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Screening and Development of New Immnomodulatory Drugs using PAF Receptor Gene as a Probe

Research Project

Project/Area Number 03557017
Research Category

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

Allocation TypeSingle-year Grants
Research Field Pathological medical chemistry
Research InstitutionThe University of Tokyo

Principal Investigator

SHIMIZU Takao  The University of Tokyo, Faculty of Medicine, Professor, 医学部(医), 教授 (80127092)

Co-Investigator(Kenkyū-buntansha) TERAO Shinji  Takeda Chemical Institute, Director, 化学研究所, 所長
HONDA Zenichiro  The University of Tokyo, Health Service Center, Assistant, 保健センター, 助手 (70238814)
SEYAMA Yousuke  The University of Tokyo, Faculty of Medicine, Professor, 医学部(医), 教授 (90010082)
和泉 孝志  東京大学, 医学部(医), 助手 (70232361)
Project Period (FY) 1991 – 1992
Project Status Completed (Fiscal Year 1992)
Budget Amount *help
¥15,900,000 (Direct Cost: ¥15,900,000)
Fiscal Year 1992: ¥7,500,000 (Direct Cost: ¥7,500,000)
Fiscal Year 1991: ¥8,400,000 (Direct Cost: ¥8,400,000)
KeywordsPAF / Receptor / Endotoxin / Phospholipases / Transformants / Antagonists / 遺伝子 / platelet-activating factor / receptor / inflammation / endotoxin
Research Abstract

Platelet-activating factor (PAF) is a potent mediator of inflammation, immunological disorders, and endotoxin shock. We have recently isolated cDNA clones of human and guinea pig PAF receptors. Using these clones as probe, we have obtained following results.
1. Isolation and structure of PAF receptor gene.
PAF receptor gene is consisted of three exons which are separated by >20kb introns. All exons are localized on chromosome 1. By alternative splicing, the leukocyte- and heart-type transcripts are produced. They have differentially regulated by distinct promoters.
2. Elucidation of signal transduction through a cloned PAF receptor.
A stable transfectant cell (CHO) was established carrying a cloned PAF receptor. By the application of PAF, phospholipase C and A_2, and MAP (mitogen-associated protein) are all activated, while adenylate cyclase was inhibited. These cellular events appear to be regulated by different types of G-proteins. Furthermore, we found that endotoxin. LPS, stimulated PAF receptor and yielded a Ca increase in human platelets as well as CHO transfectants. Thus, a part of LPS signaling, especially that related to platelet-aggregation might be due to the direct activation of PAF receptor.
3. Development of Screening System of PAF Receptor Agonists and Antagonists.
PAF receptor was expressed in Xenopus oocytes and a sensitive assay system of PAF receptor agonists/antagonists was made. Furthermore, COS cells/CHO cells carrying an excess amount of PAF receptors were constructed. By using membrane fractions of these cells, the highly specific screening system of PAF receptor modulator (either receptor antagonists or uncoupler of receptor-G-protein) was established. Through screening of naturally-occurring and synthetic compounds, several candidate chemicals have been obtained, which have potentiality for immunomodulatory drugs.

Report

(3 results)
  • 1992 Annual Research Report   Final Research Report Summary
  • 1991 Annual Research Report
  • Research Products

    (23 results)

All Other

All Publications (23 results)

