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神経突起伸長と血管新生におけるグリコサミノグリカン糖鎖の分子認識

神经突生长和血管生成中糖胺聚糖糖链的分子识别

基本信息

批准号：
09470509
负责人：
SUGAHARA Kazuyuki
金额：
$ 8万
依托单位：
KOBE PHARMACEUTICAL UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B).
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 2000
项目状态：
已结题

项目摘要

1) The so-called D disaccharide unit was demonstrated in the chondroitin sulfate preparation purified from neonatal mouse brains. Neurite outgrowth promoting activity was also demonstrated for the commercial shark cartilage chondroitin sulfate D preparation which contained a high proportion of the D disaccharide unit.2) It was demonstrated that the commercial squid cartilage chondroitin sulfate E preparation had neurite outgrowth promoting activity toward cultured neuronal cells derived from embryonic rat brains. The chondroitin sulfate E preparation was further demonstrated to bind midkine and inhibit the midkine-mediated neuronal cell adhesion to the culture substrate.3) The tumor-derived adhesion factor, angiomodulin, promotes the cord formation towards the cultured human tumor cell line ECV304, and has been proposed to be associated with tumor angiogenesis. The angiomodulin-binding domain on heparan sulfate chains was shown to be larger than dodecasaccharides and highly sulfated.4) Sulfation of the chondroitin sulfate chains and sulfotransferase activities in embryonic chick brains were shown to be regulated during embryonic development and neonatal growth.5) Glucuronyltransferase that is involved in the synthesis of the glycosaminoglycan-protein linkage region tetrasaccharide sequence, GlcA-Gal-Gal-Xyl, was molecularly cloned and its properties were characterized.6) A truncated tetrasaccharide fragment, GlcA-Gal-Gal-Xyl, which corresponded to the glycosaminoglycan-protein linkage region, was demonstrated on a part-time proteoglycan, α-thrombomodulin.7) α-GalNAc transferase purified from the culture medium of a human sarcoma cell line was shown to be identical with the EXTL2 protein encoded by the EXTL2 gene, which belonged to the tumor suppressor EXT gene family, and to harbor the α-GlcNAc transferase activity that initiates and determines the heparan sulfate synthesis.

1) 在从新生小鼠脑中纯化的硫酸软骨素制剂中证实了所谓的 D 二糖单元。含有高比例 D 二糖单元的市售鲨鱼软骨硫酸软骨素 D 制剂也显示出神经突生长促进活性。2) 市售鱿鱼软骨硫酸软骨素 E 制剂对来自胚胎大鼠脑的培养神经元细胞具有神经突生长促进活性。硫酸软骨素 E 制剂进一步被证明可以结合中期因子并抑制中期因子介导的神经元细胞与培养基质的粘附。3) 肿瘤源性粘附因子血管调节蛋白可促进培养的人肿瘤细胞系 ECV304 的索状形成，并被认为与肿瘤血管生成有关。硫酸乙酰肝素链上的血管调节蛋白结合域比十二糖更大，并且高度硫酸化。4) 硫酸软骨素链的硫酸化和胚胎鸡大脑中的磺基转移酶活性在胚胎发育和新生儿生长过程中受到调节。5) 参与合成硫酸软骨素的葡萄糖醛酸转移酶糖胺聚糖-蛋白质连接区四糖序列GlcA-Gal-Gal-Xyl被分子克隆并表征其性质。6)在部分蛋白聚糖上证明了与糖胺聚糖-蛋白质连接区相对应的截短四糖片段GlcA-Gal-Gal-Xyl， α-血栓调节蛋白。7) 从人肉瘤细胞系培养基中纯化的α-GalNAc 转移酶与 EXTL2 基因编码的 EXTL2 蛋白相同，属于肿瘤抑制 EXT 基因家族，并且具有启动和决定硫酸乙酰肝素合成的 α-GlcNAc 转移酶活性。