| Project/Area Number |
13307019
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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 |
Gastroenterology
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| Research Institution | The University of Tokyo |
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Principal Investigator |
OMATA Masao The University of Tokyo, Faculty of Medicine, Professor, 医学部附属病院, 教授 (90125914)
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| Co-Investigator(Kenkyū-buntansha) |
KATO Naoya The University of Tokyo, Faculty of Medicine, Research Associate, 医学部附属病院, 助手 (90313220)
OTSUKA Motoyuki The University of Tokyo, Faculty of Medicine, Medical Staff, 医学部附属病院, 医員
TANIGUCHI Hiroyoshi The University of Tokyo, Faculty of Medicine, Medical Staff, 医学部附属病院, 医員
TANAKA Yasuo The University of Tokyo, Faculty of Medicine, Medical Staff, 医学部附属病院, 医員
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| Project Period (FY) |
2001 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥52,390,000 (Direct Cost: ¥40,300,000、Indirect Cost: ¥12,090,000)
Fiscal Year 2004: ¥12,870,000 (Direct Cost: ¥9,900,000、Indirect Cost: ¥2,970,000)
Fiscal Year 2003: ¥12,350,000 (Direct Cost: ¥9,500,000、Indirect Cost: ¥2,850,000)
Fiscal Year 2002: ¥12,350,000 (Direct Cost: ¥9,500,000、Indirect Cost: ¥2,850,000)
Fiscal Year 2001: ¥14,820,000 (Direct Cost: ¥11,400,000、Indirect Cost: ¥3,420,000)
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| Keywords | Hepatitis B virus / Hepatitis C virus / Hepatitis delta virus / Signal transduction / Apoptosis / Innate Immunity / Persistent infection / NF-κB / A型肝炎ウイルス / 線維化 / TGF-β / インターフェロン / p53 / cDNA array / シグナル伝導 / NF-KB / Bcl-Xr / SRF |
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| Research Abstract |
In this study, we aimed to clarify the mechanism of hepatocyte injury via survival and death signaling induced by hepatitis viruses. 1)Hepatitis C virus(HCV) core protein activated NF-κB-dependent signaling pathway through tumor necrosis factor receptor-associated factor. This function of HCV core protein may play an important role in the inflammatory reaction induced by this virus. In fact, HCV core protein activated also interteukin(IL)-8 promoter through NF-κB. Moreover, differences in the amino acid sequence of HCV core protein correlates with hepatitis activity through modulation of IL-8 induction in HCV infected patients. In addition, HCV core protein upregulated transforming growth factor(TGF)β-1 expression, suggesting a new paradigm for exacerbation of liver fibrosis by HCV infection. 2)HCV NS3 protein interacts directly with TBK1,and that this binding results in the inhibition of the association between TBK1 and IRF-3,a key transcriptional factor to produce interferon-b, which
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leads to the inhibition of IRF-3 activation. This might show the mechanisms in the inhbition of innate immune responses and in the persistence of HCV infection by NS3 protein. 3)HCV NS4A and NS4B proteins inhibited cellular protein synthesis by targeting the process of translation. HCV NS4A and NS4B proteins have an effect of translational inhbition. This novel function may be involved in HCV infection and help its survival in host cells. 4)HCV NS5A protein interacts with and partially sequestrates p53 and hTAFII32,a component of TFIID and an essential coactivator of p53, in the cytoplasm and suppresses p53-mediated transcriptional transactivation and apoptosis during HCV infection, which may contribute to the hepatocarcinogenesis of HCV infection. 5)Uncerstanding the function of hepatitis B virus(HBV) X protein(HBx) is fundamental to elucidating the underlying mechanisms of hepatitis and hepatocarcinogenesis caused by HBV infection. We identified heat shock protein 60(Hsp60) as a novel cellular target of HBx by the combination of affinity purification and mass spectrometry. Confocal laser microscopy demonstrated that HBx and Hsp60 colocalized in mitochondria. Furthermore, TUNEL revealed that the introduction of HspGO into cells facilitated HBx-induced apoptosis. These findings suggest the importance of the molecular chaperon protein Hsp60 to the function of HBV viral proteins. 6)Hepatitis delta virus(HDV) is a naturally occurring satellite of HBV. HBx, alone or with the large isoform of HDV antigens(LHDAg), synergistically activated the serum response element(SRE)-dependent pathway. HBx activated the transcriptional ability of Elk-1,whereas LHDAg activated the transcritional ability of serum response factor(SRF). Thus, HBx and LHDAg synergistically activated the SRE-dependent pathway. These results may help us understand clinical phenomena in patients coinfected with HBV and HDV. Less
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