Microdomain abnormalities due to aberrant glycolipids

异常糖脂导致的微区异常

基本信息

批准号：
14082102
负责人：
FURUKAWA Koichi
金额：
$ 147.26万
依托单位：
Nagoya University
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

In this project, we have tried to investigate roles of glycosphingolipids expressed on cancer cells and neuronal cells in the regulation of biosignals, and to clarify mechanisms for the pathogenesis due to their abnormalities. In order to achieve these aims, we analysed ; 1. regulatory mechanisms of signaling with glycilipids in melanomas and small cell lung cancers based on the remodeling of glycosylation patterns, 2. establishment and analysis of abnormal phenotypes of gene knockout mice of glycosyltransferases to elucidate roles of glycolipids in vivo. In melanoma cells, characteristic expression of GD3 induced enhancement of tyrosine phosphorylation of adaptor molecules such as p130Cas and paxillin, and increased cell growth and invasion activity. Furthermore, focal adhesion kinase (FAK) was also activated more strongly in GD3+ cells than in GD3- cells. On the other hand, GD2 expression resulted in the enhancement of cell proliferation and invasion in small cell lung cancer cells, … More and binding of anti-GD2 antibodies could trigger apoptosis of small cell lung cancer cells. It was, then, demonstrated that anti-GD2 antibodies could induce dephosphorylation of FAK and activation of p38, leading to anoikis. Consequently, it was concluded that anti-GD2 antibodies trigger anoikis, and it was essential to destroy molecular complex sonsisting of GD2. Integrin and FAK as an efficient strategy toward cancer therapeutics.As for roles of glycosphingolipids in nervous tissues, it has been suspected that acidic glycosphingolipids paly important roles in the development and function of nervous systems based on their high levels of expression. In order to clarify their roles in the nervous tissues, we generated gene knockout mice lines, i. e. knockout mice of GM2/GD2 synthase, GD3 synthase, double knockout of those two, GM3 synthase, and lactosylceramide synthase. As results of phenotypic analyses of these mutant mice, we have demonstrated that they showed abnormal phenotypic changes according to the range of defects in ganglioside structures. Generally, acidic glycolipids appeared to be essential in the maintenance of the integrity of the nervous tissues and repair after neuronal damages. Furthermore, comparison of gene expression profiles in the nerve tissues between wild type and double knockout mice revealed that neurodegeneration detected in the mutant mice are not mere atrophic changes, but active changes with inflammatory process as indicated by the activation of complementary system and cytokine production or secretion. Less

在这个项目中，我们试图研究癌细胞和神经元细胞上表达的鞘糖脂在生物信号调节中的作用，并阐明其在黑色素瘤和小细胞肺癌中与糖脂信号传导异常的发病机制。糖基化模式重塑的研究，2.基因敲除小鼠异常表型的建立及分析在黑色素瘤细胞中，GD3 的特征性表达可诱导 p130Cas 和桩蛋白等接头分子的酪氨酸磷酸化增强，并增加细胞生长和侵袭活性。另一方面，GD2 表达导致细胞增殖和侵袭增强。在小细胞肺癌细胞中，抗 GD2 抗体的结合可以引发小细胞肺癌细胞的凋亡，随后证明抗 GD2 抗体可以诱导 FAK 去磷酸化和 p38 激活，从而导致失巢凋亡。经过检查，得出的结论是，抗GD2抗体会引发失巢凋亡，并且破坏GD2和FAK的分子复合物作为癌症治疗的有效策略至关重要。神经组织中的糖鞘脂，由于其高水平的表达，人们怀疑酸性鞘糖脂在神经系统的发育和功能中发挥着重要作用。 GM2/GD2 合酶、GD3 合酶敲除小鼠、这两种酶、GM3 合酶和乳糖苷神经酰胺合酶双敲除小鼠作为表型分析的结果。通过对这些突变小鼠的研究，我们发现它们根据神经节苷脂结构缺陷的范围表现出异常的表型变化。一般来说，酸性糖脂似乎对于维持神经组织的完整性和神经元损伤后的修复至关重要。野生型和双敲除小鼠神经组织中的基因表达谱显示，突变型小鼠中检测到的神经变性不仅仅是萎缩性变化，而是伴随炎症过程的活跃变化，如补充系统的激活和细胞因子的产生或分泌较少。

项目成果

期刊论文数量（92）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Knockout mice and glycolipids.

基因敲除小鼠和糖脂。

DOI：
发表时间：
2007
期刊：
Comprehensive glycoscience (Elsevier) Article No. : 00086
影响因子：
0
作者：
Furukawa;K.;et al.
通讯作者：
et al.

Targeted disruption of Gb3/CD77 synthase gene resulted in the complete deletion of globo-series glycosphingolipids and loss of sensitivity to veritoxins

Gb3/CD77 合酶基因的靶向破坏导致 globo 系列鞘糖脂完全缺失并丧失对 Vertoxin 的敏感性

DOI：
发表时间：
2006
期刊：
J. Biol. Chem. (in press)
影响因子：
0
作者：
Okudia T;Tokuda N;Numata S;Furukawa K;et al.
通讯作者：
et al.

Disruption of GM2/GD2 synthase gene resulted in neo-expression of 9-O-acetyl GD3 irrespective of Tis21.

GM2/GD2 合酶基因的破坏导致 9-O-乙酰基 GD3 的新表达，与 Tis21 无关。

DOI：
发表时间：
2008
期刊：
J.Neurochem. 105
影响因子：
0
作者：
Furukawa K.;Aixinjueluo W.;Kasama T.;Ohkawa Y.;Yoshihara M.;Ohmi Y.;Tajima O.;Suzumura A.;Kittaka D.
通讯作者：
Kittaka D.

Chen, H.H.et al.: "Suppression of lung metastasis of mouse Lewis lung cancer P29 with transfection of the ganglioside GM2/GD2 synthase gene."Int.J.Cancer. 103. 169-176 (2003)

Chen, H.H. 等人：“通过转染神经节苷脂 GM2/GD2 合酶基因抑制小鼠 Lewis 肺癌 P29 的肺转移。”Int.J.Cancer。