ヒト肝細胞キメラマウスと超高密度アレイによる肝臓の網羅的トランスクリプトーム解析

2011 年度 研究成果報告書

• 研究課題/領域番号: 21390229
• 研究種目: 基盤研究(B)
• 配分区分: 補助金
• 応募区分: 一般
• 研究分野: 消化器内科学
• 研究機関: 広島大学
• 研究代表者: 茶山 一彰 広島大学, 大学院・医歯薬学総合研究科, 教授 (00211376)
• 研究期間 (年度): 2009 – 2011
• キーワード: 肝臓学

研究概要

肝炎ウイルスの持続感染機構を解明するため、感染時に起きる変化と、IFN応答性変化をヒト肝細胞キメラマウスで超高密度のマイクロアレイを使用して解析した。C型ではIFN応答遺伝子が誘導されていたが、ウイルスは排除されなかった。このマウスにIFNを投与すると、抗ウイルス遺伝子の一部の発現が低下していた。B型でも部分的にIFN応答が低下していた。C型、B型ともIFN signalを阻害する因子を有するが、阻害機序が異なることが推察された

研究成果

• [雑誌論文] Severe necroinflammatory reaction caused by natural killer by Fas/ FasL interaction and dendritic cells in human hepatocyte chimeric mouse (2012)
  • 著者名/発表者名: Okazaki A, Hiraga N, Imamura M, NelsonHayes C, Tsuge M, Takahashi S, AikataH, Abe H, Miki D, Ochi H, Tateno C, Yoshizato K, Ohdan H, Chayama K
  • 雑誌名: Hepatology
  • DOI: doi:10.1002/hep.25651.
  • 査読あり
• [雑誌論文] Toward the establishment of a prediction system for thepersonalized treatment of chronic hepatitis C (2012)
  • 著者名/発表者名: Ochi H, Hayes CN, Abe H, Hayashida Y, Uchiyama T, Kamatani N, Nakamura Y, Chayama K
  • 雑誌名: J Infect Dis 巻: 205 ページ: 204-210
  • DOI: doi:10.1093/infdis/jir726.
  • 査読あり
• [雑誌論文] Telaprevir with peginterferon and ribavirin for treatment-naive patients chronically infected with HCV of genotype 1 inJapan (2012)
  • 著者名/発表者名: Kumada H, Toyota J, Okanoue T, ChayamaK, Tsubouchi H, Hayashi N
  • 雑誌名: J Hepatol 巻: 56 ページ: 78-84
  • DOI: doi:10.1016/j.jhep.2011.07.016.
  • 査読あり
• [雑誌論文] Dual therapy with the nonstructural protein 5A inhibitor, daclatasvir, and the nonstructural protein 3 protease inhibitor, asunaprevir, inhepatitis C virus genotype1b-infected null responders (2012)
  • 著者名/発表者名: Chayama K, Takahashi S, Toyota J, Karino Y, Ikeda K, Ishikawa H, Watanabe H, McPhee F, Hughes E, KumadaH
  • 雑誌名: Hepatology 巻: 55 ページ: 742-748
  • DOI: doi:10.1002/hep.24724.
  • 査読あり
• [雑誌論文] Will there be an HCV meeting in 2020? Summary of the 17th international meeting on hepatitis C virus and related viruses (2011)
  • 著者名/発表者名: Wakita T, Suzuki T, Evans MJ, Shimotohno K, Chayama K, Matsuura Y, Hijikata M, Moriishi K, Seya T, Enomoto N, Koike K, Kato N, Kanto T, Hotta H
  • 雑誌名: Gastroenterology 巻: 141 ページ: e1-5
  • DOI: doi:10.1053/j.gastro.2011.05.027.
  • 査読あり
• [雑誌論文] Effects of hepatitis B virus infection on the interferon response in immunodeficient human hepatocyte chimeric mice (2011)
  • 著者名/発表者名: Tsuge M, Takahashi S, Hiraga N, Fujimoto Y, Zhang Y, Mitsui F, Abe H, Kawaoka T, Imamura M, Ochi H, Hayes CN, Chayama K
  • 雑誌名: J Infect Dis 巻: 204 ページ: 224-228
  • DOI: doi:10.1093/infdis/jir247.
  • 査読あり
• [雑誌論文] Hepatitis C virus infectionsuppresses the interferon response inthe liver of the human hepatocytechimeric mouse (2011)
  • 著者名/発表者名: Tsuge M, Fujimoto Y, Hiraga N, ZhangY, Ohnishi M, Kohno T, Abe H, Miki D, Imamura M, Takahashi S, Ochi H, HayesCN, Miya F, Tsunoda T, Chayama K
  • 雑誌名: PLoS One 巻: 6 ページ: e23856
  • DOI: doi:10.1371/journal.pone.0023856.
