Sirt6通过调节自噬形成参与肺纤维化发病的机制研究

Idiopathic pulmonary fibrosis (IPF) is a chronic and ultimately fatal interstitial lung disease with unknown pathogenesis. Currently, there is no effective therapeutic approach for the treatment of IPF. mTOR signaling, autophagy and SIR2-Like Protein 6 have been suggested to play a role in the fibrogenesis. Our published studies have shown that activated mTOR signaling is present in lung tissues from patients with IPF, and the hyperactivated mTOR signaling can inhibit autophagy during pulmonary fibrogenesis. Very recently, we observed a decreased expression of SIR2-Like Protein 6 (Sirt6) in human lung myfibroblasts, and the decreased Sirt6 expression is associated with mTOR signaling activation and deficiency of autophagy. Based on these findings, we hypothesize that a decreased expression of Sirt6 leads to activation of mTOR signaling which inhibit autophagy and thus promotes pulmonary fibrosis. Therefore, in this project we aim to investigate the role of the Sirt6-mTOR-Autophagy axis in development of IPF. This study will not only help us to understand the pathogenesis of IPF but also aid to search for novel therapeutics for the diseases.

特发性肺纤维化(IPF)是一种病因未明的致死性肺间质疾病，目前临床上尚缺乏治疗该疾病的有效药物。雷帕霉素靶蛋白(mTOR)信号通路、自噬(Autophagy)以及沉默信息调节蛋白6 (Sirt6)被认为可能参与了纤维化过程的发生，但其中的机理还不明确。我们已发表的研究表明IPF患者肺内存在mTOR信号活化以及活化的mTOR信号可通过抑制自噬形成介导肺纤维化发病。我们最近尚未发表的实验数据发现肺肌纤维母细胞分化中存在Sirt6表达下降并伴有mTOR信号活化以及自噬缺乏。根据这些发现，我们假设Sirt6的表达下调介导了自噬形成缺乏从而促进纤维化发病，且这种调节作用是依赖于mTOR通路来实现的。在这项研究里，我们将对Sirt6-mTOR-Autophagy这一信号轴在IPF的发生过程中的作用进行研究。这一项研究不仅将帮助我们了解IPF的发病机理，而且也将为IPF的治疗提供新的靶点。

特发性肺纤维化（IPF)以成纤维细胞和肌纤维母细胞聚集为主要特征并伴有细胞外基质蛋白沉积。Sirt6在肺纤维化发病中发挥重要作用。尽管如此，在IPF发病过程中Sirt6如何影响肌纤维母细胞分化的作用机制仍不清楚。我们检测了IPF患者肺内Sirt6蛋白表达量。同时利用博来霉素诱导的小鼠肺纤维化模型和TGF-β诱导的成纤维细胞分化模型。结果显示在IPF肺内和小鼠肺纤维化病灶内Sirt6蛋白表达升高。TGF-β诱导的Sirt6表达是通过mTORC1信号通路实现的。过度表达的Sirt6通过增加自噬形成促进了TGF-β诱导的成纤维细胞分化。进一步用雷帕霉素处理抑制了Sirt6但却失败的诱导自噬表达。从而得出Sirt6通过mTORC1通路调节了肌纤维母细胞分化但自噬诱导是通过非依赖于mTORC1通路实现的。本研究表明调控Sirt6表达可能是阻止或逆转肺纤维化病变的一种新的治疗策略。