| Project/Area Number |
16590580
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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 Tokyo Medical and Dental University, Department of Gastroenterology and Hepatology, Instructor, 医学部附属病院, 助手 (90361691)
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| Co-Investigator(Kenkyū-buntansha) |
SAKAMOTO Naoya Tokyo Medical and Dental University, Department of Gastroenterology and Hepatology, Instructor, 医学部附属病院, 助手 (10334418)
NAKAGAWA Mina Tokyo Medical and Dental University, Department of Gastroenterology and Hepatology, Fellow, 医学部附属病院, 医員 (30401342)
ENOMOTO Nobuyuki Yamanashi University, First Department of internal Medicine, Professor, 大学院・医学工学総合研究部, 教授 (20251530)
WATANABE Mamoru Tokyo Medical and Dental University, Department of Gastroenterology and Hepatology, Professor, 大学院・医歯学総合研究科, 教授 (10175127)
柿沼 晴 東京医科歯科大学, 医学部附属病院, 助手 (30372444)
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| Project Period (FY) |
2004 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2005: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2004: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Keywords | Cyclosporin A / HCV replicon system / cyclophilin / 抗ウイルス療法 / レトロウイルスベクター / サイクロフィリン / small interfering RNA |
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| Research Abstract |
Cyclosporin A specifically suppresses hepatitis C virus replication in vitro at clinically achievable concentrations. In this study, we investigated the mechanisms of action of cyclosporin A against HCV replication. The in-vitro effects of cyclosporin A on HCV replication were analyzed using HCV replicon system that expresses chimeric luciferase reporter protein. The significant effects of cyclosporin A on expression of an HCV replicon, and the absence of such effects of FK506 which shares mechanisms of action with cyclosporin A, suggested the involvement of intracellular ligands of cyclosporin A, the cyclophilins. Transient and stable knock-down of the expression of cytoplasmic cyclophilins A, B and C by shRNA-expressing vectors suppressed HCV replication significantly. A cyclosporin analogue, cyclosporin D, which lacks immunosuppressive activity but exhibits cyclophilin binding, induced a similar suppression of HCV replication. Furthermore, cyclosporin A treatment of Huh7 cells induced an unfolded protein response exemplified by expression of cellular BiP/GRP78. Treatment of cells with thapsigargin and mercaptoethanol, which induce the unfolded protein responses, suppressed HCV replication, suggesting that the cyclosporin-induced unfolded protein responses mignt contribute to the suppression of HCV protein processing and replication. The anti-HCV activity of cyclosporin A is mediated through a specific blockade of cyclophilins and these molecules may constitute novel targets for anti-HCV therapeutics.
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