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Investigation of molecular mechanisms for common diseases caused by aging and oxidative stress and development of drug candidates aiming the molecular targets

Research Project

Project/Area Number 15390029
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Biological pharmacy
Research InstitutionKumamoto University

Principal Investigator

NAKAYAMA Hitoshi  Kumamoto University, Graduate School of Medical and Pharmaceutical Sciences, Professor, 大学院・医学薬学研究部, 教授 (70088863)

Co-Investigator(Kenkyū-buntansha) KUNIYASU Akihiko  Kumamoto University, Graduate School of Medical and Pharmaceutical Sciences, Associate Professor, 大学院・医学薬学研究部, 助教授 (90241348)
ISHIZUKA Tadao  Kumamoto University, Graduate School of Medical and Pharmaceutical Sciences, Associate Professor, 大学院・医学薬学研究部, 助教授 (60176203)
KAWAHARA Kohichi  Kumamoto University, Graduate School of Medical and Pharmaceutical Sciences, Assistant Professor, 大学院・医学薬学研究部, 助手 (10347015)
MIYAZAKI Akira  Showa University, School of Medicine, Professor, 医学部, 教授 (70253721)
Project Period (FY) 2003 – 2005
Project Status Completed (Fiscal Year 2005)
Budget Amount *help
¥15,200,000 (Direct Cost: ¥15,200,000)
Fiscal Year 2005: ¥2,900,000 (Direct Cost: ¥2,900,000)
Fiscal Year 2004: ¥4,500,000 (Direct Cost: ¥4,500,000)
Fiscal Year 2003: ¥7,800,000 (Direct Cost: ¥7,800,000)
Keywordsscavenger receptors / adipocytes / microglia / Alzheimer's disease / β-amyloid peptide / clearance / CD36 / 肥満 / Aβクリアランス / ACAT阻害剤 / 脳虚血 / CD3b
Research Abstract

In this project we aim to investigate the molecular mechanisms for adipocytokine production from adipocytes and clearance of β-amyloid peptide in microglia, which apply to develop drug candidates aiming the molecular targets. During the passed three years, we have obtained several novel findings and drug candidates as follows. (1)Production of some adipocytokines including resistin increased by stimulation of ox-LDL via translation modulated mechanism. (2)We found a novel clearance mechanism of oligomeric β-amyloid peptides, which is induced selectively in type-2 microglia by IL-4 stimulation. (3)The clearance mechanism was proved to induce in vivo using transgenic AD model mice. We also found that some compounds of low molecular weight are able to induce the clearance mechanism. (4)We are succeeded in generating specific monoclonal antibodies to discriminate type-1 and type-2 microglia (Patent is applied.)
All the results described above are more than we expected, and they are very promising to create new drugs for recovering from Alzheimer's disease, in particular.

Report

(4 results)
  • 2005 Annual Research Report   Final Research Report Summary
  • 2004 Annual Research Report
  • 2003 Annual Research Report
  • Research Products

    (32 results)

All 2005 2004 2003 Other

All Journal Article (24 results) Patent(Industrial Property Rights) (2 results) Publications (6 results)

  • [Journal Article] Use of photoaffinity labeling and site-directed mutagenesis for identification of key residue.2005

    • Author(s)
      Katsuki, M. et al.
    • Journal Title

      J. Biol. Chem. 280

      Pages: 1384-1391

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Characterization of benzodiazepine binding site on human d1-acid glycoprotein2005

    • Author(s)
      Chuang, V.T.G.et al.
    • Journal Title

      Biochim. Biophys. Acta 1725

      Pages: 385-393

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Use of photoaffinity labeling and site-directed mutagenesis for identification of key residue responsible for extraordinarily high affinity binding of UCN-01 in human alpha 1-acid glycoprotein2005

    • Author(s)
      M.Katsuki, et al.
    • Journal Title

      J.Biol.Chem. 280

      Pages: 1384-1391

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Proteasomal degradation of Kir6.2 channel protein and its inhibition by Na+ channel blacker aprindine.2005

    • Author(s)
      H.Tanaka, et al.
    • Journal Title

      Biochem.Biophys.Res.Commun. 331

      Pages: 1001-1006

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Glycolaldehyde-modified BSA down-regulates leptin expression in mouse adipocytes via a CD36-mediated pathway.2005

    • Author(s)
      Y.Unno, et al.
    • Journal Title

      Ann.N.Y.Acad.Sci. 1043

      Pages: 696-701

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Characterization of benzodiazepine binding site on human a-1 glycoprotein using flunitrazepam as a photolabeling agent.2005

    • Author(s)
      V.T.G.Chuang, et al.
    • Journal Title

      Biochim.Biophys.Acta 1725

      Pages: 385-393

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Characterization of benzodiazepine binding site on human α-1-acid glycoprotein.2005

    • Author(s)
      Chuang, V.T.G.et al.
    • Journal Title

      Biochim.Biophys.Acta 1725

      Pages: 385-393

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Proteasomal degradation of Kir6.2 channel protein and its inhibition by Na^+ channel blocker aprindine.2005

    • Author(s)
      Tanaka, H. et al.
    • Journal Title

      Biochem.Biophys.Res.Commun. 331

      Pages: 1001-1006

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Use of photoaffinity labeling and site-directed mutagenesis for identification of the key residue2005

    • Author(s)
      Katsuki M. et al.
    • Journal Title

      J.Biol Chem. 280(2)

      Pages: 1384-1391

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Glycoaldehyde-modified BSA downregulates leptin expression in nouse adipocytes via a CD36-mediated.2005

