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Development of a fundamental technology, which is applicable to drug development and therapeutic applications through analysis of sulfated glycosaminoglycan chains

通过分析硫酸糖胺聚糖链开发适用于药物开发和治疗应用的基础技术

基本信息

批准号：
16390026
负责人：
SUGAHARA Kazuyuki
金额：
$ 9.54万
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：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

项目摘要

(1)It has been demonstrated that congenital human spondyloepiphysial dysplasia is caused by a mutation of the chondroitin 6-O-sulfotransferase 1 gene.(2)The nematode ortholog PAR2.4 of the human chondroitin polymerizing factor (ChPF) that is involved in the biosynthesis of chondroitin has been cloned. Furthermore it was found that downregulation of PAR2.4 by RNAi resulted in the cytokinesis defect during embryonic development of the nematode, which resembled the defect caused by RNAi of chondroitin synthase, indicating the essential role of PAR2.4 in the synthesis of chondroitin as well as the critical role of chondroitin in cytokinesis.(3)Various biological activities have been demonstrated for CS/DS hybrid chains isolated from shark skin, suggesting a possible therapeutic applications of the CS/DS chains.(4)It has been proved that the neurite outgrowth promoting activity of CS/DS chains from embryonic mouse brains is exhibited by molecular interactions with a growth factor pleiotrophin. Sulfated decasaccharides derived from the functional domains have also been isolated and sequenced.(5)A monoclonal antibody specific for dermatan sulfate was developed using an oversulfated dermatan sulfate preparation with a potent neurite outgrowth promoting activity, which was purified from marine ascidian. The antibody apecifically bound to mouse hippocampal neurons, and inhibited the neurite outgrowth promoting activity, which was exhibited by the DS preparation used as an immunogen.(6)Conventionally herpes simplex virus (HSV-1 and HSV-2) have been considered to infect cells through attachment to heparan sulfate chains on cell surface. In this study it has been demonstrated the infection is more strongly inhibited by CS-E than heparin. Furthermore the CS-E structure has beendemonstrated on cell surface. There results suggest that the viruses use CS-E more efficiently than heparan sulfate for their infection.

(1)It已经证明先天性人脊椎骨骺发育不良是由软骨素6-O-磺基转移酶1基因突变引起的。（2）已克隆了参与软骨素生物合成的人软骨素聚合因子（ChPF）的线虫直系同源物PAR 2.4。进一步发现，通过RNAi下调PAR 2.4导致线虫胚胎发育过程中的胞质分裂缺陷，这类似于软骨素合酶的RNAi引起的缺陷，表明PAR 2.4在软骨素合成中的重要作用以及软骨素在胞质分裂中的关键作用。（3）从鲨鱼皮中分离的CS/DS杂合链具有多种生物学活性，提示CS/DS杂合链可能具有治疗应用价值。(4)It已经证明，来自胚胎小鼠脑的CS/DS链的神经突生长促进活性是通过与生长因子多效生长因子的分子相互作用来表现的。硫酸化十糖衍生的功能结构域也已被分离和测序。(5)A使用从海洋海鞘中纯化的具有有效的神经突生长促进活性的过硫酸化硫酸皮肤素制剂，开发了对硫酸皮肤素特异的单克隆抗体。抗体apecipirin与小鼠海马神经元结合，并抑制神经突生长促进活性，这是由用作免疫原的DS制剂表现出来的。（6）以往认为单纯疱疹病毒（HSV-1、HSV-2）通过附着于细胞表面的硫酸乙酰肝素链而感染细胞。在这项研究中，已经证明CS-E比肝素对感染的抑制作用更强。此外，在细胞表面也发现了CS-E结构。这些结果表明，病毒使用CS-E比硫酸乙酰肝素更有效地进行感染。