线粒体异常分裂是脑缺血/再灌注(IR)时神经细胞死亡重要原因之一。本项目预实验首次发现大鼠脑IR时，线粒体E3泛素蛋白连接酶1(Mul1)表达上调、伴随分裂蛋白DRP1苏素化和蛋白水平升高，融合蛋白Mfn2含量和调节Mul1的miR-125b水平下降。基于上述结果，我们率先从以下方面探讨Mul1促线粒体分裂作用及机制：① 建立大鼠脑IR模型，结合药物干预、Mul1 RNA干扰或miR-125b agomir干预，检测脑梗死体积、Mul1表达、DRP1苏素化和Mfn2泛素化水平等指标，确定脑缺IR时Mul1促线粒体分裂作用及机制；② 建立神经细胞低氧/复氧损伤模型，结合药物干预、Mul1基因沉默、miR-125b mimics干预及荧光素报告基因技术，检测上述相关指标,阐明Mul1促线粒体分裂及其表达调节机制。该研究有助于阐明脑IR损伤机制，为寻找防治脑IR损伤新药靶点和新药提供理论依据。

The aberrant fission of mitochondria is thought as one of the important reasons for neuron death following cerebral ischemia/reperfusion (IR).The preliminary data of this project showed that in rat model of cerebral IR, the expression of mitochondrial E3 ubiquitin protein ligase 1 (Mul1) increased accompanied by the increased levels of DRP1(fission protein) and DRP1-SUMO as well as the decreased levels of Mfn2(fusion protein) and miR-125b which targets Mul1 gene. Based on the preliminary data, we will take the lead to explore the downstream pathway of Mul1 in promoting the mitochondrial fission and the mechanisms responsible for the up-regulation of Mul1 expression as follows: 1)Establish a rat model of cerebral ischemia/reperfusion injury and finish the measurements of infarct volume, expression levels of Mul1, DRP1-SUMO and Mfn2-UB, to determine the role of Mul1 in promoting mitochondrial fission and the possible mechanisms through combining the strategies of interferences with drug, Mul1 siRNAs and miR-125b agomir; 2) Establish a cell model of hypoxia/reoxygenation injury and finish the measurements of the associated parameters, to elucidate the underlying mechanisms of Mul1 expression and function through combining the strategies of interferences with drug, Mul1 siRNAs or miR-125b mimics, as well as the luciferase reporter genes. This project will lay a theoretic foundation and provide the new idea for seeking novel drugs targeting against cerebral ischemia.