    • Author(s)
      Unno, Y. et al.
    • Journal Title

      Ann.NY Acad.Sci 1043

      Pages: 696-701

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Use of photoaffinity labeling and site-directed mutagenesis for identification of the key residue.2005

    • Author(s)
      Katsuki, M. et al.
    • Journal Title

      J.Biol.Chem. 280(2)

      Pages: 1384-1391

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Adiponectin down-regulates ACAT-1 in cultured human monocyte-derived macrophages.2004

    • Author(s)
      Furukawa, K. et al.
    • Journal Title

      Biochem. Biophys. Res. Commun. 311

      Pages: 300-306

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] AGE-modified proteins and oxidized LDL mediate down-regulation of leptin via CD362004

    • Author(s)
      Unno, Y. et al.
    • Journal Title

      Biochem. Biophys. Res. Commun. 325

      Pages: 151-156

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] NO-induced apoptosis and ER stress in microglia (Review).2004

    • Author(s)
      Kawahara, K. et al.
    • Journal Title

      Folia pharmacol. Jpn. 124

      Pages: 401-408

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Adiponectin down-regulates acyl-coenzyme A : cholesterol acyl. transferase-1 in cultured human macrophages.2004

    • Author(s)
      K.Furukawa, et al.
    • Journal Title

      Biochem.Biophys.Res.Commun. 311

      Pages: 300-306

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Advanced glycation end products-modified proteins and oxidized-LDL mediate down-regulation of leptin in mouse adipocytes via CD36.2004

    • Author(s)
      Y.Unno, et al.
    • Journal Title

      Biochem.Biophys.Res.Commun. 325

      Pages: 151-156

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] NO-induced apoptosis and ER stress in microglia (Review).2004

    • Author(s)
      K.Kawahara, et al.
    • Journal Title

      Folia Pharmacol.Jpn. 124

      Pages: 401-408

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] AGE-modified proteins and oxidized LDL mediate down-regulation of leptin in mouse adipocytes.2004

    • Author(s)
      Unno, Y. et al.
    • Journal Title

      Biochem.Biophys.Res.Commun. 325

      Pages: 151-156

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Adiponectin down-regulates ACAT-1 in cultured human monocyte-derived macrophage.2004

    • Author(s)
      Furukawa, K. et al.
    • Journal Title

      Biochem.Biophys.Res.Commun. 317

      Pages: 831-836

    • Related Report
      2004 Annual Research Report
  • [Journal Article] No-induced apoptosis and ER stress in microglia (review)2004

    • Author(s)
      Kawahara, K. et al.
    • Journal Title

      Folia Pharmacol.Jpn. 124

      Pages: 401-408

    • Related Report
      2004 Annual Research Report
  • [Journal Article] CD36-mediated endocytotic uptake of AGE products in 3T3-L1 and subcutaneous adipocytes.2003

    • Author(s)
      Kuniyasu, A. et al.
    • Journal Title

      FEBS Lett. 537

      Pages: 85-90

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] CD36-mediated endocytic uptake of AGE in mouse 3T3-L1 and human subcutaneous adipocytes.2003

    • Author(s)
      A.Kuniyasu, et al.
    • Journal Title

      FEBS Lett. 537

      Pages: 85-90

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Molecular assembly and cellular distribution of ATP-sensitive potassium channel proteins in rat hearts.2003

    • Author(s)
      A.Kuniyasu, et al.
    • Journal Title

      FEBS Lett. 552

      Pages: 259-263

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Photochemical identification of the binding region for (s)-semotiadil on sodium channels.2003

    • Author(s)
      H.Yoshikawa, et al.
    • Journal Title

      Heterocycles 59(2)

      Pages: 613-622

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Patent(Industrial Property Rights)] 特許願2005

    • Inventor(s)
      川原浩一, 中山仁
    • Industrial Property Rights Holder
      熊本大学 川原浩一 中山仁
    • Industrial Property Number
      2005-025153
    • Filing Date
      2005-02-01
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Patent(Industrial Property Rights)] ラットI型ミクログリアを特異的に認識するモノクローナル抗体2005

    • Inventor(s)
      川原 浩一, 中山 仁
    • Industrial Property Rights Holder
      熊本大学, 川原 浩一, 中山 仁
    • Industrial Property Number
      2005-025153
    • Filing Date
      2005-02-01
    • Related Report
      2004 Annual Research Report
  • [Publications] H.Yoshikawa, et al.: "Photochemical identification of the binding region for (S)-semotiadil on sodium channels"Heterocycles. 59. 613-622 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] A.Kuniyasu, et al.: "CD36-mediated endocytic uptake of advanced glycation end products (AGE) in mouse 3T3-L1 and human subcutaneous adipocytes"FEBS Letters. 537. 85-90 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] A.Kuniyasu, et al.: "Molecular assembly and cellular distribution of ATP-sensitive potassium channel proteins in rat hearts"FEBS Letters. 552. 259-263 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] N.Ohgami, et al.: "Advanced Glycation End Products (AGE) Inhibit Scavenger Receptor Class B type-I-Mediated Reverse Cholesterol Transport"J.Atheroscler.Thromb.. 10. 1-6 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] N.Usami, et al.: "Cloning, expression and tissue distribution of a tetrameric form of pig carbonyl reductase"Chem.Biol.Interact.. 143-144. 353-361 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] K.Furukawa, et al.: "Adiponectin down-regulates acyl-coenzyme A : cholesterol acyltransferase-1 in human monocyte-derived macrophages"Biochem.Biophys.Res.Commun.. (in press). (2004)

    • Related Report
      2003 Annual Research Report

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Published: 2003-04-01   Modified: 2016-04-21  

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