Development of novel anti-viral treatment using primary human hepatocyte and stable isotope.

• Project/Area Number: 15K15293
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Gastroenterology
• Research Institution: Hiroshima University
• Principal Investigator: CHAYAMA KAZUAKI 広島大学, 医歯薬保健学研究院(医), 教授 (00211376)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: B型肝炎ウイルス / ヒト肝細胞 / キメラマウス / Hepg2 / NTCP / HepaRG / HepG2

Outline of Final Research Achievements

We administered mouse food that is used to make stable isotope containing diet. uPA-scid based mouse did not eat this food and weakened. Thus it became clear to create stable isotope labelled primary hepatocyte using this diet. As the diet is quite expensive and difficult to purchase a different diet, we decided to make a different strain of human hepatocyte chimeric mouse. We attempted to establish a human hepatocyte chimeric mouse using different immune deficient mouse strain and succeeded to establish enough human hepatocyte chimerism. We also confirmed to establish stable hepatitis B and hepatitis C virus viremia using this human hepatocyte chimeric mouse. We will try to feed this mouse with stable isotope labelled diet and create labelled primary human hepatocytes.

Research Products

• [Journal Article] Interferon stimulated genes and innate immune activation following infection with hepatitis B and C viruses. (2017)
  • Author(s): Hayes CN, Chayama K.
  • Journal Title: J Med Virol. Volume: 89 Issue: 3 Pages: 388-396
  • DOI: 10.1002/jmv.24659
  • Peer Reviewed / Open Access
• [Journal Article] The relationship between HBcrAg and HBV reinfection in HBV related post-liver transplantation patients. (2017)
  • Author(s): Urabe A, Imamura M, Tsuge M, Kan H, Fujino H, Fukuhara T, Masaki K, Kobayashi T, Ono A, Nakahara T, Kawaoka T, Hiramatsu A, Kawakami Y, Aikata H, Hayes CN, Maki N, Ohdan H, Chayama K.
  • Journal Title: J Gastroenterol. Volume: 52 Issue: 3 Pages: 366-375
  • DOI: 10.1007/s00535-016-1240-y
  • Peer Reviewed / Open Access
• [Journal Article] Interferon-stimulated gene of 20 kDa protein (ISG20) degrades RNA of Hepatitis B virus to impede the replication of HBV in vitro and in vivo. (2016)
  • Author(s): Leong CR, Funami K, Oshiumi H, Mengao D, Takaki H, Matsumoto M, Aly HH, Watashi K, Chayama K, Seya T.
  • Journal Title: Oncotarget. Volume: 7 Issue: 42 Pages: 68179-68193
  • DOI: 10.18632/oncotarget.11907
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Antiviral effects of anti-HBs immunoglobulin and vaccine on HBs antigen seroclearance for chronic hepatitis B infection. (2016)
  • Author(s): Tsuge M, Hiraga N, Uchida T, Kan H, Miyaki E, Masaki K, Ono A, Nakahara T, Abe-Chayama H, Zhang Y, Naswa MG, Kawaoka T, Miki D, Imamura M, Kawakami Y, Aikata H, Ochi H, Hayes CN, Chayama K.
  • Journal Title: Journal of Gastroenterology Volume: In press Issue: 11 Pages: 1073-1080
  • DOI: 10.1007/s00535-016-1189-x
  • Peer Reviewed / Open Access
• [Journal Article] Highly multiplexed CRISPR-Cas9-nuclease and Cas9-nickase vectors for inactivation of hepatitis B virus. (2016)
  • Author(s): Sakuma T, Masaki K, Abe-Chayama H, Mochida K, Yamamoto T, Chayama K.
  • Journal Title: Genes Cells. Volume: 21 Issue: 11 Pages: 1253-1262
  • DOI: 10.1111/gtc.12437
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Novel pH-sensitive multifunctional envelope-type nanodevice for siRNA-based treatments for chronic HBV infection (2016)
  • Author(s): Yamamoto, N. Sato, Y. Munakata, T. Kakuni, M. Tateno, C. Sanada, T. Hirata, Y. Murakami, S. Tanaka, Y. Chayama, K. Hatakeyama, H. Hyodo, M. Harashima, H. Kohara, M.
