Studies on neuronal functions by modulators of glycosphingolipid synthesis

鞘糖脂合成调节剂对神经元功能的研究

• 批准号: 11672155
• 负责人: INOKUCHI Jin-ichi
• 金额: $ 2.3万
• 依托单位: HOKKAIDO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11672155/
• 关键词: Gangliosides; Inhibitor; Stimulator; Neuronal Function; Apoptosis; VDAC; type 2 Diabetes; Insulin Resistance; ガングリオシド; スルファチド; ラミニン; フィブロネクチン; インテグリン; 造腫瘍能; 細胞接着; スフィンゴ糖脂質; 記憶; シナプス

Recent achievement on the molecular cloning of various ganglioside synthtase genes as well as the development of ganglioside biosynthesis inhibitor (D-PDMP) and accelerator (L-PDMP) leads us the new dimension for the elucidation of the physiological function of gangliosides. Based on these remarkable progress, we could demonstrate here that 1 ) The anti-apoptotic action of L-PDMP in neuronal cells may be the specific binding ability of this ceramide analog to voltage-dependent anion channel (VDAC) protein. Since VDAC localizes the mitochondrial outer membrane and regulates the release of cytochrome C (an executor of apoptosis through mitochondria), further study to elucidate the inhibitory mechanism of VDAC function by L-PDMP will open a new strategy for anti-apoptotic therapy. ; 2) Acquisition of a state of insulin resistance in adipocytes induced by TNF-α may depend upon increased GM3 biosynthesis through upregulation of GM3 synthase gene expression. Pharmacological depletion of GM3 in adipocytes by D-PDMP prevented the TNF-α-induced defect in insulin-dependent signaling. The increased synthesis of cellular GM3 by TNF may participate in the pathological conditions of insulin resistance in type 2 diabetes.

最近的各种神经节苷脂合酶基因的分子克隆以及神经节苷脂生物合成抑制剂（D-PDMP）和加速剂（L-PDMP）的发展取得了新的成就，这为我们带来了新的维度，以阐明神经节功能的物理功能。基于这些显着的进步，我们可以在这里证明1）L-PDMP在神经元细胞中的抗凋亡作用可能是该神经酰胺类似于电压依赖性阴离子通道（VDAC）蛋白的特定结合能力。由于VDAC定位了线粒体外膜，并调节细胞色素c的释放（通过线粒体凋亡的执行者）的释放，因此进一步的研究阐明了通过L-PDMP的VDAC功能的抑制作用机制，将为抗蛋白质治疗的新策略打开一种新的策略。 ; 2）通过TNF-α诱导的脂肪细胞中胰岛素抵抗状态的采集可能取决于通过上调GM3合酶基因表达的上调GM3生物合成的增加。 D-PDMP在脂肪细胞中GM3的药理耗竭阻止了TNF-α诱导的胰岛素依赖性信号传导中的缺陷。 TNF对细胞GM3的合成增加可能参与2型糖尿病中胰岛素抵抗的病理条件。

项目成果

Mitsuru Nakamura: "UDP-GloNAC:Galβ1→3GalNAc β1→6N-acetylglucosaminyltransferase holds a key role on the cotrol of CD15s expression in human pre-B cell lines"Glycobiology. 9. 1-12 (1999)

Mitsuru Nakamura：“UDP-Glo​​NAC：Galβ1→3GalNAc β1→6N-乙酰葡糖胺基转移酶在人前 B 细胞系中 CD15 表达的控制中起着关键作用”糖生物学 9. 1-12 (1999)。

Inokuchi, J., Uemura, K., Kabayama, K., Igarashi, Y.: "Glycosphingolipid Deficiency Affects Functional Microdomain Formation in Lewis Lung Carcinoma Cells"Glycoconjugate J. 17. 239-246 (2000)

Inokuchi, J.、Uemura, K.、Kabayama, K.、Igarashi, Y.：“鞘糖脂缺乏影响 Lewis 肺癌细胞中功能性微结构域的形成”Glycoconjugate J. 17. 239-246 (2000)

Tagami, S. et al.: "Ganglioside GM3 participates in the pathological conditions of insulin Resistance"J.Biol.Chem.. 277. 3085-3092 (2002)

Tagami, S. 等人：“神经节苷脂 GM3 参与胰岛素抵抗的病理状况”J.Biol.Chem.. 277. 3085-3092 (2002)

Igarashi, K., Furuse. H., Fujii, S., Ito, K., Kaneko, K., Kato, H., Inokuchi, J., Waki, H, Ando, S.: "Effects of mono- and tetra-sialogangliosides, GM1 and GQ1b, and a ceramide analog, L-PDMP, on ATP-induced long-term potentiation in hippocampal CA1 neuro

五十岚，K.，古濑。

井ノ口 仁一: "ラクトシルセラミド分岐とドメイン形成"蛋白質 核酸 酵素. 47. 371-378 (2002)

Jinichi Inoguchi：“乳糖神经酰胺分支和结构域形成”蛋白质核酸酶 47. 371-378 (2002)