Construction and analysis of model organisms for human liver diseases

2010 Fiscal Year Final Research Report

• Project/Area Number: 20390022
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Biological pharmacy
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: NISHINA Hiroshi Tokyo Medical and Dental University, 難治疾患研究所, 教授 (60212122)
• Co-Investigator(Kenkyū-buntansha): ASAOKA Yoichi 東京医科歯科大学, 難治疾患研究所, 助教 (10436644)
• Project Period (FY): 2008 – 2010
• Keywords: ノックアウトマウス / メダカ / 肝形成 / 肝再生 / 脂肪肝 / 肝機能 / シグナル伝達 / モデル生物

Research Abstract

We previously performed a screen in medaka to isolate mutants with impaired liver development. The medaka hio mutants exhibit a profound (but transient) defect in liver specification that resembles the liver formation defect found in the zebrafish prometheus (prt) mutants, whose mutation occurs in the wnt2bb gene. Positional cloning revealed that the hio mutation affects the raldh2 gene encoding retinaldehyde dehydrogenase type2 (RALDH2), the enzyme principally responsible for retinoic acid (RA) biosynthesis. Our data reveal the unexpected finding that RA signaling positively regulates the wnt2bb gene expression required for liver specification in medaka. Furthermore, we have succeeded in isolating ken mutation that models human disease non-alcoholic steatohepatitis (NASH). NASH are serious human diseases in the modern world, so ken mutation may shed a new light on the molecular mechanisms of these diseases and the preventive medicine.

Research Products

• [Journal Article] Retinoic acid signaling positively regulates liver specification by inducing wnt2bb gene expression in medaka. (2010)
  • Author(s): Takahiro Negishi, Yoko Nagai, Yoichi Asaoka, Mami Ohno, Misako Namae, Hiroshi Mitani, Takashi Sasaki, Nobuyoshi Shimizu, Shuji Terai, Isao Sakaida, Hisato Kondoh, Toshiaki Katada, Makoto Furutani-Seiki, Hiroshi Nishina
  • Journal Title: Hepatology 51 Pages: 1037-1045
• [Journal Article] Filamin Associates with Stress Signaling Kinases MKK7 and MKK4 and Regulates JNK Activation. (2010)
  • Author(s): Kentaro Nakagawa, Misato Sugahara, Tokiwa Yamasaki, Hiroaki Kajiho, Shinya Takahashi, 平山順, Yasuhiro Minami, Yasutaka Ohta, Toshio Watanabe, Yutaka Hata, Toshiaki Katada, Hiroshi Nishina
  • Journal Title: Biochem.J. 427 Pages: 237-245
• [Journal Article] p38 Mitogen-Activated Protein Kinase Controls a Switch between Cardiomyocyte and Neuronal Commitment of Murine Embryonic Stem Cells by Activating Myocyte Enhancer Factor 2C-Dependent Bone Morphogenetic Protein 2 Transcription. (2010)
  • Author(s): Jinzhan Wu, Junko Kubota, Jun Hirayama, Yoko Nagai, Sachiko Nishina, Tadashi Yokoi, Yoichi Asaoka, Jungwon Seo, Nao Shimizu, Hiroaki Kajiho, Takashi Watanabe, Noriyuki Azuma, Toshiaki Katada, Hiroshi Nishina
  • Journal Title: Stem Cells and Development 19 Pages: 1723-1734
• [Journal Article] Negative regulation of wnt11 by JNK signaling is required for convergent extension during vertebrate gastrulation. (2010)
  • Author(s): Jungwon Seo, Yoichi Asaoka, Yoko Nagai, Jun Hirayama, Tokiwa Yamasaki, Misako Namae, Shinya Ohata, Nao Shimizu, Takahiro Negishi, Daiju Kitagawa, Hisato Kondoh, Makoto Furutani-Seiki, Josef M.Penninger, Toshiaki Katada, Hiroshi Nishina
  • Journal Title: J.Cell.Biochem. 110 Pages: 1022-1037
• [Journal Article] The LIM protein Ajuba is required for ciliogenesis and left-right axis determination in medaka. (2010)
