Role of cGAS-STING in cardiomyocyte cell cycle regulation

项目摘要 心力衰竭进展是一个复杂的生物过程，是由适应不良引起的 心肌对损伤的反应，再加上成人心脏不能取代丢失或受损的心脏 心肌细胞。我们的实验室之前已经概述了新生儿的再生能力 并概述了调节这一过程的几种机制。具体来说，我们 证明新生儿心脏的内源性再生能力是由 原存在的心肌细胞的增殖，当心肌细胞退出细胞周期时 出生后几天。我们描述了调节细胞周期退出的几种基本机制 包括心肌细胞自发性DNA损伤，这是由于 线粒体氧化磷酸化。我们还证明了DNA损伤会激活DNA 损伤反应(DDR)，介导心肌细胞周期停滞，从而抑制 延缓心肌细胞增殖窗口期。我们还研究了其他潜力 DNA损伤的后果，即形成游离细胞质的微核 在有丝分裂过程中，通常由于DNA损伤而产生的DNA。我们的初步结果表明， 在细胞周期停止时，在心肌细胞中检测到微核。我们还发现， DNA传感通路cGAS-STING在出生后的心脏中也在相同的时间范围内被诱导。 有趣的是，抑制cGAS会导致心肌细胞出生后窗口的延长 扩散。因此，本项目将重点研究心肌细胞内cGAS-STING在心肌中的作用。 心脏再生的调节。我们将研究cGAS-STING的激活机制 心肌细胞，抑制cGAS-sting对心肌细胞增殖的影响，以及 心肌细胞中调节cGAS功能的下游机制。

Project Summary 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. We also demonstrated that DNA damage activates DNA damage response (DDR), which mediates cell cycle arrest of cardiomyocytes whereby inhibitors of DDR prolong the window of cardiomyocyte proliferation. We also examined other potential consequences of DNA damage, namely the formation of micronuclei, which is free cytoplasmic DNA that often results from DNA damage during mitosis. Our preliminary results indicate that the micronuclei are detected in cardiomyocytes at the time of cell cycle arrest. We also found that the DNA sensing pathway cGAS-STING is induced in the postnatal heart within the same timeframe. Intriguingly, inhibiting cGAS results in prolongation of the postnatal window of cardiomyocyte proliferation. Therefore, this project will focus on the role of intra-cardiomyocyte cGAS-STING in regulation of heart regeneration. We will examine the mechanism of activation of cGAS-STING in cardiomyocytes, the effect of inhibiting cGAS-STING on cardiomyocyte proliferation, and the downstream mechanisms that regulate cGAS function in cardiomyocytes.