STING-IRF3信号通路介导2型糖尿病胰岛β细胞损伤及干预的机制研究

2型糖尿病（T2DM）患者存在胰岛β细胞功能受损，线粒体损伤及内质网应激是参与β细胞功能受损的重要机制，但是线粒体损伤及内质网应激如何调控β细胞损伤仍有待研究。干扰素基因刺激因子（STING）是一种位于内质网膜并参与内质网应激的关键因子，同时线粒体损伤所致线粒体DNA泄漏可以激活STING信号。本课题组首次发现高脂刺激INS-1细胞，STING信号被激活。但是，STING与β细胞功能的关系，迄今国内外尚无报道。前期研究中，我们发现STING敲除小鼠胰岛素抵抗减轻。故我们推测高脂可激活STING导致β细胞受损，使用抑制STING信号的药物，如青蒿素能够改善β细胞功能。为证明该假说，我们将建立T2DM和胰岛β细胞特异性敲除STING小鼠模型及细胞模型，采用分子生物学、动物基因敲除、细胞转染等技术，从整体－组织－细胞三个层次，观察STING信号通路激活对β细胞功能的影响机制及青蒿素干预机制。

Type 2 diabetes mellitus (T2DM) patients have showed impaired islet beta cell function. Several studies have reported that mitochondrial dysfunction and endoplasmic reticulum (ER) stress are involved in β-cell dysfunction, but how β-cell injury is induced by mitochondrial damage and ER stress remains to be studied. Stimulator of Interferon genes (STING) is a key factor located in the ER and is involved in ER stress. Meanwhile, mitochondrial DNA leakage caused by damage can also activate the STING signaling pathway. For the first time, our group found that the STING signaling pathway was activated by FFAs in INS-1 cells. However, the relationship between STING and β-cell function has not been reported domestically and abroad. In previous studies, we found that STING-knockout mice fed with high-fat-diet showed improved insulin resistance. Therefore, we speculated that FFAs can activate STING leading to β-cell damage, and drugs can improve β-cell function via inhibiting STING signaling, such as Artemisinin. To prove this hypothesis, we will establish pancreatic islet β cell specific STING knockout T2DM mice model and FFAs mediated INS-1 cell model, using molecular biology, cell transfection and other technologies, to investigate the effect of STING signaling pathway on β-cell function and the intervention mechanism of Artemisinin from the whole - tissue - cell three levels.