  • Author(s): Yoko Nagai, Yoichi Asaoka, Misako Namae, Kota Saito, Haruka Momose, Hiroshi Mitani, Makoto Furutani-Seiki, Toshiaki Katada, Hiroshi Nishina
  • Journal Title: Biochem.Biophys.Res.Commun. 396 Pages: 887-893
• [Journal Article] A Global In VivoDrosophila RNAi Screen Identifies NOT3 as a Conserved Regulator of Heart Function. (2010)
  • Author(s): G.Gregory Neely, Keiji Kuba, Anthony Cammarato, Kazuya Isobe, Sabine Amann, Liyong Zhang, Mitsushige Murata, Lisa Elmen, Vaijayanti Gupta, Suchir Arora, Rinku Sarangi, Debasis Dan, Susumu Fujisawa, Takako Usami, Cui-ping Xia, Alex C.Keene, Nakissa N.Alayari, Hiroyuki Yamakawa, Ulrich Elling, Christian Berger, Maria Novatchkova, Rubina Koglgruber, Keiichi Fukuda, Hiroshi Nishina, Mitsuaki Isobe, J.Andrew Pospisilik, Yumiko Imai, Arne Pfeufer, Andrew A.Hicks, Peter P.Pramstaller, Sai Subramaniam, Akinori Kimura, Karen Ocorr, Rolf Bodmer, Josef M.Penninger
  • Journal Title: Cell 141 Pages: 142-153
• [Journal Article] Involvement of JNK in the regulation of autophagic cell death. (2010)
  • Author(s): Shigeomi Shimizu, Akimitsu Konishi, Yuya Nishida, Takeshi Mizuta, Hiroshi Nishina, Akitsugu Yamamoto, Yoshihide Tsujimoto
  • Journal Title: Oncogene 29 Pages: 2070-2082
• [Journal Article] Mice lacking Dok-1, Dok-2, and Dok-3 succumb to aggressive histiocytic sarcoma. (2010)
  • Author(s): Ryuichi Mashima, Kazuho Honda, Yi Yang, Yohei Morita, Akane Inoue, Sumimasa Arimura, Hiroshi Nishina, Hideo Ema, Hiromitsu Nakauchi, Brian Seed, Hideaki Oda, Yuji Yamanashi
  • Journal Title: Laboratory Investigation 90 Pages: 1357-1364
• [Journal Article] Medaka as a Novel and Accurate Model for Human Nonalcoholic Steatohepatitis. (2010)
  • Author(s): Toshihiko Matsumoto, Shuji Terai, Toshiyuki Oishi, Shinya Kuwashiro, Koichi Fujisawa, Naoki Yamamoto, Yusuke Fujita, Yoshihiko Hamamoto, Makoto Furutani-Seiki, Hiroshi Nishina, Isao Sakaida
  • Journal Title: Disease Models & Mechanisms 3 Pages: 431-440
• [Journal Article] An improved method for cell-to-cell transmission of infectious prion. (2010)
  • Author(s): Masahiko Tanaka, Hideyuki Hara, Hiroshi Nishina, Kentaro Hanada, Kenichi Hagiwara, Tomohiko Maehama
  • Journal Title: Biochem.Biophys.Res.Commun. 397 Pages: 505-508
• [Journal Article] [review] Diverse Physiological Functions of MKK4 and MKK7 during Early Embryogenesis. (2010)
  • Author(s): Yoichi Asaoka, Hiroshi Nishina
  • Journal Title: J.Biochem. 148 Pages: 393-401
• [Journal Article] [review] A common origin : signaling similarities in the regulation of the circadian clock and DNA damage responses. (2010)
  • Author(s): 内田好海, 平山順, 仁科博史
  • Journal Title: Biol.Pharm.Bull. 33 Pages: 535-544
• [Journal Article] [review] Utility and limitations of SP600125, an inhibitor of stress- responsive c-Jun N-terminal kinase. (2010)
  • Author(s): Shuhei Tanemura, Tokiwa Yamasaki, Toshiaki Katada, Hiroshi Nishina
  • Journal Title: Curr.Enzym.Inhib. 6 Pages: 26-33
• [Journal Article] 小型魚類メダカを用いた肝形成および肝疾患研究:肝細胞研究会ホームページ (2010)
  • Author(s): 仁科博史
  • Journal Title: 研究交流
• [Journal Article] 概日リズムによる生理機能の制御機構 (2010)
  • Author(s): 平山順、内田好海、宮村憲央、沢登健治、仁科博史
  • Journal Title: 自律神経 47 Pages: 297-300
• [Journal Article] 「メタボロームの分布可視化法について」メタボロミクス:その解析技術と臨床・創薬応用研究の最前線、メディカルドゥ (2010)
  • Author(s): 中村貴、早坂孝宏、井上菜穂子、仁科博史、瀬藤光利
  • Journal Title: 遺伝子医学MOOK 16 Pages: 131-135
• [Journal Article] Common light signaling pathways controlling DNA repair and circadian clock entrainment. (2009)
