Development of novel therapies targeting host factors in Hepatitis B virus replication

• Project/Area Number: 21K07906
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: The University of Tokyo
• Principal Investigator: Tanaka Yasuo 東京大学, 医学部附属病院, 届出研究員 (40422290)
• Co-Investigator(Kenkyū-buntansha): 建石 良介 東京大学, 医学部附属病院, 准教授 (50444089) ; 工藤 洋太郎 東京大学, 医学部附属病院, 助教 (90608358)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2023: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: HBV / HBx / ユビキチン・プロテアソーム系 / CUL4-DDB1 / CHIP / IGFBP1 / ユビキチン化 / ユビキチンリガーゼ / HBV Xタンパク

Outline of Research at the Start

肝炎や肝癌の原因の一つであるB型肝炎ウイルス（HBV）は現在用いられている核酸アナログ製剤により増殖を抑制することが可能だが、休薬により再増殖をきたすなどHBVを完全に排除することは困難であり、新規治療法の開発が望まれている。本研究ではプロテオミクスの手法を用いてHBVの増殖抑制因子を網羅的に同定し機能解析を行うことにより、これらを標的とした新規抗ウイルス療法の開発を目指す。

Outline of Final Research Achievements

In this study, we searched for the host restriction factors in HBV replication. We identified twenty molecules as candidates for host restriction factors degraded by HBx. We also identified ubiquitin-ligase CHIP as a molecule that degrade HBx and inhibit HBV replication. Our results suggest that these molecules could be an attractive therapeutic target for inhibiting HBV replication.

Academic Significance and Societal Importance of the Research Achievements

B型肝炎ウイルスは現在使用可能な核酸アナログ製剤によりウイルスの増殖を抑えることは可能だが、薬剤耐性株の出現や薬剤中止による肝炎再燃が大きな問題となっており、新規抗ウイルス薬の開発は喫緊の課題である。本研究ではB型肝炎ウイルスの産生するタンパクの一つであるHBxに着目し、ウイルスの増殖を抑制する宿主タンパクを同定し得た。本研究の結果が新規治療法の開発へ寄与することが期待される。

