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Molecular mechanism of abnormal hemolysis in paroxysmal nocturnal hemoglobinuria

Research Project

Project/Area Number 04671530
Research Category

Grant-in-Aid for General Scientific Research (C)

Allocation TypeSingle-year Grants
Research Field Hematology
Research InstitutionKumamoto University

Principal Investigator

NAKAKUMA Hideki  Kumamoto University school of Medicine, Lecturer, 医学部, 講師 (90207746)

Project Period (FY) 1992 – 1993
Project Status Completed (Fiscal Year 1993)
Budget Amount *help
¥2,100,000 (Direct Cost: ¥2,100,000)
Fiscal Year 1993: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 1992: ¥1,000,000 (Direct Cost: ¥1,000,000)
KeywordsPNH / Hemolysis / GPI anchor / GlcNAc / T cell lines
Research Abstract

Paroxysmal nocturnal hemoglobinuria (PNH) is currently accepted as being due to a somatic mutation of stem cells that is clonal in nature and that leads to an increaased susceptibility of the affected blood cells to autologous complement. The increase in sensitivity is mainly explained by a deficiency in such complement regulatory membrane proteins as decay-accelerating factor (DAF) and CD59. These proteins are covalently attached to the cell membrane by glycosylphosphatidylinositol (GPI)-anchor structures and share a common carbohydrate structure (core sequence). Regarding the step at which mutation may affect the biosynthesis or breakdown of this GPI-anchor, or the anchoring process of the proteins, recent investigations suggest a defect in the anchor synthesis in affected cells. We then prepared sufficient affected cells by establishing cultured T cell lines with PNH phenotype using human T-lymphotropic virus type 1 (HTLV-1). Using the cultured T cells, we soon examined the interruption site in the synthesis of the anchor by biochemical analysis. An results, metabolic labeling with [^3H]sugars in vivo or [^3H]sugar nucleotides in vitro of the GPI-anchor precursors showed a synthetic defect of the GPI-anchor. Among the precursors, phosphatidylinositol (PI) was normally produced, while glucosaminyl-PI and subsequent mannolipids were not synthesized. The defect in the synthesis of GPI-anchor in PNH is thus attributed to interrupted glycosylation (impaired trasfer of N-acetylglucosamine) in the core structure of the anchor.

Report

(2 results)
  • 1993 Annual Research Report   Final Research Report Summary
  • Research Products

    (15 results)

All Other

All Publications (15 results)

  • [Publications] 日高道弘,中熊秀喜 他: "Impaired glycosylation of glycosylphophatidylinositol-anchor synthesis in paroxysmal nocturnal hemoglobinuria leukocytes." Biochemical and Biophysical Research Communications. 191. 571-579 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] 長倉祥一,中熊秀喜 他: "Expression of decay-accelerating factor and CD59 in lymphocytes subsets of healthy individuals and paroxysmal nocturnal hemoglobinuria patients." American Journal of Hematology. 43. 14-18 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] 長倉祥一,中熊秀喜 他: "a deficiency in CDw52(CAMPATH-1 antigen)of paroxysmal nocturnal hemoglobinuria lymphocytes." BLOOD. 82. 3790-3792 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] 中熊秀喜: "(総説)発作性夜間血色素尿症-その異常溶血の分子機構について" 蛋白質 核酸 酵素. 38. 2333-2346 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] 中熊秀喜: "Interleukin-2-dependent T cell lines established from paroxysmal nocturnal hemoglobinuria patients." Blood. (in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Hidaka M, Nagakura S, Horikawa K, Kawaguchi T, Iwamoto N, Kagimoto T, Takatsuki K.: "Impaired glycosylation of glycosylphosphatidylinositol-anchor synthesis in paroxysmal nocturnal hemoglobinuria leukocytes." Biochemical and Biophysical Research Communications. 191. 571-579 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Nagakura S, Nakakuma H, Horikawa K, Hidaka M, Kagimoto T, Kawakita M, Tomita M, Takatsuki K.: "Expression of decay-accelerating factor and CD59 in lymphocyte subsets of healthy individuals and paroxysmal nocturnal hemoglobinuria patients." American Journal of Hematology. 42. 14-18 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Nagakura S, Kawaguchi T, Horikawa K, Hidaka M, Iwamoto N, Kagimoto T, Takatsuki K, Nakakuma H.: "A deficiency in CDw52 (CAMPATH-1 antigen) of paroxysmal nocturnal hemoglobinuria lymphocytes." Blood. 82. 3790-3792 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Nakakuma H.: "Paroxysmal nocturnal hemoglobinuria - Molecular mechanism of abnormal hemolysis." Protein, Nucleic acid and enzyme. 38. 2333-2346 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Nakakuma H, Nagakura S, Horikawa K, Hidaka M, Kawaguchi T, Iwamoto N, Sanada I, Kagimoto T, Takatsuki K.: "Interleukin-2-dependent T cell lines established from paroxysmal nocturnal hemoglobinuria patients." Blood. in press.

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] 日高道弘、中熊秀喜他: "Impaired glycosylation of glycosylphophatidylinositol-anchor synthesis in paroxysmal noctumal hemoglobinuria leukocytes." Biochemical and Biophysical Research Communications. 191. 571-579 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] 長倉祥一、中熊秀喜他: "Expression of decay-accelerating factor and CD59 in lymphocytes subsets of healthy individuals and paroxysmal nocturnal hemoglobinuria patients." American Journal of Hematology. 43. 14-18 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] 長倉祥一、中熊秀喜他: "a deficiency in CDw52(CAMPATH-1 antigen)of paroxysmal noctumal hemoglobinuria lymphocytes." BLOOD. 82. 3790-3792 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] 中熊秀喜: "(総説)発作性夜間血色素尿症-その異常溶血の分子機構について" 蛋白質核酸酵素. 38. 2333-2346 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] 中熊秀喜: "Interleukin-2-dependent T cell lines established from paroxysmal noctumal hemoglobinuria patients." Blood. (in press).

    • Related Report
      1993 Annual Research Report

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Published: 1992-04-01   Modified: 2016-04-21  

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