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New assay systems for the development of inhibitory drugs against activated mast cell function

Research Project

Project/Area Number 04557108
Research Category

Grant-in-Aid for Developmental Scientific Research (B)

Allocation TypeSingle-year Grants
Research Field Biological pharmacy
Research InstitutionKYOTO UNIVERSITY

Principal Investigator

ICHIKAWA Atsushi  Kyoto University, Physiological Chemistry, Professor, 薬学部, 教授 (10025695)

Co-Investigator(Kenkyū-buntansha) HARA Kiyoto  Kissei Medicine, Research worker, 創薬品研究所, 研究員
KURASHINA Kichi  Kissei Medicine, the head, 創薬品研究所, 所長
KUDO Ichiro  Univ.of Tokyo, Fac.Pharmaceutical Sci., Associate Professor, 薬学部, 助教授 (30134612)
INOUE Keizo  Univ.of Tokyo, Fac.Pharmaceutical Sci., Professor, 薬学部, 教授 (30072937)
FUKUI Tetsuya  Kyoto University, Physiological Chemistry, Associate Professor, 薬学部, 助教授 (90111971)
Project Period (FY) 1992 – 1994
Project Status Completed (Fiscal Year 1994)
Budget Amount *help
¥17,800,000 (Direct Cost: ¥17,800,000)
Fiscal Year 1994: ¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 1993: ¥5,000,000 (Direct Cost: ¥5,000,000)
Fiscal Year 1992: ¥9,600,000 (Direct Cost: ¥9,600,000)
Keywordsmast cell function / inflammation / histidine decarboxylase / histamine / phospholipase A_2 / arachidonate / 翻訳後修飾 / エラスターゼ / ノックアウトマウス / 肥満細胞 / elastase / プロテインキナーゼ / ヒスタミン合成 / 脱顆粒 / チロシンキナーゼ
Research Abstract

(Kyoto University)
We have isolated mouse histidine decarboxylase (HDC), and cloned its cDNA and partial genomic DNA.Mouserecombinant HDC expressed in Baculovirus-SF9 cells has a 74 kDa in size mostly present in the particulate fraction with a low enzyme activity, whereas a C-termial delated mutant recombinant HDC which is a homodimer of 54 kDa subunit is a fullly active enzyme Present in soluble fraction. Particulate recombinant 74 kDa HDC was interconvertedinto the soluble form having intensified activity by porcine pancreatic elastase treatment. We further obtained that mouse HDC in mastocytoma cells was specifically induced by treatment with a combination of dexamethasone and TPA,of Ca^<2+> and cAMP.Furthermore, the regulatory elements involved in the increased transcription of the HDC gene with dexamethasone/TPA of Ca^<2+>/cAMP were determined in the promoter regions of the genomic DHA clone of the mouse HDC gene. These results contribute the study for developing a new type drug which acts on the regulation of histamine synthesis in histamine-producing cells such as mast cells.
(Tokyo Univercity)
We detect at least two kinda of phospholipase A_2 in rat and mouse mast cells. One of the enzyme, c-phospholipase A_2 was phospholylated shorty after cell stimulation, and this process may play an importaut role for releasing arachidonate during cell activation. Type II secretory phospholipase A_2 was secreted and bound to the surface membrane when mast cells were stimulated. It was suggested that the enzyme may be involved in the process leading to release of histamine. Inhibitors of either c-or secretory phospholipases A_2 may be useful for suppression of mast cell activation.

Report

(4 results)
  • 1994 Annual Research Report   Final Research Report Summary
  • 1993 Annual Research Report
  • 1992 Annual Research Report
  • Research Products

    (28 results)

All Other

All Publications (28 results)

