GSK-3β/RIP3-MLKL/Necroptosis途径介导RIPC保护移植肾缺血再灌注损伤的机制研究

远程缺血预处理（RIPC）是移植肾缺血再灌注损伤（IRI）有效防治策略但机制未明。程序性坏死（necroptosis，Necp）是新近发现的一种IRI重要效应形式。课题组前期研究发现RIPC减轻移植肾IRI，其效应与RIP3-MLKL/Necp途径相关。国际上新近研究发现GSK-3β为RIPC保护信号传导的关键因子，新近研究又发现GSK-3β诱导Necp。本项目拟利用目的基因SiRNA干扰技术行细胞表达干预，并建立肾移植IRI模型，利用RIP3敲除小鼠、MLKL敲除小鼠并模拟临床心脏死亡捐献（DCD）肾移植过程，评价RIPC干预后GSK-3β/RIP3-MLKL/Necp信号途径相关因子表达变化、Necp程度改变，阐明RIPC的移植肾IRI保护作用由GSK-3β/RIP3-MLKL/Necp介导。本研究将深化移植肾IRI病理机制探索，为DCD肾移植IRI防治提供新方法及新治疗靶点。

Remote ischemic preconditioning (RIPC) is an effective strategy for the prevention and treatment of renal transplant ischemia-reperfusion injury (IRI), but the mechanism is not clear. Necroptosis (Necp) is an important form of IRI recently discovered. Previous studies of our group have found that RIPC treatment reduces IRI in transplanted kidneys, and its effect is related to RIP3-MLKL/Necp pathway. Recent international studies have found that GSK-3βis a key factor in RIPC protection signal transduction, and other studies have found that GSK-3βinduces Necp. In this study, we intend to use the target gene SiRNA interference technology to intervene in cell expression, establish IRI models of renal transplantation using RIP3 knockout mice and MLKL knockout mice, simulate the process of clinical cardiac death donation (DCD) renal transplantation, evaluate the changes of GSK-3β/RIP3-MLKL/Necp signaling pathway, apoptosis and Necp changes after RIPC intervention, and clarify the protective effect of RIPC on renal transplantation IRI by GSK-3β/ RIP3-MLKL/Necp mediated. This study will deepen the exploration of the pathological mechanism of IRI in renal transplantation, and provide new methods and targets for the prevention and treatment of IRI in DCD renal transplantation.