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Development of gene therapy utilizing fibrinolytic system for pulmonary fibrosis

Research Project

Project/Area Number 17590809
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Respiratory organ internal medicine
Research InstitutionHIROSHIMA UNIVERSITY

Principal Investigator

HATTORI Noboru  Hiroshima University, Graduate School of Medical Sciences, Assistant Professor, 大学院医歯薬学総合研究科, 講師 (00283169)

Co-Investigator(Kenkyū-buntansha) MIYAKE Masayuki  Tazuke Kofukai, Medical Research Institute, Director, 田附興風会医学研究所・第5研究部, 部長 (90250076)
YOKOYAMA Akihito  Hiroshima University, Graduate School of Biomedical Sciences, Associate Professor, 大学院医歯薬学総合研究科, 助教授 (30191513)
KOHNO Nobuoki  Hiroshima University, Graduate School of Biomedical Sciences, Professor, 大学院医歯薬学総合研究科, 教授 (80215194)
Project Period (FY) 2005 – 2006
Project Status Completed (Fiscal Year 2006)
Budget Amount *help
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2006: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2005: ¥2,300,000 (Direct Cost: ¥2,300,000)
KeywordsPulmonary fibrosis / Fibrinolytic system / Gene therapy / RNA interference
Research Abstract

At the end stage of various inflammatory lung diseases, pulmonary fibrosis eventually develops. This disease condition is very difficult to be controlled in spite of intensive anti-inflammatory and immunosuppressant therapies. In the development of pulmonary fibrosis, fibrinolytic activity is known to be retarded. In the previous studies, we have demonstrated that this retarded fibrinolytic activity in the lung is caused by the overexpression of plasminogen activator inhibitor-1 (PAI-1) and PAI-1 deficient mice are protected from the development of pulmonary fibrosis induced by bleomycin administration. Based on these data, we hypothesized that upregulation of fibrinolytic activity using gene therapy may limit the development of pulmonary fibrosis. First, we administered adenoviral vector encoding urokinase cDNA into bleomycin-injured mice to enhance fibrinolytic activity in the lungs. However, this strategy provoked very severe inflammation in the mice lungs, and, thus, we failed to see whether it worked to suppress the fibrotic process. Then, we intended to passively enhance fibrinolytic activity through knockdown of PAI-1 using small interfering RNA against PAI-1 (PAI-1-siRNA). We have shown that repeated direct instillations of PAI-1-siRNA into the bleomycin-injured mice lungs resulted in inhibiting PAI-1 production and reducing the development of pulmonary fibrosis. These results suggest the feasibility to utilize PAI-1-siRNA in the treatment of pulmonary fibrosis.

Report

(3 results)
  • 2006 Annual Research Report   Final Research Report Summary
  • 2005 Annual Research Report
  • Research Products

    (24 results)

All 2007 2006 2005

All Journal Article (24 results)

  • [Journal Article] Overproduction of collagen and diminished SOCS1 expression are causally linked in fibroblasts from idiopathic pulmonary fibrosis2007

    • Author(s)
      Shoda H
    • Journal Title

      Biochemical and Biophysical Research Communications 353

      Pages: 1004-1010

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Adenoviral transduction of MRP-1/CD9 and KAI-1/CD82 inhibits lymph node metastasis in orthotopic lung cancer model2007

    • Author(s)
      Takeda T
    • Journal Title

      Cancer Research 67

      Pages: 1744-1749

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Overproduction of collagen and' diminished SOCS1 expression are causally' linked in fibroblasts from idiopathic pulmonary fibrosis2007

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

      Biochemical and Biophysical Research Communications 353

      Pages: 1004-1010

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Adenoviral transduction of MRP-1/CD9 and KAI-1/CD82 inhibits lymph node metastasis in orthotopic lung cancer model2007

    • Author(s)
      Takeda T, et al.
    • Journal Title

      Cancer Research 67

      Pages: 1744-1749

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Anti-tumor effect of the anti-KL-6/MUCI monoclonal antibody through exposure of surface molecules by MUC1 capping2006

    • Author(s)
      Doi M
    • Journal Title

      Cancer Science 97

      Pages: 420-429

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Clinical significance of aminopeptidase N in non-small cell lung cancer2006

    • Author(s)
      Tokuhara T
    • Journal Title

      Clinical Cancer Research 12

      Pages: 3971-3978

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Effect of CPAP on brachial-ankle pulse wave velocity in patients with OSAHS : An open-labelled study2006

