2006 Fiscal Year Final Research Report Summary
Development of gene therapy utilizing fibrinolytic system for pulmonary fibrosis
| Project/Area Number |
17590809
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Respiratory organ internal medicine
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| Research Institution | HIROSHIMA UNIVERSITY |
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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)
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| 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)
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| Project Period (FY) |
2005 – 2006
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| Keywords | Pulmonary fibrosis / Fibrinolytic system / Gene therapy / RNA interference |
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| 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.
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