MEKK1-MKK4-JNK1信号模块与HO-1的结合位点在神经炎症中的作用和机制

项目名称： MEKK1-MKK4-JNK1信号模块与HO-1的结合位点在神经炎症中的作用和机制

项目编号： No.81501042

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 付燕燕

作者单位： 徐州医科大学

项目金额： 17.5万元

中文摘要： 神经炎症是促进神经退行性疾病发生发展的关键因素。研究显示：MEKK1-MKK4-JNK1信号模块的组装可增强JNK1的磷酸化，导致神经细胞的损伤和学习记忆障碍。预实验表明：神经炎症中，血红素加氧酶-1（HO-1）可与MEKK1-MKK4-JNK1信号模块结合，并促进其组装；当HO-1激活后，促使该模块解体，减轻神经细胞损伤。但是，HO-1与MEKK1、MKK4、JNK1还是与其支架蛋白JSAP1直接结合，及具体结合位点，尚不明确。本项目拟采用哺乳动物双杂交、GST pull-down等多种技术，从MEKK1、MKK4、JNK1和JSAP1中筛选并验证与HO-1直接结合的靶蛋白；再分别突变HO-1和靶蛋白，用上述技术筛选并验证突变位点；研究该结合位点在神经细胞损伤和学习记忆障碍中的作用及机制。本项目旨在为神经炎症的治疗提供新的药物靶点，为神经退行性疾病的治疗提供新思路。

中文关键词： 神经炎症；丝裂原活化蛋白激酶激酶激酶1；丝裂原活化蛋白激酶激酶4；c-Jun氨基末端激酶1；血红素加氧酶-1

英文摘要： Neuroinflammation is considered as an importmant contributor to the occurrence and development of neurodegenerative diseases. Some studies have revealed that the assembly of MEKK1-MKK4-JNK1 signal module can enhance the phosphorylation of JNK1 during nerve inflammation period, ultimately cause neuronal injury and disorder of learning and memory. The preliminary experimental results indicated that inflammation could facilitate heme oxygenase-1 (HO-1) to combine with MEKK1-MKK4-JNK1 signal module, and promote the assembling of the signal module. Activation of HO-1 could induce the disassembling of the module and alleviate the neuronal damage. However, it is still unclear that which target protein(s) of MEKK1, MKK4, JNK1 or JSAP1, can directly combine with HO-1, and where are specific binding sites between them. In this project, a variety of techniques such as mammalian two-hybrid system, GST pull-down will be used to screen and validate the target protein(s) which can directly combine with HO-1. The sites mutagenesis of HO-1 and target protein will be prepared to screen and validate the specific binding sites between them using the above technologies. Finally, the specific binding sites will be mutated to explore the effects and relative mechanisms of neuronal injury and learning and memory disorder induced by neuroinflammation. This project may provide new drug targets for the therapy of neuroinflammation and new ideas for the treatment of neurodegenerative diseases.

英文关键词： Neuroinflammation;MEKK1;MKK4;JNK1;HO-1