缺血性脑损伤中血红素加氧酶-1/一氧化碳系统对JNK信号通路调控的分子机制

项目名称： 缺血性脑损伤中血红素加氧酶-1/一氧化碳系统对JNK信号通路调控的分子机制

项目编号： No.30800446

项目类型： 青年科学基金项目

立项/批准年度： 2009

项目学科： 轻工业、手工业

项目作者： 宋远见

作者单位： 徐州医学院

项目金额： 20万元

中文摘要： c-Jun-N-末端激酶（JNK）的激活是脑缺血后神经细胞损伤的重要原因，因此，探明靶向于该酶的调控因子及与之作用的相关机制，对缺血性脑损伤的基础研究和临床治疗具有重要意义。血红素加氧酶-1/一氧化碳（HO-1/CO）系统对神经细胞保护至关重要，因而有必要深入研究与之相关的信号通路及相关分子机制。HO-1/CO系统会不会通过JNK信号通路调节神经细胞功能是一个非常值得研究的问题。本项目以大鼠脑缺血再灌注模型为基础，采用免疫共沉淀、免疫印迹、HE和TUNEL染色等方法研究了HO-1在JNK信号通路调控中的重要作用。研究结果表明：HO-1能够通过作用于MLK3-MKK7-JNK3信号模块抑制JNK3及其下游底物c-Jun的磷酸化和Caspase3的表达，进而有效对抗脑缺血诱导的大鼠海马CA1区神经细胞的凋亡。本项目的研究工作探明了HO-1对JNK信号通路调控的分子机制及对神经细胞的保护作用，为神经保护药物的研发提供了潜在靶点，为缺血性脑损伤的基础研究和临床治疗提供了可靠的实验基础和理论依据。

中文关键词： 缺血；脑损伤；血红素加氧酶-1；c-Jun-N-末端激酶

英文摘要： Activation of c-Jun N-terminal kinase (JNK) is an important cause of neuron injury during cerebral ischemia, thus it is very critical for basic research and clinical therapy of ischemic brain injury to research the regulatory factors and the relative mechanisms aim at JNK. Heme oxygenase-1/carbon monoxide (HO-1/CO) system is critical to the protection of neuron, so it is necessary to study the signaling pathways and molecular mechanisms associated with it. It is worth to explore whether HO-1/CO system can regulate neuron's function through JNK signaling pathway. In this project, we investigated the important effect of HO-1 on the regulation of JNK signaling pathway by using immunoprecipitation, immunoblotting, HE and TUNEL staining base on cerebral ischemia and reperfusion model in rat. The results show that HO-1 can inhibit the phosphorylation of JNK3 and its downstream substrate c-Jun, and the expression of Caspase3 by interact with the MLK3-MKK7-JNK3 signal module, then effectively protect hippocampal CA1 neuron against cerebral ischemia-induced apoptosis. Our work find out the protective effect of HO-1 on neuron and the relative molecular mechanism of it aim at JNK signaling pathway. This work may provide potential target for the development of neuroprotective drug and reliable experimental and theoretical groundwork for the basic research and clinical therapy of ischemic brain injury.

英文关键词： ischemia;brain injury;heme oxygenase-1;JNK