Drug screening for Diamond-Blackfan anemia using zebrafish as a model animal

• Project/Area Number: 15K15367
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Hematology
• Research Institution: University of Miyazaki
• Principal Investigator: Kenmochi Naoya 宮崎大学, フロンティア科学実験総合センター, 教授 (00133124)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: ダイアモンド・ブラックファン貧血 / 先天性貧血 / リボソーム / 化合物ライブラリー / 創薬 / ゼブラフィッシュ / 疾患モデル / 化合物スクリーニング / ダイヤモンド・ブラックファン貧血 / 造血異常 / 低分子化合物 / リボソーム病

Outline of Final Research Achievements

Diamond-Blackfan anemia (DBA) is a congenital bone marrow failure syndrome characterized by red blood cell aplasia. Although the ribosomal dysfunction is implicated in this disease, the molecular pathogenesis remains unknown, thereby no effective treatment exists. In this study, we performed in vivo screening of 1,280 small compounds using zebrafish to identify the drug candidates for DBA. We found that four compounds effectively rescued the anemia phenotype in zebrafish, suggesting that these are the promising pharmaceutical seed materials for DBA treatment.

Research Products

• [Int'l Joint Research] Nitte University(India)
• [Int'l Joint Research] University of Toulouse(France)
• [Int'l Joint Research] Harvard Medical School/University of Toledo(米国)
• [Journal Article] Cross talk between TP53 and c-Myc in the pathophysiology of Diamond-Blackfan anemia: Evidence from RPL11-deficient in vivo and in vitro models (2018)
  • Author(s): Chakraborty A, Uechi T, Nakajima Y, Gazda HT, O'Donohue MF, Gleizes PE, Kenmochi N
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 495 Issue: 2 Pages: 1839-1845
  • DOI: 10.1016/j.bbrc.2017.12.019
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Characterization of Human Telomere RNA G-Quadruplex Structures in vitro and in Living Cells using 19F NMR Spectroscopy (2017)
  • Author(s): H. L. Bao, T. Ishizuka, T. Sakamoto, K. Fujimoto, T. Uechi, N. Kenmochi, Y. Xu*
  • Journal Title: Nucleic Acids Res. Volume: － Issue: 9 Pages: 5501-5511
  • DOI: 10.1093/nar/gkx109
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Identification and characterization of 5alpha-cyprinol-sulfating cytosolic sulfotransferases (Sults) in the Zebrafish (Danio rerio). (2017)
  • Author(s): Kurogi, K., Yoshihama, M., Horton, A., Schiefer, I.T., Krasowski, M.D., Hagey, L.R., Williams, F.E., Sakakibara, Y., Kenmochi, N., Suiko, M., Liu, M.-C.
  • Journal Title: The Journal of Steroid Biochemistry and Molecular Biology Volume: 174 Pages: 120-127
  • DOI: 10.1016/j.jsbmb.2017.08.005
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] TBCD may be a causal gene in progressive neurodegenerative encephalopathy with atypical infantile spinal muscular atrophy (2017)
  • Author(s): Ikeda T, Nakahara A, Nagano R, Utoyama M, Obara M, Moritake H, Uechi T, Mitsui J, Ishiura H, Yoshimura J, Doi K, Kenmochi N, Morishita S, Nishino I, Tsuji S, and Nunoi H
  • Journal Title: J Hum Genet Volume: 62 Issue: 4 Pages: 473-480
  • DOI: 10.1038/jhg.2016.149
  • NAID: 40021158250
  • Peer Reviewed / Open Access
• [Journal Article] Exome sequencing identified RPS15A as a novel causative gene for Diamond-Blackfan anemia. (2017)
  • Author(s): Ikeda F, Yoshida K, Toki T, Uechi T, Ishida S, Nakajima Y, Sasahara Y, Okuno Y, Kanezaki R, Terui K, Kamio T, Kobayashi A, Fujita T, Sato-Otsubo A, Shiraishi Y, Tanaka H, Chiba K, Muramatsu H, Kanno H, Ohga S, Ohara A, Kojima S, Kenmochi N, Miyano S, Ogawa S, Ito E.
