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細胞の生存と死におけるスフィンゴ糖脂質の役割

Research Project

Project/Area Number 12140205
Research Category

Grant-in-Aid for Scientific Research on Priority Areas

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionThe Institute of Physical and Chemical Research

Principal Investigator

平林 義雄  独立行政法人理化学研究所, 平林研究ユニット, ユニットリーダー (90106435)

Co-Investigator(Kenkyū-buntansha) 古屋 茂樹  独立行政法人理化学研究所, 平林研究ユニット, 研究員 (00222274)
大須賀 壮  独立行政法人理化学研究所, 平林研究ユニット, リサーチアソシエイト (10332321)
三好 一郎  名古屋市立大学, 大学院・医学研究科・実験動物研究教育センター, 助教授 (10183972)
長塚 靖子  独立行政法人理化学研究所, 平林研究ユニット, 研究員 (70108497)
竹田 潤二  大阪大学, 医学研究科・社会環境医学, 教授 (50163407)
古金谷 綾子(香山 綾子) (古金谷 綾子 / 香山 綾子)  理化学研究所, 神経回路メカニズム研究グループ, 研究員 (70312270)
Project Period (FY) 2000 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥136,000,000 (Direct Cost: ¥136,000,000)
Fiscal Year 2004: ¥32,100,000 (Direct Cost: ¥32,100,000)
Fiscal Year 2003: ¥34,700,000 (Direct Cost: ¥34,700,000)
Fiscal Year 2002: ¥34,600,000 (Direct Cost: ¥34,600,000)
Fiscal Year 2001: ¥34,600,000 (Direct Cost: ¥34,600,000)
Keywordsスフィンゴ脂質 / スフィンゴミエリン / グルコシルセラミド / ノックアウトマウス / プルキンエ細胞 / セリンパルミチン酸転移酵素 / グルコース転移酵素 / セリン / ラフト / アポトーシス / 糖脂質 / セリンパルミトイル転移 / ノックストマウス / セリンパルミトイル転移酵素 / プルコンルセラミド / セリンパルミトイルトランスフェラーゼ
Research Abstract

Stlc2ノックアウトマウス:L7CreトランスジェニックマウスとSptlc2floxマウスとを交配させることによりプルキンエ細胞特異的にスフィンゴ脂質合成が欠損したノックアウトマウスを確立した。驚いたことに、プルキンエ細胞は、小脳の領域特異的に生存している細胞が存在していた。プルキンエ細胞は、生後4週目から6週の間に急激に死ぬ。しかし、小脳lobule X, XIにおいて、特徴的にプルキンエ細胞は生存していた。ノックアウトマウスはマイルドな行動異常を示し、特に歩行時の後肢の運動に異常が認められ、coordination異常と(特定領域の)プルキンエ細胞の関連性が示唆された。
ノックアウト動物:GlcT-1トランスジェニックバエとEigerの強制発現により神経細胞死を示すハエとを交配させることにより完全に細胞死を抑制できることを見いだした。この抑制は、GlcT-1に特異的であり、他のスフィンゴ脂質代謝関連遺伝子による抑制効果は全く認められなかった。
また、スフィンゴミエリン合成に関わるセラミド輸送タンパクCERTの遺伝子の機能解析の目的で、ノックアウトマウスの作製を進めているが、そのターゲッティングベクターを調製した。
新しい生理活性糖脂質:HL60細胞より精製した新規糖脂質PtdGlcの画分中に、強力な神経ガイダンス因子活性を有している事を見いだした。この活性を示す因子の本体を同定とその作用機構の解析に着手した。

Report

(5 results)
  • 2004 Annual Research Report
  • 2003 Annual Research Report
  • 2002 Annual Research Report
  • 2001 Annual Research Report
  • 2000 Annual Research Report
  • Research Products

    (29 results)

All 2005 2004 Other

All Journal Article (11 results) Publications (18 results)

  • [Journal Article] Three dimensional structural studies of alpha-N-acetylgalactosaminidase (alpha-NAGA) in alpha-NAGA deficiency (Kanzaki disease): different gene mutations cause peculiar structural changes in alpha-NAGAs resulting in different substrate specificities and clinical phenotypes.2005

    • Author(s)
      Kanekura T
    • Journal Title

      J Dermatol Sci. 37(1)

      Pages: 15-20

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Astroglial expression of ceramide in Alzheimer's disease brains : A role during neuronal apoptosis.2005

    • Author(s)
      Satoi H
    • Journal Title

      Neuroscience 130(3)

      Pages: 657-666

    • Related Report
      2004 Annual Research Report
  • [Journal Article] A lipid-specific toxin reveals heterogeneity of sphingomyelin-containing membranes.2004

    • Author(s)
      Ishitsuka R
    • Journal Title

      Biophys J 86

      Pages: 296-307

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Targeted disruption of the mouse 3-phosphoglycerate dehydrogenase gene causes severe neurodevelopmental defects and results in embryonic lethality.2004

    • Author(s)
      Yoshida K
    • Journal Title

      J.Biol.Chem. 279

      Pages: 3573-3577

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Functional identification of ASCT1 neutral amino acid transporter as the predominant system for the uptake of L-serine in rat neurons in primary culture.2004

    • Author(s)
      Yamamoto T
    • Journal Title

      Neurosci Res. 49

      Pages: 101-111

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Synaptic function of cholinergic-specific Chol-lalpha ganglioside.2004

    • Author(s)
      Ando S
    • Journal Title

      Neurochem Res. 29

      Pages: 857-867

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Functional analysis of mouse 3-phosphoglycerate dehydrogenase (Phgdh) gene promoter in developing brain.2004

