MSS1对LPS介导的神经炎症反应的调节及其在帕金森病中的作用研究

项目名称： MSS1对LPS介导的神经炎症反应的调节及其在帕金森病中的作用研究

项目编号： No.81200930

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 神经系统疾病、精神疾病

项目作者： 毕伟

作者单位： 暨南大学

项目金额： 23万元

中文摘要： 脑内小胶质细胞的活化引起的神经炎症是帕金森病（Parkinson's Disease，PD）重要的发病机制之一。通过抑制、减轻神经炎症反应为靶点改善和阻断PD的进展，是防治PD的一个有效新策略。我们前期研究发现：利福平可通过抑制TLR-4介导的NF-κB通路的激活，减轻神经炎症从而发挥神经元的保护作用。我们进一步运用蛋白质组学技术研究发现：利福平可抑制MSS1的表达，而MSS1是泛素-蛋白酶体途径重要的调节亚基，可以启动相关炎症基因的表达，但其作用的分子机制尚未阐明。根据预实验结果我们推测：调控MSS1的表达可能成为防治PD的一个潜在靶点。因此，本研究拟通过体内、外实验，阐明调控MSS1的表达致NF-κB的活化受抑制从而引起促炎症细胞因子水平的降低在PD疾病中发挥重要作用的分子机制，这将为PD的防治提供全新的视角和靶点。

中文关键词： 26S蛋白酶体调节亚基7；神经炎症；小胶质细胞；脂多糖；帕金森病

英文摘要： There was abundant evidence showing that the constant activation and release of pro-inflammatory factors promoted the development of Parkinson's Disease. Thus, the inhibition of these pro-inflammatory mediators offers a potential therapeutic strategy for the treatment of Parkinson's Disease. We previously found that rifampicin improved survival of catecholamine and α-synuclein-containing cells, which degenerate in PD, thus might be therapeutic in this disease. Rifampicin suppressed the release of pro-inflammatory mediators including nitric oxide (NO), prostaglandin E2 (PGE2), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) from BV2 microglial cells that were pre-treated with lipopolysaccharides (LPS). It acted as a neuroprotector to increase neuronal survival against microglia-induced neuron death. Our results strongly supported rifampicin as a potential therapeutic for the treatment of neurodegenerative diseases. Despite of the above findings, the mechanism through which rifampicin inhibits inflammation in microglial cells is not completely understood. NF-κB is an important transcription factor for the expression of proinflammatory mediators. In unstimulated cells, nuclear factor-kappa B (NF-kB) binds to IkappaBalpha (IκBα) and its activity is inhibited. The activation of NF-kB is initiated by sign

英文关键词： MSS1；Neuroinflammation；Microglia；LPS；PD