  • Author(s): Jun Hirayama, Norio Miyamura, Yoshimi Uchida, Yoichi Asaoka, Reiko Honda, Kenji Sawanobori, Takeshi Todo, Takuro Yamamoto, Paolo Sassone-Corsi, Hiroshi Nishina
  • Journal Title: Cell Cycle 8 Pages: 2794-2801
• [Journal Article] Blockage by SP600125 of Fce Receptor-induced degranulation and cytokine gene expression in mast cells is mediated through inhibition of phosphatidylinositol 3-kinase signaling pathway. 平成22年度JB論文賞受賞 (2009)
  • Author(s): Shuhei Tanemura, Haruka Momose, Nao Shimizu, Daiju Kitagawa, Jungwon Seo, Tokiwa Yamasaki, Kentaro Nakagawa, Hiroaki Kajiho, Josef M.Penninger, Toshiaki Katada, Hiroshi Nishina
  • Journal Title: J.Biochem. 145 Pages: 345-354
• [Journal Article] CrxOS Maintains Self-Renewal Capacity of Murine Embryonic Stem Cells. (2009)
  • Author(s): Ryota Saito, Tokiwa Yamasaki, Yoko Nagai, Jinzhan Wu, Hiroaki Kajiho, Tadashi Yokoi, Eiichiro Noda, Sachiko Nishina, Hitoshi Niwa, Noriyuki Azuma, Toshiaki Katada, Hiroshi Nishina
  • Journal Title: Biochem.Biophys.Res.Commun. 390 Pages: 1129-1135
• [Journal Article] Hematopoiesis-dependent expression of CD44 in murine hepatic progenitor cells. (2009)
  • Author(s): Shinya Ohata, Makiko Nawa, Takeshi Kasama, Tokiwa Yamasaki, Kenji Sawanobori, Shoji Hata, Takashi Nakamura, Yoichi Asaoka, Toshio Watanabe, Hitoshi Okamoto, Takahiko Hara, Shuji Terai, Isao Sakaida, Toshiaki Katada, Hiroshi Nishina
  • Journal Title: Biochem.Biophys.Res.Commun. 379 Pages: 817-823
• [Journal Article] CLOCK : BMAL-independent circadian oscillation of zebrafish Cryptochrome1a gene. (2009)
  • Author(s): Norio Miyamura, Jun Hirayama, Kenji Sawanobori, Teruya Tamaru, Yoichi Asaoka, Reiko Honda, Takuro Yamamoto, Hatsume Uno, Ken Takamatsu, Hiroshi Nishina
  • Journal Title: Biol.Pharm.Bull 32 Pages: 1183-1187
• [Journal Article] Pax6-5a Promotes Neuronal Differentiation of Murine Embryonic Stem Cells. (2009)
  • Author(s): Nao Shimizu, Hajime Watanabe, Junko Kubota, Jinzhan Wu, Ryota Saito, Tadashi Yokoi, Takumi Era, Takeshi Iwatsubo, Takashi Watanabe, Sachiko Nishina, Noriyuki Azuma, Toshiaki Katada, Hiroshi Nishina
  • Journal Title: Biol.Pharm.Bull. 32 Pages: 999-1003
• [Journal Article] Medaka : a promising model animal for comparative population genomics. (2009)
  • Author(s): Yoshifumi Matsumoto, Hiroki Oota, Yoichi Asaoka, Hiroshi Nishina, Koji Watanabe, Janusz M Bujnicki, Shoji Oda, Shoji Kawamura, Hiroshi Mitani
  • Journal Title: BMC Research Notes 2 Pages: 88
• [Journal Article] [review] Liver development : lessons from knockout mice and mutant fish. (2009)
  • Author(s): 中村貴, 仁科博史
  • Journal Title: Hepatol.Res. 39 Pages: 633-644
• [Journal Article] Upf1 potentially serves as a RING-related E3 ubiquitin ligase via its association with Upf3 in yeast. (2008)
  • Author(s): Shinya Takahashi, Yasuhiro Araki, Yuriko Ohya, Takeshi Sakuno, Shin-ichi Hoshino, Kenji Kontani, Hiroshi Nishina, Toshiaki Katada
  • Journal Title: RNA 14 Pages: 1950-1958
• [Journal Article] RalA functions as an indispensable signal mediator for nutrient sensing system. (2008)
  • Author(s): Tomohiko Maehama, Masahiko Tanaka, Hiroshi Nishina, Makoto Murakami, Yasunori Kanaho, Kentaro Hanada
  • Journal Title: J.Biol.Chem. 283 Pages: 35053-35059
• [Journal Article] Antagonistic control of cell fates by JNK and p38-MAPK signaling. (2008)
  • Author(s): Wada T, Stepniak E, Hui L, Leibbrandt A, Katada T, Nishina H, Wagner EF, Penninger JM.
