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Development of a new drug for heart failure

Research Project

Project/Area Number 14370032
Research Category

Grant-in-Aid for Scientific Research (B)

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

Principal Investigator

INUI Makoto  Yamaguchi University, School of Medicine, Professor, 医学部, 教授 (70223237)

Co-Investigator(Kenkyū-buntansha) KIMURA Yoshihiro  Yamaguchi University, School of Medicine, Associate Professor, 医学部, 助教授 (90301308)
YAMADA Yasue  Yamaguchi University, School of Medicine, Assistant Professor, 医学部, 講師 (00166737)
KO Ji-ae  Yamaguchi University, School of Medicine, Research Associate, 医学部, 助手 (70314797)
Project Period (FY) 2002 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥13,600,000 (Direct Cost: ¥13,600,000)
Fiscal Year 2004: ¥4,100,000 (Direct Cost: ¥4,100,000)
Fiscal Year 2003: ¥4,900,000 (Direct Cost: ¥4,900,000)
Fiscal Year 2002: ¥4,600,000 (Direct Cost: ¥4,600,000)
KeywordsA drug for heart failure / SERCA / Phospholamban / Cardiac sarcoplasmi reticulum / Intracellular Ca^<2+> transport / Protein-protein interaction / Screening / 蛋白質精製法 / 蛋白質結 / 蛋白質相互作用 / カルシウム・ポンプ / 強心薬 / リン脂質 / 心不全 / 融合蛋白質
Research Abstract

Contraction and relaxation of heart muscle is regulated by intracellular calcium ions (Ca). Especially, Ca pumps (SERCA) and Ca release channels of cardiac sarcoplasmic reticulum (SR) play pivotal roles in these processes. SERCA of heart muscle is modulated by another SR protein phospholamban which inhibits the activity of SERCA. Removal of the inhibition by phospholamban facilitates relaxation of heart muscle and increases the contractility. It has been shown that removal of phospholamban inhibition improves heart failure. In order to develop a new drug for heart failure, we investigated the molecular interaction between SERCA and phospholamban and factors that modulate the interaction. The followings are the summary of our results.
1.Development of a screening method for a drug which targets the SERCA-phospholamban system
We reconstituted the molecular interaction between SERCA and phospholamban using fusion proteins of cytoplasmic regions of each protein. Optimizing the conditions for … More a 384-well plate, we succeeded in development of a screen method for a drag which targets the SERCA-phospholamban system
2.Searching for factors which modulate oligomeric structure of phospholamban
Since only the monomeric form, not a pentameric form, of phospholamban inhibits SERCA, it is important to gain insight into the dynamic equilibrium between these two forms. Factors that increase the monomeric form dissociating the oligomer can potentially affect the contractility of heart muscle. Among the eight phospholipids examined, phosphatidic acid was an effective inducer of pentamer dissociation, whereas the other phospholipids exhibited pentamer-stabilizing activity. Lysophosphatidylcholine, lysophosphatidylethanolamine, and phosphatidylglycerol were highly effective stabilizers of the pentamer. The phospholipids in the SR membrane are thus important determinants of the equilibrium between the monomeric and pentameric forms of this protein. Our results suggest that a drug that directly or indirectry through phospholipase D increases the pentameric form of phospholamban potentially improves heart muscle function. Less

Report

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

    (23 results)

All 2005 2004 2003 2002 Other

All Journal Article (14 results) Patent(Industrial Property Rights) (3 results) Publications (6 results)

  • [Journal Article] Sensitizing effect of substance P on corneal epithelial migration induced by IGF-1, fibronectin, or interleukin-6.2005

    • Author(s)
      Naoyuki Yamada
    • Journal Title

      Investigative Ophthalmology and Visual Science 46

      Pages: 833-839

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Requirement of the transmembrane semaphorin Sema4C for myogenic differentiation.2005

    • Author(s)
      Ji-Ae Ko
    • Journal Title

      FEBS Letters 576

      Pages: 2236-2242

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Requirement of the transmembrane semaphorin Scma4C for myogenic differentiation.2005

    • Author(s)
      Ji-Ae Ko
    • Journal Title

      FEBS Letters 576

      Pages: 2236-2242

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Sensitizing effect of substance P on corneal epithelial migration induced by IGF-1,fibronectin, or interleukin-6.2005

    • Author(s)
      Naoyuki Yamada
    • Journal Title

      Invest.Ophthalmol.Vis.Sci. 46

      Pages: 833-839

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Requirement of the transmembrane semaphorin Sema4C for myogenic differentiation.2005

    • Author(s)
      Ji-Ae Ko
    • Journal Title

      FEBS Lett. (In press)

