一个复杂的生物过程，由适应性不良的心肌细胞引起。 对损伤的反应，再加上成人心脏不能替换丢失或受损的心肌细胞。我们的实验室 之前已经概述了新生哺乳动物心脏的再生能力，并概述了几个 调节这一过程的机制。具体地说，我们证明了内生再生能力 新生心脏是由先前存在的心肌细胞的增殖所介导的，当心肌细胞 在出生后几天内退出细胞周期。我们描述了几种调节细胞的基本机制 心肌细胞的周期退出，包括由于增加而发生的自发性DNA损伤 线粒体氧化磷酸化。随后，我们证明了渐进性严重的全身缺氧 可以诱导成年小鼠心脏的心肌细胞增殖，并与减少DNA损伤有关。 这些发现表明，氧代谢是介导出生后心肌细胞的上游信号 在出生后的心脏中循环。有趣的是，我们发现体内的Pro代谢显著上调。 低氧条件下再生的心肌细胞。从机械论的观点来看，我们想要更好地 了解在低氧条件下调节心肌细胞增殖的因素。因此，这项提议将 检测脯氨酸代谢在低氧下心肌细胞适应和增殖调节中的作用 在老鼠和猪身上都是如此。此外，我们还将研究低氧诱导因子(HIF)在调节 新生儿心脏和低氧条件下的脯氨酸代谢和心肌细胞增殖。

ABSTRACT (Project 3) Role of Proline Metabolism in Regulation of Mammalian Cardiomyocyte Proliferation Heart failure progression is a complex biological process that is precipitated by the maladaptive myocardial response to injury, compounded by failure of the adult heart to replace lost or damaged cardiomyocytes. Our lab has previously outlined the regenerative capacity of the newborn mammalian heart and outlined several mechanisms that regulate this process. Specifically, we demonstrate that the endogenous regenerative capacity of the newborn heart is mediated by proliferation of preexisting cardiomyocytes and is lost when cardiomyocytes exit cell cycle within a few days after birth. We described several fundamental mechanisms that regulate cell cycle exit of cardiomyocytes, including spontaneous DNA damage that occurs as a result of increased mitochondrial oxidative phosphorylation. Subsequently, we demonstrated that gradual severe systemic hypoxia can induce cardiomyocyte proliferation in the adult mouse heart and is associated with decreased DNA damage. These finding suggest that oxygen metabolism is an upstream signal that mediates postnatal cardiomyocyte cell cycle in the postnatal heart. Intriguingly, we found that proline metabolism was markedly upregulated in regenerative cardiomyocytes under hypoxic conditions. From a mechanistic standpoint, we want to better understand the factors that regulate cardiomyocyte proliferation under hypoxia. Therefore, this proposal will examine the role of proline metabolism in regulation of cardiomyocyte adaptation and proliferation under hypoxia in both mice and pigs. In addition, we will examine the role of Hypoxia inducible factors (Hifs) in regulation of proline metabolism and cardiomyocyte proliferation in the neonatal heart and under hypoxic conditions.