  • 査読あり
• [雑誌論文] Influence of ITPA polymorphisms on decreases of hemoglobin during treatment with pegylated interferon, ribavirin, and telaprevir (2011)
  • 著者名/発表者名: Suzuki F, Suzuki Y, Akuta N, Sezaki H, Hirakawa M, Kawamura Y, Hosaka T, Kobayashi M, Saito S, Arase Y, IkedaK, Kobayashi M, Chayama K, Kamatani N, Nakamura Y, Miyakawa Y, Kumada H
  • 雑誌名: Hepatology 巻: 53 ページ: 415-421
  • DOI: doi:10.1002/hep.24058.
  • 査読あり
• [雑誌論文] In vivo adaptation of hepatitis C virus in chimpanzees for efficient virus production and evasion of apoptosis (2011)
  • 著者名/発表者名: Saeed M, Shiina M, Date T, Akazawa D, Watanabe N, Murayama A, Suzuki T, Watanabe H, Hiraga N, Imamura M, Chayama K, Choi Y, Krawczynski K, Liang TJ, Wakita T, Kato T
  • 雑誌名: Hepatology 巻: 54 ページ: 425-433
  • DOI: doi:10.1002/hep.24399.
  • 査読あり
• [雑誌論文] Impact of radiation and hepatitis virus infection on risk of hepatocellular carcinoma (2011)
  • 著者名/発表者名: Ohishi W, Fujiwara S, Cologne JB, Suzuki G, Akahoshi M, Nishi N, TsugeM, Chayama K
  • 雑誌名: Hepatology 巻: 53 ページ: 1237-1245
  • DOI: doi:10.1002/hep.24207.
  • 査読あり
• [雑誌論文] Elimination of hepatitis C virus by short term NS3-4A and NS5B inhibitor combination therapy in human hepatocyte chimeric mice (2011)
  • 著者名/発表者名: Ohara E, Hiraga N, Imamura M, Iwao E, Kamiya N, Yamada I, Kono T, Onishi M, Hirata D, Mitsui F, Kawaoka T, TsugeM, Takahashi S, Abe H, Hayes CN, OchiH, Tateno C, Yoshizato K, Tanaka S, Chayama K
  • 雑誌名: JHepatol 巻: 54 ページ: 872-878
  • DOI: doi:10.1016/j.jhep.2010.08.033.
  • 査読あり
• [雑誌論文] IL-28B predicts response to chronic hepatitis Ctherapy-fine-mapping and replication study in Asian populations (2011)
  • 著者名/発表者名: Ochi H, Maekawa T, Abe H, Hayashida Y, Nakano R, Imamura M, Hiraga N, Kawakami Y, Aimitsu S, Kao JH, Kubo M, Tsunoda T, Kumada H, Nakamura Y, HayesCN, Chayama K
  • 雑誌名: J Gen Virol 巻: 92 ページ: 1071-1081
  • DOI: doi:10.1099/vir.0.029124-0.
  • 査読あり
• [雑誌論文] Variation in the DEPDC5 locus is associated with progression to hepatocellular carcinoma in chronic hepatitis C virus carriers (2011)
  • 著者名/発表者名: Miki D, Ochi H, Hayes CN, Abe H, Yoshima T, Aikata H, Ikeda K, KumadaH, Toyota J, Morizono T, Tsunoda T, Kubo M, Nakamura Y, Kamatani N, Chayama K
  • 雑誌名: Nat Genet 巻: 43 ページ: 797-800
  • DOI: doi:10.1038/ng.876.
  • 査読あり
• [雑誌論文] A genome-wide association study of chronic hepatitis B identified novel risk locus in a Japanese population (2011)
  • 著者名/発表者名: Mbarek H, Ochi H, Urabe Y, Kumar V, Kubo M, Hosono N, Takahashi A, Kamatani Y, Miki D, Abe H, Tsunoda T, Kamatani N, Chayama K, Nakamura Y, Matsuda K
  • 雑誌名: Hum Mol Genet 巻: 20 ページ: 3884-3892
  • DOI: doi:10.1093/hmg/ddr301.