  • Journal Title: Haematologica. Volume: - Issue: 3 Pages: e93-e96
  • DOI: 10.3324/haematol.2016.153932
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Incomplete splicing of neutrophil-specific genes affects neutrophil development in a zebrafish model of poikiloderma with neutropenia (2015)
  • Author(s): Patil P, Uechi T, Kenmochi N
  • Journal Title: RNA Biology Volume: 12 Issue: 4 Pages: 426-434
  • DOI: 10.1080/15476286.2015.1017240
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Analysis of the translational efficiencies of mRNAs in a zebrafish model of Diamond-Blackfan anemia (2018)
  • Author(s): Tamayo Uechi, Yukari Nakajima, Maki Yoshihama, Etsuro Ito, Yutaka Suzuki, Naoya Kenmochi
  • Organizer: 15th Diamond Blackfan Anemia International Consensus Conference
  • Int'l Joint Research
• [Presentation] Decreased translational efficiency of mRNAs required for hematopoiesis in a zebrafish model of Diamond-Blackfan anemia (2017)
  • Author(s): Tamayo Uechi, Maki Yoshihama, Yukari Nakajima, Yutaka Suzuki, Sumio Sugano, Naoya Kenmochi
  • Organizer: "Translation Machinery in Health & Disease" Gordon Research Conference
  • Place of Presentation: Galveston, USA
  • Year and Date: 2017-03-19
  • Int'l Joint Research
• [Presentation] ゼブラフィッシュを用いたダイアモンド・ブラックファン貧血発症機構の解析 (2017)
  • Author(s): 上地珠代, 吉浜麻生, 中島由香里, 鈴木穣, 菅野純夫, 伊藤悦朗, 剣持直哉
  • Organizer: 2017年度生命科学系学会合同年次大会
• [Presentation] ゼブラフィッシュを用いたリボソーム病発症機構の解析および創薬スクリーニング (2017)
  • Author(s): 上地珠代, 吉浜麻生, 中島由香里, 鈴木穣, 伊藤悦朗, 剣持直哉
  • Organizer: 第３回ゼブラフィッシュ創薬研究会
• [Presentation] Zebrafish as a tool for studying disease pathogenesis and drug discovery: A zebrafish model of Diamond-Blackfun anemia (2017)
  • Author(s): Naoya Kenmochi
  • Organizer: International Meeting on Non-Mammalian models in Biomedical Research,
  • Int'l Joint Research / Invited
• [Presentation] リボソーム病モデルにおけるmRNAの飜訳制御と疾患発症の分子機構 (2017)
  • Author(s): 上地珠代, 吉浜麻生, 中島由香里, 鈴木穣, 伊藤悦朗, 剣持直哉
  • Organizer: 第19回日本RNA学会年会
• [Presentation] Ribosomal dysfunction and defective erythropoiesis in a zebrafish model of Diamond-Blackfan anemia (2017)
  • Author(s): Tamayo Uechi, Maki Yoshihama, Yukari Nakajima, Yutaka Suzuki, Sumio Sugano, Etsuro Ito, Naoya Kenmochi
  • Organizer: The 22nd Annual Meeting of the RNA Society
  • Int'l Joint Research
• [Presentation] ゼブラフィッシュを用いたリボソーム病発症機構の解析 (2017)
  • Author(s): 上地珠代, 中島由香里, 吉浜麻生, 鈴木穣, 伊藤悦朗, 剣持直哉
  • Organizer: 平成29年度日本生化学会九州支部例会
• [Presentation] Zebrafish: an in vivo model for human congenital disorders (2016)
  • Author(s): Prakash Patil, K.J. Palaksha, Tamayo Uechi, Naoya Kenmochi
