| Project/Area Number |
14207005
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
General medical chemistry
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| Research Institution | Osaka University |
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Principal Investigator |
NAKAMURA Toshikazu Osaka University, Graduate School of Medicine, Professor, 医学系研究科, 教授 (00049397)
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| Co-Investigator(Kenkyū-buntansha) |
MATSUMOTO Kunio Osaka University, Graduate School of Medicine, Associate Professor, 医学系研究科, 助教授 (90201780)
FUNAKOSHI Hiroshi Osaka University, Graduate School of Medicine, Associate Professor, 医学系研究科, 助教授 (40273685)
MIZUNO Shinya Osaka University, Graduate School of Medicine, Assistant, 医学系研究科, 助手 (10219644)
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| Project Period (FY) |
2002 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥45,110,000 (Direct Cost: ¥34,700,000、Indirect Cost: ¥10,410,000)
Fiscal Year 2005: ¥9,750,000 (Direct Cost: ¥7,500,000、Indirect Cost: ¥2,250,000)
Fiscal Year 2004: ¥9,750,000 (Direct Cost: ¥7,500,000、Indirect Cost: ¥2,250,000)
Fiscal Year 2003: ¥11,180,000 (Direct Cost: ¥8,600,000、Indirect Cost: ¥2,580,000)
Fiscal Year 2002: ¥14,430,000 (Direct Cost: ¥11,100,000、Indirect Cost: ¥3,330,000)
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| Keywords | HGF / Chronic Organ Failure / Anti-fibrosis System / Myofibroblasts / TGF-β / Extra-cellular Matrix / Self-repair System / Regenerative Medicine / 抗線維化機構 / 筋線維芽細胞 / 組織線維化 / 慢性臓器疾患 / 組織再生 / 慢性疾患 |
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| Research Abstract |
Myofibroblast formation and overproduction of extra-cellular matrix (ECM) are common events in the pathogenesis of tissue fibrosis under chronic injuries, such as liver cirrhosis, pulmonary fibrosis and cardiomyopathy. In the present study, we found that HGF directly targeted the interstitial myofibroblasts and reduced ECM accumulation using the animal model of pulmonary fibrosis, liver cirrhosis and dilated cardiomyopathy.
1) Regression of pulmonary fibrosis by HGE :
We used bleomycin-injected mice as a model of lung fibrosis and found that HGF elicited apoptotic changes in the myofibroblast cell population in vivo. Furthermore, we obtained in vitro evidence that : (i) HGF degraded ECM proteins (i.e., cell anchorage) around the myofibroblasts, via induction of proteinases such as MMP-9/-1/-2 ; (ii) under such ECM-deficient conditions, the myofibroblasts lose the anchorage then anoikis-like apoptotic cell death occurred. Importantly, an MMP-inhibitor diminished HGF-mediated apoptotic cell death of myofibroblasts, in vitro as well as in vivo, thus indicating that HGF-induced anti-fibrotic effects largely depended on inductions of MMPs by HGF. We published these results in FASEB-Journal 19 : 580 (2005)
2) Reduction of interstitial fibrosis in liver cirrhosis and cardiomyopathy by HGF :
In the rat model of liver cirrhosis, HGF enhanced myofibroblast apoptosis and inhibited proliferation of interstitial myofibroblasts. These effects were associated with the reduction of ECM-accumulated areas. In vitro, HGF counteracted the PDGF-mediated proliferation of the lipocyte-derived myofibroblasts. In the hamster model of cardiomyopathy, HGF reduced TGF-beta production in the interstitial myofibroblasts, followed by the reduction of ECM as well as improvement in the cardiac functions. These outcomes were published in Am-J-Pathol 166 : 1017 (2005) and in Am-J-Physiol 288 : H2131 (2005), respectively.
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