AMPK-PINK1介导线粒体自噬调控NLRP3炎症小体在狼疮性肾炎发病中的作用机制

狼疮性肾炎是导致系统性红斑狼疮不良预后的重要因素。我们既往的研究显示NLRP3炎症小体及其相关信号通路在狼疮性肾炎发病中起关键作用，但具体调控机制不明。最新研究显示线粒体自噬调控NLRP3炎症小体，AMPK-PINK1介导线粒体自噬调控免疫炎症反应。我们的预实验结果提示在免疫复合物作用下AMPK-PINK1调控巨噬细胞NLRP3炎症小体活化。本项目在前期研究工作和预实验结果基础上，通过体外免疫复合物刺激的免疫细胞模型、体内干预狼疮小鼠模型，结合基因敲除小鼠及临床患者标本，从不同层次阐明AMPK-PINK1介导线粒体自噬调控NLRP3炎症小体通路在狼疮性肾炎发病中的作用及机制，明确潜在的重要靶点和关键分子。本项目将阐明AMPK-PINK1介导线粒体自噬调控NLRP3炎症小体在狼疮性肾炎的机制，为临床防治狼疮性肾炎提供新的理论依据和研究方向。

Lupus nephritis (LN) is a major poor prognostic factor for systemic lupus erythematosus. Our previous studies have shown that activation of the NLRP3 inflammasome and related pathways play key roles in the pathogenesis of LN, but its specific regulatory mechanisms remain unclear. Recent studies show that mitophagy regulates the NLRP3 inflammasome and AMPK-PINK1-mediated mitophagy is involved in immune and inflammatory response. Thus, our preliminary experiment results suggest that AMPK-PINK1 regulates macrophage NLRP3 inflammasome activation in the presence of immune complex. Based on our previous research work and preliminary experimental results, this current project will employ immune cell models stimulated by in vitro immune complexes, in vivo intervention of lupus mouse models, combined with gene knockout mice and clinical specimens, in order to determine the mechanism of AMPK-PINK1-mediated mitophagy regulating the NLRP3 inflammasome pathway in the pathogenesis of LN from different levels, leading to the identification of potential important targets and key molecules. This project will clarify the mechanisms of AMPK-PINK1-mediated mitophagy in regulating NLRP3 inflammasome in LN, and provide novel theoretical basis and and research direction for prevention and treatment of LN.