Genetic dissection of Cardiac Conduction System homeostasis and regeneration

摘要 心脏传导系统稳态和再生的基因解剖 心脏传导系统（CCS）是启动和维持有规律的节律性心跳所必需的。 CCS缺陷通常引起心律失常，这是全球发病和死亡的主要原因。CCS 功能障碍可以是遗传的或由于诸如药物毒性或心肌梗塞的状况而获得的。是 有必要阐明CCS稳态的分子机制，以促进 心脏治疗重要的是，由于许多技术上的限制， 挑战Hippo信号传导，一种关键的器官大小控制途径，抑制心肌细胞增殖， 再生然而，Hippo信号在CCS中的作用尚不清楚。在这里，我们将确定是否河马 信号传导调节CCS稳态。此外，我们还将确定Hippo信号转导的调节因子和靶点， CCS。我们的初步观察显示，CCS中Hippo信号的破坏引起心脏 这表明Hippo信号传导在CCS稳态中的重要作用。值得注意的是， Hippo信号在CCS细胞消融后挽救了心脏节律和功能，这表明Hippo信号的抑制 发信号保护CCS免受损害。此外，我们确定了候选的microRNA调控因子， 河马信号的下游目标。在这里，我们打算研究功能和分子调控 通过以下具体目标来研究CCS中Hippo信号传导的机制：1）定义Hippo信号传导 CCS稳态的功能，并阐明了Hippo信号转导抑制保护CCS稳态的机制。 2）鉴定CCS中Hippo信号传导的上游microRNA调节剂，以及3）鉴定CCS中Hippo信号传导的上游microRNA调节剂， Hippo通路的下游靶点，其调节CCS功能。

Abstract Genetic dissection of Cardiac Conduction System homeostasis and regeneration The cardiac conduction system (CCS) is required for initiating and maintaining regular rhythmic heartbeats. CCS defects commonly give rise to arrhythmia, a leading cause of morbidity and death worldwide. CCS dysfunction can be inherited or acquired due to conditions such as drug toxicity or myocardial infarction. It is imperative to elucidate the molecular mechanisms underlying CCS homeostasis to facilitate development of cardiac therapies. Importantly, these mechanisms are poorly understood owing to numerous technical challenges. Hippo signaling, a pivotal organ size control pathway, inhibits cardiomyocyte proliferation and regeneration. However, the role of Hippo signaling in the CCS is unclear. Here we will determine whether Hippo signaling regulates CCS homeostasis. Additionally, we will identify regulators and targets of Hippo signaling in the CCS. Our preliminary observations revealed that disruption of Hippo signaling in the CCS caused cardiac arrhythmias in mice, suggesting an important role of Hippo signaling in CCS homeostasis. Notably, deletion of Hippo signaling rescued cardiac rhythm and function after CCS cell ablation, suggesting that repression of Hippo signaling protects the CCS from damage. In addition, we identified candidate microRNA regulators and downstream targets of Hippo signaling. Here we propose to investigate the function and molecular regulatory mechanism of Hippo signaling in the CCS through in the following specific aims: 1) To define Hippo signaling function in CCS homeostasis and elucidate the mechanism by which repression of Hippo signaling protects the CCS from damage, 2) Identify upstream microRNA regulators of Hippo signaling in the CCS, and 3) Identify downstream targets of the Hippo pathway that modulate CCS function.