| Project/Area Number |
21590832
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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 |
Gastroenterology
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| Research Institution | Tokyo Medical and Dental University |
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Principal Investigator |
OOOKA Shinya 東京医科歯科大学, 医学部・附属病院, 講師 (90361691)
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| Co-Investigator(Kenkyū-buntansha) |
SAKAMOTO Naoya 東京医科歯科大学, 大学院・医歯学総合研究科, 寄付講座教員 (10334418)
AZUMA Seishin 東京医科歯科大学, 医学部附属病院, 助教 (10376783)
WATANABE Mamoru 東京医科歯科大学, 大学院・医歯学総合研究科, 教授 (10175127)
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| Project Period (FY) |
2009 – 2011
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| Project Status |
Completed (Fiscal Year 2011)
|
| Budget Amount *help |
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2011: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2010: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2009: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
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| Keywords | HCVレプリコン / HCV-JFH1培養系 / プラークアッセイ / 細胞障害効果 / ヒト肝臓キメラマウス / 小胞体ストレス / RNAポリメラーゼ |
|---|
| Research Abstract |
HCV-JFH1 yields subclones that develop cytopathic plaques(Sekine-Osajima Y, et al., Virology 2008 ; 371 : 71). Here, we investigated viral amino acid substitutions in cytopathic mutant HCV-JFH1 clones and their characteristics in vitro and in vivo. The mutant viruses with individual C2441S, P2938S or R2985P signature substitutions, and with all three substitutions, showed significantly higher intracellular replication efficiencies and greater cytopathic effects than the parental JFH1 in vitro. The mutant HCV-inoculated mice showed significantly higher serum HCV RNA and higher level of expression of ER stress-related proteins in early period of infection. At 8 weeks post inoculation, these signature mutations had reverted to the wild type sequences. HCV-induced cytopathogenicity is associated with the level of intracellular viral replication and is determined by certain amino acid substitutions in HCV-NS5A and NS5B regions. The cytopathic HCV clones exhibit high replication competence in vivo but may be eliminated during the early stages of infection
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