Analyses on the progression of liver fibrosis induced by hepatitis B virus infection

2012 Fiscal Year Final Research Report

• Project/Area Number: 23890255
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Single-year Grants
• Research Field: Gastroenterology
• Research Institution: Research Institute, International Medical Center of Japan
• Principal Investigator: SUGIYAMA Masaya 独立行政法人国立国際医療研究センター, 肝炎・免疫研究センター, 肝疾患研究部 (20612427)
• Project Period (FY): 2011 – 2012
• Keywords: B型肝炎ウイルス / 肝線維化 / 自然免疫 / 活性酸素種 / 細胞周期

Research Abstract

Chimeric mice with human hepatocyte was infected with hepatitis B virus to mimic liver fibrosis triggered by virus infection. To prevent liver fibrosis, a newly developed antibody specific for Toll-like receptor 4 was administrated with the chimeric mice. The antibody successfully prevented the progression of liver fibrosis. The severe side effect induced by the antibody was not observed in the mice. Along with these results, the antibody could be a potential as a new drug. Further study is needed to reveal the molecular basis of this effect.

Research Products

• [Journal Article] 2'-Fluoro-6'-methylene-carbocyclic adenosine phosphoramidate (FMCAP) prodrug: In vitro anti-HBV activity against the lamivudine-entecavir resistant triple mutant and its mechanism of action. (2013)
  • Author(s): Rawal RK, Singh US, Chavre SN, Wang J, Sugiyama M, Hung W, Govindarajan R, Korba B, Tanaka Y, Chu CK
  • Journal Title: Bioorg Med Chem Lett. Volume: 23(2) Pages: 503-6
• [Journal Article] Hepatitis C virus kinetics by administration of pegylated interferon-α in human and chimeric mice carrying human hepatocytes with variants of the IL28B gene. (2012)
  • Author(s): Watanabe T, Sugauchi F, Tanaka Y, Matsuura K, Yatsuhashi H, Murakami S, Iijima S, Iio E, Sugiyama M, Shimada T, Kakuni M, Kohara M, Mizokami M
  • Journal Title: Gut
• [Journal Article] Soluble MICA and a MICA variation as possible prognostic biomarkers for HBV-induced hepatocellular carcinoma. (2012)
  • Author(s): Kumar V, Yi Lo PH, Sawai H, Kato N, Takahashi A, Deng Z, Urabe Y, Mbarek H, Tokunaga K, Tanaka Y, Sugiyama M, Mizokami M, Muroyama R, Tateishi R, Omata M, Koike K, Tanikawa C, Kamatani N, Kubo M, Nakamura Y, Matsuda K
  • Journal Title: PLoS One Volume: 7(9) Pages: e44743
• [Journal Article] Genome-wide association study confirming association of HLA-DP with protection against chronic hepatitis B and viral clearance in Japanese and Korean. (2012)
  • Author(s): Nishida N, Sawai H, Matsuura K, Sugiyama M, Ahn SH, Park JY, Hige S, Kang JH, Suzuki K, Kurosaki M, Asahina Y, Mochida S, Watanabe M, Tanaka E, Honda M, Kaneko S, Orito E, Itoh Y, Mita E, Tamori A, Murawaki Y, Hiasa Y, Sakaida I, Korenaga M, Hino K, Ide T, Kawashima M, Mawatari Y, Sageshima M, Ogasawara Y, Koike A, Izumi N, Han KH, Tanaka Y, Tokunaga K, Mizokami M
  • Journal Title: PLoS One Volume: 7(6) Pages: e39175
• [Journal Article] No association for Chinese HBV-related hepatocellular carcinoma susceptibility SNP in other East Asian populations. (2012)
  • Author(s): Sawai H, Nishida N, Mbarek H, Matsuda K, Mawatari Y, Yamaoka M, Hige S, Kang JH, Abe K, Mochida S, Watanabe M, Kurosaki M, Asahina Y, Izumi N, Honda M, Kaneko S, Tanaka E, Matsuura K, Itoh Y, Mita E, Korenaga M, Hino K, Murawaki Y, Hiasa Y, Ide T, Ito K, Sugiyama M, Ahn SH, Han KH, Park JY, Yuen MF, Nakamura Y, Tanaka Y, Mizokami M, Tokunaga K
