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Construction and analysis of viral hepatocarcinogenesis model using HCV transgenic mouse model

Research Project

Project/Area Number 11670557
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Gastroenterology
Research InstitutionTokyo Metropolitan Institute for Neuroscience

Principal Investigator

WAKITA Takaji  Tokyo Metropolitan Institute for Neuroscience, Department of Microbiology and Immunology, Research Scientist, 東京都神経科学総合研究所, 副参事研究員 (40280789)

Co-Investigator(Kenkyū-buntansha) KOHARA Michinori  Tokyo Metropolitan Institute for Neuroscience, Department of Microbiology, Research Scientist, 東京都臨床医学総合研究所, 副参事研究員 (10250218)
MIYAMOTO Michiko  Tokyo Metropolitan Institute for Neuroscience, Department of Microbiology and Immunology, Research Scientist, 東京都神経科学総合研究所, 研究員 (40190821)
YASUI Kotaro  Tokyo Metropolitan Institute for Neuroscience, Department of Microbiology and Immunology, Research Scientist, 東京都神経科学総合研究所, 参事研究員 (90073080)
Project Period (FY) 1999 – 2000
Project Status Completed (Fiscal Year 2000)
Budget Amount *help
¥3,900,000 (Direct Cost: ¥3,900,000)
Fiscal Year 2000: ¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 1999: ¥2,100,000 (Direct Cost: ¥2,100,000)
KeywordsHCV / TRANSGENIC MOUSE / Cre / loxP / CTL / Hepatocarcinogenesis
Research Abstract

Missing of proper culture system and animal model has hampered fine analysis of viral life cycle and pathogenesis of HCV infection, especially hepatocarcinogenesis. We established hepatitis C virus (HCV) transgenic mice mediated by Cre/loxP system using HCV cDNA including core, E1, E2 and NS2 gene. Intravenous infection of a recombinant adenovirus which expresses Cre DNA recombinase (AxCANCre) induced HCV structural protein expression in the liver of the transgenic mouse. HCV core protein production and transgene recombination in the mouse liver were serially evaluated after AxCANCre infusion. Core protein was efficiently expressed and transgene was almost totally recombinated in mouse liver after 3 days, then the levels of both core protein production and transgene recombination continuously decreased for 28 days. However, 30.6% of trasgene recombination remained at 28 days and only 2.7% of core production remained at 28 days after infection. Compared with non-transgenic controls, serum alanine aminotransferase levels of transgenic mice were significantly higher 10, 14 and 21 days after adenovirus infection. Histological scoring also indicated severe pathological changes in the liver of transgenic mice after adenovirus injection. AxCANCre infusion increased CD8^+ lymphocyte infiltration into the liver of transgenic mice compared with that of non-transgenic controls. Furthermore, cytotoxic T lymphocytes (CTLs) isolated from transgenic mice during liver injury were specific for the HCV proteins, E1, E2 and NS2 but not for core protein. These results suggest that HCV structural proteins expressed in the liver of transgenic mouse enhanced liver injury. The function of HCV-specific CTLs may be to enhance hepatitis. This transgenic mouse model system allows us to analyze the functions of viral products and host immune system in HCV infection and hepatocellular carcinogenesis of HCV.

Report

(3 results)
  • 2000 Annual Research Report   Final Research Report Summary
  • 1999 Annual Research Report
  • Research Products

    (60 results)

All Other

All Publications (60 results)

