基于Rictor/mTORC2通路探讨线粒体自噬-凋亡平衡在肾血管内皮细胞-间充质细胞转分化（EndMT）参与移植肾间质纤维化形成中的作用及机制研究

移植肾间质纤维化是影响移植肾长期存活的关键因素，机制至今不明。我们已证实肾血管EndMT在移植肾间质纤维化形成中起重要作用；近来又发现自噬可通过调控肾小管EMT减缓移植肾间质纤维化进展；而慢性移植肾失功患者移植肾血管内皮细胞中又出现线粒体自噬、细胞凋亡与Rictor/mTORC2通路异常。但线粒体自噬-凋亡平衡在肾血管EndMT形成中的作用迄今未见报道。据此我们推测：线粒体自噬-凋亡平衡可能通过调控肾血管EndMT进而在移植肾间质纤维化形成中起关键作用。为验证假说，本课题拟通过同种异体肾移植、内皮细胞ATG7或Rictor基因敲除小鼠及人血管内皮细胞模型，探讨线粒体自噬-凋亡平衡在肾血管EndMT及移植肾间质纤维化中的作用，并深入研究Rictor/mTORC2通路在其中的作用及机制。本课题预期成果将为从调控线粒体自噬-凋亡平衡和肾血管EndMT角度研发防治移植肾间质纤维化的措施提供新靶标。

Renal allograft interstitial fibrosis is a key factor affecting the long-term survival of transplanted kidney, and the mechanism is still unknown. We have confirmed that renal vascular endothelial-to-mesenchymal transition (EndMT) play an important role in the formation of renal allograft interstitial fibrosis. Recently, we found that autophagy can slow down the progression of transplanted renal interstitial fibrosis by regulating renal tubular Epithelial-Mesenchymal Transition (EMT) formation, and we also found that abnormal mitophagy, apoptosis and Rictor/mTORC2 pathway are present in transplanted renal vascular endothelial cells of recipients with chronic renal interstitial fibrosis. However, the function and mechanism of mitophagy-apoptosis balance involved in transplanted renal vascular EndMT have not been reported so far. On these grounds, we speculate that the mitophagy-apoptosis balance maybe play a key role in the formation of renal allograft interstitial fibrosis through regulating transplanted renal vascular EndMT. This project intends to adopt allogeneic kidney transplantation mice and conditional endothelial cells ATG7 or Rictor gene knockout mice, human vascular endothelial cells model to explore the actions of mitophagy-apoptosis balance in the formation of transplanted renal vascular EndMT and renal allograft interstitial fibrosis. On the basis of this, the role and mechanism of Rictor/mTORC2 pathway in this process will be discussed in-depth. The expected results of this project will provide new targets for the development of measures to prevent and treat renal allograft interstitial fibrosis from the perspective of regulating mitophagy-apoptotic balance and renal vascular EndMT.