    • Author(s)
      Kitahara Y
    • Journal Title

      Respiratory Medicine 100

      Pages: 2160-2169

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Anti-tumor effect of the anti-KL-6/MUC1 monoclonal antibody through exposure of surface molecules by MUC1 capping2006

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

      Cancer Science 97

      Pages: 420-429

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Clinical significance of aminopeptidase N in non-small cell lung cancer2006

    • Author(s)
      Tokuhara T, et al.
    • Journal Title

      Clinical Cancer Research 12

      Pages: 3971-3978

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Effect of CPAP on brachial-ankle pulse wave velocity in patients with OSAHS : An open-labelled study2006

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

      Respiratory Medicine 100

      Pages: 2160-2169

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Anti-tumor effect of the anti-KL-6/MUC1 monoclonal antibody through exposure of surface molecules by MUC1 capping.2006

    • Author(s)
      Doi M.
    • Journal Title

      Cancer Science 97

      Pages: 420-429

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Clinical significance of aminopeptidase N in non-small cell lung cancer.2006

    • Author(s)
      Tokuhara T.
    • Journal Title

      Clinical Cancer Research 12

      Pages: 3971-3978

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Effect of CPAP on brachial-ankle pulse wave velocity in patients with OSAHS : An open-labelled study.2006

    • Author(s)
      Kitahara Y.
    • Journal Title

      Respiratory Medicine 100

      Pages: 2160-2169

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Prognostic value of circulating KL-6 in idiopathic pulmonary fibrosis.2006

    • Author(s)
      Yokoyama A.
    • Journal Title

      Respirology 11

      Pages: 164-168

    • Related Report
      2006 Annual Research Report
  • [Journal Article] 間質性肺炎の理解 : 肺繊維化の機序について2006

    • Author(s)
      服部 登
    • Journal Title

      治療学 40

      Pages: 11-14

    • Related Report
      2006 Annual Research Report
  • [Journal Article] 肺繊維化マーカーの測定意義2006

    • Author(s)
      服部 登
    • Journal Title

      検査と技術 34

      Pages: 1170-1171

    • Related Report
      2006 Annual Research Report
  • [Journal Article] 間質性肺炎・肺線維症:遺伝子多型をめぐる最近の進歩をみる2006

    • Author(s)
      服部 登
    • Journal Title

      分子呼吸器病 10

      Pages: 21-22

    • Related Report
      2005 Annual Research Report
  • [Journal Article] KL-6, a human MUC1 mucin, promotes proliferation and survival of lung fibroblasts2005

    • Author(s)
      Ohshimo S.
    • Journal Title

      Biochemical and Biophysical Research Communications 338

      Pages: 1845-1852

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] KL-6, a human MUC1 mucin, promotes proliferation and survival of lung fibroblasts2005

    • Author(s)
      Ohshimo S, et al.
    • Journal Title

      Biochemical and Biophysical Research Communications

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Circulating aminopeptidase N/CD13 is an independent prognostic factor in patients with non-small cell lung cancer.2005

    • Author(s)
      Murakami H.
    • Journal Title

      Clin Cancer Res. 11

      Pages: 8974-8679

    • Related Report
      2005 Annual Research Report
  • [Journal Article] KL-6, a human MUC1 mucin, promotes proliferation and survival of lung fibroblasts.2005

    • Author(s)
      Ohshimo S.
    • Journal Title

      Biochem Biophys Res Commun. 338

      Pages: 1845-1852

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Polymorphism of the MUC1 mucin gene is associated with susceptibility to lung adenocarcinoma and poor prognosis.2005

    • Author(s)
      Mitsuta K
    • Journal Title

      Oncol Rep. 14

      Pages: 185-189

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Adoptive transfer of T-helper cell type 1 clones attenuates a asthmatic phenotype in mice.2005

    • Author(s)
      Irifune K
    • Journal Title

      Eur Respir J. 25

      Pages: 653-659

    • Related Report
      2005 Annual Research Report
  • [Journal Article] 肺線維症における線溶系の役割を知る2005

    • Author(s)
      服部 登
    • Journal Title

      分子呼吸器病 9

      Pages: 492-493

    • Related Report
      2005 Annual Research Report

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Published: 2005-04-01   Modified: 2016-04-21  

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