Molecular control of cardiac regenerative potential

项目总结/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， 适应子宫外的生活。有趣的是，这个过程伴随着组织再生的损失。 包括心脏、皮肤和大脑在内的许多器官中的潜力。导致围产期死亡的上游信号 器官的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， 产热途径，如围产期循环甲状腺激素水平的增加和肾上腺素能 在外温-吸热转变期间的受体活性抑制心肌细胞增殖潜力， 个体发育和胚胎发育中的心脏再生（Hirose等人，Science 2019; Payumo等人，Circulation 2021）。 沿着这个方向，我们最近进行了初步但有趣的观察， 这条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 产热组织是否控制出生后哺乳动物心肌细胞周期停滞。它们在这方面的影响 还将在成年小鼠中测定心肌梗塞后的心肌细胞再生和心脏修复。 此外，将检查介导产热器官-心脏串扰的信号分子。 总的来说，我们的实验将揭示分子机制和基本原理 控制获得恒温动物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.