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Identification of novel intracellular signaling molecules and clarification of their signal transduction mechanism which regulate abnormal vascular contraction.

Research Project

Project/Area Number 14370014
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field General physiology
Research InstitutionYamaguchi University

Principal Investigator

KOBAYASHI Sei  Yamaguchi University, School of Medicine, Department of Molecular Physiology, Professor, 医学部, 教授 (80225515)

Co-Investigator(Kenkyū-buntansha) KISHI Hiroko  Yamaguchi University, School of Medicine, Department of Molecular Physiology, Assistant Professor, 医学部, 講師 (40359899)
MOGAMI Kimiko  Yamaguchi University, School of Medicine, Department of Molecular Physiology, Research Associate, 医学部, 助手 (80263771)
佐藤 正史  山口大学, 医学部, 助手 (20346547)
Project Period (FY) 2002 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥14,800,000 (Direct Cost: ¥14,800,000)
Fiscal Year 2004: ¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 2003: ¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2002: ¥8,400,000 (Direct Cost: ¥8,400,000)
Keywordsabnormal contraction of vascular smooth muscle / mass spectrometry / calcium-independent contraction / Rho-kinase / sphingolipid / intracellular signal transduction / RNA interference / Src family tyrosine kinase / 細胞内シグナル伝達 / 血管平滑筋 / 血管異常収縮 / エイコサペンタエン酸 / Ca^<2+>非依存性収縮 / カルシウム
Research Abstract

Mortality of vascular diseases is comparable to that of cancer in Japan. It has been reported that C^<2+>-dependent contraction (Ca^<2+>-sensitization) plays a pivotal role in abnormal vascular contraction observed in vascular diseases. The purpose of this study was to identify novel intracellular signaling molecules and to clarify their signal transduction mechanisms.
In the first year, we identified sphingosylphosphorylcholine (SPC) as a novel mediator to induce abnormal vascular contraction. We found that SPC induces Ca^<2+> psensitization through the activation of Src family tyrosine kinase and Rho-kinase in this order
In the second year, in order to find the downstream mediators of Src family tyrosine kinase, we focused on the changes in tyrosine phosphorylation induced by SPC and we succeed in extracting some molecules as downstream mediators of Src family tyrosine kinase.
In the third year, we obtained the following results :
1.We established the cell culture system of vascular smooth muscle which has contractile ability.
2.The siRNA-mediated knock down of Fyn inhibited the SPC-induced contraction of the cultured vascular smooth muscles, indicating the involvement of Fyn in the SPC induced signal transduction.
3.The functional proteomics analysis identified p60, p160, and p200 as the downstream mediators of Fyn.
From these results, we identified Fyn as an intracellular signaling molecule which mediates abnormal vascular contraction. In addition, we propose that Fyn induces abnormal vascular contraction through the tyrosine phosphorylation of p60, p160, and/or p200.

Report

(4 results)
  • 2004 Annual Research Report   Final Research Report Summary
  • 2003 Annual Research Report
  • 2002 Annual Research Report
  • Research Products

    (12 results)

All 2005 2004 2003 2002 Other

All Journal Article (7 results) Publications (5 results)

  • [Journal Article] Sphingomyelinase causes endothelium-dependent vasorelaxation through endothelial nitric oxide production without cytosolic Ca^<2+> elevation.2005

    • Author(s)
      Mogami K
    • Journal Title

      FEBS Lett. 579

      Pages: 393-397

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] ERK1/2 regulates intracellular ATP levels through alpha-enolase expression in cardiomyocytes exposed to ischemic hypoxia and reoxygenation.2004

    • Author(s)
      Mizukami Y
    • Journal Title

      J.Biol.Chem. 279

      Pages: 50120-50131

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] Identification of the active metabolite of ticlopidine from rat in vitro metabolites.2004

    • Author(s)
      Yoneda K
    • Journal Title

      Br.J.Pharmacol. 142

      Pages: 551-557

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Ca^<2+> and voltage dependence of cardiac ryanodine receptor channel block by sphingosylphosphorylcholine.2003

    • Author(s)
      Yasukochi M
    • Journal Title

      Pflugers Arch. 445

      Pages: 665-673

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Proteasome-dependent decrease in Akt by growth factors in vascular smooth muscle cells.2003

    • Author(s)
      Adachi M
    • Journal Title

      FEBS Lett. 554

      Pages: 77-80

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Sphingosylphosphorylcholine is a novel messenger for Rho-kinase-mediated Ca^<2+> sensitization in the bovine cerebral artery : unimportant role for protein kinase C.2002

    • Author(s)
      Shirao S
    • Journal Title

      Circ.Res. 91

      Pages: 112-119

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Involvement of Src family protein tyrosine kinases in Ca^<2+> sensitization of coronary artery contraction mediated by a sphingosylphosphorylcholine-Rho-kinase pathway.2002

    • Author(s)
      Nakao F
    • Journal Title

      Circ.Res. 91

      Pages: 953-960

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Publications] 岸 博子: "エイコサペンタエン酸(EPA)による血管攣縮の予防効果"月刊バイオインダストリー. 20巻. 5-13 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Adachi M: "Proteasome-dependent decrease in Akt by growth factors in vascular smooth muscle cells"FEBS Letters. 554. 77-80 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Yasukochi M: "Ca2+ and voltage dependence of cardiac ryanodine receptor channel block by sphingosylphosphorylcholine"Pflugers Arch Eur.J.Physiol.. 445. 665-673 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Shirao S et al.: "Sphingosylphosphorylcholine is a novel messenger for Rho-kinase-mediated Ca^<2+> sensitization in the bovine cerebral artery : unimportant role for protein kinase C"Circulation Research. 91. 112-119 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Nakao F et al.: "Involvement of Src family protein tyrosine kinases in Ca^<2+> sensitization of coronary artery contraction mediated by a sphingosylphosphorylcholine-Rho-kinase pathway"Circulation Research. 91. 953-960 (2002)

    • Related Report
      2002 Annual Research Report

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Published: 2002-04-01   Modified: 2016-04-21  

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