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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，并阐明其异常的发病机制。为了实现这些目标，我们分析了； 1.基于糖基化模式重塑的黑色素瘤和小细胞肺癌中糖脂信号传导的调节机制，2.糖基转移酶基因敲除小鼠异常表型的建立和分析，以阐明糖脂在体内的作用。在黑色素瘤细胞中，GD3 的特征性表达诱导 p130Cas 和桩蛋白等接头分子酪氨酸磷酸化增强，并增加细胞生长和侵袭活性。此外，粘着斑激酶（FAK）在 GD3+ 细胞中的激活也比在 GD3- 细胞中更强。另一方面，GD2的表达导致小细胞肺癌细胞的细胞增殖和侵袭增强，并且抗GD2抗体的结合可以触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。因此，得出结论：抗GD2抗体引发失巢凋亡，并且必须破坏GD2的分子复合物。整合素和FAK是癌症治疗的有效策略。至于鞘糖脂在神经组织中的作用，人们怀疑酸性鞘糖脂由于其高水平表达而在神经系统的发育和功能中发挥重要作用。为了阐明它们在神经组织中的作用，我们产生了基因敲除小鼠品系，即。 e. GM2/GD2合酶、GD3合酶的基因敲除小鼠，以及这两种合酶、GM3合酶和乳糖神经酰胺合酶的双敲除小鼠。作为这些突变小鼠的表型分析结果，我们证明它们根据神经节苷脂结构缺陷的范围表现出异常表型变化。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。此外，对野生型和双敲除小鼠神经组织中基因表达谱的比较表明，在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所表明的。较少的

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.

GD3 synthase gene knockout mice exhibit thermal hyperalgesia and mechanical allodynia but decreased response to formalin-induced prolonged noxious stimulation

DOI：
10.1016/j.pain.2005.06.016
发表时间：
2005-10-01
期刊：
PAIN
影响因子：
7.4
作者：
Handa, Y;Ozaki, N;Sugiura, Y
通讯作者：
Sugiura, Y

Ganglioside GD3 promotes cell growth and invasion through p130Cas and paxillin in malignant melanoma cells

DOI：
10.1073/pnas.0503658102
发表时间：
2005-08-02
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
影响因子：
11.1
作者：
Hamamura, K;Furukawa, K;Furukawa, K
通讯作者：
Furukawa, K

Complex formation of Plk1 and INCENP required for metaphase-anaphase transition