NOD2在多系统萎缩发病机制中的研究

Multiple system atrophy (MSA) is a fatal, adult-onset, neurodegenerative movement disorder, and the underlying molecular mechanism of the disease remains unknown. Accumulative evidences suggest that neuroinflammation may contribute to the development of MSA, including abnormal alpha-synuclein positive cytoplasmic inclusions presented in oligodendrocytes, neuronal loss, gliosis, myelin pallor and axonal degeneration in striatonigral and/or olivopontocerebellar systems. In this process，it is of vital importance that microglia is activated from resting state. However, the mechanisms that which pattern or how microglia is activated are unclear. Our previous study found the promoter region of the nucleotide binding oligomerization domain containing 2 (NOD2) was hypomethylation in MSA patients than that in controls, and the expression of NOD2 mRNA was increased. The overexpression mRNA level of NOD2 was also been found in our second stage study including more MSA patients. Moreover, over-expression of NOD2/RIP2 has been identified in the substantia nigra of the B6(Cg)-SNCAtm1.2Vlb/J MSA transgenic mice (Tg mice) than that in wild type mice (WT mice); The BV2 cell was activated when it was stimulated by the supernatant of substantia nigra from transgenic MSA mice. Therefore, we hypothesis that NOD2 involves in the pathogenesis of MSA through activating the microglia. In the current study, we will explore the pattern or pathway of microglial activation mediated by NOD2 in MSA. First, in order to reveal the risk factors of increased expression of NOD2 and the effects of NOD2 for the clinical phenotypes of MSA, the expression level of NOD2/RIP2 will be analyzed in a larger simple size including MSA patients and health controls. Second, in order to clarify the mechanism that the neuroinflammation mediated by NOD2 in MSA will be clarified by testing the downstream related protein of NOD2/RIP2 pathways after the BV2 cells stimulated by different ligand of NOD2. Finally, we will explore the relationship between the neuroinflammation mediated by NOD2 and the pathogenesis of MSA by building animal models. Overall, the results of the present project will propose the novel mechanism involved in the pathogenesis of MSA and can provide a new clue or target for prevention and treatment of MSA.

多系统萎缩(MSA)是一种发病机制不清的神经变性疾病。越来越多的证据提示炎症反应，特别是小胶质细胞的激活，在MSA的发生发展中发挥重要的作用，然而其具体机制不清。我们前期发现MSA患者NOD2基因启动子区低甲基化和NOD2表达的mRNA升高；在MSA转基因小鼠黑质发现NOD2/RIP2表达升高；BV2小胶质细胞受到转基因小鼠黑质上清液刺激后活化。因此，我们提出假设NOD2介导的小胶质细胞炎症反应参与了MSA的发生发展。本研究拟从临床角度，扩大样本量探讨NOD2对疾病表型的影响；在细胞层面，采用三种不同的配体刺激BV2细胞，检测NOD2/RIP2下游通路相关蛋白，明确NOD2/RIP2在MSA中的具体炎症机制；在动物模型，从整体水平探讨NOD2激活与MSA疾病发生发展的关系。本研究有助于揭示MSA发病的新机制，为新的干预治疗策略提供理论基础。

多系统萎缩(Multiple system atrophy，MSA)是一种发病机制不清的神经变性疾病。越来越多的证据提示炎症反应，特别是小胶质细胞的激活，在MSA的发生发展中发挥重要的作用，然而其具体机制不清。我们前期发现MSA患者NOD2基因启动子区低甲基化和NOD2 mRNA表达升高；在MSA转基因小鼠黑质发现NOD2/RIP2表达升高；BV2胶质细胞受到转基因鼠黑质上清液刺激后活化。因此，我们提出假设NOD2介导的小胶质细胞炎症反应参与了MSA的发生发展。在本项研究中我们通过临床研究、细胞模型、MSA和NOD2动物模型探讨了NOD2/RIP2通路参与的炎症反应在MSA发病中的具体机制，初步阐明了NOD2在MSA发病中的作用，揭示了NOD2/STAT3通路是其介导炎症反应的主要机制，从而影响了α-SYN的聚集导致了神经元的损伤。我们的研究揭示NOD2可能是MSA发病过程重要的修饰因子，为MSA新的干预治疗策略提供了理论基础。