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Clinical Application of Cell Cycle Control Therapy to Rheumatoid Arthritis

Research Project

Project/Area Number 13854014
Research Category

Grant-in-Aid for Scientific Research (S)

Allocation TypeSingle-year Grants
Research Field 内科学一般
Research InstitutionTokyo Medical and Dental University

Principal Investigator

MIYASAKA Nobuyuki  Tokyo Medical and Dental University, Department of Medicine and Rheumatology, Professor, 大学院・医歯学総合研究科, 教授 (30157622)

Co-Investigator(Kenkyū-buntansha) KOHSAKA Hitoshi  Tokyo Medical and Dental University, Department of Medicine and Rheumatology, Associate Professor, 大学院・医歯学総合研究科, 助教授 (00251554)
Project Period (FY) 2001 – 2005
Project Status Completed (Fiscal Year 2005)
Budget Amount *help
¥122,850,000 (Direct Cost: ¥94,500,000、Indirect Cost: ¥28,350,000)
Fiscal Year 2005: ¥21,060,000 (Direct Cost: ¥16,200,000、Indirect Cost: ¥4,860,000)
Fiscal Year 2004: ¥20,800,000 (Direct Cost: ¥16,000,000、Indirect Cost: ¥4,800,000)
Fiscal Year 2003: ¥20,280,000 (Direct Cost: ¥15,600,000、Indirect Cost: ¥4,680,000)
Fiscal Year 2002: ¥19,890,000 (Direct Cost: ¥15,300,000、Indirect Cost: ¥4,590,000)
Fiscal Year 2001: ¥40,820,000 (Direct Cost: ¥31,400,000、Indirect Cost: ¥9,420,000)
Keywordsrheumatoid arthritis (RA) / cyclin-dependent kinase inhibitors / adenovirus vector / animal model / 関節リウマチ / 膠原病 / 内科 / 治療 / 細胞周期 / 増殖抑制 / 低分子化合物 / サイクリン依存性キナーゼ / サイクリン依存性キナーゼインヒビター / 遺伝子治療 / 慢性関節リウマチ
Research Abstract

Forced expression of a cyclin-dependent kinase inhibitor (CDKI) gene, p16^<INK4a> or p21^<Cip1> in the synovial tissues was effective in treating animal models of rheumatoid arthritis (RA). Subsequently, we have studied molecular mechanism and application of cell cycle control for treatment of rheumatoid arthritis (RA).
1) Anti-inflammatory effects of CDKI gene therapy : CDKI gene therapy suppressed expression of inflammatory mediators and proteinases via both CDK inhibition dependent- and CDK inhibition independent-pathways.
2) Improvement of gene transfer efficacy by modified adenovirses : Because of a fatal accident by gene therapy using adenovirus vector, safety of adenovirus vector is strongly demanded. Efficacies of gene transfer to rheumatoid synovial fibroblasts (RSF) by type 5 adenoviruses (Ad5) vector were improved by modification fiber-coat proteins expressing Arg-Gly-Asp (RGD) motif or by Ad5 carrying a part of the fiber molecule of adenovirus serotype 35. Comparing with non- … More modified Ad5, fewer quantities of these fiber-modified Ad5 vectors were required to treat synovitis of RA animal model.
3) Development of CDKI-'biologics : CDKI therapy without viral vector was studied. Protein can be delivered intracellularly if it HIV transmembrane domain (TAT) is conjugated. TAT-conjugated p16^<INK4a> fusion protein inhibited RSF proliferation, and therapeutic effects for RA animal model is investigated.
4) Synthetic small molecule (sm)-CDKI for treatment of RA : Some synthetic sm-CDKI compounds were effective for synovitis of RA animal model, and we have applied patents of two sm-CDKI compounds for RA therapy.
5) Selective p16^<INK4a> induction in RSF by p21^<Cip1> : Forced expression of p21^<Cip1> in RSF induced p16^<INK4a> expression. This p16^<INK4a> induction was not observed in the other fibroblasts. Using fluorescent differential display or GeneChip (Affimetrix) techniques, we screened a group of molecules that might be involved in the p21^<Cip1>-p16^<INK4a> pathway. One of the candidate molecules, that is related to pregnancy, increased p16^<INK4a> promoter activity Less

Report

(6 results)
  • 2005 Annual Research Report   Final Research Report Summary
  • 2004 Annual Research Report
  • 2003 Annual Research Report
  • 2002 Annual Research Report
  • 2001 Annual Research Report
  • Research Products

    (16 results)

All 2006 2005 2004 2003 2001 Other

All Journal Article (11 results) Patent(Industrial Property Rights) (2 results) Publications (3 results)

  • [Journal Article] Pathogenic role of the CXCL16-CXCR6 pathway in rheumatoid arthritis2005

    • Author(s)
      Nanki T., Shimaoka T., Hayashida K., Taniguchi K., Yonehara S., Miyasaka N.
    • Journal Title

      Arthritis Rheum. 52(10)

