TCDD经SSeCKS/TRAF6通路诱导星形胶质细胞激活致神经毒性的机制研究

项目名称： TCDD经SSeCKS/TRAF6通路诱导星形胶质细胞激活致神经毒性的机制研究

项目编号： No.21477058

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 化学工业

项目作者： 吴启运

作者单位： 南通大学

项目金额： 87万元

中文摘要： 环境污染物TCDD具有明显的神经毒性，但其作用机制尚未明确。课题组前期研究发现，低剂量TCDD体外可激活星形胶质细胞，上调SSeCKS的表达，同时发现SSeCKS可以与神经炎症密切相关的TRAF6形成复合物。基于此我们提出TCDD可能通过激活星形胶质细胞，诱导SSeCKS的表达，继而引发TRAF6的泛素化修饰并激活已知的NF-κB信号通路而产生神经毒性的假设。本研究拟以TCDD 处理大鼠，观察其对星形胶质细胞激活、SSeCKS及TRAF6的表达、相互结合的关系；分析TCDD促进SSeCKS与TRAF6复合物的形成以及调节TRAF6的泛素化修饰的机制；最后，在体内干预SSeCKS与TRAF6的相互结合及运用天麻素处理，探索减轻TCDD神经毒性的药物靶点。本课题的研究将为阐明TCDD诱导星形胶质细胞激活而致神经毒性的机制提供实验依据，对预防和减轻TCDD的神经毒性具有重要意义。

中文关键词： 2；3；7；8-四氯二苯并二噁英；神经毒性；星形胶质细胞；SSeCKS；TRAF6

英文摘要： TCDD, a common environmental pollutants, has significant neurotoxicity. However, its mechanism is still unclear. Our previous study found that low doses of TCDD can activate brain astrocytes regulate the expression of SSeCKS, and found that SSeCKS can closely associated with nerve inflammation TRAF6 complex formation.Based on this, we propose neurotoxic effects of TCDD through the activation of astrocytes induce SSeCKS, which in turn lead to ubiquitination of TRAF6 and follow activation of NF-κB, which generate assuming neurotoxicity. This study intends to use TCDD-treated rats to evaluate astrocyte activation and expression of its SSeCKS, TRAF6 and mutually binding relationship; Analyze TCDD and SSeCKS promote the formation of complexes with TRAF6 and the regulation of TRAF6 ubiquitination mechanism; Finally, to intervent TRAF6 and SSeCKS combined with each other in vivo to explore lower TCDD neurotoxic drug targets. Provide an experimental basis for research of this subject will clarify the mechanism of neurotoxicity of TCDD, the prevention and treatment of neurological toxicity of TCDD has important significance.

英文关键词： TCDD;Neurotoxity;Astrocyte;SSeCKS;TRAF6