NOD2介导的免疫炎症反应在帕金森病中的作用及调控机制

Neuroinflammation is a major pathogenesis of Parkinson’s disease (PD).NOD2 (nucleotide-binding oligomerization domain protein 2),an important cytoplasmic pattern recognition receptor, is the key molecule and research hot point in innate immunity; however its role and mechanism in PD are unknown. Our recent studies firstly found that the expressions of NOD2 in both mRNA and protein levels was significantly increased in striatum and substantia nigra pars compacta (SNpc) of PD mice induced by 6-hydroxydopamine (6-OHDA), moreover, microglial proliferation activation, and dopaminergic (DA) neuronal loss were seen after striatal injection of muramyl dipeptide(MDP), an extrinsic ligand of NOD2. NADPH oxidase mediated oxidative stress is an important factor in DA neurodegeneration. Recently β-arrestin2 was reported to produce neuroprotection via negatively regulating of immuno-inflammation, but the relationship and the detailed mechanisms among NADPH oxidase, β-arrestin2 and NOD2 is far from being fully characterized. Therefore, based on our previous data and the research progression, we will explore the role and mechanism of NOD2-mediated immuno-inflammation in the PD by using the NOD2 knockout mice in cellular and animal models of PD. We will also investigate the regulatory mechanism of NADPH oxidase and β-arrestin2 on NOD2 signalling pathway in PD. Our study will firstly provide evidence that NOD2-mediated innate immunity play a critical role in the pathogenesis of PD and suggests that targeting NOD2 signaling pathway may provide novel therapies for PD.

神经免疫炎症损伤是帕金森病（PD）的主要发病机制之一，胞浆内的模式识别受体NOD2是固有免疫领域的重要分子和研究热点，其在PD中的作用及调控机制迄今未见报道。申请者在前期工作中首次证实PD小鼠黑质纹状体的NOD2蛋白表达明显升高，NOD2特异性配体MDP可损伤多巴胺神经，提示NOD2可能参与了PD的病理进程。NADPH氧化酶介导的氧化应激是导致PD多巴胺神经损伤的重要诱发机制，β-arrestin2可能通过负调控免疫信号通路成为PD治疗的新靶点，但NADPH氧化酶和β-arrestin2与NOD2的关系尚不清楚。为此，结合我们的研究基础和该领域的前沿进展，我们拟在该项目中阐明NOD2介导的炎症反应在PD中的作用，并深入探索NADPH氧化酶、β-arrestin2对 NOD2信号通路的分子调控机制。该研究将充实完善PD的病理生理机制，为PD的防治提供新的靶点和思路。

神经免疫炎症损伤是帕金森病（PD）的主要发病机制之一，胞浆内的模式识别受体NOD2是固有免疫领域的重要分子和研究热点。近来临床流行病学资料提示 NOD2 基因突变可 能与PD相关，但是迄今尚无 NOD2 在PD中的明确作用及调控机制的研究。本项目研究发现在6-OHDA诱导的PD模型中黑质和纹状体内的NOD2表达上调，而NOD2缺失可抑制6-OHDA诱导的星型胶质细胞和小胶质细胞的增殖与活化及炎症反应，保护多巴胺能神经元损伤和凋亡。此外，小胶质细胞中沉默NOX2抑制NOD2的表达及6-OHDA诱导的炎症反应，NADPH氧化酶抑制剂Apocynin抑制6-OHDA和MDP诱导的野生小鼠黑质中NOD2的上调和DA的变性。另外，我们还发现在体外培养小胶质细胞中β-arrestin2负性调控NOD2信号通路。本课题首次揭示了NOD2 信号通路在PD 中的作用及机制，充实完善了PD 的病理生理机制，为PD的防治提供了新的靶点和思路，具有重要的理论意义和潜在的应用价值。