| Project/Area Number |
23390202
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Gastroenterology
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| Research Institution | The Institute of Physical and Chemical Research |
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Principal Investigator |
KOJIMA SOICHI 独立行政法人理化学研究所, ライフサイエンス技術基盤研究センター, 特別ユニットリーダー (10202061)
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| Co-Investigator(Kenkyū-buntansha) |
MIYAZAWA Keiji 山梨大学, 医学工学総合研究部, 教授 (40209896)
AIZAKI Hideki 国立感染症研究所, ウイルス第二部, 室長 (00333360)
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| Co-Investigator(Renkei-kenkyūsha) |
MATSUMOTO Takehisa 独立行政法人理化学研究所, ラ イ フ サイエンス技術基盤研究センター, 上級研究員 (20342652)
MATSUURA Tomokazu 東京慈恵会医科大学, 医学研究科, 教授 (30199749)
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| Project Period (FY) |
2011-04-01 – 2014-03-31
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| Project Status |
Completed (Fiscal Year 2013)
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| Budget Amount *help |
¥19,500,000 (Direct Cost: ¥15,000,000、Indirect Cost: ¥4,500,000)
Fiscal Year 2013: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2012: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000)
Fiscal Year 2011: ¥9,100,000 (Direct Cost: ¥7,000,000、Indirect Cost: ¥2,100,000)
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| Keywords | C型肝炎ウイルス（HCV） / NS3 / TGF-β受容体 / 肝硬変 / キメラマウス / コラーゲン / C型肝炎ウイルス / C型肝炎ウイルス(HCV) |
|---|
| Research Abstract |
Viruses sometimes mimic host proteins and hijack the host cell machinery. Hepatitis C virus (HCV) causes liver fibrosis, a process largely mediated by the overexpression of TGF-beta and collagen, although the precise underlying mechanism is unknown. We found that HCV non-structuralprotein 3 (NS3) protease affects the antigenicity and bioactivity of TGF-beta2 in (CAGA)9-Luc CCL64 cells and in human hepatic cell lines via binding to TGF-beta type I receptor (TbetaRI). TNF-alpha facilitates this mechanism by increasing the colocalization of TbetaRI with NS3 protease on the surface of HCV-infected cells. An anti-NS3 antibody against computationally predicted binding sites for TbetaRI blocked the TGF-beta mimetic activities of NS3 in vitro and attenuated liver fibrosis in HCV-infected chimeric mice. These data suggest that HCV NS3 protease mimics TGF-beta2 and functions, at least in part, via directly binding to and activating TbetaRI, thereby enhancing liver fibrosis.
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