  • [Publications] HONDA,Z.et al.: "Cloning by functional expression of guinea-pig lung platelet-activating factor receptor." Nature. 349. 342-346 (1991)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] NAKAMURA,M.et al.: "Molecular cloning and expression of human platelet-activating factor receptor" J.Biol. Chem.266. 20400-20405 (1991)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] TAKANO,T.et al.: "Demonstration of platelet-activating factor receptor in guinea pig kidney." Biochiem.Biophys.Res. Commun.177. 54-60 (1991)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] BITO,H.et al.: "Platelet-activating factor receptor in rat brain." Neuron. 9. 285-294 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] SAKANAKA,C.et al.: "Three types of Gi protein of the guinea pig lung:cDNA cloning and analysis of tissue distribution." Biochim.Biophys. Acta. 1175. 61-66 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] SHIMIZU,T.: "Molecular cloning of platelet-activating factor receptor in "PAF Receptor Signal Transduction)" CRC Press,Florida, (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Honda Z., Nakamura, M., Miki, I., Minami, M., Watanabe, T., Okado, H., Toh, H., Ito, K., Miyamoto, T. and Shimizu, T.: "Cloning by functional expression of guinea-pig lung platelet-activating factor receptor." Nature. 349. 342-346 (1991)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Nakamura, M., Honda, Z., Izumiz, T., Sakanaka, C., Mutoh, H., Minami, M., Bito, H., Seyama, Y., Matsumoto, T. Noma, M., and Shimizu, T.: "Molecular cloning and expression of human platelet-activating factor receptor." J. Biol. Chem.266. 20400-20405 (1991)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Takano, T., Honda, Z., Watanabe, T., Uchida, S., Shimizu, T. and Kurokawa, K.: "Demonstration of platelet-activating factor receptor in guinea pig kidney." Biochem. Biophys. Res. Commun.177. 54-60 (1991)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Bito, H., Nakamura, M., Honda, Z., Izumi, T., Iwatsubo, T. Seyama, Y., Ogura, A., Kudo, H., and Shimizu, T.: "Platelet activating factor receptor in rat brain; PAF mobilizes intracellular Ca in hippocampal neuron" Neuron. 9. 285-294 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Sakanaka; C., Izumi, T., Nakamura, M., Honda, Z., Watanabe, T., Minami, M., Mutoh, H., Bito, H., Seyama, Y. Ui, M., and Shimizu, T.: "Three types of Gi proteins of the guinea pig lung; cDNA cloning and tissue distribution." Biochim. Biophys.Acta 1175. 61-66 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Shimizu, T.: "Molecular cloning of phatelet-activating factor receptor. (Shkula, SD ed.)" RAF Receptor Signal Transduction. CRC Press. 29-40 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Shimizu,T.et al.: "Platelet-activating factor receptor and signal transduction." Biochem.Pharmacol.44. 1001-1008 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Shimizu,T.: "Molecular cloning of platelet-activating factor receptor." PAF receptor signal transduction.29-40 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Sugimoto,T.et al.: "Molecular cloning and characterization of the platelet-activating factor receptor gene ex-pressed in human heart." Biochem.Biophys.Res.Commun.189. 617-624 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Honda,Z.et al.: "Properties of the guinea-pig lung platelet-activating factor receptor encoded by the cloned cDNA" J.Lipid Mediator. 5. 105-107 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Minami,M.et al.: "Leukotriene A4 hydrolse,a bifunctional enzyme." FEBS Lett.309. 353-357 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Bito,H.et al.: "Platelet-activating factor (PAF) receptor in rat brain." Neuron. 9. 285-294 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Honda,Z.et al.: "Cloning by functional expression of guinea-pig lung platelet activating factor receptor" Nature. 349. 342-346 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Yamashita et al.: "Activin A/erythroid differentiating factor induces thromboxane A2 synthetic activity in murine erythro-leukemia cells." J.Biol.Chem.266. 3888-3892 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Nakamura,M.et al.: "Molecular cloning and expression of human platelet-activating factor receptor from human leukocytes." J.Biol.Chem.266. 20400-20405 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Watanabe,T.,et al.: "Characterization of partially-purified prostaglandin E receptor from canine renal medulla." Biochim.Biophys.Acta. 1074. 398-405 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Takano,T.et al.: "Demonstration of platelet-activating factor receptor in guinea pig kidney." Biochem.Biophys.Res.Commun.177. 54-60 (1991)

    • Related Report
      1991 Annual Research Report

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Published: 1991-04-01   Modified: 2017-10-06  

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