  • Journal Title: BMC Med Genet Volume: 13 Pages: 47
• [Journal Article] Development of specific and quantitative real-time detection PCR and immunoassays for λ3-interferon. (2012)
  • Author(s): Sugiyama M, Kimura T, Naito S, Mukaide M, Shinauchi T, Ueno M, Ito K, Murata K, Mizokami M
  • Journal Title: Hepatol Res. Volume: 42(11) Pages: 1089-99
• [Journal Article] Factors responsible for the discrepancy between IL28B polymorphism prediction and the viral response to peginterferon plus ribavirin therapy in Japanese chronic hepatitis C patients. (2012)
  • Author(s): Saito H, Ito K, Sugiyama M, Matsui T, Aoki Y, Imamura M, Murata K, Masaki N, Nomura H, Adachi H, Hige S, Enomoto N, Sakamoto N, Kurosaki M, Mizokami M, Watanabe S
  • Journal Title: Hepatol Res. Volume: 42(10) Pages: 958-965
• [Journal Article] LecT-hepa, a glyco-marker derived from multiple lectins, as a predictor of liver fibrosis in chronic hepatitis C patients. (2012)
  • Author(s): Ito K, Kuno A, Ikehara Y, Sugiyama M, Saito H, Aoki Y, Matsui T, Imamura M, Korenaga M, Murata K, Masaki N, Tanaka Y, Hige S, Izumi N, Kurosaki M, Nishiguchi S, Sakamoto M, Kage M, Narimatsu H, Mizokami M.
  • Journal Title: Hepatology. Volume: 56(4) Pages: 1448-56
• [Journal Article] Genetic Variation of the IL-28B Promoter Affecting Gene Expression. (2011)
  • Author(s): Sugiyama M, Tanaka Y, Wakita T, Nakanishi M, Mizokami M
  • Journal Title: PLoS ONE Volume: 6(10) Pages: e26620
• [Journal Article] Easy-to-use phylogenetic analysis system for hepatitis B virus infection. (2011)
  • Author(s): Sugiyama M, Inui A, Shin-I T, Komatsu H, Mukaide M, Masaki N, Murata K, Ito K, Nakanishi M, Fujisawa T, Mizokami M
  • Journal Title: Hepatol Res. Volume: 41(10) Pages: 936-45
• [Journal Article] Novel findings for the development of drug therapy for various liver diseases: Genetic variation in IL-28B is associated with response to the therapy for chronic hepatitis C. (2011)
  • Author(s): Sugiyama M, Tanaka Y, Nakanishi M, Mizokami M
  • Journal Title: J Pharmacol Sci. Volume: 115(3) Pages: 263-9
• [Journal Article] Pre-treatment prediction of response to pegylated-interferon plus ribavirin for chronic hepatitis C using genetic polymorphism in IL28B and viral factors. (2011)
  • Author(s): Kurosaki M, Tanaka Y, Nishida N, Sakamoto N, Enomoto N, Honda M, Sugiyama M, Matsuura K, Sugauchi F, Asahina Y, Nakagawa M, Watanabe M, Sakamoto M, Maekawa S, Sakai A, Kaneko S, Ito K, Masaki N, Tokunaga K, Izumi N, Mizokami M
  • Journal Title: J Hepatol Volume: 54(3) Pages: 439-48
• [Journal Article] Transmissibility of hepatitis B virus (HBV) infection through blood transfusion from blood donors with occult HBV infection. (2011)
  • Author(s): Yuen MF, Wong DK, Lee CK, Tanaka Y, Allain JP, Fung J, Leung J, Lin CK, Sugiyama M, Sugauchi F, Mizokami M, Lai CL
  • Journal Title: Clin Infect Dis. Volume: 52(5) Pages: 624-32
• [Journal Article] Host sphingolipid biosynthesis is a promising therapeutic target for the inhibition of hepatitis B virus replication. (2011)
  • Author(s): Tatematsu K, Tanaka Y, Sugiyama M, Sudoh M, Mizokami M.