  • [Publications] Utsunomiya S,Yoshioka K,Wakita T, et al.: "TT virus infection in hemodialysis patients"Am J Gastroenterol. 94(12). 3567-3570. (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Wakita T,Moradpour D,Tokushihge K,Wands JR: "Antiviral effects of antisense RNA on hepatitis C virus RNA translation and expression."J Med Virol.. 57(3). 217-222. (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Iriyama M,Kimura H,Nishikawa K,Yoshioka K,Wakita T, et al.: "The prevalence of TT virus (TTV) infection and its relationship to hepatitis in children"Med Microbiol Immunol.. 188. 83-89 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Wakita T, et al.: "A possible role of cytotoxic T cells on acute liver injury in HCV cDNA transgenic mice mediated by Cre/loXP system."J Med Virol. 62・3. 308-317 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kato T, et al.: "Sequence Analysis of Hepatitis C Virus Isolated from a Fulminant Hepatitis Patient"J Med Virol. (in press). (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Isoyama T,Kamoshita N,Yasui K,Iwai A,Shiroki K,Toyoda H, et al.: "Lower concentration of La protein required for internal ribosome entry on hepatitis C virus RNA than on poliovirus RNA."J Gen Virol.. 80(9). 2319-2327. (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] An J.Kimura-Kuroda J,Hirabayashi Y,Yasui K: "Development of a novel mouse model for dengue virus infection."Virology. 263(1). 70-77. (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Shishido-Hara Y,Hara Y,Larson T,Yasui K, et al.: "Analysis of capsid formation of human polyomavirus JC (Tokyo-1 strain) by a eukaryotic expression system:"J Virol. 74(4). 1840-1853. (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Suzuki,T.,Ogata,A.,Tashiro,K.,Nagashima,K.,Tamura,M.,Yasui,K.,Nishihara,J.: "A method for detection of a cytokine and its mRNA in the central nervous system of the developing rat."Brain Res Protocols,. 4. 271-279 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kohara M.: "Hepatitis C virus replication and pathogenesis."J Dermatol Sci.. 22・3. 161-168 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] A.Honda,Y.Arai,N.Hirota,T.Sato,J.Ikegaki,T.Koizumi,M.Hatano,M.Kohara,T et al.: "Hepatitis C virus structural proteins induce liver cell injury in transgenic mice."J.Hepatol.. 33. 440-447 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] M.Matsumura,M.Ijichi,Y.Shiratori,G.Togo,Y.Hikiba,K.Inoue,M.Kohara and M.Omata: "Simple quantitative assay of alpha-petoprotein mRNA in liver tissue using the real-time detection polymerase chain assay-Its application for clinical use"Hepatology. (in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] S.Ishida,M.Kaitou,M.Kohara,K. et al: "Icosahedral hepatitis C virus core particles detected by immunoelectron microscopy and rotation technique."Hepatology Research.. (in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] K.Machida,K. et al. and M.Kohara: "Inhibition of cytochrome C release in Fas-mediated signaling pathway in transgenic mice induced to express hepatitis C viral proteins."J.Biol.Chem.. (in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Tanaka T,Hess G,Schlueter V,Zdunek D,Tanaka S,Kohara M: "Correlation of interferon treatment response with GBV-C/HGV genomic RNA and anti-envelope 2 protein antibody."J Med Virol.. 57(4). 370-375. (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Takeuchi T, et al and Kohara M: "Real-time detection system for quantification of hepatitis C virus genome."Gastroenterology.. 116(3). 636-642. (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Hirota M,Satoh S,Asabe S,Kohara M, et al.: "Phosphorylation of nonstructural 5A protein of hepatitis C virus : HCV group-specific hyperphosphorylation."Virology. 257(1). 130-137. (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Inoue K,Yoshiba M,Sekiyama K,Kohara M: "Possible association between serum GB virus C RNA level and disease activity in fulminant hepatitis type G."J Hepatol.. 30(5). 801-806. (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Honda A,Arai Y,Hirota N,Sato T,Ikegaki J,Koizumi T,Hatano M,Kohara M, et al.: "Hepatitis C virus structural proteins induce liver cell injury in transgenic mice."J Med Virol.. 59(3). 281-289. (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Sabile A,Perlemuter G,Bono F,Kohara K,Demaugre F,Kohara M, et al.: "Hepatitis C virus core protein binds to apolipoprotein All and its secretion is modulated by fibrates."Hepatology.. 30(4). 1064-1076. (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kato T, Furusaka A, Miyamoto M, Date T, Yasui K, Hiramoto J, Nagayama K, Tanaka T, Wakita T: "Sequence Analysis of Hepatitis C Virus Isolated from a Fulminant Hepatitis Patient"J Med Virol. (in press). (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Wakita T, Katsume A, Kato J, Taya C, Yonekawa H, Kanegae Y, Saito I, Hayashi Y, Koike M, Miyamoto M, Hiasa Y, Kohara M.: "A possible role of cytotoxic T cells on acute liver injury in hepatitis C virus cDNA transgenic mice mediated by Cre/loxP system."J Med Virol. 