  • Journal Title: Journal of hepatology Volume: 64 Issue: 3 Pages: 547-455
  • DOI: 10.1016/j.jhep.2015.10.014
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] RNA exosome complex regulates stability of Hepatitis B Virus's X-mRNA transcript in a Non-Stop mediated (NSD) RNA quality control mechanism. (2016)
  • Author(s): Hussein H. Aly, Junya Suzuki, Koichi Watashi, Kazuaki Chayama, Shin-ichi Hoshino, Makoto Hijikata, Takanobu Kato, and Takaji Wakita
  • Journal Title: J Biol Chem Volume: 291 Issue: 31 Pages: 15958-15974
  • DOI: 10.1074/jbc.m116.724641
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Elimination of HCV via a non-ISG-mediated mechanism by vaniprevir andBMS-788329 combination therapy in human hepatocyte chimeric mice. (2016)
  • Author(s): Uchida T, Hiraga N, Imamura M, Yoshimi S, Kan H, Miyaki E, Tsuge M, Abe H, Hayes CN, Aikata H, Ishida Y, Tateno C, Ellis JD, Chayama K.
  • Journal Title: Virus Res. Volume: 213 Issue: 1 Pages: 62-68
  • DOI: 10.1016/j.jinf.2015.09.038
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Early events in hepatitis B virus infection: From the cell surface to the nucleus. (2016)
  • Author(s): Hayes CN, Zhang Y, Makokha GN, Hasan MZ, Omokoko MD, Chayama K.
  • Journal Title: Journal of Gastroenterology and Hepatology Volume: Volume 31, Issue 2, Issue: 2 Pages: 302-309
  • DOI: 10.1111/jgh.13175
  • Peer Reviewed / Open Access
• [Journal Article] HBV culture and infectious systems. (2016)
  • Author(s): Hayes CN, Chayama K.
  • Journal Title: Hepatology International Volume: 無し Issue: 4 Pages: 559-566
  • DOI: 10.1007/s12072-016-9712-y
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Development of new therapies using an animal model of hepatitis virus infection（肝炎ウイルスの動物モデルと治療開発） (2015)
  • Author(s): Chayama K, Imamura M.
  • Journal Title: Nihon Rinsho.（日本臨床2015年増刊号 新ウイルス性肝炎学） Volume: 無し
• [Presentation] Targeting Host and Viral Interactions: Insights from Mice Model (2017)
  • Author(s): Kazuaki Chayama
  • Organizer: Asian Pacific Association for the Study of the Liver 2017（APASL 2017） (アジア太平洋肝臓病学会議)
  • Place of Presentation: 上海（中国）
  • Int'l Joint Research / Invited
• [Presentation] A mouse model of human CTL mediated severe acute hepatitis B (2016)
  • Author(s): 茶山 一彰
  • Organizer: 第52回日本肝臓学会総会 特別企画1-JSH主催EASL Joint Meeting
  • Place of Presentation: 幕張
• [Presentation] B型肝炎 (2016)
  • Author(s): 茶山 一彰
  • Organizer: 第52回日本肝臓学会総会前期教育講演会
  • Place of Presentation: 幕張
• [Presentation] Best Strategy for Curing HCV Genotype 1 and 4: East vs. West (2016)
  • Author(s): Kazuaki Chayama
  • Organizer: 2016 APASL Single Topic Conference on Hepatitis C
  • Place of Presentation: 高雄（台湾）
  • Int'l Joint Research / Invited
• [Presentation] Integrated safety and Tolerability of DCV+ASV in Patients with Chronic HCV Genotype 1b Infection (2016)
  • Author(s): Kazuaki Chayama
  • Organizer: 2016 APASL Single Topic Conference on Hepatitis C
  • Place of Presentation: 高雄（台湾）
  • Int'l Joint Research
• [Presentation] B型慢性肝炎治療の軌跡 (2016)
  • Author(s): 茶山 一彰
  • Organizer: 第20回日本肝臓学会大会
  • Place of Presentation: 神戸
• [Presentation] Recent Progress in Treatment for Chronic Hepatitis C (2016)
  • Author(s): 茶山 一彰
  • Organizer: 2016アジア太平洋消化器病週間(APDW2016)
  • Place of Presentation: 神戸
  • Int'l Joint Research
• [Remarks] 広島大学病院消化器・代謝内科ホームページ
  • URL: http://shounai.hiroshima-u.ac.jp/liver.html
• [Remarks] 広島大学病院消化器・代謝内科ホームページ
  • URL: http://home.hiroshima-u.ac.jp/naika1/research_profile/liver_lab/