  • Journal Title: J Med Virol Volume: 83(4) Pages: 587-93
• [Journal Article] Genome-wide association study identified ITPA/DDRGK1 variants reflecting thrombocytopenia in pegylated interferon and ribavirin therapy for chronic hepatitis C. (2011)
  • Author(s): Tanaka Y, Kurosaki M, Nishida N, Sugiyama M, Matsuura K, Sakamoto N, Enomoto N, Yatsuhashi H, Nishiguchi S, Hino K, Hige S, Itoh Y, Tanaka E, Mochida S, Honda M, Hiasa Y, Koike A, Sugauchi F, Kaneko S, Izumi N, Tokunaga K, Mizokami M
  • Journal Title: Hum Mol Genet Volume: 20(17) Pages: 3507-16
• [Journal Article] Antiviral activity of novel 2'-fluoro-6'-methylene-carbocyclic adenosine against wild-type and drug-resistant hepatitis B virus mutants. (2011)
  • Author(s): Wang J, Singh US, Rawal RK, Sugiyama M, Yoo J, Jha AK, Scroggin M, Huang Z, Murray MG, Govindarajan R, Tanaka Y, Korba B, Chu CK
  • Journal Title: Bioorg Med Chem Lett Volume: 21(21) Pages: 6328-31
• [Journal Article] An updated analysis of hepatitis C virus genotypes and subtypes based on the complete coding region. (2011)
  • Author(s): Nakano T, Lau GM, Lau GM, Sugiyama M, Mizokami M
  • Journal Title: Liver Int.
• [Presentation] Genetic variation in IL-28B promoter region consisting of TA dinucleotide repeat could improve the prediction of chronic hepatitis C and spontaneous clearance with rs8099917 genotyping. (2012)
  • Author(s): 」Masaya Sugiyama, Akio Ido, Hirohito Tsubouchi, Hisayoshi Watanabe, Yoshiyuki Ueno, and Masashi Mizokami
  • Organizer: American Association for the Study of Liver Diseases
  • Place of Presentation: Boston(Poster P-1765)
  • Year and Date: 2012-10-13
• [Presentation] The influence of specific mutations observed in core promoter region of HBV genotype D1 on viral replication. (2012)
  • Author(s): Masaya Sugiyama, Yasuhito Tanaka, Makoto Nakanishi and Masashi Mizokami
  • Organizer: 2012 International Meeting on Molecular Biology of Hepatitis B Viruses
  • Place of Presentation: Oxford, England(Poster P-109)
  • Year and Date: 2012-09-25
• [Presentation] IL28B特異的測定系の開発と臨床的意義の検討 (2012)
  • Author(s): 杉山真也,村田一素,溝上雅史
  • Organizer: シンポジウムS1-1 第77階日本インターフェロン・サイトカイン学会学術集会
  • Place of Presentation: 神戸商工会議所 神戸
  • Year and Date: 2012-06-21
• [Presentation] C型慢性肝炎と自然治癒に関連する第二遺伝要因の探索とその応用 (2012)
  • Author(s): 杉山真也、平峯智、西田奈央、伊藤清顕、村田一素、正木尚彦、井戸章雄、坪内博仁、溝上雅史
  • Organizer: ワークショップWS25-3 第48回日本肝臓学会総会
  • Place of Presentation: ポルテ金沢 金沢
  • Year and Date: 2012-06-07
• [Presentation] 活性酸素種を中心としたB型肝炎ウイルスの病態進展に関わる分子機序の解析 (2012)
  • Author(s): 杉山真也、田中靖人、溝上雅史
  • Organizer: シンポジウムS4 Liver forum in Kyoto第14回学術集会
  • Place of Presentation: 京都
  • Year and Date: 2012-03-31
• [Presentation] スフィンゴ脂質合成経路の阻害によるHBV複製の抑制 (2012)
  • Author(s): 」杉山真也、田中靖人、溝上雅史
  • Organizer: 肝炎ウイルス研究シンポジウムS4
  • Place of Presentation: 東京
  • Year and Date: 2012-03-24
• [Presentation] 宿主・ウイルスゲノム解析によるC型肝炎の病態解明にむけて"Host and viral genome analyses on hepatitis C" (2012)
  • Author(s): 杉山真也
  • Organizer: ワークショップB1 国立遺伝学研究所研究会 NIG Workshop
  • Place of Presentation: 国立遺伝学研究所 三島
  • Year and Date: 2012-03-12
• [Presentation] No infectivity of HBV DNA and HBsAb double-positive sera in uPA/SCID chimeric mouse (2012)
  • Author(s): Masaya Sugiyama, Miki Yoshida, Yuji Hoshi, Yasumi Furui, Shigeharu Uchida, Masashi Mizokami