  • 査読あり
• [雑誌論文] Predictive value of the IL28B polymorphism on the effect of interferon therapy in chronic hepatitis C patients with genotypes 2a and 2b (2011)
  • 著者名/発表者名: Kawaoka T, Hayes CN, Ohishi W, Ochi H, Maekawa T, Abe H, Tsuge M, Mitsui F, Hiraga N, Imamura M, Takahashi S, KuboM, Tsunoda T, Nakamura Y, Kumada H, Chayama K
  • 雑誌名: J Hepatol 巻: 54 ページ: 408-414
  • DOI: doi:10.1016/j.jhep.2010.07.032.
  • 査読あり
• [雑誌論文] Rapidemergence of telaprevir resistanthepatitis C virus strain from wildtypeclone in vivo (2011)
  • 著者名/発表者名: Hiraga N, Imamura M, Abe H, Hayes CN, Kono T, Onishi M, Tsuge M, TakahashiS, Ochi H, Iwao E, Kamiya N, Yamada I, Tateno C, Yoshizato K, Matsui H, KanaiA, Inaba T, Tanaka S, Chayama K
  • 雑誌名: Hepatology 巻: 54 ページ: 781-788
  • DOI: doi:10.1002/hep.24460.
  • 査読あり
• [雑誌論文] Impact of viral aminoacid substitutions and hostinterleukin-28b polymorphism on replication and susceptibility tointerferon of hepatitis C virus (2011)
  • 著者名/発表者名: Hiraga N, Abe H, Imamura M, Tsuge M, Takahashi S, Hayes CN, Ochi H, TatenoC, Yoshizato K, Nakamura Y, KamataniN, Chayama K
  • 雑誌名: Hepatology 巻: 54 ページ: 764-711
  • DOI: doi:10.1002/hep.24453.
  • 査読あり
• [雑誌論文] HCV substitutions and IL28B polymorphisms on outcome ofpeg-interferon plus ribavirincombination therapy (2011)
  • 著者名/発表者名: Hayes CN, Kobayashi M, Akuta N, SuzukiF, Kumada H, Abe H, Miki D, Imamura M, Ochi H, Kamatani N, Nakamura Y, Chayama K
  • 雑誌名: Gut 巻: 60 ページ: 261-267
  • DOI: doi:10.1136/gut.2010.223495.
  • 査読あり
• [雑誌論文] A single nucleotidepoly morphism in activated Cdc42 associated tyrosine kinase 1influences the interferon therapy in hepatitis C patients (2011)
  • 著者名/発表者名: Fujimoto Y, Ochi H, Maekawa T, Abe H, Hayes CN, Kumada H, Nakamura Y, Chayama K
  • 雑誌名: J Hepatol 巻: 54 ページ: 629-639
  • DOI: doi:10.1016/j.jhep.2010.07.021.
  • 査読あり
• [雑誌論文] IL28B butnot ITPA polymorphism is predictive ofresponse to pegylated interferon, ribavirin, and telaprevir tripletherapy in patients with genotype 1hepatitis C (2011)
  • 著者名/発表者名: Chayama K, Hayes CN, Abe H, Miki D, Ochi H, Karino Y, Toyota J, NakamuraY, Kamatani N, Sezaki H, Kobayashi M, Akuta N, Suzuki F, Kumada H
  • 雑誌名: J Infect Dis 巻: 204 ページ: 84-93
  • DOI: doi:10.1093/infdis/jir210.
  • 査読あり
• [雑誌論文] ME3738 enhances the effect of interferon andinhibits hepatitis C virusreplication both in vitro and in vivo (2011)
  • 著者名/発表者名: Abe H, Imamura M, Hiraga N, Tsuge M, Mitsui F, Kawaoka T, Takahashi S, OchiH, Maekawa T, Hayes CN, Tateno C, Yoshizato K, Murakami S, Yamashita N, Matsuhira T, Asai K, Chayama K
  • 雑誌名: J Hepatol 巻: 55 ページ: 11-18
  • DOI: doi:10.1016/j.jhep.2010.10.017.
  • 査読あり
• [雑誌論文] IL28 variationaffects expression of interferonstimulated genes and peg-interferonand ribavirin the rapy (2011)
  • 著者名/発表者名: Abe H, Hayes CN, Ochi H, Maekawa T, Tsuge M, Miki D, Mitsui F, Hiraga N, Imamura M, Takahashi S, Kubo M, Nakamura Y, Chayama K
  • 雑誌名: J Hepatol 巻: 54 ページ: 1094-1101
  • DOI: doi:10.1016/j.jhep.2010.09.019.
