USP38调控TBK1/Akt信号通路在心力衰竭小鼠室性心律失常中的作用及机制研究

心力衰竭（心衰）患者猝死的主要原因是室性心律失常。细胞内信号转导通路介导的电重构和结构重构是心衰后室性心律失常的重要发生机制。TANK结合激酶1（TBK1）/蛋白激酶B（Akt）信号通路在心脏重构中具有重要调节作用。文献提示泛素特异性蛋白酶38（USP38）可通过调控TBK1活性发挥抗病毒作用。我们前期研究证实心衰心脏组织中USP38表达显著上调，并且在血管紧张素II诱导的原代心肌细胞中沉默USP38基因可抑制TBK1/Akt信号通路，逆转心肌细胞肥大和心肌离子通道表达异常，提示USP38可能通过TBK1/Akt信号对心衰后室性心律失常发挥重要调控作用。然而，目前尚无研究报道USP38对心衰后室性心律失常的影响。本项目拟从电重构和结构重构的角度，在整体动物水平和细胞水平上，阐明USP38通过TBK1/Akt信号通路调控心衰后室性心律失常的作用机制，以期发现防治心衰后室性心律失常的新靶点。

The leading cause of sudden cardiac death in patients with heart failure (HF) is ventricular arrhythmia. Electrical and structural remodeling mediated by intracellular signaling pathways are the main mechanisms underlying ventricular arrhythmia after HF. Among diverse signal transduction pathways, the TANK binding kinase 1 (TBK1)/protein kinase B (PKB, also known as Akt) signaling pathway plays a profound regulatory role in cardiac remodeling. Ubiquitin specific protease 38 (USP38) has been shown to plays an antiviral role in the pathophysiological process by regulating TBK1 activity. Our preliminary experiments confirmed that the expression of USP38 was significantly up-regulated in the HF tissues. Moreover, the silencing of USP38 gene in primary cardiomyocytes which have been induced hypertrophic by angiotensin II（Ang II）can inhibit TBK1/Akt signaling pathway and reverse the cardiac hypertrophy as well as increase the mRNA expression of ion channels. These evidences suggest that USP38 may regulate ventricular arrhythmia after HF through TBK1/Akt signaling pathway. However, the effects and the underlying mechanisms of USP38 on ventricular arrhythmia after HF have not yet been reported. Therefore, the present proposal intends to elucidate the mechanism of USP38 regulating ventricular arrhythmia after HF through TBK1/Akt signal pathway from the perspective of electrical reconstruction and structural reconstruction at the overall animal and cell level, aiming to provide a new target for the prevention and treatment of ventricular arrhythmia after HF.