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.

近年来各种神经节苷脂合成酶基因的分子克隆以及神经节苷脂生物合成抑制剂（D-PDMP）和促进剂（L-PDMP）的开发为我们阐明神经节苷脂的生理功能提供了新的维度。显着的进展，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这种神经酰胺类似物与电压依赖性阴离子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（通过线粒体进行凋亡的执行者）的释放，进一步研究阐明L-PDMP对VDAC功能的抑制机制将为抗VDAC开辟新的策略。 -细胞凋亡治疗；2) TNF-α 诱导的脂肪细胞胰岛素抵抗状态的获得可能依赖于通过上调 GM3 合酶基因表达来增加 GM3 生物合成。 D-PDMP 对脂肪细胞中 GM3 的药理学消耗可防止 TNF-α 诱导的胰岛素依赖性信号传导缺陷。 TNF 增加的细胞 GM3 合成可能参与 2 型糖尿病胰岛素抵抗的病理状况。

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)

Kabayama, K. et al.: "Suppression of Integrin Expression and Tumorigenicity by Sulfation of Lactosylceramide"J.Biol.Chem.. 276. 26777-26783 (2001)

Kabayama，K.等：“通过乳糖神经酰胺的硫酸化抑制整联蛋白表达和致瘤性”J.Biol.Chem.. 276. 26777-26783 (2001)

Seigou Usuki: "GM2 ganglia side regulates the function of ciliary neurotropic factor receptor in murine immortalized Motor neuron-like cells"Neuro chemical Research. 26. 375-382 (2001)

Seigou Usuki：“GM2神经节侧调节小鼠永生化运动神经元样细胞中睫状神经营养因子受体的功能”神经化学研究。