2001 Fiscal Year Final Research Report Summary
Studies on neuronal functions by modulators of glycosphingolipid synthesis
| Project/Area Number |
11672155
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Biological pharmacy
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| Research Institution | HOKKAIDO UNIVERSITY |
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Principal Investigator |
INOKUCHI Jin-ichi Hokkaido Univ., Grad. School of Pharm.Sci., Assoc. Prof., 大学院・薬学研究科, 助教授 (70131810)
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| Co-Investigator(Kenkyū-buntansha) |
IGARASHI Yasuyuki Hokkaido Univ., Grad. School of Pharm.Sci., Prof., 大学院・薬学研究科, 教授 (70091965)
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| Project Period (FY) |
1999 – 2001
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| Keywords | Gangliosides / Inhibitor / Stimulator / Neuronal Function / Apoptosis / VDAC / type 2 Diabetes / Insulin Resistance |
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| Research Abstract |
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.
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[Publications] Nakamura, M., Fufukawa, Y., Sasaki, R., Masuyama, J., Kikuchi, J., Iwase, S., Kudo, T., Narimatsu, H., Asakura, S., Fujiwara, S., Inokuchi, J.: "UDP-GlcNAc : Galβ1->3GalNAc(GlcNAc to GalNAc) β1->6 acetylglucosaminyltransferase Holds a Key Role on the Control of CD15s Expression in Human Pre-B Lymphoid cell lines"Glycobiology. 9. 1-12 (1999)
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[Publications] Jimbo, M., Yamagishi, K., Yamaki, N., Nunomura, K., Kabayama, K., Igarashi, Y., Inokuchi, J: "Development of a New Inhibitor of Glucosylceramide Synthase"J. Biochem.. 127. 485-491 (2000)
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[Publications] Usuki, S., Ren, J., Utsunimiya, I., Cashman, N.R., Inoktchi, J., Miyatake, T.: "GM2 Ganglioside Regulates the Function of Ciliary Neurotropic Factor Receptor in Murine Immortalized Motor Neuron-Like Cells (NSC-34)"Neurochemical Research. 26. 375-382 (2001)
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[Publications] Togayachi, A., Akashima T., Ookubo, R., Kudo, T., Nishihara, S., Iwasaki, H., Inokuchi, J., Irimura, T,. Sasaki, K., Narimatsu, H.: "Molecular Cloning and Characterization of UDP-GlcNAc : Lactosylceramide β-1,3-N-acetylglucosaminyltransferase (β3Gn-T5), an essential enzyme, for the expression of HNK-1 and Lewis X Epitopes on Glycolipids"J. Biol. Chem.. 276. 22032-22040 (2001)
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[Publications] 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 (2002)
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[Publications] 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 neurons"Glycobiology. (in press).
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