Nur77活化抑制星形胶质细胞激活及其保护帕金森病的分子机制研究

Neuroinflammation is recognized as an important therapeutic target for Parkinson’s disease (PD). Over activated glia cells produce excessive proinflammatory factors and lead to neuroinflammation. Astrocytes played critical roles in regulating the progress of neuroinflammation. We firstly found that Nur77 was increased in activated astrocyte and its special agonist CsnB suppressed the expression of proinflammatory factors. In addition, Nur77 overexpression also enhanced the neuroprotective function of astrocyte. Importantly, in vivo studies found that pretreatment with CsnB reduced the behavioral abnormalities and attenuates the neuronal loss in substantia nigra pars compacta of MPTP-PD mouse models. Based on these data, our project will focus on (1) the function of Nur77 in regulating astrocyte activation and the mechanisms involved; (2) the role of Nur77 in astrocyte protects dopaminergic neurons against insults; (3) the therapeutic effect by Nur77 in astrocyte of MPTP-PD models and the underlying mechanisms involved. Our project will not only reveal the effect and mechanisms of Nur77 in regulating astrocyte activation, but also help to search the novel therapeutic target for PD.

靶向抑制神经炎症已成为治疗帕金森病（Parkinson’s disease，PD）的重要研究方向。神经炎症的产生主要由于胶质细胞过度激活释放炎性因子，而星形胶质细胞在神经炎症发生中具有重要调控作用。我们首次发现核孤儿受体Nur77在星形胶质细胞表达且其特异性激动剂CsnB剂量依赖性降低其激活后炎性因子上调；星形胶质细胞过表达Nur77抑制小胶质细胞激活继发反应对多巴胺能神经元的损伤；CsnB给药后改善MPTP-PD小鼠行为学症状，并且减轻黑质多巴胺能神经元损伤。基于此，本课题将深入研究（1）Nur77对星型胶质细胞激活的调控作用及分子机制；（2）研究星型胶质细胞内Nur77对多巴胺能神经元的保护作用；（3）Nur77活化后对PD行为学改善作用及分子机制。本课题将揭示Nur77对星形胶质细胞激活的重要调控作用，系统阐明Nur77活化后缓解PD的作用和分子机制，为PD的治疗提供潜在的药物靶点。

抑制胶质细胞激活产生的炎症反应已成为治疗帕金森病（Parkinson’s disease，PD）的重要研究方向之一。在星形胶质细胞细胞中，Nur77的功能和作用尚未明确。我们的研究结果表明Nur77在星形胶质细胞中表达，并且随着其激活表达下调。Nur77特异性激动剂CsnB可以改善MPTP诱导的PD小鼠行为学症状，并且降低中脑内多巴胺能神经元的损伤。其原因是CsnB可以抑制iNOS、COX-2、IL-1β和TNF-α的mRNA水平等，并且抑制小胶质细胞进一步激活诱导的神经炎症。Nur77抑制星形胶质细胞激活的机制可能是通过阻止NF-κB入核，明确的实验结果有待重复。此外我们发现一种新化合物PP-7a对高脂饮食诱导肥胖小鼠代谢失调具有较好的调控作用。本项目共发表SCI论文5篇，培养博士研究生，1名，硕士生2名。