2017 Fiscal Year Research-status Report
| Project/Area Number |
17K19647
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| Research Institution | Tokyo Medical and Dental University |
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Principal Investigator |
朝比奈 靖浩 東京医科歯科大学, 大学院医歯学総合研究科, 寄附講座教授 (00422692)
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| Co-Investigator(Kenkyū-buntansha) |
柿沼 晴 東京医科歯科大学, 大学院医歯学総合研究科, 寄附講座准教授 (30372444)
中川 美奈 東京医科歯科大学, 統合教育機構, 准教授 (30401342)
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| Project Period (FY) |
2017-06-30 – 2020-03-31
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| Keywords | iPS細胞 / 肝細胞癌 |
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| Outline of Annual Research Achievements |
これまで申請者らは肝細胞癌のゲノム変異プロファイルを次世代シークエンサーを用いて網羅的に解析し、肝発癌リスク因子とともに病因・予後との関連を解明してきた(Hepatology 2010, 2013, 2014, J Gastroenterol 2016)。本研究では、ヒトiPS細胞由来肝細胞系譜に最新ゲノム情報に基づく遺伝子改変を順次加えることで人工的肝発癌モデルを開発し、肝発癌機序の詳細を解明することを目的としている。本年度は、ヒトiPS細胞から肝細胞系譜への分化誘導を改良し、肝幹細胞マーカーでFACS分離を繰り返すことで、未分化細胞の混入のないヒトiPS細胞由来肝幹・前駆細胞の純化・培養法を確立した。さらにヒトiPS細胞から間葉系細胞への分化誘導法を開発し、これにより得られたヒトiPS細胞由来星細胞様細胞と共培養することでさらに成熟した肝細胞様細胞を得ることが可能となった。これと並行して、次世代シークエンサーを用いて肝腫瘍のゲノム変異およびウイルスゲノムの宿主ゲノムへのintegrationを網羅的に解析し、発癌過程に重要なゲノム異常とHBV-宿主キメラDNAを探索した。特に、HBV起因性肝癌におけるHBV遺伝子の宿主ゲノムへのintegrationはhTERT変異とは相互排他的にhTERT近傍に多く、ウイルス側ではHBx遺伝子のintegrationが多かったが、これ以外にも特定の宿主遺伝子領域への挿入を認めた。これらの情報に基づき人工発癌モデル作成に必要な遺伝子候補を選定し、遺伝子改変を試みた。
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| Current Status of Research Progress |
Current Status of Research Progress
2: Research has progressed on the whole more than it was originally planned.
Reason
人工発癌モデル作成に関わる解析可能なヒトiPS細胞由来肝細胞系譜を樹立する必要があったため、これまでの分化・培養法の改良を行った。また、ヒトiPS細胞における改変遺伝子および導入遺伝子を同定するために、肝癌組織におけるゲノム情報を網羅的に解析した。
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| Strategy for Future Research Activity |
肝癌組織における網羅的ゲノム解析の結果、HBV起因性肝細胞癌は、C型肝癌やNBNC肝癌とはそのプロファイルが大きく異なることが明らかとなったため、今後この点にも着目し、臨床サンプルから同定されたHBV‐ヒトキメラ遺伝子のbreak pointにHBV遺伝子を挿入した遺伝子改変iPS細胞を樹立することで、HBV integration発癌モデルを構築し、腫瘍性に関わる表現型および幹細胞機能に与える影響を解析し、非HBV起因性肝癌と本質的に病態を異にするHBV肝癌に特異的な発癌メカニズムの詳細を明らかとする予定である。
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| Causes of Carryover |
理由： 試薬等が計画当初より廉価で購入可能であったため。
使用計画：検討する数・種類を拡大して解析を行うため、試薬を増量して購入する予定である。
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Research Products
(35 results)
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[Journal Article] Ledipasvir-sofosbuvir for treating Japanese patients with chronic hepatitis C virus genotype 2 infection.2018
Author(s)
Asahina Y, Itoh Y, Ueno Y, Matsuzaki Y, Takikawa Y, Yatsuhashi H, Genda T, Ikeda F, Matsuda T, Dvory-Sobol H, Jiang D, Massetto B, Osinusi AO, Brainard DM, McHutchison JG, Kawada N, Enomoto N.
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Journal Title
Liver Int
Volume: 印刷中
Pages: 印刷中
DOI
Peer Reviewed / Int'l Joint Research
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[Journal Article] Up-to-seven criteria as a useful predictor for tumor downstaging to within Milan criteria and Child-Pugh grade deterioration after the initial conventional TACE.2018
Author(s)
Yasui Y, Tsuchiya K, Kurosaki M, Takeguchi T, Takeguchi Y, Okada M, Wang W, Kubota Y, Goto T, Komiyama Y, Higuchi M, Takaura K, Hayashi T, Takada H, Tamaki N, Nakanishi H, Itakura J, Takahashi Y, Asahina Y, Enomoto N, Himeno Y, Izumi N.