  • Journal Title: Cell Death Differ. 15 Pages: 89-93
• [Journal Article] Novel antibody to human BASP1 labels apoptotic cells post-caspase activation. (2008)
  • Author(s): Shizue Ohsawa, Tomomi Watanabe, Toshiaki Katada, Hiroshi Nishina, Masayuki Miura
  • Journal Title: Biochem.Biophys.Res.Commun. 371 Pages: 639-643
• [Journal Article] Continuous high expression of XBP1 and GRP78 is important for the survival of bone marrow cells in CCl4-treated cirrhotic liver. (2008)
  • Author(s): Yoshio Marumoto, Shuji Terai, Yohei Urata, Toshihiko Matsumoto, Yuko Mizunaga, Naoki Yamamoto, Haiyan Jin, Koichi Fujisawa, Tomoaki Murata, Koh Shinoda, Hiroshi Nishina, Isao Sakaida
  • Journal Title: Biochem.Biophys.Res.Commun. 367 Pages: 546-552
• [Presentation] 小型魚類メダカを用いた肝形研究 (2010)
  • Author(s): 仁科博史
  • Organizer: 第22回分子糖尿病研究会
  • Place of Presentation: 東京
  • Year and Date: 20101200
• [Presentation] 高橋良輔世話人ワークショップ;小型魚類メダカやゼブラフィッシュを用いた疾患研究 (2010)
  • Author(s): 仁科博史
  • Organizer: BMB2010
  • Place of Presentation: 神戸
  • Year and Date: 20101200
• [Presentation] 小型魚類ゼブラフィッシュおよびメダカを用いた器官形成機構の解明 (2010)
  • Author(s): 仁科博史
  • Organizer: 徳島大学大学院ヘルスバイオサイエンス研究部セミナー
  • Place of Presentation: 徳島
  • Year and Date: 20101200
• [Presentation] Regulation of ES cell differentiation (2010)
  • Author(s): 仁科博史
  • Organizer: Lectures on Organogenesis and Regeneration in Fayoum University
  • Place of Presentation: Fayoum, Egypt
  • Year and Date: 20101000
• [Presentation] Generation and Regeneration of liver (2010)
  • Author(s): 仁科博史
  • Organizer: Fayoum University International Symposium on Stem Cells
  • Place of Presentation: Fayoum, Egypt
  • Year and Date: 20101000
• [Presentation] マウスやメダカを用いた肝形成機構の解明 (2010)
  • Author(s): 仁科博史
  • Organizer: 北里大学セミナー
  • Place of Presentation: 東京
  • Year and Date: 20101000
• [Presentation] ストレス応答性JNKシグナル伝達系のゼブラフィッシュ初期胚における役割 (2010)
  • Author(s): 浅岡洋一、仁科博史
  • Organizer: 第16回小型魚類研究会
  • Place of Presentation: 埼玉
  • Year and Date: 20100900
• [Presentation] The LIM protein Ajuba is required for ciliogenesis andleft-right axis determination in medaka (2010)
  • Author(s): 仁科博史
  • Organizer: FASEB Summer Research Conferences 2010
  • Place of Presentation: Aspen, USA
  • Year and Date: 20100800
• [Presentation] Negative Regulation of Wnt11 Expression by Jnk Signaling during Convergent Extension (2010)
  • Author(s): 浅岡洋一, 仁科博史
  • Organizer: 9 th International meeting on ZEBRAFISH DEVELOPMENT AND GENETICS
  • Place of Presentation: Wisconsin, USA
