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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)小鼠表现为髓鞘功能障碍和精子发生停滞所致的神经系统疾病，表明硫脂和半脂脂分别是髓鞘形成和精子发生所必需的。CST-KO小鼠兰维尔结节髓鞘外侧环与轴鞘之间的粘连恶化，导致钠、钾通道丛集性恶化。这种缺陷不是在开发阶段出现的，而是在维护过程中出现的。CST-KO小鼠少突胶质细胞终末分化和形态成熟增强，提示硫脂是少突胶质细胞终末分化负调控的关键分子。系统表达绿色荧光蛋白的绿色小鼠精原细胞移植发现，CST-KO小鼠的缺陷不在支持细胞，而在生殖细胞。半脂类在精原细胞、精母细胞、精子细胞和精子的质膜上均有表达。此外，Cst缺乏改善了输尿管梗阻后L依赖的单核细胞在肾间质炎症模型中的浸润，表明硫脂是L选择素的内源性配体。用CST-KO小鼠制备了抗硫酸酯糖脂的单抗(MOAB)。我们制备了基于单抗基因的重组单链可变区抗体。最后，我们将CST基因家族中的GP3ST基因导入到高表达唾液酸化Lewis X抗原的人肺腺癌细胞中。结果表明，癌细胞表达S-L-L抗原，肿瘤血管转移被GP3ST基因所抑制。

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）。