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

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.

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。

TCDD是目前发现的二噁英家族成员中毒性最强的一种化合物，具有明显的神经毒性。先前研究表明TCDD可以促进星型胶质细胞活化，但相关分子机制仍不清楚。本项目探究SSeCKS与TRAF6复合物在TCDD促进星型胶质细胞活化中的作用，并评价天麻素对该过程的干预作用。首先，我们检测了TCDD对SSeCKS与TRAF6表达的影响。此外，我们发现SSeCKS与TRAF6存在相互作用，并且这种作用在TCDD暴露后进一步增强。进一步的分析显示SSeCKS促进TRAF6的泛素化修饰。敲降SSeCKS或TRAF6可以减轻TCDD诱导的NF-kB活化和炎症反应。天麻素可以通过抑制SSeCKS或TRAF6相互作用从而对TCDD诱导的NF-kB活化和炎症反应有保护作用。此外，天麻素抑制TCDD处理星型胶质细胞的条件培养基引起的神经元凋亡。本研究进一步阐明了TCDD诱导的星型胶质细胞活化的可能途径，对TCDD相关神经毒性的分子机制提供了新的思路。更重要的是，我们证实了天麻素对TCDD的神经毒性具有保护作用。研究结果共发表5篇SCI期刊收录论文。