Studies on the molecular pathogenesis of the congenital anemia using zebrafish as a model

• Project/Area Number: 15K09656
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: University of Miyazaki
• Principal Investigator: Uechi Tamayo 宮崎大学, フロンティア科学実験総合センター, 研究員 (10381104)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 翻訳異常 / リボソームタンパク質遺伝子 / ゼブラフィッシュ / ダイアモンド・ブラックファン貧血

Outline of Final Research Achievements

Diamond-Blackfan Anemia (DBA) is a congenital disease, which is predominantly thought to be caused by abnormalities in protein synthesis. Our studies using zebrafish as a model (developed by knocking down zebrafish orthologous genes that are mutated in DBA patients) indicates that the expressions of genes involved in glycosylation modification are suppressed at translational level but not at transcription level. Functional analysis of one of those genes in vivo suggests that the gene is involved in erythropoiesis during early development of zebrafish. These data indicate the glycosylation pathway may be implicated in the pathogenesis of DBA. To address this important questions we have developed a zebrafish strain carrying mutations in DBA-associated ribosomal protein genes using CRISPR/Cas9, genome-editing technology. The results from these studies will provide new insights into rational design of new treatments.

Research Products

• [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] 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] 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
• [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先天性貧血の新規原因遺伝子の同定 (2017)
  • Author(s): 上地 珠代, 中島 由香里, 澤田 尚史, 石田 詩織, 土岐 力, 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] 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] 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] 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 and Naoya Kenmochi
  • Organizer: The 14th Diamond Blackfan Anemia International Consensus Conference
  • Place of Presentation: アトランタ（米国）
  • Year and Date: 2016-03-05
  • 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
  • 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: 津
  • Year and Date: 2015-11-06
• [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, and Naoya Kenmochi
  • Organizer: International Conference on Ribosome Synthesis
  • Place of Presentation: ブリュッセル（ベルギー）
  • Year and Date: 2015-08-19
  • Int'l Joint Research
• [Book] 第2章 動物実験の対象：ゼブラフィッシュ, 第3章 動物の飼育管理・基本的手技：魚類（ゼブラフィッシュ）, 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. 大・中・小動物実験プロトコル (2016)
  • Author(s): 上地珠代, 剣持直哉
  • Total Pages: 146
  • Publisher: 宮日文化情報センター