HLA区基因多态性与帕金森病的关联分析及其分子机制研究

项目名称： HLA区基因多态性与帕金森病的关联分析及其分子机制研究

项目编号： No.81471292

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 徐评议

作者单位： 广州医科大学

项目金额： 70万元

中文摘要： 帕金森病（PD）是衰老、遗传和环境毒素相互作用的结果，HLA-DR及相邻PSMB区基因可能参与了中枢DA神经元内α-syn蛋白的降解及其免疫应答，在抗原呈递过程中发挥作用。我们初步发现：①男性PD患者HLA-DRB1*0301的携带率明显升高；②PSMB9基因SNP（rs17587）与女性PD相关；③过量α-syn积聚可诱导DA神经元内蛋白酶体功能下降及免疫蛋白酶体代偿性增加，以维持细胞内蛋白代谢平衡。但我们对上述基因变异介导的黑质区炎症反应及其免疫紊乱机制并不清楚。本项目拟在前期基础上，扩大PD病例-对照研究，对HLA-DR及相邻PSMB区基因多态性进行系统分析，以确定相关基因SNPs在PD发生、发展过程中的作用。分析不同条件下，动物黑质区及模型细胞内α-syn积聚过程中，蛋白酶体下降、免疫蛋白酶体上调的机制及相关分子信号的磷酸化改变，从而揭示炎性/免疫紊乱介导DA神经元变性的分子机制。

中文关键词： 多巴胺能神经元；分子调控；HLA多态性；免疫蛋白酶体；神经炎症

英文摘要： Gene-age-environment interaction is related to the landmarkable pathogenesis of Parkinson's disease (PD). Variation in HLA-DR/PSMB genomics may contribute to the mechanism in α-syneulein degradation as well as its chronic immune response in the process of antigen presentation during dopaminergic (DA) neuron degeneration. We have preliminarily found that: ①allele frequency of HLA-DRB1*0301 was obviously increased in male PD patients；②rs17587 in PSMB9 gene was associated with female PD；③ α-syneulein accumulation could induce the proteasome dysfunction and compansated immunoproteasome activation in DA neuron to maintain intracellular protein homeostasis. But it is still uncleared about the molecular mechanism of inflammatory response and related immune disorder based on these gene mutations in substantia nigra.Based on our initial data, this study aims to expand case -control study, systematically analyse the polymorphisms of HLA-DR and adjacent PSMB genomics, confirm the related genes and their function in the pathogenesis and development of PD,and explore the mechanism of proteasome dysfunction with compansated immunoproteasome activation and related phosphorylated molecular signal pathways during α-synuclein accumulation in cell model or substantia nigra in vivo under different conditions,so that to disclose the molecular mechanism of DA neuron degeneration involved chronic inflammatory immunological disorder.

英文关键词： Dopaminergic neuron;molecular regulation;HLA polymorphism;Immunoproteasomesh;Neuroinflammation