  • 査読あり
• [雑誌論文] Long-term use ofentecavir in nucleoside-naiveJapanese patients with chronichepatitis B infection (2010)
  • 著者名/発表者名: Yokosuka O, Takaguchi K, Fujioka S, Shindo M, Chayama K, Kobashi H, Hayashi N, Sato C, Kiyosawa K, Tanikawa K, Ishikawa H, Masaki N, Seriu T, Omata M
  • 雑誌名: J Hepatol 巻: 52 ページ: 791-799
  • DOI: doi:10.1016/j.jhep.2009.12.036.
  • 査読あり
• [雑誌論文] HBx protein is indispensable for development of viraemia in human hepatocyte chimericmice (2010)
  • 著者名/発表者名: Tsuge M, Hiraga N, Akiyama R, TanakaS, Matsushita M, Mitsui F, Abe H, Kitamura S, Hatakeyama T, Kimura T, Miki D, Mori N, Imamura M, TakahashiS, Hayes CN, Chayama K
  • 雑誌名: J Gen Virol 巻: 91 ページ: 1854-1864
  • DOI: doi:10.1099/vir.0.019224-0.
  • 査読あり
• [雑誌論文] IL-6-mediated intersubgenotypic variation of interferon sensitivity in hepatitis C virus genotype 2a/ 2b chimeric clones (2010)
  • 著者名/発表者名: Suda G, Sakamoto N, Itsui Y, NakagawaM, Tasaka-Fujita M, Funaoka Y, Watanabe T, Nitta S, Kiyohashi K, Azuma S, Kakinuma S, Tsuchiya K, Imamura M, Hiraga N, Chayama K, Watanabe M
  • 雑誌名: Virology 巻: 407 ページ: 80-90
  • DOI: doi:10.1016/j.virol.2010.07.041.
  • 査読あり
• [雑誌論文] ITPA polymorphism affects ribavirin-induced anemia and outcomes of therapy-a genome-wide study ofJapanese HCV virus patients (2010)
  • 著者名/発表者名: Ochi H, Maekawa T, Abe H, Hayashida Y, Nakano R, Kubo M, Tsunoda T, Hayes CN, Kumada H, Nakamura Y, Chayama K
  • 雑誌名: Gastroenterology 巻: 139 ページ: 1190-1197
  • DOI: doi:10.1053/j.gastro.2010.06.071.
  • 査読あり
• [雑誌論文] Cellculture and in vivo analyses of cytopathic hepatitis C virus mutants (2010)
  • 著者名/発表者名: Mishima K, Sakamoto N, Sekine-OsajimaY, Nakagawa M, Itsui Y, Azuma S, Kakinuma S, Kiyohashi K, Kitazume A, Tsuchiya K, Imamura M, Hiraga N, Chayama K, Wakita T, Watanabe M
  • 雑誌名: Virology 巻: 405 ページ: 361-369
  • DOI: doi:10.1016/j.virol.2010.06.020.
  • 査読あり
• [雑誌論文] Practical evaluation of a mouse with chimeric human liver model for hepatitis C virus infection using an NS3-4A protease inhibitor (2010)
  • 著者名/発表者名: Kamiya N, Iwao E, Hiraga N, Tsuge M, Imamura M, Takahashi S, Miyoshi S, Tateno C, Yoshizato K, Chayama K
  • 雑誌名: J Gen Virol 巻: 91 ページ: 1668-1677
  • DOI: doi:10.1099/vir.0.019315-0.
  • 査読あり
• [雑誌論文] Amino acidsubstitution in hepatitis C virus core region and genetic variation near the interleukin 28B gene predict viral response to telaprevir with peginterferon and ribavirin (2010)
  • 著者名/発表者名: Akuta N, Suzuki F, Hirakawa M, Kawamura Y, Yatsuji H, Sezaki H, Suzuki Y, Hosaka T, Kobayashi M, Saitoh S, Arase Y, Ikeda K, Chayama K, Nakamura Y, Kumada H
  • 雑誌名: Hepatology 巻: 52 ページ: 421-4293
  • DOI: doi:10.1002/hep.23690.
  • 査読あり
• [雑誌論文] Common variation of IL28 affects gamma-GTP levels and inflammation of the liver in chronically infected hepatitis C virus patients (2010)
  • 著者名/発表者名: Abe H, Ochi H, Maekawa T, Hayes CN, Tsuge M, Miki D, Mitsui F, Hiraga N, Imamura M, Takahashi S, Ohishi W, Arihiro K, Kubo M, Nakamura Y, ChayamaK
  • 雑誌名: J Hepatol 巻: 53 ページ: 439-443
  • DOI: doi:10.1016/j.jhep.2010.03.022.
