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，我们试图研究在癌细胞和神经元细胞调节生物信号中表达的糖磷脂的作用，并阐明由于其异常而引起的发病机理的机制。为了实现这些目标，我们分析了； 1。基于糖基化模式的重塑，黑色素瘤和小细胞肺癌的信号传导的调节机制，2。建立和分析基因基因敲除小鼠的糖基转移酶异常表型的建立和分析，以阐明糖基质酶的糖基化酶的糖基糖基糖基糖基因的糖基化酶。在黑色素瘤细胞中，GD3的特征表达诱导了适配器分子（如P130CAS和Paxillin）的酪氨酸磷酸化的增强，并增加了细胞的生长和侵袭活性。此外，在GD3+细胞中，焦点粘合剂激酶（FAK）也比在GD3细胞中更强烈。另一方面，GD2表达导致小细胞肺癌细胞中细胞增殖和侵袭的增强，…更多和抗GD2抗体的结合可能会触发小细胞肺癌细胞的凋亡。因此，这证明了抗GD2抗体可以诱导FAK的去磷酸化和p38的激活，从而导致厌氧。因此，得出结论，抗GD2抗体会触发Anoikis，并且必须破坏GD2的分子复合物儿子。整联蛋白和FAK作为癌症治疗的有效策略。作为神经组织中糖磷脂的作用，人们怀疑基于其高水平的表达水平，酸性糖磷脂脂在神经系统的发展和功能中的重要作用。为了阐明它们在神经组织中的作用，我们产生了基因基因敲除小鼠系，即GM2/GD2合酶的基因敲除小鼠，GD3合酶，这两个，GM3合酶和乳糖基质酶合酶的双重敲除。作为这些突变小鼠的表型分析的结果，我们证明它们根据神经节结构中缺陷的范围显示出异常的表型变化。通常，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修复至关重要。此外，野生型和双基因敲除小鼠之间神经组织中基因表达谱的比较表明，突变小鼠中检测到的神经退行性不仅仅是萎缩性的变化，而是在炎症过程中的主动变化，这表明由完成系统和细胞因子产生和细胞因子产生或分泌物或分泌物的激活所表明。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）

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.

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.

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。

DOI：
发表时间：
期刊：
影响因子：
0
作者：
通讯作者：

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.

Biosynthesis of Glycolipids. In Comprehensive glycoscience. Article No. : 00037

糖脂的生物合成。