      Pages: 3004-3014

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Inhibition of CX3CL1(Fractalkine) improves experimental autoimmune myositis in SJL/J mice.2005

    • Author(s)
      Suzuki F., Nanki T., Imai T., Kikuchi H., Hirohata S., Kohsaka H., Miyasaka N.
    • Journal Title

      J.Immunol 175(10)

      Pages: 6987-6996

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Effect of a small molecule inhibitor of nuclear factor-κB nuclear translocation in a murine model of arthritis and cultured human synovia cells.2005

    • Author(s)
      Wakamatsu K., Nanki T., Miyasaka N., Umezawa K., Kubota T.
    • Journal Title

      Arthritis Res.Ther. 7(6)

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Development of TCRB CDR3 length repertoire of human lymphocytes2004

    • Author(s)
      Nishio J, Suzuki M, Nanki T, Miyasaka N, Kohsaka H.
    • Journal Title

      Int Immunol 16(3)

      Pages: 423-431

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Gene transfer of a cell cycle modulator exerts anti-inflammatory effects in the treatment of arthritis.2003

    • Author(s)
      Nonomura Y, Kohsaka H, Nagasaka K, Miyasaka N
    • Journal Title

      J Immunol 171(9)

      Pages: 4913-4919

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Gene transfer of a cell cycle modulator exerts anti-inflammatory effects in the treatment of arthritis.2003

    • Author(s)
      Nonomura Y, Kohsaka H, Nagasaka K, Miyasaka N.
    • Journal Title

      J.Immunol 171(9)

      Pages: 4913-4919

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Suppression of arthritis by forced expression of cyclin-dependent kinase Inhibitor p21^<Cipl> gene into the joints.2001

    • Author(s)
      Nonomura Y, Kohsaka H, Nasu K, Terada Y, Ikeda M, Miyasaka N
    • Journal Title

      Int Immunol 13(6)

      Pages: 723-731

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Suppression of arthritis by forced expression of cyclin-dependent kinase Inhibitor p21^<Cip1> gene into the joints.2001

    • Author(s)
      Nonomura Y, Kohsaka H, Nasu K, Terada Y, Ikeda M, Miyasaka N.
    • Journal Title

      Int Immunol 13(6)

      Pages: 723-731

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Cyclin-dependent kinase 4/6 directly modulates expression of rheumatoid inflammatory mediators in retinoblastoma protein-dependent and independent pathways

    • Author(s)
      Nonomura Y, Nagasaka K, Hagiyama H, Sekine C, Nanki T, Tamamori-Adachi M, Miyasaka N, Kohsaka H
    • Journal Title

      Arthritis Rheum (in press)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Cyclin-dependent kinase 4/6 directly modulates expression of rheumatoid inflammatory mediators in retinoblastoma protein-dependent and independent pathways

    • Author(s)
      Nonomura Y, Nagasaka K, Hagiyama H, Sekine C, Nanki T, Tamamori-Adachi M, Miyasaka N, Kohsaka H.
    • Journal Title

      Arthritis Rheum. (in press)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Cyclin-dependent kinase 4/6 directly modulates expression of rheumatoi inflammatory mediators in retinoblastoma protein-dependent and independent pathways

    • Author(s)
      Nonomura Y, Nagasaka K, Hagiyama H, Sekine C, Nanki T, Tamamori-Adachi M, Miyasaka N, Kohsaka N.
    • Journal Title

      Arthritis Rheum. in press

    • Related Report
      2005 Annual Research Report
  • [Patent(Industrial Property Rights)] 抗関節リウマチ活性を有する物質のスクリーニング方法及び評価方法。2006

    • Inventor(s)
      宮坂信之, 上阪 等
    • Industrial Property Rights Holder
      東京医科歯科大学 理化学研究所
    • Filing Date
      2006-02-20
    • 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)] 滑膜細胞増殖抑制剤2005

    • Inventor(s)
      宮坂信之, 上阪 等
    • Industrial Property Rights Holder
      東京医科歯科大学 理化学研究所
    • Filing Date
      2005-07-18
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Publications] Yoshinori Nonomura, Hitoshi Kohsaka, Nobuyuki Miyasaka, et al.: "Gene transfer of a cell cycle modulator exerts anti-inflammatory effects in the treatment of arthritis."J.Immunol.. 171(9). 4913-4919 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Nonomura Y, Kohsaka H, Nasu K, Miyasaka N, et al.: "Suppression of arthritis by forced expression of cyclin-dependent kinase Inhibitor p21cip1 gene into the joints"Int Immunol. 13(6). 723-731 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Kohsaka H, Nasu K, Nonomura Y, Miyasaka N.: "Treatment of Arthritis with Cyclin-dependent Kinase Inhibitor Gene"Jpn.J. Clin Immunol. 23(6). 550-552 (2001)

    • Related Report
      2001 Annual Research Report

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Published: 2001-04-01   Modified: 2016-04-21  

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