62. 318-317 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Iriyama M, Kimura H, Nishikawa K, Yoshioka K, Wakita T, Nishimura N, Shibata M, Ozaki T, Morishima T: "The prevalence of TT virus (TTV) infection and its relationship to hepatitis in children."Med Microbiol Immunol.. 188. 83-89 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Utsunomiya S, Yoshioka K, Wakita T, Seno H, Takagi K, Ishigami M, Yano M, Watanabe K, Kobayashi M, Watanabe K, Kishimoto H, Kakumu S.: "TT virus infection in hemodialysis patients."Am J Gastroenterol. 94. 3567-3570 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Wakita T, Moradpour D, Tokushige K, and Wands JR: "Antiviral effects of antisense RNA on hepatitis C virus RNA translation and expression."Journal of Medical Virology. 57. 217-222 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Isoyama, T.Kamoshita, N.Yasui, K.Iwai, A.Shiroki, K.Toyoda, H.Yamada, A.Takasaki, Y.Nomoto, A.: "Lower concentration of La protein required for internal ribosome entry on hepatitis C virus RNA than on poliovirus RNA."J General Virol. 80. 1319-2327 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] An, J.Kimura-Kuroda, J., Hirabayashi, Y.and Yasui, K.: "Development of a Novel Mouse Model for Dengue Virus Infection"Virology. 263 (1). 70-77 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Suzuki, T., Ogata, A., Tashiro, K., Nagashima, K., Tamura, M., Yasui, K., Nishihara, J.: "A method for detection of a cytokine and its mRNA in the central nervous system of the developing rat."Brain Res Protocols.. 4. 271-279 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Shishido-Hara, Y., Hara, Y., Larson, T., Yasui, K., Nagashima, K., Stoner, G.L.: "Analysis of capsid formation of human polyomavirus JC (Tokyo-1 strain) by a eukaryotic expression system : splicing of late RNAs, translation and nuclear transport of major capsid protein VP1, and caps, id assembly."J Virol. 74 (4). 1840-1853 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] M.Kohara: "Hepatitis C virus replication and pathogenesis"J.Dermatological Science. 22. 161-168 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] A.Honda, Y.Arai, N.Hirota, T.Sato, J.Ikegaki, T.Koizumi, M.Hatano, M.Kohara, T.Moriyama, M.Imawari, K.Shimotohno, and T.Tokuhisa: "Hepatitis C virus structural proteins induce liver cell injury in transgenic mice."J.Hepatol.. 33. 440-447 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] M.Matsumura, M.Ijichi, Y.Shiratori, G.Togo, Y.Hikiba, K.Inoue, M.Kohara and M.Omata: "Simple quantitative assay of alpha-petoprotein mRNA in liver tissue using the real-time detection polymerase chain assay - Its application for clinical use -"Hepatology. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] S.Ishida, M.Kaitou, M.Kohara, K.Tsukiyama-Kohara, N.Fujita, J.Ikoma, Y.Adachi and S.Watanabe: "Icosahedral hepatitis C virus core particles detected by immunoelectron microscopy and rotation technique."Hepatology Research. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] K.Machida, K.Tsukiyama-Kohara, E.Seike, S.Tone, F.Shibasaki, M.Shimizu, H.Takahashi, Y.Hayashi, N.Funada, C.Taya, H.Yonekawa and M.Kohara: "Inhibition of cytochrome C release in Fasmediated signaling pathway in transgenic mice induced to express hepatitis C viral proteins."J.Biol. Chem.. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Honda A, Arai Y, Hirota N, Sato T, Ikegaki J, Koizumi T, Hatano M, Kohara M, Moriyama T, Imawari M, Shimotohno K, Tokuhisa T.: "Hepatitis C virus structural proteins induce liver cell injury in transgenicmice"J.Med Virol.. 59 (3). 281-289 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Sabile A, Perlemuter G, Bono F, Kohara K, Demaugre F, Kohara M, Matsuura Y, Miyamura T, Brechot C, Barba G: "Hepatitis C virus core protein binds to apolipoprotein All and its secretion is modulated by fibrates"Hepatology. 30 (4). 1064-1076 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Abe A, Inoue K, Tanaka T, Kato J, Kajiyama N, Kawaguchi R, Tanaka S, Yoshiba M, Kohara M: "Quantitation of hepatitis B virus genomic DNA by real-time detection PCR."J Clin Microbiol.. 37 (9). 2899-2903 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Tanaka T, Hess G, Tanaka S, Kohara M.: "The significance of hepatitis G virus infection in patients with-non-A to C hepatic diseases."Hepatogastroenterology.. 46 (27). 1870-1873 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Inoue K, Yoshiba M, Sekiyama K, Kohara M: "Possible association between serum GB virus C RNA level and disease activity in fulminant hepatitis type G."J Hepatol. 30 (5). 801-806 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Hirota M, Satoh S, Asabe S, Kohara M, Tsukiyama-Kohara K, Kato N, Hijikata M, Shimotohno K: "Phosphorylation of nonstructural 5A protein of hepatitis C virus : HCV group-specific hyperphosphorylation."Virology. 25 : 257 (1). 