自噬在病毒性心肌炎中的作用机制研究

Autophagy is a highly conserved process existing in eukaryotic cell related to protein and cell organelle degradation. The function of autophagy is involved in intracellular environment stability, organization development and so on a variety of cellular activities. Studies have shown that autophagy can participate and significantly influence the many kinds of disease, such as cancer, neurodegenerative and cardiovascular diseases. We previously found that the autophagy as well as the viral replication and proinflammatory factors increased in myocardial tissue taken from coxsackievirus B3 (CVB3) induced viral myocarditis mice, both of which have been proven to closely related to the disease process in viral myocarditis. Inhibition of autophagy in CVB3 infected cells can obviously reduce the viral replication, suggesting that autophagy may play an important role in the pathogenesis of CVB3 induced viral myocarditis. In this study we are going to apply the shRNA plasmids and small molecular chemical drugs targeting to autophagy. Our purpose is to address the specific mechanism of CVB3 induced autophagy and its related signaling pathways at cellular level. Furthermore, we also want to investigate how autophagy influences the production of inflammatory factors and finally the outcome of disease through NLRP3 inflammasome. Our research not only provides a new view in the research field of viral myocarditis, but also provides potential targets for the clinical treatment of viral myocarditis in the future.

自噬是一种存在于真核细胞内高度保守的蛋白质和细胞器降解过程，与细胞内环境稳定和组织发育等多种细胞活动相关。研究表明自噬参与并显著影响了多种疾病的发生发展，例如癌症、神经变性和心血管疾病等。我们近期研究发现，在柯萨奇病毒 B3(CVB3)诱导的病毒性心肌炎小鼠中，心肌组织的自噬增加，同时病毒复制和促炎因子分泌增加，两者均已被证实与病毒性心肌炎疾病进程密切相关。在CVB3感染的细胞中抑制自噬，可明显减少病毒复制和炎性因子，因此我们推测自噬可能在CVB3诱导的病毒性心肌炎致病过程中起重要作用。本研究我们拟利用自噬下调shRNA质粒和化学小分子药物系统性的研究自噬在病毒性心肌炎中的调控作用机制，包括CVB3诱导自噬的具体机制和相关信号通路，通过NLRP3炎性小体对炎性因子的调控等。本研究将阐明自噬调控病毒性心肌炎全新机制，也有望为病毒性心肌炎的临床治疗提供潜在靶点。

自噬是一种存在于真核细胞内高度保守的蛋白质和细胞器降解过程，与细胞内环境稳定和组织发育等多种细胞活动相关。研究表明自噬参与并显著影响了多种疾病的发生发展，例如癌症、神经变性和心血管疾病等。我们近期研究发现，在柯萨奇病毒 B3(CVB3)诱导的病毒性心肌炎小鼠中，心肌组织的自噬增加，同时病毒复制和促炎因子分泌增加，两者均已被证实与病毒性心肌炎疾病进程密切相关。在CVB3感染的细胞中抑制自噬，可明显减少病毒复制和炎性因子，因此我们推测自噬可能在CVB3诱导的病毒性心肌炎致病过程中起重要作用。本研究我们拟利用自噬下调shRNA质粒和化学小分子药物系统性的研究自噬在病毒性心肌炎中的调控作用机制，包括CVB3诱导自噬的具体机制和相关信号通路，通过NLRP3炎性小体对炎性因子的调控等。本研究将阐明自噬调控病毒性心肌炎全新机制，也有望为病毒性心肌炎的临床治疗提供潜在靶点。