Molecular control of cardiac regenerative potential

项目摘要/摘要 在出生前后，哺乳动物经历了最复杂和最深刻的生理和代谢变化 对宫外生活的适应。有趣的是，这一过程伴随着再生组织的丧失。 在包括心脏、皮肤和大脑在内的许多器官中都有潜力。驱动围产期损失的上游信号 器官再生能力在很大程度上是未知的。我们对心脏再生的研究表明，激活心脏 产热途径，如围产期循环甲状腺激素水平升高和肾上腺素能 外温向吸热转变过程中的受体活性抑制心肌细胞的增殖能力和 个体发育和系统发育中的心脏再生(Hirose等人，《科学》2019；Payumo等人，《循环2021》)。 按照这个方向，我们最近进行了初步但耐人寻味的观察，发现另一个产热物质 该通路还调节哺乳动物心肌细胞的更新潜能。在这份提案中，我们将调查 生热组织是否控制着哺乳动物出生后的心肌细胞周期停滞。它们对以下方面的影响 心肌梗死后的心肌细胞再生和心脏修复也将在成年小鼠身上进行测定。 此外，还将研究调节生热器官-心脏串扰的信号分子。 总而言之，我们提出的实验将阐明分子机制和基本原理。 管理获得吸热后器官再生能力的丧失。

Project Summary/Abstract Around birth, mammals undergo the most complex and profound physiologic and metabolic changes for adaptations to the extrauterine life. Intriguingly, this process is accompanied with loss of tissue regenerative potential in many organs including the heart, skin and brain. The upstream signals that drive the perinatal loss of organ regenerative capacity are largely unknown. Our study of heart regeneration suggests that activation of thermogenic pathways such as the perinatal increase of circulating thyroid hormone levels and adrenergic receptor activity during the ectotherm-to-endotherm transition inhibits cardiomyocyte proliferative potential and heart regeneration in ontogeny and phylogeny (Hirose et al., Science 2019; Payumo et al., Circulation 2021). Following this direction, we recently made preliminary yet intriguing observations that another thermogenic pathway also regulates mammalian cardiomyocyte renewal potential. In this proposal, we will investigate whether thermogenic tissues control mammalian cardiomyocyte cell-cycle arrest after birth. Their impact on cardiomyocyte regeneration and heart repair after myocardial infarction will also be determined in adult mice. Furthermore, the signaling molecules mediating the thermogenic organ-heart crosstalk will be examined. Collectively, our proposed experiments will shed lights into the molecule mechanism and fundamental principle governing the loss of organ regenerative capacity after the acquisition of endothermy.