130-137 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Tanaka T, Hess G, Schlueter V, Zolunek D, Tanaka S, Kohara M: "Correlation of interferon treatment response with GBV-C/HGV genomic RNA and anti-envelope 2 protein antibody."J Med Virol.. 57 (4). 370-375 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Takeuchi T, Katsuma A, Tanaka T, Abe A, Inoue K, Tsukiyama-Kohara K, Kawaguchi R, Tanaka S, Kohara M: "Real-time detection system for quantification of hepatitis C virus genome."Gastroenterology. 116 (3). 636-642 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kato T, et al.: "Sequence Analysis of Hepatitis C Virus Isolated from a Fulminant Hepatitis Patient"J Med Virol. (in press). (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Wakita T, et al.: "A possible role of cytotoxic T cells on acute liver injury in HCV cDNA transgenic mice mediated by Cre/loxP system."J Med Virol. 62・3. 308-317 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Shishido-Hara Y, et al.: "Analysis of capsid formation of human polyomavirus JC (Tokyo-1. strain) by a eukaryotlc expression systern : splicing of late RNAs trahslation and nucleartransport of major capsid protein VP1, and capsid assembly."J Virol.. 74・4. 1840-53 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Honda A, et al.: "HCV-core protein accelerates recovery from the insensitivity of liver cells to Fas-mediated apoptosis induced by an injection of anti-Fas antibody in mice"J Hepatol.. 33・3. 440-7 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Kohara M.: "Hepatitis C virus replication and pathogenesis."J Dermatol Sci.. 22・3. 161-8 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Utsunomiya S., Yoshioka K., Wakita T., et al.: "TT virus infection in hemodialysis patients"Am J Gastroenterol. 94(12). 3567-3570 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Wakita T., Moradpour D., Tokushihge K., Wands JR: "Antiviral effects of antisens RNA on hepatitis C virus RNA translation and expression"J Med Virol.. 57(3). 217-222 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Shishido-Hara Y., Hara Y., Larson T., Yasui K., Nagashima K., Stoner GL: "Analysis of capsid formation of human polyomavirus JC (Tokyo-1 strain) by a eukaryotic expression system"J Virol. 74(4). 1840-1853 (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] An J, Kimura-Kuroda J., Hirabayashi Y., Yasui K.: "Development of a novel mouse model for dengue virus infection"Virology. 263(1). 70-77 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Isoyama T., Kamoshita N., Yasui K., Iwai A., Shiroki K., Toyoda H., et al.: "Lower concentration of La protein required for internal ribosome entry on hepatitis C virus RNA than on poliovirus RNA"J Gen Virol.. 80(9). 2319-2327 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Honda A., Arai Y., Hirota N., Sato T., Ikegaki J., Koizumi T., Hatano M., Kohara M., et al.: "Hepatitis C virus structural proteins induce liver cell injury in transgenic mice"J Med Virol.. 59(3). 281-289 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Sabile A., Perlemuter G., Bono F., Kohara K., Demaugre F., Kohara M., et al.: "Hepatitis C virus core protein binds to apolipoprotein AII and its secretion is modulated by fibrates"Hepatology. 30(4). 1064-1076 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Abe A., Inoue K., Tanaka T., Kato J., Kajiyama N., Kawaguchi R., Tanaka S., Yoshiba M., Kohara M.: "Quantitation of hepatitis B virus genomic DNA by real-time detection PCR"J Clin Microbiol.. 37(9). 2899-2903 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Tanaka T., Hess G., Tanaka S., Kohara M.: "The significance of hepatitis G virus infection in patients with non-A to C hepatic diseases"Hepatogastroenterology. 46(27). 1870-1973 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Inoue K., Yoshiba M., Sekiyama K., Kohara M.: "Possible association between serum GB virus C RNA level and disease activity in fulminant hepatitis type G"J Hepatol.. 30(5). 801-806 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Hirota M., Satoh S., Asabe S., Kohara M., Tsukiyama-Kohara K., et al.: "Phosphorylation of nonstructural 5A protein of hepatitis C virus : HCV group-specific hyperphosphorylation"Virology. 257(1). 130-137 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Tanaka T., Hess G., Schlueter V., Zdunek D., Tanaka S., Kohara M.: "Correlation of interferon treatment response with GBV-C/HGV genomic RNA and anti-envelope 2 protein antibody"J Med Virol.. 57(4). 370-375 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Takeuchi T., Katsume A., Tanaka T., Abe A., Inoue K., Tsukiyama-Kohara K., Kawaguchi R., Tanaka S., Kohara M.: "Real-time detection system for quantification of hepatitis C virus genome"Gastroenterology. 116(3). 636-642 (1999)

    • Related Report
      1999 Annual Research Report

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Published: 1999-04-01   Modified: 2016-04-21  

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