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Biological roles of sulfated glycolipids and pathophysiology of their deficiency

硫酸化糖脂的生物学作用及其缺乏的病理生理学

基本信息

批准号：
14082204
负责人：
HONKE Koichi
金额：
$ 30.72万
依托单位：
Kochi University (2003-2006)Osaka University (2002)
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

Glycolipid sulfotransferase (CST)-knockout (KO) mice manifest neurological disorders due to myelin dysfunction and an arrest of spermatogenesis, indicating that sulfatide and seminolipid are essential for myelin formation and spermatogenesis, respectively. The adhesion between the lateral loop of myelin sheath and the axolemmma at the nodes of Ranvier is deteriorated in CST-KO mice, resulting in deterioration of clustering of sodium and potassium channels. This defect occurs not at development but at maintenance process. In CST-KO mice, terminal differentiation and morphological maturation of oligodendrocytes are enhanced, indicating that sulfatide is a key molecule for the negative regulation of oligodendrocyte terminal differentiation. Transplantation of spermatogonia from the green mouse, in which green fluorescent protein is systemically expressed, revealed that defect of CST-KO mice is not in the Sertoli cells but in the germ cells. Seminolipid is found to be expressed on the plasma membranes of spermatogonia, spermatocytes, spermatids, and spermatozoa. Moreover, CST-deficiency ameliorates L-selectin-dependent monocyte infiltration in the kidney after ureteral obstruction, an experimental model of renal interstitial inflammation, indicating that sulfatide is an endogenous ligand of L-selectin. CST-KO mice were employed to raise a monoclonal antibodiy (MoAb) against sulfated glycolipids. We produced a recombinant single-chain variable-fragment (scFv) antibody based on the gene on the MoAb. Finally, we introduced the GP3ST gene, which is a member of the CST gene family, into human lung adnocarcinoma cells that highly express sialyl Lewis X antigen. As the result, the cancer cells turn to express sulfo Lewis X antigen instead of sialyl Lewis X antigen and tumor metastasis via blood vessels was suppressed by the expression of GP3ST gene.

糖脂磺基转移酶（CST）基因敲除（KO）小鼠表现出神经系统疾病，由于髓鞘功能障碍和精子发生的逮捕，表明硫苷脂和磷脂是必不可少的髓鞘形成和精子发生，分别。在CST-KO小鼠中，髓鞘的侧环与朗维尔结处的轴膜之间的粘附恶化，导致钠和钾通道的聚集恶化。该缺陷不是发生在开发过程中，而是发生在维护过程中。在CST-KO小鼠中，少突胶质细胞的终末分化和形态成熟增强，表明硫苷脂是负调控少突胶质细胞终末分化的关键分子。从全身表达绿色荧光蛋白的绿色小鼠中移植精原细胞，揭示了CST-KO小鼠的缺陷不是在支持细胞中，而是在生殖细胞中。发现精脂在精原细胞、精母细胞、精子细胞和精子的质膜上表达。此外，CST缺乏可改善输尿管梗阻后肾脏中L-选择素依赖性单核细胞浸润，这是肾间质炎症的实验模型，表明硫苷脂是L-选择素的内源性配体。采用CST-KO小鼠制备抗硫酸化糖脂的单克隆抗体（MoAb）。我们根据单克隆抗体上的基因制备了重组单链可变片段（scFv）抗体。最后，我们将CST基因家族的一员GP 3ST基因导入高表达唾液酸刘易斯X抗原的人肺腺癌细胞中。结果，癌细胞转而表达磺基刘易斯X抗原而不是唾液酸基刘易斯X抗原，并且通过血管的肿瘤转移被GP 3ST基因的表达抑制。

项目成果

期刊论文数量（70）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Dysregulation of TGF-β1 receptor activation leads to abnormal lung development and emphysema-like phenotype in core fucose-deficient mice

DOI：
10.1073/pnas.0507375102
发表时间：
2005-11-01
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
影响因子：
11.1
作者：
Wang, XC;Inoue, S;Taniguchi, N
通讯作者：
Taniguchi, N

Honke, K. et al.: "Biological roles of sulfoglycolipids and pathophysiology of their deficiency"Glycoconj.J.. (印刷中). (2004)

Honke, K. 等人：“磺基糖脂的生物学作用及其缺陷的病理生理学”Glycoconj.J.（出版中）。