转录因子C/EBPβ在甲基苯丙胺诱导的神经毒性损伤中的作用及分子机制研究

甲基苯丙胺滥用可导致神经细胞损伤，研究显示，线粒体损伤、自噬和凋亡均参与了METH神经毒性，但其整体调控机制尚不清楚。在预实验中，我们发现：METH处理神经细胞后，转录因子C/EBPβ的表达显著升高，下降C/EBPβ的表达后能减少细胞凋亡的发生。文献调研发现，C/EBPβ与神经细胞损伤的上述机制均密切相关。因此，我们推测“C/EBPβ的关键靶蛋白作用”是METH神经毒性的一个新机制。本项目使用C/EBPβ基因敲除小鼠和原代培养神经细胞，利用细胞生物学、分子生物学及神经生物学等方法确定：C/EBPβ在METH诱导的神经细胞自噬和凋亡中起重要作用；C/EBPβ通过调节TRIB3、DDIT4和IGFBP5的启动子调控mTOR信号传导通路和线粒体凋亡途径发挥作用。通过本研究阐明C/EBPβ的关键靶点作用，同时也为防治METH神经毒性提供新理论。

Methamphetamine (METH) abuse can lead to nerve cell damage, previous studies have shown that mitochondrial damage, autophagy and apoptosis are involved in the METH-induced neurotoxicity, but the regulatory mechanism is still unclear. We found that the expression of transcription factor C/EBPβ significantly increased, knockdown of C/EBPβ reduced the cell apoptosis in nerve cells after METH treatment. Through the previous research, it was found that C/EBPβ is closely related to nerve cells, mitochondria, autophagy and apoptosis. Therefore, we speculate that “the key target role of C/EBPβ”is a new mechanism of METH-induced neurotoxicity. The C/EBPβ knockout mice and primary cultured neurons, the methods and technologies of cell biology, molecular biology and neurobiology will be used to determine: The key role of C/EBPβ in METH-induced autophagy and apoptosis; the mechanism of C/EBPβ adjust mTOR signaling pathway and the mitochondrial apoptotic pathway by regulating the promoters of TRIB3, DDIT4 and IGFBP5. This study will not only clarify the key target role of C/EBPβ, but also provide a new theory for prevention and treatment of METH-induced neurotoxicity.