帕金森病（PD）在我国65岁以上人口中发病率为1.7%，严重威胁人民健康。课题组之前报道了NLRP3炎症小体激活促进小胶质细胞活化参与PD发生，而NLRP3激活的机制至今尚不清楚。M2型丙酮酸激酶（PKM2）近年来被发现是肿瘤代谢、细胞凋亡和炎症反应中的关键调节因子。申请者前期的研究发现，小胶质细胞内PKM2在PD造模后显著升高，过表达PKM2能够激活NLRP3并活化小胶质细胞，提示PKM2可能参与了小胶质细胞介导的神经炎症。本项目将基于现有工作基础，利用Crispr-Cas9、免疫共沉淀、蛋白质谱等技术，在细胞水平研究PKM2能否激活NLRP3并阐明其调控机制，揭示PKM2与小胶质细胞活化之间的关系。同时使用PKM2条件敲除小鼠，在体研究PKM2对小胶质细胞活化和PD进程的作用。预期结果将开拓PKM2在神经炎症领域的研究，同时为发展靶向小胶质细胞炎症治疗PD的药物提供新的策略。

Parkinson’s disease (PD) is the most common serious movement disorder in China, affecting about 1.7% of adults older than 65 years. Our previous study has shown that Nod-like receptor protein 3 (NLRP3) inflammasome activation promotes microglia activation and plays a crucial role in the pathogenesis of PD. However, mechanisms under NLRP3 activation remains unknown. M2 pyruvate kinase (PKM2) is a key regulator of tumor metabolism, apoptosis and inflammation. We have found that PKM2 is upregulated in PD model mice. Overexpression of PKM2 activates NLRP3 inflammasome and microglia, suggesting that PKM2 participates in microglia mediated neuroinflammation. In this study, we will use Crispr-Cas9, Co-IP and mass spectrum to investigate the mechanism under PKM2 mediated NLRP3 inflammasome activation. Furthermore, we will use microglia-specific PKM2 knockout mice to investigate the role of PKM2 in microglia activation and PD pathology in vivo. We hope to demonstrate the importance of PKM2 in neuroinflammation and offer new strategies for anti-PD treatments by targeting microglia mediated neuroinflmmation.