DAP5介导的线粒体自噬逃逸在急性肾损伤中的作用及机制

各种致病因素导致的肾小管上皮细胞线粒体损伤是急性肾损伤（AKI）发生发展的重要原因。自噬是细胞重要的防御保护机制，但AKI时损伤的线粒体并不能被有效清除，其自噬逃逸的机制尚不清楚。DAP5在炎症反应和细胞凋亡中发挥着重要的调控作用。我们前期研究显示，急性损伤能显著抑制肾小管上皮细胞线粒体自噬"分子开关"Mss4的表达；而过表达DAP5能上调Mss4的表达，增强线粒体自噬活性。据此我们推测，各种损伤因素通过抑制DAP5/Mss4通路，导致损伤的线粒体发生自噬逃逸，进而促进AKI的发生发展。本课题首先在动物模型中证明DAP5在AKI线粒体自噬、炎症反应及细胞凋亡等病理生理过程中的调控作用；并通过体外实验干预线粒体自噬识别的不同环节，探明DAP5介导损伤线粒体自噬逃逸的分子机制；进一步选择调控DAP5的关键分子在AKI模型中进行干预研究，为AKI线粒体自噬逃逸提供新的理论依据和干预靶点。

Inflammation and apoptosis, triggered by mitochondrial dysfunction in renal tubular epithelial cells, is the fundamental cause of the progression of acute kidney injury (AKI). Autophagy can eliminate damaged mitochondria and the pathogenic component and block the pro-inflammatory and pro-apoptotic effect. But damaged mitochondria of renal tubular epithelial cells can not be effectively eliminated in AKI. And the mechanism is unclear. Our previous study found that overexpression of DAP5 can increase the expression of Mss4, the molecular switch of mitochondrial autophagy, and upregulate the activity of mitochondrial autophagy. We speculate defective DAP5 expression might induce damaged mitochondria to escape autophagic degradation, trigger the inflammation and apoptosis and promote disease progression. We plan to investigate the process and molecular mechanism of DAP5-defect-induced mitochondrial autophagy escape and explore the signaling pathway of mitochondrial autophagy escape related inflammation and apoptosis in vitro and in vivo experiments. The further step is to provide a new theoretical basis and intervention targets for mitochondrial autophagy escape in AKI.