  • Year and Date: 20100600
• [Presentation] Liver biology and disease: lessons from mutant fish (2010)
  • Author(s): 浅岡洋一, 仁科博史
  • Organizer: The Joint Symposium of the 5^<th> International Symposium of Institute Network and the International Symposium Commemorating Inauguration of Kanazawa University Cancer Research Institute
  • Place of Presentation: Kanazawa
  • Year and Date: 20100600
• [Presentation] 小型魚類メダカを用いた肝臓左右性決定機構の解明 (2010)
  • Author(s): 仁科博史
  • Organizer: 第17回肝細胞研究会
  • Place of Presentation: 秋田
  • Year and Date: 20100600
• [Presentation] ストレス応答性キナーゼMKK7欠損マウスにおける脳形成異常 (2010)
  • Author(s): 山崎世和、仁科博史
  • Organizer: 第9回生命科学研究会
  • Place of Presentation: 筑波
  • Year and Date: 20100600
• [Presentation] マウスやメダカを用いたMAPキナーゼシグナル伝達系の生理機能の解析 (2010)
  • Author(s): 仁科博史
  • Organizer: 東京女子医大セミナー
  • Place of Presentation: 東京
  • Year and Date: 20100500
• [Presentation] 小型魚類メダカを用いた肝臓研究 (2010)
  • Author(s): 仁科博史
  • Organizer: 第7回日本胎盤臨床研究会
  • Place of Presentation: 東京
  • Year and Date: 20100500
• [Presentation] 肝細胞の増殖を制御するシグナル伝達の解析 (2010)
  • Author(s): 仁科博史
  • Organizer: 第12回日本肝臓医生物学研究会
  • Place of Presentation: 静岡
  • Year and Date: 20100400
• [Presentation] 小型魚類を用いたトランスポートソーム下流シグナル伝達系の解析 (2010)
  • Author(s): 仁科博史
  • Organizer: 膜輸送公開シンポジウム
  • Place of Presentation: 大阪
  • Year and Date: 20100300
• [Presentation] 細胞死調節因子Daxxによる分子時計制御 (2010)
  • Author(s): 仁科博史
  • Organizer: 細胞死研究会
  • Place of Presentation: 京都
  • Year and Date: 20100100
• [Presentation] 小型魚類を用いた器官形成シグナルの解析 (2009)
  • Author(s): 仁科博史
  • Organizer: 東京大学薬学セミナー
  • Place of Presentation: 東京
  • Year and Date: 20091100
• [Presentation] メダカ扁平胚hirame変異体の単離と解析 (2009)
  • Author(s): 仁科博史
  • Organizer: 理化学研究所CDB
  • Place of Presentation: 神戸
  • Year and Date: 20091000
• [Presentation] 畑裕世話人シンポジウム;細胞死・細胞増殖制御を司る新しいシグナル伝達系Hippo pathway (2009)
  • Author(s): 仁科博史
  • Organizer: 第82回日本生化学会大会
  • Place of Presentation: 神戸
  • Year and Date: 20091000
• [Presentation] 共培養系を用いた高効率な異常型プリオンタンパク質伝播実験系の確立 (2009)
  • Author(s): 田中正彦、前濱朝彦、仁科博史
  • Organizer: 平成21年度文部科学省科学研究費補助金特定領域「G蛋白質シグナル」研究班会議
  • Place of Presentation: 千葉
  • Year and Date: 20090900
• [Presentation] NMD制御因子Upf1はユビキチンリガーゼとして機能する (2009)
  • Author(s): 高橋真也, 堅田利明, 仁科博史
  • Organizer: RNA学会
  • Place of Presentation: 新潟
  • Year and Date: 20090700
• [Presentation] 顕微質量分析装置を用いた再生肝の解析 (2009)
  • Author(s): 中村貴、仁科博史
  • Organizer: 第16回肝細胞研究会
  • Place of Presentation: 山形
  • Year and Date: 20090600
• [Presentation] Physiological roles of Hippo signaling pathway using Medaka, Oryzias Latipes. (2009)
