炎症小体在帕金森病神经炎症反应中作用角色的研究

帕金森病（PD）是中老年神经系统退行性疾病，在我国发病情况日趋严重。神经炎症贯穿PD退行性病变全程,被认为参与多巴胺神经元（DA）病变形成，但其作用规律依然不清。我们初步研究发现黑质纹状体脑区炎症小体在PD病理反应过程中上调表达，敲除小鼠中炎症小体分子可抑制MPTP诱导的胶质细胞增生和DA神经元死亡，提示炎症小体介导的炎症效应参与了PD发生，然而其具体角色和作用机制仍需深入阐明。在本项目中我们将以NLRP3和AIM2炎症小体类为主要研究对象，运用骨髓移植方法和条件型敲除小鼠来研究不同神经和外周免疫细胞中炎症小体在PD形成过程中的确切功能，探讨其参与PD炎症反应引起DA神经元渐行性死亡的作用机制。通过这些研究，将有望发现参与PD退行性病变过程的重要蛋白质机器，并为寻找针对该疾病新的干预途径奠定基础。

Parkinson's disease (PD) is a neurodegenerative disease with a high incidence in aged people and is becoming more and more common in China. Neuroinflammation lies throughout the slow-progression of PD and is generally believed to contribute to dopamine (DA) neuron degeneration, but the nature of it has not been fully understood. Our study found that the inflammasome was widely expressed in the nigrostriatal brain and their expression was also upregulated after MPTP-induced pathogenesis of PD. Deficiency of inflammasome in mice significantly inhibits MPTP-induced proliferation of activated glial cells and death of DA neuron in substantia nigra. These results indicate inflammasome-mediated inflammation might have important functions in PD degeneration. However, their exact roles and mechanisms remain largely unknown and need to be further investigated. In this project we will focus on NLRP3 and AIM2 inflammasome and utilize bone marrow transplant and conditional knockout mouse to clarify the roles of inflammasome in different nerve and peripheral immune cells during PD pathogenesis, and to further explore the likely mechanisms of inflammasome underlying PD neuroinflammation and DA neuronal degeneration. Taken together, our studies will unveil an important protein complex involved in PD degenerative pathogenesis, providing clues for the establishment of effective clinical treatments in Parkinson's disease.