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Role of the C domain of IGFs in the synergistic promotion with a substance P-derived peptide of rabbit corneal epithelial wound healing.2004

    • Author(s)
      Noyuki Yamada
    • Journal Title

      Investigative Ophthalmology and Visual Science 45

      Pages: 1125-1131

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Differential modulation of NR1-NR2A and NR1-NR2B subtypes of NMDA receptor by PDZ domain-containing proteins.2004

    • Author(s)
      Takashi Iwamoto
    • Journal Title

      Journal of Neurochemistry 89

      Pages: 100-108

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Role of the C domain of IGFs in the synergistic promotion with a substance P-derived peptide of rabbit corneal epithelial wound healing.2004

    • Author(s)
      Naoyuki Yamada
    • Journal Title

      Invest.Ophthalmol.Vis.Sci. 45

      Pages: 1125-1131

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Differential modulation of NR1-NR2A and NR1-NR2B subtypes of NMDA receptor by PDZ domain-containing proteins.2004

    • Author(s)
      Takashi Iwamoto
    • Journal Title

      J.Neurochem. 89

      Pages: 100-108

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Reconstitution of the cytoplasmic interaction between phospholamban and Ca^<2+>-ATPase of cardiac sarcoplasmic reticulum.2002

    • Author(s)
      Yoshihiro Kimura
    • Journal Title

      Molecular Pharmacology 61

      Pages: 667-673

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] PSD-95 eliminates src induced potentiation of NRI/NR2A-subtype NMDA receptor channels and reduces high-affinity zinc inhibition.2002

    • Author(s)
      Yasue Yamada
    • Journal Title

      Journal of Neurochemistry 81

      Pages: 758-764

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Mitogenic and anti apoptotic effects of various growth factors on human corneal fibroblasts.2002

    • Author(s)
      Ryoji Yanai
    • Journal Title

      Investigative Ophthalmology and Visual Science 43

      Pages: 2212-2216

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] The postsynaptic density and dendritic raft localization of PSD-Zip70, which contains an N-myristoylation sequence and leucine-zipper motifs.2002

    • Author(s)
      Daijiro Konno
    • Journal Title

      Journal of Cell Science 115

      Pages: 4695-4706

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] PSD-95 eliminates src induced potentiation of NR1/NR2A-subtype NMDA receptor channels and reduces high-affinity zinc inhibition.2002

    • Author(s)
      Yasue Yamada
    • Journal Title

      Journal of Neurochemistry 81

      Pages: 758-764

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Patent(Industrial Property Rights)] アミノ酸配列がSer-Ser-Ser-Argで表されるペプチドの医薬用途2004

    • Inventor(s)
      西田 輝夫
    • Industrial Property Rights Holder
      山口大学
    • Industrial Property Number
      2004-305132
    • Filing Date
      2004-10-20
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Patent(Industrial Property Rights)] Method of screening remedy for heart failure2003

    • Inventor(s)
      Makoto Inui
    • Industrial Property Rights Holder
      Yamaguchi TLO
    • Filing Date
      2003-03-03
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Patent(Industrial Property Rights)] 新規ペプチド及びその医薬用途2002

    • Inventor(s)
      西田 輝夫
    • Industrial Property Rights Holder
      西田 輝夫
    • Industrial Property Number
      2002-350636
    • Filing Date
      2002-12-03
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Publications] Naoyuki Yamada: "Role of the C domain of IGFs in the synergistic promotion with a substance P-derived peptide of rabbit corneal epithelial wound healing"Invest.Ophthalmol.Vis.Sic.. (in press). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Takashi Iwamoto: "Differential modulation of NR1-NR2A and NR1-NR2B subtypes of NMDA receptor by PDZ domain-containing proteins"J.Neurochem.. (in press). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Kimura, Y.: "Reconstitution of the cytoplasmic interaction between phospholamban and Ca^<2+>-ATPase of cardiac sarcoplasmic reticulum"Mol.Pharmacol.. 61. 667-673 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Yamada, Y.: "PSD-95 eliminates src induced potentiation of NR1/NR2A-subtype NMDA receptor channels and reduces high-affinity zinc inhibition"J.Neurochem.. 81. 758-764 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Yanai R.: "Mitogenic and anti apoptotic effects of various growth factors on human corneal fibroblasts"Invest.Ophthalmol.Vis.Sci.. 43. 2212-2216 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Konno, D.: "The postsynaptic density and dendritic raft localization of PSD-Zip7O, which contains an N-myristoylation sequence and leucine-zipper motifs"J.Cell Sci.. 115. 4695-4706 (2002)

    • Related Report
      2002 Annual Research Report

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

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