  • Author(s): 仁科博史
  • Organizer: RASSF First International Symposium
  • Place of Presentation: Banff, Canada
  • Year and Date: 20090200
• [Presentation] モデル生物を用いた「細胞の生と死」を制御するシグナル伝達系の解析 (2009)
  • Author(s): 仁科博史
  • Organizer: 埼玉大学セミナー
  • Place of Presentation: 浦和
  • Year and Date: 20090200
• [Presentation] 小型魚類を用いたSAPK/JNKシグナル系の解析 (2009)
  • Author(s): 仁科博史
  • Organizer: 生理学研究所セミナー
  • Place of Presentation: 岡崎
  • Year and Date: 20090200
• [Presentation] 脊椎動物の初期胚形成制御におけるSAPK/JNKシグナル伝達系の役割 (2008)
  • Author(s): 仁科博史
  • Organizer: BMB2008
  • Place of Presentation: 神戸
  • Year and Date: 20081200
• [Presentation] 肝臓学の動向 (2008)
  • Author(s): 仁科博史
  • Organizer: 早稲田大学先進理工学部
  • Place of Presentation: 東京
  • Year and Date: 20081000
• [Presentation] 小型魚類を用いた組織や器官形成に関わるシグナル伝達系の解析 (2008)
  • Author(s): 仁科博
  • Organizer: 千葉大学医学部発生生物学セミナー
  • Place of Presentation: 千葉
  • Year and Date: 20080900
• [Presentation] ヒト疾患を模倣するメダカ変異体の単離と薬剤スクリーニング系の開発 (2008)
  • Author(s): 仁科博史
  • Organizer: JAXA宇宙生物学研究室セミナー
  • Place of Presentation: 東京
  • Year and Date: 20080900
• [Presentation] 小型魚類を用いたシグナル伝達系の解析 (2008)
  • Author(s): 仁科博史
  • Organizer: Metabolic Research : Cutting Edge
  • Place of Presentation: 東京
  • Year and Date: 20080900
• [Presentation] Caf1 regulates translocation of ribonucleotide reductase by releasing nucleoplasmic Spd1-Suc22 assembly (2008)
  • Author(s): 高橋真也, 堅田利明, 仁科博史
  • Organizer: RNA 2008 Thirteenth Annual Meeting of the RNA Society
  • Place of Presentation: Berlin, Germany
  • Year and Date: 20080728-20080803
• [Presentation] 小型魚類を用いた肝疾患モデルスクリーニング (2008)
  • Author(s): 仁科博史
  • Organizer: 日本製薬工業協会・創薬部会
  • Place of Presentation: 東京
  • Year and Date: 20080600
• [Presentation] マウスやメダカを用いた器官形成の研究 (2008)
  • Author(s): 仁科博史
  • Organizer: 東京工業大学
  • Place of Presentation: 横浜
  • Year and Date: 20080600
• [Presentation] (2008)
  • Author(s): 仁科博史主催
  • Organizer: 第7回日本肝臓医生物学研究会
  • Place of Presentation: 東京
  • Year and Date: 20080500
• [Presentation] 細胞の生死および組織・器官の形成を制御するHippoシグナル伝達系 (2008)
  • Author(s): 仁科博史
  • Organizer: 山口肝臓シンポジウム
  • Place of Presentation: 宇部
  • Year and Date: 20080300
• [Book] 分子細胞生物学第6版(Lodish et al.)(翻訳分担) (2010)
  • Author(s): 仁科博史
  • Publisher: 東京化学同人
• [Book] 生物学事典(執筆分担) (2010)
  • Author(s): 仁科博史
  • Publisher: 東京化学同人
• [Book] ベーシックマスター生化学(シグナル伝達の分子機構)(執筆分担) (2008)
  • Author(s): 仁科博史
  • Total Pages: 325-345
  • Publisher: オーム社
• [Remarks] ホームページ
  • URL: http://www.tmd.ac.jp/mri/dbio/index.html