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Study on Physiological Functions of Synthetic Enzymes for Prostaglandins by Genetically Engineered Mice

Research Project

Project/Area Number 12480195
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Functional biochemistry
Research InstitutionNational Cardiovascular Center Research Institute

Principal Investigator

TANABE Tadashi  National Cardiovascular Center Research Institute, Department of Pharmacology, Director, 薬理部, 部長 (60025624)

Co-Investigator(Kenkyū-buntansha) HATAE Toshihisa  National Cardiovascular Center Research Institute, Department of Pharmacology, Research Staff, 薬理部, 室員 (10251026)
YOKOYAMA Chieko  National Cardiovascular Center Research Institute, Department of Pharmacology, Section Chief, 薬理部, 室長 (90200914)
Project Period (FY) 2000 – 2001
Project Status Completed (Fiscal Year 2001)
Budget Amount *help
¥14,700,000 (Direct Cost: ¥14,700,000)
Fiscal Year 2001: ¥5,800,000 (Direct Cost: ¥5,800,000)
Fiscal Year 2000: ¥8,900,000 (Direct Cost: ¥8,900,000)
KeywordsProstacyclin / PRARδ / Pulmonary hypertension / Gene therapy / Prostaglandin / ノックアウトマウス / トロンボキサン / プロスタグランジンE
Research Abstract

Prostaglandins (PGs) are important in maintenance of homeostasis of cardiovascular system. However, their detailed physiological roles are still remained to be investigated. Here physiological role of prostacyclin (PGI) has been studied in vivo with PG1 synthase (PGIS)-deficient mice. As it is possible that the deficiency of PGIS increase the production of other PGs such as thromboxane (TX) and PGE, we also made TX syntase knock-out miceand PGE synthase-trangenic mice. Results obtained are followings.
1. PGIS-deficient (PGID) mice producing little PGI showed severe ischemic renal diseases and thickening of kidney arteries. By gene chip analysis of PGID mice, many inflammation-related genewere expressed in the kidneies.
2. Human PGIS was expressed with the HVJ-liposome method in lungs of monocrotaline-treated rats, a model for pulmonary hypertension. The overexpression of PGIS reduced thikening of lung arteires and increased the suvival rate.
3. Overexpression of human PGIS in HEK293 cells induced apoptosis of the cells. The apoptosis was suppressed by antisense DNA for PPARδ or a dominant negative form of PPARδ, suggesting that apoptosis of cells by PGI is induced via PPARδ and reduced in the presence of cAMP. The apoptosis by PGI is also observed in vascular endothelial cells and smooth muscle cells.

Report

(3 results)
  • 2001 Annual Research Report   Final Research Report Summary
  • 2000 Annual Research Report
  • Research Products

    (17 results)

All Other

All Publications (17 results)

  • [Publications] Yokoyama, C, Tanabe, T et al.: "Gene transfer of human prostacyclin synthase ameliorates monocrtaline-induced pulmonary hypertension in rats"Circulation. 102. 2005-2010 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Yokoyama, C, Tanabe, T et al.: "Cloning and characterization of 5'-flanking region of mouse prostacyclin synthase"Biochim Biophys Acta. 1495. 155-161 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Ueno, N, Tanebe, T et al.: "Coupling between cyclooxygenase ; terminal prostanoid synthase and phospholipase A_2"J Biol Chem. 276. 34918-34927 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Hatae, T, Yokoyama, C, Tanabe, T et al.: "Prostacyclin-dependent apoptosis mediated by PPARδ"J Biol Chem. 276. 46260-46267 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Suhara, H, Sawa, Y, Yokoyama, C, Tanabe, T et al.: "Gene transfer of human prostacyclin synthase into the liver is effective for a treatment of pulmonary hypertension in rats"J Thorac Cardiovasc Surg. (in press). (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Tanabe, T., N.Tohnai: "Isozymes and their gene structures and expression in Molecular Biology of the Arachidonate Cascade, (S.Yamamoto, W.L.Smith.eds.)"Elsevier, Amsterdam (in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Tanabe, T. et al: "Gene transfer of human prostacyclin ameliorates monocrotaline-induced pulmonary hypertension in rats"Circulation. 102. 2005-2010 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Yokoyama, C. et al: "Cloning and characterization of %'-flanking regikon of mouse prostacyclin synthase"Biochim. Biophys. Acta. 1495. 155-161 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Ueno, N. et al: "Coupling between cyclooxygenase, terminal prostanoid synthase and phopholipase A_2"J. Biol. Chem.. 276. 34918-34927 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Hatae, T. et al: "Prostacyclin-dependent apoptosis mediated by apoptosis"J. Biol. Chem.. 276. 46260-46267 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Suhara, H. et al: "Gene transfer of human prostacyclin synthase into the liver is effective for a treatment of pulmonary hypertension in rats"J. Thorac. Cardiovasc. Surg.. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Tanabe, T. and Tohnai, N.: "Isozymes and their gene structures and expression"Molecular Biology of the Arachidonate Cascade, (S. Yamamoto and W.L. Smith, eds.) Elsevier, Amsterdam. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Ueno, N, Tanebe, T et al.: "Coupling between cyclooxygenases, terminal prostanoid synthasesand phospholipase A2s"J Biol Chem. 276,14. 34918-34927 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Hatae, T, Yokoyama, C, Tanabe, T et al.: "Prostacyclin-dependent apoptosis mediated by PPARδ"J Biol Chem. 276,49. 46260-46267 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Suhara, H, Sawa, Y, Yokoyama, C, Tanabe, T et al.: "Gene transfer of human prostacyclin synthase into the liver is effective for a treatment of pulmonary hypertension in rats"J Thorac Cardiovasc Surg. (in press). (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Yokoyama,C,Tanabe,T. et al.: "Gene transfer of human prostacyclin synthase ameliorates monocrotaline-induced pulmonary hypertension in rats"Circulation. 102,16. 2005-2010 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Yokoyama,C,Tanabe,T. et al.: "Cloning and characterization of 5'-flanking region of mouse prostacyclin synthase gene"Biochim.Biophys.Acta. 1495. 155-161 (2000)

    • Related Report
      2000 Annual Research Report

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Published: 2000-04-01   Modified: 2016-04-21  

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