  • Organizer: 9th Karnataka Science and Technology Academy (KSTA) Conference
  • Place of Presentation: Bangalore, India
  • Year and Date: 2016-12-20
  • Int'l Joint Research
• [Presentation] リボソームによる翻訳制御と疾患：ゼブラフィッシュを用いた解析 (2016)
  • Author(s): 上地 珠代, 中島 由香里, 吉浜 麻生, 鈴木 穣, 菅野 純夫, 剣持 直哉
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2016-11-30
• [Presentation] ゼブラフィッシュDBAモデルを用いた創薬のための in vivo スクリーニング (2016)
  • Author(s): 吉浜 麻生, 上地 珠代, 中島 由香里, 引間 園美, 剣持 直哉
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2016-11-30
• [Presentation] ゼブラフィッシュを用いたダイアモンド・ブラックファン貧血の発症機構の解析 (2016)
  • Author(s): 上地 珠代, 中島 由香里, 吉浜 麻生, 鈴木 穣, 菅野 純夫, 剣持 直哉
  • Organizer: 第89回日本生化学会大会
  • Place of Presentation: 仙台
  • Year and Date: 2016-09-25
• [Presentation] ゼブラフィッシュを用いたダイアモンド・ブラックファン貧血発症機構の解析および創薬スクリーニング (2016)
  • Author(s): 上地 珠代, 吉浜 麻生, 中島 由香里, 鈴木 穣, 伊藤 悦朗, 剣持 直哉
  • Organizer: 第4回RIBOSOME MEETING
  • Place of Presentation: 大阪
  • Year and Date: 2016-09-17
• [Presentation] ダイアモンド・ブラックファン貧血で同定された新たな原因候補遺伝子RPS15Aに関するゼブラフィッシュモデルを用いた解析 (2016)
  • Author(s): 石田 詩織, 上地 珠代, 池田 史圭, 土岐 力, 吉田 健一, 小川 誠司, 伊藤 悦朗, 剣持 直哉
  • Organizer: 第4回RIBOSOME MEETING
  • Place of Presentation: 大阪
  • Year and Date: 2016-09-17
• [Presentation] Selected mRNA translation and ribosomopathies: analyzing the zebrafish model of congenital pure red-cell aplasia (2016)
  • Author(s): Tamayo Uechi, Yukari Nakajima, Maki Yoshihama, Yutaka Suzuki, Sumio Sugano, Naoya Kenmochi
  • Organizer: RNA2016
  • Place of Presentation: 京都
  • Year and Date: 2016-06-28
  • Int'l Joint Research
• [Presentation] Ribosomal dysfunction leads to erythropoiesis failure in a zebrafish model of Diamond-Blackfan anemia (2016)
  • Author(s): Naoya Kenmochi, Tamayo Uechi, Yukari Nakajima, Maki Yoshihama, Yutaka Suzuki, Sumio Sugano
  • Organizer: The 13th International Congress of Human Genetics
  • Place of Presentation: 京都
  • Year and Date: 2016-04-03
  • Int'l Joint Research
• [Presentation] Aberrant translation and ribosomopathies: studying the molecular pathogenesis of human diseases using zebrafish as a model animal (2016)
  • Author(s): Tamayo Uechi, Yukari Nakajima, Maki Yoshihama, Shiori Ishida, Tsutomu Toki, Yutaka Suzuki, Sumio Sugano, Etsuro Ito, Naoya Kenmochi
  • Organizer: The International Meeting on Aquatic Model Organism for Human Disease and Toxicology Research
  • Place of Presentation: 基礎生物学研究所（岡崎市明大寺町）
  • Year and Date: 2016-03-18
  • Int'l Joint Research
• [Presentation] Decreased translation efficiency of mRNAs required for hematopoiesis in a zebrafish model of Diamond-Blackfan anemia (2016)
