星形胶质细胞RORα在多巴胺神经元损伤中的作用及机制

Abnormal nerve inflammation and oxidative stress are two common causes of dopaminergic neurons degeneration. The nuclear receptor RORα (Retinoid-relatedorphan receptor α, RORα) expressed by astrocyte inhibits activation of NF-κB to restrict inflammation, activates the HIF-1α signaling pathway to reduce oxidative stress and promotes neuronal survival. These findings suggest an important role of RORα in the dopaminergic neurons degenerative diseases. However, the function of RORα during dopaminergic neurons injury is still unknown. In our study, we use MPTP to establish the PD animal models and MN9D cell injury models. We regulate the expression of RORα by drug intervention, gene intervention and both of them. Our detection items include mouse behavioral, AS activation, TH-positive cell numbers, production of dopamine and its metabolism as well as the expression of neurotrophic factors, apoptosis-related factors, members of NF-κB and HIF-1α pathway. We are aim to confirm that AS RORα protects dopaminergic neurons from MPTP induced injuries through the RORα/NF-κB pathway and/or RORα/HIF-1α pathway. In addition, we will clarify the function and mechanism of RORα in dopaminergic neurons injury to provide a theoretical foundation for PD treatment and prevention.

异常神经炎症和氧化应激共同导致多巴胺（DA）神经元退行性病变。星形胶质细胞（AS）RORα可抑制NF-κB激活，限制炎症扩大；还可正性调控HIF-1α通路，缓解氧化应激损伤；激活RORα促进神经元存活；这表明AS RORα在DA神经元退行性病变中扮演重要角色。目前RORα与DA神经元损伤的作用和机制未明。本项目采用MPTP构建PD动物和MN9D细胞损伤模型，分别应用药物干预、基因干预及两者交叉处理干预RORα表达；检测小鼠行为学数据、AS活化与TH阳性细胞数、DA及代谢产物含量、神经营养因子、凋亡相关因子、NF-κB和HIF-1α通路相关因子的表达。证实AS RORα通过RORα/NF-κB和/或RORα/HIF-1α通路拮抗MPTP所致DA神经元损伤。阐明RORα在DA神经元损伤过程中的保护作用及机制，为PD防治提供理论基础。

帕金森病（Parkinson’s disease，PD）是由于黑质多巴胺(Dopamine，DA)神经元退行性病变引起纹状体内DA绝对含量减少所致。异常神经炎症和氧化应激共同导致多巴胺神经元退行性病变。既往文献研究表明，星形胶质细胞（AS）RORα可抑制NF-κB激活，限制炎症扩大；还可正性调控HIF-1α通路，缓解氧化应激损伤；激活RORα促进神经元存活。为探索AS RORα在DA神经元退行性病变中扮演的角色。课题组采用药物干预和基因干预的方式，运用Transwell技术构建PD细胞损伤模型共培养体系和趋化性实验，并将构建的真核载体通过尾经脉注射到MPTP PD动物模型，结果发现RORα能够拮抗MPTP所致的多巴胺能神经元的损伤。实验结果，基本证实了提出的假说之一：AS RORα可拮抗MPTP诱导所致DA神经元损伤，其机制研究正在进行当中。由于核受体能结合经药物设计的小分子，进而调控相关疾病。因此，该研究结果为开发防治PD药物提供理论基础，对提高老年人生活质量具有较强的现实意义。