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Journal Title
Hepatol Res
Volume: 48
Pages: 442-450
DOI
Peer Reviewed
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[Journal Article] Association Between Alanine Aminotransferase Elevation And UGT1A1*6 Polymorphisms In Daclatasvir And Asunaprevir Combination Therapy For Chronic Hepatitis C.2017
Author(s)
Maekawa S, Sato M, Kuratomi N, Inoue T, Suzuki Y, Tatsumi A, Miura M, Matsuda S, Muraoka M, Nakakuki N, Amemiya F, Takano S, Fukasawa M, Nakayama Y, Yamaguchi T, Sato T, Sakamoto M, Murakawa M, Nakagawa M, Asahina Y, Enomoto N.
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Journal Title
J Gastroenterol
Volume: 印刷中
Pages: 印刷中
DOI
Peer Reviewed
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[Journal Article] Effect of interferon-based and -free therapy on early occurrence and recurrence of hepatocellular carcinoma in chronic hepatitis C.2017
Author(s)
Nagata H, Nakagawa M, Asahina Y, Sato A, Asano Y, Tsunoda T, Miyoshi M, Kaneko S, Otani S, Kawai-Kitahata F, Murakawa M, Nitta S, Itsui Y, Azuma S, Kakinuma S, Nouchi T, Sakai H, Tomita M, Watanabe M, and the Ochanomizu Liver Conference Study Group.
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Journal Title
J Hepatol
Volume: 67
Pages: 933-939
DOI
Peer Reviewed
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[Journal Article] Hepatic IFNL4 expression is associated with non-response to interferon-based therapy through the regulation of basal interferon-stimulated gene expression in chronic hepatitis C patients.2017
Author(s)
Murakawa M, Asahina Y, Kawai-Kitahata F, Nakagawa M, Nitta S, Otani S, Nagata H, Kaneko S, Asano A, Tsunoda T, Miyoshi M, Itsui Y, Azuma S, Kakinuma S, Tanaka Y, Iijima S, Tsuchiya K, Izumi N, Tohda T, and Watanabe M.
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Journal Title
J Med Virol
Volume: 89
Pages: 1241-1247
DOI
Peer Reviewed
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[Journal Article] ITPA gene variation and ribavirin-induced anemia in patients with genotype 2 chronic hepatitis C treated with sofosbuvir plus ribavirin.2017
Author(s)
Murakawa M, Asahina Y, Nagata H, Nakagawa M, Kakinuma S, Nitta S, Kawai-Kitahata F, Otani S, Kaneko S, Miyoshi M, Tsunoda T, Asano Y, Sato A, Itsui Y, Azuma S, Nouchi T, Furumoto Y, Asano T, Chuganji Y, Tohda S, Watanabe M.
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Journal Title
Hepatol Res
Volume: 47
Pages: 1212-1218
DOI
Peer Reviewed
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[Journal Article] Hepatitis B Surface Antigen Reduction by Switching from Long-term Nucleoside/nucleotide Analog Administration to Pegylated Interferon.2017
Author(s)
Tamaki N, Kurosaki M, Kusakabe A, Orito E, Joko K, Kojima Y, Kimura H, Uchida Y, Hasebe C, Asahina Y, Izumi N.
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Journal Title
J Viral Hepat
Volume: 24
Pages: 672-678
DOI
Peer Reviewed
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[Journal Article] Morphogenetic Protein-4 Modulates Proliferation and Terminal Differentiation of Fetal Hepatic Stem/Progenitor Cells.2017
Author(s)
Goto F, Kakinuma S, Miyoshi M, Tsunoda T, Kaneko S, Sato A, Asano Y, Otani S, Azuma S, Nagata H, Kawai-Kitahata F, Murakawa M, Nitta S, Itsui Y, Nakagawa M, Asahina Y, Watanabe M.
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Journal Title
Hepatol Res
Volume: 47
Pages: 941-952
DOI
Peer Reviewed
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[Presentation] Twelve Weeks of Ledipasvir/Sofosbuvir All-oral Regimen for Patients with Chronic Hepatitis C Genotype 2 Infection: Integrated Analysis of Three Clinical Studies.2018
Author(s)
Asahina Y, Liu CJ, Gane E, Itoh Y, Kawada N, Ueno Y, Wang CY, Llewellyn J, Osinusi A, Svarovskaia J, Mo H, Crans G, Chuang WL, Chen PJ, Enomoto N.