  • [Publications] Kawai, Hiroshi: "Synergistic effects of 12-O-tetradecanoylphorbor-13-acetate and dexamethasone de novo synthesis of histidine decarboxylase in mouse mastocytoma P-815 cells" Biochim. Biophys.Acta. 1133. 172-178 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Yamamoto, Jun: "Expression and characterization of recombinant mouse mastcytoma histidine decarboxylase" Biochim. Biophys. Acta. 1216. 431-440 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Yatsunami. Kimio: "Structure of the L-Histidine Decarboxylase Gene" Journal of Biological Chemistry. 269. 1554-1559 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Murakami. Makoto: "Release of 14-kDa groupe-II phospholipase A2 from activated mast cells and its possible involvement in the regulation of the degranulation process" Eur. J. Biochem.209. 257-265 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Murakami, Makoto: "Triggering of degranulation in mast cells by exogenous type II phospholipase A2" J. Immunol.151. 5675-5684 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Nakatani, Yoshihito: "Dual regulation of cytosolic phospholipase A2 in mast cells after Cross-Linking of Fce-receptor" J. Immunol.153. 796-803 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Kawai, Hiroshi: "Synergistic effects of 12-O-tetradecanoylphorbor-13-acetate and dexamethasone on de novo synthesis of histidine decarboxylase in mouse mastocytoma P-815 cells" Biochim.Biophys.Acta. 1133. 172-178 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Yamamoto, Jun: "Expression and characterization of recombinant mouse mastocytoma histidine decarboxylase." Biochim.Biophys.Acta. 1216. 431-440 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Yatsunami, Kimio: "Structure of the L-Histidine Decarboxylase Gene" J.Biol.Chem.269. 1554-1559 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Murakami, Makoto: "Release of 14-kDa group-II phospholipase A2 from activated mast cells and its Possible involvement in the regulation of the degranulation process" Eur.J.Biochem.209. 257-265 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Murakami, Makoto: "Triggering of degranulation in mast cells by exogenous type II phospholipase A2" J.Immunol.151. 5675-5684 (1933)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Nakatani, Yoshihito: "Dual regulation of cytosolic phospholipase A in mast cell after Cross-Linking of Fcepsilon-receptor" J.Immunol. 153. 796-803 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Yatsunami,Kimio: "Structure of the L-Histidine Decarboxylase Gene" Journal of Biological Chemistry. 269. 1554-1559 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Kakutani,M.: "Role of type II phospholipase A2 in the inflammatry process of carrageenan-induced pleurisy in rats" FEBS Letters. 339. 76-78 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Nakatani,Yoshihito: "Dual regulation of cytosolic phosphplipase A2 in mast cells after Cross-Linking of Fcz-receptor" J.Immunol.153. 796-803 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Hara,Kiyoto: "Suppressive effects of the anti-allergic drugs,tranilast and azelastine,on the lysophpsphatidylserine-dependent activation of rat mast cells" Biol.Pharm.Bull.17. 1121-1123 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Yatsunami Kimio: "12-O-Tetradecanoylphorbol-13-acetate stimulates the transcription of the histidine decarboxylase gene" Agents Actions. 38. C155-C157 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Ohgoh Makoto: "Enhanced expression of the mouse L-histidine decarboxylase gene with a combination of dexamethasone and 12-O-tetradecanoyl---" Biochem.Biophys.Res.Commun.196. 1113-1119 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Yamamoto Jun: "Expression and characterization of recombinant mouse mastcytoma histidine decarboxylase" Biochimica et Biophysica Acta. 1216. 431-440 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Asaoka,Y.: "Possible role of mammalian secretory group II phospholipase A_2 in T-lymphocyte activation" Proc.Natl.Acad.Sci.USA. 90. 716-719 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Kudo Ichiro: "Mammalian non-pancreatic phospholipase A_2" Biochimica et Biophysica Acta. 1170. 217-231 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Suga H.: "Participation in cellular prostaglandin synthesis of type-II phospholipase A_2 secreted and anchored on cell-surface---" Eur.J.Biochem.218. 807-813 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Hitoshi Kawai: "Synergistic effects of 12-O-tetradecanoylphorbol-13-acetate and dexamethasone on de novo synthesis of histidine decarboxylase in mouse mastocytoma P-815 cells" Biochimica et Biophysica Acta. 1133. 172-178 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Tomoko Kiyazaki: "Synmergistic effects of cyclic AMP and Ca^<2+> ionophore A23187 on de novo synthesis of histidine decarboxylase in mastocytoma P-815 cells" Biochimica et Biophysica Acta. 1133. 179-186 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Akiko Watabe: "Purification and properties of L-histidine decarboxylase from mouse stomach" Biochemical pharmacology. 43. 587-593 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Makoto Murakami: "Release of 14-kDa group II phospholipase A_2 from activated mast cells and its possible involvement in the regulation of the degranulation process" Eur.J.Biochem.209. 257-265 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] 工藤 一郎: "高等動物非脾型ホスホリパーゼA_2:構造、性伏、機能" 生化学. 64. 1330-1344 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Makoto Murakami: "Molecular nature of phospholipase A_2 involved in prostaglandin I_2 synthesis in human umbilieal vein endothelial cells" J.Biol.Chem.268. 839-844 (1993)

    • Related Report
      1992 Annual Research Report

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

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