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.

近年来，神经节苷脂合成酶基因的克隆以及神经节苷脂生物合成抑制剂（D-P β）和促进剂（L-P β）的开发为神经节苷脂的生理功能研究开辟了新的方向。基于这些显著的进展，我们可以在这里证明：1）L-PdR在神经元细胞中的抗凋亡作用可能是该神经酰胺类似物与电压依赖性阴离子通道（VDAC）蛋白的特异性结合能力。由于VDAC定位于线粒体外膜并调节细胞色素C（通过线粒体的凋亡执行者）的释放，因此进一步研究L-PdR抑制VDAC功能的机制将为抗凋亡治疗开辟新的策略。2）TNF-α诱导脂肪细胞胰岛素抵抗状态的获得可能依赖于通过上调GM 3合成酶基因表达而增加GM 3生物合成。通过D-β-D-葡聚糖药理学耗竭脂肪细胞中的GM 3可防止TNF-α诱导的胰岛素依赖性信号传导缺陷。TNF增加细胞GM 3的合成可能参与了2型糖尿病胰岛素抵抗的病理过程。

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)。

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)

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., Inokuchi, J^*., Kabayama, S., Yoshimura, H., Uemura, S., Ogawa, C., Ishii, A., Saito, M., Ohtsuka, Y., Sakaue, S., Igarashi, Y.: "Ganglioside GM3 Participates in the Pathological Conditions of Insulin Resistance"J. Biol. Chem.. 277. 3085-3092

田上 S.、井之口 J^*.、蒲山 S.、吉村 H.、上村 S.、小川 C.、石井 A.、齐藤 M.、大冢 Y.、坂上 S

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。