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Functions of chondroitin sulfate polysaocharide in the central nervous system

硫酸软骨素多糖对中枢神经系统的作用

基本信息

批准号：
14082210
负责人：
OOHIRA Atsuhiko
金额：
$ 35.84万
依托单位：
Institute for Developmental Research, Aichi Human Service Center
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research on Priority Areas
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2006
项目状态：
已结题

项目摘要

Functions of chondroitin sulfate proteoglycans (CSPGs) in the central nervous system were investigated in the two ways; functional analyses of a brain-specific CSPG, neuroglycan C (NGC), that we originally found in the developing rat brain and chondroitin sulfate (CS) polysaccharides as a major microenvironmental molecule of cells in the brain.I. Functions of neuroglycan CSite-directed mutagenesis revealed that a CS chain was introduced to S^<123> of the mouse NGC core protein. In addition to this CS-attachment domain, the extracellular region of NGC contains two other unique domains; a cluster of acidic amino acids (AA-domain) and an epidermal growth factor-like domain (EGF-domain). Both CS- and AA-domains had a high affinity to midkine, a growth factor. Both AA- and EGF- domains have a promotive activity for neurite extension. EGF-domain promotes growth of cells with EGF-receptors. Mouse strains with low and no expressions of NGC were produced. These mice show behavioral abnormalities. All these findings indicate that NGC is a functional molecule in the central nervous system.II. Functions of chondroitin sulfate polysaccharidesCS polysaccharides isolated and purified from developing rat brains promote fibroblast growth factor (FGF)-2-mediated proliferation of neural stem cells. Commercial preparations of CS, CS-B and CS-E, also promote FGF-2-mediated neural stem cell growth, suggesting that an iduronic acid-containing structure (B-structure) and an over sulfated structure formed by GalNAc-4,6-disulfate (E-structure) in the CS polysaccharides are involved in this promotion of neural stem cell growth. Additionally, CS-E protects neurons from glutamate-induced excitatory neural cell death, that occurs immediately after brain injuries. Thus, CS polysaccharide is a bioactive molecule in the brain.

本文从两个方面研究了硫酸软骨素蛋白聚糖（CSPG）在中枢神经系统中的功能：一是对我们最初在发育中的大鼠脑中发现的脑特异性CSPG--神经聚糖C（NGC）的功能分析，二是硫酸软骨素多糖（CS）作为脑细胞的主要微环境分子。神经聚糖CS的功能定点突变表明，小鼠NGC核心蛋白的S^中引入了CS链<123>。除了这个CS-附着结构域之外，NGC的胞外区还包含另外两个独特的结构域;酸性氨基酸簇（AA-结构域）和表皮生长因子样结构域（EGF-结构域）。CS-和AA-结构域都对中期因子（一种生长因子）具有高亲和力。AA-和EGF-结构域都具有促进神经突延伸的活性。EGF结构域促进具有EGF受体的细胞的生长。产生具有低表达和不表达NGC的小鼠品系。这些小鼠表现出行为异常。这些结果表明NGC是中枢神经系统的一种功能分子。硫酸软骨素多糖的功能从发育中的大鼠脑中分离纯化的CS多糖促进成纤维细胞生长因子（FGF）-2介导的神经干细胞增殖。CS、CS-B和CS-E的商业制剂也促进FGF-2介导的神经干细胞生长，这表明CS多糖中的含艾杜糖醛酸的结构（B-结构）和由GalNAc-4，6-二硫酸盐形成的过度硫酸化的结构（E-结构）参与神经干细胞生长的这种促进。此外，CS-E保护神经元免受脑损伤后立即发生的谷氨酸诱导的兴奋性神经细胞死亡。因此，CS多糖是脑中的生物活性分子。