  • 査読あり
• [雑誌論文] A polymorphism in MAPKAPK3 affects response to interferon therapy for chronic hepatitis C (2009)
  • 著者名/発表者名: Tsukada H, Ochi H, Maekawa T, Abe H, Fujimoto Y, Tsuge M, Takahashi H, Kumada H, Kamatani N, Nakamura Y, Chayama K
  • 雑誌名: Gastroenterology 巻: 136 ページ: 1796-1805e1796
  • DOI: doi:10.1053/j.gastro.2009.01.061.
  • 査読あり
• [雑誌論文] Adoptive immunotherapy with liver allograft-derived lymphocytes induces anti-HCV activity after liver transplantation in humans and humanized mice (2009)
  • 著者名/発表者名: Ohira M, Ishiyama K, Tanaka Y, DoskaliM, Igarashi Y, Tashiro H, Hiraga N, Imamura M, Sakamoto N, Asahara T, Chayama K, Ohdan H
  • 雑誌名: J Clin Invest 巻: 119 ページ: 3226-3235
  • DOI: doi:10.1172/JCI38374.
  • 査読あり
• [雑誌論文] G-to-A hypermutation in hepatitis B virus(HBV) and clinical course of patients with chronic HBV infection (2009)
  • 著者名/発表者名: Noguchi C, Imamura M, Tsuge M, HiragaN, Mori N, Miki D, Kimura T, TakahashiS, Fujimoto Y, Ochi H, Abe H, MaekawaT, Tateno C, Yoshizato K, Chayama K
  • 雑誌名: J Infect Dis 巻: 199 ページ: 1599-1607
  • DOI: doi:10.1086/598951.
  • 査読あり
• [雑誌論文] Deletion of angiotensin II type I receptor reduces hepatic steatosis (2009)
  • 著者名/発表者名: Nabeshima Y, Tazuma S, Kanno K, HyogoH, Chayama K
  • 雑誌名: J Hepatol 巻: 50 ページ: 1226-1235
  • DOI: doi:10.1016/j.jhep.2009.01.018.
  • 査読あり
• [雑誌論文] Amphipathic DNA polymers inhibit hepatitis C virus infection by blocking viral entry (2009)
  • 著者名/発表者名: Matsumura T, Hu Z, Kato T, Dreux M, Zhang YY, Imamura M, Hiraga N, JuteauJM, Cosset FL, Chayama K, Vaillant A, Liang TJ
  • 雑誌名: Gastroenterology 巻: 137 ページ: 673-681
  • DOI: doi:10.1053/j.gastro.2009.04.048.
  • 査読あり
• [雑誌論文] Amphipathic DNA polymers inhibit hepatitis C virus infection by blocking viral entry (2009)
  • 著者名/発表者名: Kamatani Y, Wattanapokayakit S, OchiH, Kawaguchi T, Takahashi A, Hosono N, Kubo M, Tsunoda T, Kamatani N, KumadaH, Puseenam A, Sura T, Daigo Y, ChayamaK, Chantratita W, Nakamura Y, MatsudaK
  • 雑誌名: Nat Genet 巻: 41 ページ: 591-595
  • DOI: doi:10.1038/ng.348.
  • 査読あり
• [雑誌論文] Absence of viral interference and different susceptibility to interferon between hepatitis B virus and hepatitis C virus in human hepatocyte chimeric mice (2009)
  • 著者名/発表者名: Hiraga N, Imamura M, Hatakeyama T, Kitamura S, Mitsui F, Tanaka S, TsugeM, Takahashi S, Abe H, Maekawa T, OchiH, Tateno C, Yoshizato K, Wakita T, Chayama K
  • 雑誌名: J Hepatol 巻: 51 ページ: 1045-1054
  • DOI: doi:10.1016/j.jhep.2009.09.002.
  • 査読あり
• [学会発表] Dual Oral Combination Therapy with the NS5A Inhibitor BMS-790052 and the NS3 Protease Inhibitor BMS-650032 Achieved 90% Sustained Virologic Response(SVR12) in HCV Genotype 1b-Infected Null Responders (2011)
  • 著者名/発表者名: Chayama Kazuaki
  • 学会等名: The 62nd Annual Meeting ofAmerican Association for the Study ofLiver Diseases(AASLD)
  • 発表場所: SanFrancisco U. S. A
  • 年月日: 2011-11-07
• [備考] ホームページ
  • URL: http://home.hiroshima-u.ac.jp/naika1/