基于Nurr1/NFκB/TNF-α通路研究人参皂苷Rg1抗帕金森病的作用机制

人参皂苷Rg1是人参的活性化合物，被证实有神经保护作用，但其抗PD的作用机制尚未阐明。Nurr1分子是孤儿核受体超家族的转录因子，最近研究表明Nurr1在LPS诱导的小胶质细胞模型中可阻断NF-kB/p65与炎症基因启动子结合发挥抗炎作用，调节Nurr1活性可能成为治疗PD的新策略。由此提出“Rg1可调控Nurr1/NFκB/TNF-α通路抑制神经炎症反应从而发挥抗PD作用”这一科学假说。本课题拟以原代、传代小胶质细胞及A53T小鼠为研究对象，从动物行为学、细胞生物学及分子生物学等方面研究Rg1对小胶质细胞数量形态，Nurr1分子核转位和表达以及对Nurr1/NFκB/TNF-α通路的影响；通过慢病毒敲减Nurr1的表达，观察Rg1抗PD的作用是否受到干扰；最后对Rg1影响Nurr1活性过程中可能参与的上游分子机制进行探究，进而阐明Rg1的抗PD作用机制，为研发新型抗PD药物提供实验依据。

The Ginsenoside Rg1, an active component of ginseng, has been proved to have neuroprotective effects, but the underlying mechanisms have not been clarified. Nurr1 is a member of orphan nuclear receptors and has been studied extensively in PD recently. Nurr1 has been shown to inhibit the expression of proinflammatory mediators by docking to NF-κB-p65 on target inflammatory gene promoters in microglia. Nurr1 may be an important molecular target in the treatment of PD. Therefore, we propose a scientific hypothesis that "Ginsenoside Rg1 plays neuroprotective effects by regulating the Nurr1/NFκB/TNF-α pathway ". The primary microglia, BV-2 microglia cells and A53T transgenic mice were studied in this experiment. The purpose of this study is to show the effects of Rg1 on the number and morphology of microglia, the nuclear translocation and expression of Nurr1, and the Nurr1/NFκB/TNF-α pathway by the ethology, cell biology and molecular biology. When the expression of Nurr1 is knocked down by lentivirus, whether the neuroprotective effects of Rg1 are disturbed. Finally, the upstream molecular mechanisms that Rg1 may influence the activity of Nurr1 are explored. In conclusion, the present study will clarify the underlying mechanisms of Rg1, providing experimental basis for the development of new drugs.