cGAS-STING-IFN I 通路在系统性红斑狼疮发病机制中的作用

系统性红斑狼疮(SLE)发病率高、危害大，且缺乏安全、根本有效治疗措施，亟需深入探索其发病机制及寻找新的治疗靶点。SLE中高水平游离DNA引起的I型干扰素(IFN-I)产生对其免疫失衡起决定作用。干扰素基因刺激因子(STING)通路是细胞内识别DNA引起IFN-I产生的重要通路，但其在SLE发病机制中作用未明。我们前期发现SLE患者中STING通路活化，且小鼠狼疮模型显示STING缺陷显著降低过度活化的免疫反应及器官损伤。故我们猜想SLE中异常活化的STING通路导致免疫失衡进而引起SLE病理损伤。本研究拟进一步研究SLE患者中STING通路活化水平及其与SLE临床表现及治疗效果间相关性，并利用基因敲除小鼠探讨STING及其通路上游cGAMP合成酶(cGAS)和下游IFN-I对SLE发病影响及机制，同时通过靶向抑制STING研究其作为靶点的价值，为深入理解SLE发病机制及靶向治疗提供依据。

Systemic lupus erythematosus (SLE) is a serious, debilitating autoimmune disease with high prevalence. Further understanding of disease pathogenesis and searching for new therapeutic target are in great need due to the adverse effects and insufficient disease control of the majority of therapies. In SLE, the presence of excessive circulating DNA triggers the production of type I IFN (IFN-I), which plays a critical role in breaking immune tolerance. cGAMP synthase (cGAS)-STING (Stimulator of interferon genes) pathway, which senses DNA in the cytosol, is critical in IFN-I production. However, the role of this pathway in the pathogenesis of SLE remains unclear. Our previous data shows that STING pathway is activated in patients with SLE. Further, STING deficiency attenuated lupus associated organ damage and reduced aberrant immune responses in a murine model of lupus. We hypothesize that inappropriate activation of STING signaling pathway is an important mechanism leading to immune dysregulation, and thereby contributing to lupus pathogenesis. The proposed research will address: 1) the associations between STING pathway activation and different clinical spectrum and treatment outcomes in patients with SLE; 2). the mechanisms of how STING and STING pathway upstream molecule cGAS and downstream molecule IFN I contribute to lupus pathogenesis by applying multiple genetic modified mice in a murine model of lupus; 3). therapeutic potential of targeting STING in the treatment of lupus. Our proposal will provide us important insights into lupus pathogenesis and into the design of more disease-specific therapeutic options.