  • Author(s): Tamayo Uechi, Yukari Nakajima, Maki Yoshihama, Tsutomu Toki, Yutaka Suzuki, Sumio Sugano, Etsuro Ito, Naoya Kenmochi
  • Organizer: The 14th Diamond Blackfan Anemia International Consensus Conference
  • Place of Presentation: Atlanta, USA
  • Year and Date: 2016-03-05
  • Int'l Joint Research
• [Presentation] ノックダウン胚を用いた化合物スクリーニングおよび薬物代謝の in vivo 解析 (2016)
  • Author(s): 吉浜 麻生, 上地 珠代, 黒木 勝久, 鈴木 穣, Ming-Cheh Liu, 剣持 直哉
  • Organizer: 第2回ゼブラフィッシュ創薬研究会
  • Place of Presentation: 岐阜
• [Presentation] ゼブラフィッシュを用いたダイアモンド・ブラックファン貧血の新たな原因遺伝子の同定 (2015)
  • Author(s): 石田詩織, 上地珠代, 池田史圭, 土岐力, 吉田健一, 小川誠司, 伊藤悦朗, 剣持直哉
  • Organizer: 第38回日本分子生物学会年会・第88回日本生化学会大会合同大会
  • Place of Presentation: 神戸コンベンションセンター（神戸市中央区）
  • Year and Date: 2015-12-01
• [Presentation] ゼブラフィッシュを用いたリボソーム病発症メカニズムの解明 (2015)
  • Author(s): 上地珠代, 中島由香里, 吉浜麻生, 鈴木穣, 菅野純夫, 剣持直哉
  • Organizer: 第38回日本分子生物学会年会・第88回日本生化学会大会合同大会
  • Place of Presentation: 神戸コンベンションセンター（神戸市中央区）
  • Year and Date: 2015-12-01
• [Presentation] リボソーム病モデルを用いた発症機序の解明と化合物スクリーニング (2015)
  • Author(s): 上地珠代, 吉浜麻生, 中島由香里, 上米良美香, 剣持直哉
  • Organizer: 第1回ゼブラフィッシュ創薬研究会
  • Place of Presentation: 三重大学医学部（津市江戸橋）
  • Year and Date: 2015-11-06
• [Presentation] Loss of U6 biogenesis protein causes incomplete splicing of neutrophil-specific genes in a zebrafish model of poikiloderma with neutropenia (2015)
  • Author(s): Prakash Patil, Tamayo Uechi, Naoya Kenmochi
  • Organizer: RNP and Disease
  • Place of Presentation: Marrakech, Morocco
  • Year and Date: 2015-10-14
  • Int'l Joint Research
• [Presentation] Selected mRNA translation and ribosomopathies: studying the molecular pathogenesis of congenital anemia using zebrafish as a model system (2015)
  • Author(s): Tamayo Uechi, Yukari Nakajima, Maki Yoshihama, Yutaka Suzuki, Sumio Sugano, Naoya Kenmochi
  • Organizer: International Conference on Ribosome Synthesis
  • Place of Presentation: Brussels, Belgium
  • Year and Date: 2015-08-19
  • Int'l Joint Research
• [Book] 大・中・小動物実験プロトコル. 第4章 動物実験手法：ゼブラフィッシュを用いた疾患モデルの作製・解析 (2016)
  • Author(s): 剣持直哉, 上地珠代
  • Total Pages: 146
  • Publisher: 宮日文化情報センター
• [Book] 動物実験プロトコール：ゼブラフィッシュを用いた疾患モデルの作製・解析 (2016)
  • Author(s): 剣持直哉，上地珠代
  • Total Pages: 146
  • Publisher: 宮日文化情報センター
• [Remarks] リボソームタンパク質遺伝子データベース
  • URL: http://ribosome.med.miyazaki-u.ac.jp
• [Remarks] 研究室ホームページ
  • URL: http://ribosome-labo.med.miyazaki-u.ac.jp
• [Remarks] リボソームタンパク質遺伝子データベース
  • URL: http://ribosome.med.miyazaki-u.ac.jp/labo/
• [Remarks] 研究室ホームページ
  • URL: http://ribosome-labo.med.miyazaki-u.ac.jp/wiki.cgi?page=FrontPage