Research Products

• [Journal Article] Metabolomics in liver diseases: A novel alternative for liver biopsy? (2024)
  • Author(s): Tanaka Yasuo
  • Journal Title: World Journal of Hepatology Volume: 16 Issue: 1 Pages: 12-16
  • DOI: 10.4254/wjh.v16.i1.12
  • Peer Reviewed / Open Access
• [Journal Article] Machine learning for individualized prediction of hepatocellular carcinoma development after the eradication of hepatitis C virus with antivirals (2023)
  • Author(s): Minami Tatsuya、Sato Masaya、et al.
  • Journal Title: Journal of Hepatology Volume: 79 Issue: 4 Pages: 1006-1014
  • DOI: 10.1016/j.jhep.2023.05.042
  • Peer Reviewed / Open Access
• [Journal Article] MNX1-HNF1B Axis Is Indispensable for Intraductal Papillary Mucinous Neoplasm Lineages (2022)
  • Author(s): Kato H, Tateishi K, Fujiwara H, Nakatsuka T, Yamamoto K, Kudo Y, Hayakawa Y, Nakagawa H, Tanaka Y, Ijichi H, Otsuka M, Iwadate D, Oyama H, Kanai S, Noguchi K, Suzuki T, Sato T, Hakuta R, Ishigaki K, Saito K, Saito T, Takahara N, Kishikawa T, Hamada T, Takahashi R, Miyabayashi K, et al.
  • Journal Title: Gastroenterology Volume: 162 Issue: 4 Pages: 1272-1287
  • DOI: 10.1053/j.gastro.2021.12.254
  • Peer Reviewed / Open Access
• [Journal Article] Impact of Obesity and Heavy Alcohol Consumption on Hepatocellular Carcinoma Development after HCV Eradication with Antivirals (2021)
  • Author(s): Minami Tatsuya、Tateishi Ryosuke、Nakatsuka Takuma、Nakagawa Hayato、et al.
  • Journal Title: Liver Cancer Volume: 10 Issue: 4 Pages: 309
  • DOI: 10.1159/000513705
  • URL: https://pure.teikyo.jp/en/publications/9501b6f6-f3aa-4d05-8db6-86c10b130078
  • Peer Reviewed
• [Journal Article] Cell fate analysis of zone 3 hepatocytes in liver injury and tumorigenesis (2021)
  • Author(s): Kurosaki Shigeyuki、Nakagawa Hayato、Hayata Yuki、Kawamura Satoshi、Matsushita Yuki、Yamada Tomoharu、Uchino Koji、Hayakawa Yoku、Suzuki Nobumi、Hata Masahiro、Tsuboi Mayo、Kinoshita Hiroto、Tanaka Yasuo、Nakatsuka Takuma、Hirata Yoshihiro、Tateishi Keisuke、Koike Kazuhiko
  • Journal Title: JHEP Reports Volume: 3 Issue: 4 Pages: 100315-100315
  • DOI: 10.1016/j.jhepr.2021.100315
  • Peer Reviewed
• [Journal Article] Post-treatment cell-free DNA as a predictive biomarker in molecular-targeted therapy of hepatocellular carcinoma (2021)
  • Author(s): Nakatsuka T、Nakagawa H、Hayata Y、Wake T、Yamada T、Nishibatake Kinoshita M、Nakagmi R、Sato M、Minami T、Uchino K、Enooku K、Kudo Y、Tanaka Y、Kishikawa T、Otsuka M、Tateishi R、Koike K
  • Journal Title: Journal of Gastroenterology Volume: - Issue: 5 Pages: 01773-4
  • DOI: 10.1007/s00535-021-01773-4
  • Peer Reviewed
• [Presentation] Long-term efficacy of rifaximin treatment in Japanese patients with hepatic encephalopathy. (2024)
  • Author(s): Tanaka Y, Saito A, Yanase M.
  • Organizer: The Asian Pacific Association for the Study of the Liver (APASL) Annual Meeting 2024
  • Int'l Joint Research
• [Presentation] Reconsidering Cholangiolocellular Carcinoma from 2 cases presenting with different characteristics. (2024)
  • Author(s): Saito A, Gamo A, Tanaka Y, Kojima Y, Yanase M, Inagaki F, Kokudo N, Miyazaki H, Nakano M.
  • Organizer: The Asian Pacific Association for the Study of the Liver (APASL) Annual Meeting 2024
  • Int'l Joint Research
• [Presentation] A rare case of methotrexate-associated lymphoproliferative disorders (large B-cell lymphoma) appeared as multiple hepatic tumors. (2024)
  • Author(s): Oshima K, Saito A, Mino M, Akazawa N, Tanaka Y, Yanase M.
  • Organizer: The Asian Pacific Association for the Study of the Liver (APASL) Annual Meeting 2024
  • Int'l Joint Research
• [Presentation] メトトレキサート関連リンパ増殖性疾患として多発肝腫瘍を認めた1例. (2023)
  • Author(s): 大島開, 斎藤明子, 美野正彰, 赤澤直樹, 田中康雄, 栁瀬幹雄.
  • Organizer: 第45回日本肝臓学会西部会
• [Presentation] 異なる病態を示した再胆管細胞癌の2切除例. (2023)
  • Author(s): 蒲生彩香, 斎藤明子, 田中康雄, 栁瀬幹雄, 稲垣冬樹, 三原史規, 竹村信行, 國土典宏, 中野雅行.
  • Organizer: 第45回日本肝臓学会西部会
• [Presentation] ユビキチンリガーゼCHIPのHBxの安定性に与える影響の検討 (2021)
  • Author(s): 田中康雄、小池和彦
  • Organizer: 第57回日本肝臓学会総会