| Project/Area Number |
15590653
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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 | Yamaguchi University |
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Principal Investigator |
HINO Keisuke Yamaguchi University, Faculty of Medicine, Professor, 医学部, 教授 (80228741)
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| Co-Investigator(Kenkyū-buntansha) |
KIMURA Teruaki Yamaguchi University, Faculty of Medicine, Endowed Chair Staff, 医学部, 寄附講座教員 (40346557)
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| Project Period (FY) |
2003 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥3,700,000 (Direct Cost: ¥3,700,000)
Fiscal Year 2005: ¥300,000 (Direct Cost: ¥300,000)
Fiscal Year 2004: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2003: ¥2,600,000 (Direct Cost: ¥2,600,000)
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| Keywords | hepatitis C / hepatocarcinogenesis / oxidative stress / mitochondria / apoptosis / iron / animal model / HCV / トランスジェニックマウス / Bcl2ファミリー |
|---|
| Research Abstract |
We have found that hepatitis C virus (HCV) core protein induces oxidative DNA damage, whereas it inhibits apoptosis that is accompanied by enhancement of reactive oxygen species production. HCV core protein inhibited apoptosis by increasing Bcl-xL protein and decreasing Bax protein, resulting in suppression of cytochrome c release from mitochondria into cytoplasm. However, magnitude of oxidative stress induced by HCV core protein itself seemed to be not enough for the development of hepatocellular carcinoma (HCC). We, therefore, focused on hepatic iron overload observed in hepatitis C as a second hit for amplifying oxidative stress. We established transgenic mice expressing the HCV polyprotein whose hepatic iron concentrations was comparable to those of patients with chronic hepatitis C. These mice showed marked hepatic steatosis including the centrilobular microvesicular type, ultrastructural alternations of the mitochondria, decreased degradation activity of fatty acid, and increased hepatic content of lipid peroxidation products and 8-hydroxy-2'-deoxyguanosine. Finally liver tumors including HCC developed in 45% of these mice. From these results, it has been shown that oxidative stress and apoptosis modulation by HCV protein are independent of each other, and that iron overload induces mitochondrial injury and increases the risk of HCC development in transgenic mice expressing the HCV polyprotein.
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