Organizer
27th conference of the Asian Pacific Association for the Study of the Liver (APASL 2018)
Int'l Joint Research
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[Presentation] Novel culture model for coinfection of hepatitis B and hepatitis C viruses using human induced pluripotent stem cell-derived hepatic cells for analyses of changes in host-innate immune responses.2017
Author(s)
Kaneko S, Kakinuma S, Asahina Y, Kamiya A, Miyoshi M, Tsunoda T, Inoue-Shinomiya E, Nitta S, Sato A, Asano Y, Nagata H, Kawai-Kitahata F, Murakawa M, Itsui Y, Nakagawa M, Azuma S, Watanabe M.
Organizer
The 68th Annual Meeting of the American Association for the Study of Liver Disease (AASLD The Liver Meeting 2017)
Int'l Joint Research
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[Presentation] Evaluation of an early occurrence and recurrence of hepatocellular carcinoma in chronic hepatitis C patients treated with DAAs - Retrospective review of a prospective database -.2017
Author(s)
Nakagawa M, Asahina Y, Nagata H, Sato A, Miyoshi M, Tsunoda T, Asano Y, Kaneko S, Kawai-Kitahata F, Murakawa M, Nitta S, Itsui Y, Azuma S, Kakinuma S, Watanabe M.
Organizer
The 68th Annual Meeting of the American Association for the Study of Liver Disease (AASLD The Liver Meeting 2017),
Int'l Joint Research
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[Presentation] The analysis of NS5A Resistance-Associated Substitutions (RAS): In vitro study of NS5A recombinant hepatitis C in infectious cell culture system for various RAS detected after treatment failure in chronic hepatitis C patients.2017
Author(s)
Nitta S, Murakawa M, Kato T, Sato A, Tsunoda T, Miyoshi M, Asano Y, Kaneko S, Nagata H, Kawai-Kitahata F, Itsui Y, Nakagawa M, Azuma S, Kakinuma S, Asahina Y.
Organizer
The 68th Annual Meeting of the American Association for the Study of Liver Disease (AASLD The Liver Meeting 2017)
Int'l Joint Research
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[Presentation] On-treatment higher levels of alpha-fetoprotein and M2BPGi are associated with development of hepatocellular carcinoma during nucleos(t)ide analog therapy in patients with HBV chronic infection.2017
Author(s)
Murakawa M, Asahina Y, Nakagawa M, Sato A, Miyoshi M, Tsunoda T, Asano Y, Nagata H, Kaneko S, Kawai-Kitahata F, Nitta S, Itsui Y, Azuma S, Kakinuma S, Watanabe M.
Organizer
The 68th Annual Meeting of the American Association for the Study of Liver Disease (AASLD The Liver Meeting 2017)
Int'l Joint Research
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[Presentation] Ledipasvir/Sofosbuvir in the Treatment of Japanese Patients with Chronic HCV Genotype 2 Infection.2017
Author(s)
Asahina Y, Itoh Y, Ueno Y, Matsuzaki Y, Takikawa Y, Yatsuhashi H, Genda T, Ikeda F, Matsuda T, Jiang D, Huang KC, Massetto B, Osinusi A, Brainard DM, McHutchison JG, Kawada N, Enomoto N.
Organizer
The 68th Annual Meeting of the American Association for the Study of Liver Disease (AASLD The Liver Meeting 2017)
Int'l Joint Research
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[Presentation] Genetic differences in hepatocellular carcinoma among chronic persistent hepatitis B virus (HBV) infection with or without viral suppression and prior HBV infection.2017
Author(s)
Asahina Y, Tanaka S, Kakinuma S, Murakawa M, Nitta S, Watanabe T, Otani S, Goto F, Nagata H, Kaneko S, Azuma S, Itsui Y, Nakagawa M, Tanabe M, Maekawa S, Enomoto N, Watanabe M.
Organizer
The 52th annual meeting of the European association for the study of the liver (EASL The International Liver Congress 2017)
Int'l Joint Research
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[Presentation] 慢性肝疾患の線維化発がん阻止への展望 ヒトiPS細胞由来肝臓系譜細胞による病態モデルの作成と先天性肝線維症の病態解析.2017
Author(s)
角田知之, 柿沼 晴, 三好正人, 佐藤綾子, 四宮恵美, 金子 俊, 浅野 侑, 村川美也子, 新田沙由梨, 井津井康浩, 東 正新, 中川美奈, 朝比奈靖浩, 渡辺 守.
Organizer
第54回日本消化器免疫学会総会
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