小胶质细胞介导的神经炎症在诺卡菌感染引起帕金森病中的作用和机制研究

帕金森病（PD）是第二常见的神经退行性疾病，是严重危害公共健康的全球性问题。目前PD与感染相关的研究越来越多。申请人前期探索首次发现诺卡菌感染可引起PD信号通路富集且脑部小胶质细胞显著激活，另外发现多巴胺能神经元数量减少，但机制不清楚。申请人拟在前期研究基础上（1）优化构建诺卡菌感染引起的PD小鼠模型，确定与PD相关的临床诺卡菌菌种（2）应用免疫荧光及多因子检测等技术明确小胶质细胞活化在诺卡菌感染引起PD中的作用（3）通过体内外实验，应用小RNA干扰、免疫组化等技术揭示小胶质细胞NLRP3及TLR2/4-MyD88-ERK/JNK/P38通路在诺卡菌感染引起神经炎症中的作用，阐明多巴胺能神经元损伤的机制。通过系统研究诺卡菌感染引起PD的分子机制，明确诺卡菌感染在PD发生中的作用，为诺卡菌感染引起PD的治疗和临床诺卡菌菌种重点预防提供科学依据；同时为加深PD诱发因素的认识和预防提供新的视角。

Parkinson's disease (PD) is the second most common neurodegenerative disease and a global problem that seriously endangers public health. There are increasing studies of PD being associated with infection. The previous exploration of the applicant found for the first time that Nocardia infection can cause enrichment of Parkinson's disease signaling pathways and significant activation of microglia in brain. In addition, it was found that the number of dopaminergic neurons was reduced, but the mechanism was unclear. The applicant intends to (1) optimize and constructe a mouse model of PD caused by Nocardia infection and determine the clinical Nocardia species related to PD (2) clarify the role of microglia activation in the occurrence of PD caused by Nocardia infection using immunofluorescence and multi-factor detection techniques (3) reveal the role of microglial NLRP3 inflammasome and TLR2/4-MyD88-ERK/JNK/P38 signaling pathway in neuroinflammation caused by Nocardia infection in vivo and in vitro using RNAi, WB and immunohistochemistry technology. This project intends to systematically explored the molecular mechanism of PD caused by Nocardia infection and elucidate the role of Nocardia infection in the occurrence of PD, so as to provide scientific basis for the treatment of PD caused by Nocardia infection and the key prevention for the infection of clinical Nocardia species. Besides, it provides a new perspective for deepening the understanding and prevention of PD inducing factors.