    • Author(s)
      Shimizu M
    • Journal Title

      J Neurosci Res. 76

      Pages: 623-632

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Charge-based separation of detergent-resistant membranes of mouse splenic B cells.2004

    • Author(s)
      Katsumata O
    • Journal Title

      Biochem Biophys Res Commnun. 319

      Pages: 826-831

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Drosophila glucosylceramide synthase : A negative regulator of cell death mediated by proapoptotic factors.2004

    • Author(s)
      Koganeya AK
    • Journal Title

      J Biol Chem. 279

      Pages: 35995-36002

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Mouse 3-phosphoglycerate dehydrogenase gene : genomic organization, chromosomal localization, and promoter analysis.2004

    • Author(s)
      Mitoma J
    • Journal Title

      Gene 334

      Pages: 15-22

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Ceramide reduction and transcriptional up-regulation of glucosylceramide synthase through doxorubicin-activated Sp1 in drug-resistant HL-60/ADR cells.2004

    • Author(s)
      Uchida Y
    • Journal Title

      Cancer Res. 64

      Pages: 6271-6279

    • Related Report
      2004 Annual Research Report
  • [Publications] Nagatsuka, Y., Hara-Yokoyama, M., Kasama, T., Takekoshi, M., Maeda, F.: "Carbohydrate-dependent signaling from the phosphatidylglucoside-based microdomain induces granulocytic differentiation of HL60 cells"Proc.Natl.Acad.Sci.USA.. 100. 7454-7459 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Stanic A.K., De Silva, D., Park, J.J., Sriram, V., Ichikawa, S., Hirabayashi, Y.: "Defective presentation of the CD1d1-restricted natural V_14J_18 NKT lymphocyte antigen caused by β-D-glucosylceramide synthase deficiency"Proc.Natl.Acad.Sci.USA.. 100. 1849-1854 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Hirabayashi, Y., Kanamori, A., Nomura S., Nomura, K: "SLC-33, acetyl-CoA transporter family"Eur.J.Physiol. 447. 760-762 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Manolova V, Hirabayashi Y, Mori L, De Libero G.: "CD1a and CD1b surface expression is independent from de novo synthesized glycosphingolipids."Eur J Immunol.. 33. 29-37 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Yamamoto, T., Nishizaki, I., Furuya S., Hirabayashi, Y., Takahashi, K., その他: "Characterization of rapid and high affinity uptake of L-serine in neurons and astrocy tes in primary culture."FEBS letter. 548. 69-73 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Yoshida K, Furuya S, Osuka S, Mitoma J, Hirabayashi, Y., その他: "Targeted disruption of the mouse 3-phosphoglycerate dehydrogenase gene causes severe neurodevelopmental defects and results in embryonic lethality"J.Biol.Chem.. 279. 3537-3577 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Kanda A, Tsuyama S, Murata F, Kodama K, Hirabayashi Y, Kanzaki T: "Immunoelectron microscopic analysis of lysosomal deposits in alpha-N-acetylgalactosaminidase deficiency with angiokeratoma corporis diffusum"J. Dermatol. Sci. 29. 42-48 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Uchida Y, Murata S, Schmuth M, Behne MJ, Lee JD, Ichikawa S, Elias PM, Hirabayashi Y, Holleran WM: "Glucosylceramide synthesis and synthase expression protect against ceramide-induced stress"J Lipid Res. 43. 1293-1302 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Yamada S, Okada Y, Ueno M, Iwata S, Deepa SS, Nishimura S, Fujita M, Van Die I, Hirabayashi Y, Sugahara K: "Determination of the Glycosaminoglycan-Protein Linkage Region Oligosaccharide Structures of Proteoglycans from Drosophila melanogaster and Caenorhabditis elegans"J Biol Chem. 277. 31877-31886 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Katsunuma., O., Yokoyama, M., et al: "Association of FegammaRII with low-density detergent-resistant membranes is important for"J. Immunology. 167. 5814-5823 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Sprong, H., Hirabayashi, Y., et al: "Glycosphingolipids are required for sorting melanosomal proteins in the Golji complex"J. Cell Biology. 155. 369-380 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Choo, Y-K., Ichikawa S., et al: "Developmental patterns of GlcT-1 expression"Mol Cell. 11. 346-351 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Mizutani, Y., Yoshida H., et al: "Nuclear localization of neutral sphingomyelinase 1"J. Cell Science. 114. 3727-3736 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Yamazaki, M., Furuya, S., et al: "3-Phosphiglycerate dehydrogenase is preferentially expressed"J Neuroscienc. 21. 7691-7704 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Nagatsuka, Y., Kasama, T., et al: "A new phosphoglycerolipid, phosphatidylglucose in human cord red cells"FEBS letters. 497. 141-147 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Komori,H.,Ichikawa,S.,Hirabayashi,Y.and Ito,M.:: "Regulation of UDP-glucose : ceramide glucosyltransferase-1 by ceramide"FEBS Letters. 475. 247-250 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Kobayashi,T.,and Hirabayashi,T.:: "Lipid microdomains in cell surface and vacuolar system."Glycoconjugates J.. 17. 163-171 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Furuya,S.,Tabata,T.,Mitoma,J.,Kano,M.,and Hirabayashi,Y.:: "L-Serine and glycine serve as major astroglia-derived trophic factors for cerebellar Purkinje neurons,"Proc.Natl.Acad.Sci.USA.. 97. 11528-11533 (2000)

    • Related Report
      2000 Annual Research Report

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Published: 2001-04-01   Modified: 2018-03-28  

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