  • Organizer: sian Pacific Association for the Study of the Liver
  • Place of Presentation: Taipei, Taiwan(Poster PP10-010)
  • Year and Date: 2012-02-17
• [Presentation] Core promoter mutations specific for hepatitis B virus genotype D1 regulating viral replication (2012)
  • Author(s): Masaya Sugiyama, Sachiko Sato, Yasuhito Tanaka, Kiyoaki Ito, Kazumoto Murata, Naohiko Masaki, and Masashi Mizokami
  • Organizer: Asian Pacific Association for the Study of the Liver
  • Place of Presentation: Taipei, Taiwan(Poster PP10-017)
  • Year and Date: 2012-02-17
• [Presentation] Host sphingolipid biosynthesis as a therapeutic target for HBV replication (2011)
  • Author(s): Makoto Nakanishi, Masayuki Sudoh, and Masashi Mizokami
  • Organizer: American Association for the Study of Liver Diseases
  • Place of Presentation: San Francisco(Poster P-1462)
  • Year and Date: 2011-11-07
• [Presentation] Polymorphism of IL-28B promoter region could improve the prediction value of response to CHC treatment following rs8099917 genotyping. (2011)
  • Author(s): Masaya Sugiyama, Yasuhito Tanaka, Masashi Mizokami
  • Organizer: American Association for the Study of Liver Diseases
  • Place of Presentation: San Francisco(Poster P-407)
  • Year and Date: 2011-11-05
• [Presentation] ホストのスフィンゴ脂質合成系を標的とした抗HBV薬のキメラマウスにおける検討 (2011)
  • Author(s): 杉山真也、田中靖人、溝上雅史
  • Organizer: パネルディスカッションPD4-3 第19回日本消化器関連学会週間
  • Place of Presentation: 福岡
  • Year and Date: 2011-10-20
• [Presentation] IL-28B遺伝子周囲に存在するSNPsの機能解析と臨床的意義 (2011)
  • Author(s): 杉山真也、田中靖人、溝上雅史
  • Organizer: シンポジウムS2-13 第19回日本消化器関連学会週間
  • Place of Presentation: 福岡
  • Year and Date: 2011-10-20
• [Presentation] The impact of core promoter mutations specific for hepatitis B virus genotype D1 on viral replication (2011)
  • Author(s): Masaya Sugiyama, Yasuhito Tanaka, Makoto Nakanishi, and Masashi Mizokami
  • Organizer: Asian Pacific Digestive Week 2011
  • Place of Presentation: Singapore(Poster 848)
  • Year and Date: 2011-10-02
• [Presentation] Influence of genetic variation in IL-28B promoter on the gene expression levels (2011)
  • Author(s): Masaya Sugiyama, Yasuhito Tanaka, Makoto Nakanishi, and Masashi Mizokami
  • Organizer: International Union of Microbiological Societies Congresses 2011
  • Place of Presentation: Sapporo(Poster VI-PO18-6)
  • Year and Date: 2011-09-13
• [Presentation] キメラマウスでのB型肝炎の病態進展に関わる分子機構の検討 (2011)
  • Author(s): 杉山真也、田中靖人、溝上雅史
  • Organizer: シンポジウムSY-1-11 第47回日本肝臓学会総会
  • Place of Presentation: 東京
  • Year and Date: 2011-06-02
• [Patent(Industrial Property Rights)] C型肝炎患者の経過予測方法 (2011)
  • Inventor(s): 溝上雅史、杉山真也
  • Industrial Property Rights Holder: 国立国際医療研究センター
  • Industrial Property Number: 特許,特願2011-211647
  • Filing Date: 2011-09-27
• [Patent(Industrial Property Rights)] B型肝炎ウイルス群を検出し、遺伝子多様性を評価するためのオリゴヌクレオチドのセット、並びにそれを用いた方法 (2011)
  • Inventor(s): 溝上雅史、杉山真也、新井 理、田村卓郎
  • Industrial Property Rights Holder: 国立国際医療研究センター,ビッツ株式会社
  • Industrial Property Number: 特許,PCT/JP2011/79353
  • Filing Date: 2011-12-19
  • Overseas
• [Patent(Industrial Property Rights)] IL-28Bの分析方法 (2011)
  • Inventor(s): 溝上雅史、杉山真也、木村達治
  • Industrial Property Rights Holder: 国立国際医療研究センター、特殊免疫研究所
  • Industrial Property Number: 特許,特願2011-287603
  • Filing Date: 2011-12-28