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Development of basic technology for intractable and rare diseases

Research Project

Project/Area Number 19K22601
Research Category

Grant-in-Aid for Challenging Research (Exploratory)

Allocation TypeMulti-year Fund
Review Section Medium-sized Section 52:General internal medicine and related fields
Research InstitutionUniversity of the Ryukyus (2021)
Yokohama City University (2019-2020)

Principal Investigator

YAMASHITA AKIO  琉球大学, 医学(系)研究科(研究院), 教授 (20405020)

Project Period (FY) 2019-06-28 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Fiscal Year 2020: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
Fiscal Year 2019: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
KeywordsmRNA分解 / mRNA翻訳 / ナンセンス変異 / mRNA監視機構 / 嚢胞性線維症 / nonsense mutation / mRNA decay / モデルマウス / SMG1
Outline of Research at the Start

本研究では、NMD阻害による遺伝性疾患治療の可能性について細胞、個体レベルで検討・検証することを目的とする。初期対象疾患として、嚢胞性線維症患者由来細胞を用い、独自のSMG1阻害剤、リドスルー剤、CFTR安定化剤(VX-770)による遺伝性疾患治療のin vitroレベルでのPOCを取得する。同時に、独自に樹立した嚢胞性線維症モデルマウスを用いて、リドスルー剤、CFTR安定化剤(VX-770)、SMG1阻害剤投与による遺伝性疾患治療のin vivoレベルでのPOCを取得する。これらの解析により、希少遺伝性疾患治療のin vitro、in vivoレベルでのPOCを取得し研究を加速させる。

Outline of Final Research Achievements

Nonsense-mediated mRNA decay (NMD) is an mRNA surveillance mechanism that eliminates aberrant mRNAs containing premature termination codons (PTCs). NMD inhibits the production of aberrant proteins that still retain, at least in part, wild-type function as well as dominant-negative peptides. Therefore, the selective inhibition of NMD has the potential to ameliorate NMD-exacerbated mutant phenotypes. However, we do not have sufficient knowledge of how to effectively suppress NMD with minimum cytotoxic effects. In present study, we identified several approved drugs which can repress NMD activity in cells. These drugs are previously not linked with NMD.

Academic Significance and Societal Importance of the Research Achievements

本研究で得られた、複数のmRNA監視機構を阻害する臨床薬は、これまで、NMDとの関わりがわかっていなかった化合物であり、培養細胞レベルではあるが、新たなNMD阻害法の発見となった。このmRNA監視機構阻害法は、臨床で用いられる薬剤による物であるため、安全性などの情報が得られている。今後、動物モデルを用いたmRNA監視機構抑制の検証後、早期に人における応用へつなげられる事が期待される。

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (23 results)

All 2022 2021 2020 2019

All Journal Article (15 results) (of which Int'l Joint Research: 8 results,  Peer Reviewed: 15 results,  Open Access: 15 results) Presentation (7 results) Book (1 results)

  • [Journal Article] Deficiency of the kidney tubular angiotensin II type1 receptor?associated protein ATRAP exacerbates streptozotocin-induced diabetic glomerular injury via reducing protective macrophage polarization2022

    • Author(s)
      Haruhara Kotaro、Suzuki Toru、Wakui Hiromichi、Azushima Kengo、Kurotaki Daisuke、Kawase Wataru、Uneda Kazushi、Kobayashi Ryu、Ohki Kohji、Kinguchi Sho、Yamaji Takahiro、Kato Ikuma、Ohashi Kenichi、Yamashita Akio、Tamura Tomohiko、Tsuboi Nobuo、Yokoo Takashi、Tamura Kouichi
    • Journal Title

      Kidney International

      Volume: 101 Issue: 5 Pages: 912-928

    • DOI

      10.1016/j.kint.2022.01.031

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Effects of tumor necrosis factor-α inhibition on kidney fibrosis and inflammation in a mouse model of aristolochic acid nephropathy2021

    • Author(s)
      Taguchi Shinya、Azushima Kengo、Yamaji Takahiro、Urate Shingo、Suzuki Toru、Abe Eriko、Tanaka Shohei、Tsukamoto Shunichiro、Kamimura Daisuke、Kinguchi Sho、Yamashita Akio、Wakui Hiromichi、Tamura Kouichi
    • Journal Title

      Scientific Reports

      Volume: 11 Issue: 1 Pages: 23587-23587

    • DOI

      10.1038/s41598-021-02864-1

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Distinct RNA polymerase transcripts direct the assembly of phase-separated DBC1 nuclear bodies in different cell lines2021

    • Author(s)
      Mannen Taro、Goto Masato、Yoshizawa Takuya、Yamashita Akio、Hirose Tetsuro、Hayano Toshiya
    • Journal Title

      Molecular Biology of the Cell

      Volume: 32 Issue: 21

    • DOI

      10.1091/mbc.e21-02-0081

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Tissue-specific expression of the SARS-CoV-2 receptor, angiotensin-converting enzyme 2, in mouse models of chronic kidney disease2021

    • Author(s)
      Tsukamoto Shunichiro、Wakui Hiromichi、Azushima Kengo、Yamaji Takahiro、Urate Shingo、Suzuki Toru、Abe Eriko、Tanaka Shohei、Taguchi Shinya、Yamada Takayuki、Kinguchi Sho、Kamimura Daisuke、Yamashita Akio、Sano Daisuke、Nakano Masayuki、Hashimoto Tatsuo、Tamura Kouichi
    • Journal Title

      Scientific Reports

      Volume: 11 Issue: 1 Pages: 16843-16843

    • DOI

      10.1038/s41598-021-96294-8

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] De novo ATP1A3 variants cause polymicrogyria2021

    • Author(s)
      Miyatake Satoko、Kato Mitsuhiro、Kumamoto Takuma、Hirose Tomonori、他
    • Journal Title

      Science Advances

      Volume: 7 Issue: 13 Pages: 2368-2368

    • DOI

      10.1126/sciadv.abd2368

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Potent mouse monoclonal antibodies that block SARS-CoV-2 infection2021

    • Author(s)
      Guo Youjia、Kawaguchi Atsushi、Takeshita Masaru、Sekiya Takeshi、Hirohama Mikako、Yamashita Akio、Siomi Haruhiko、Murano Kensaku
    • Journal Title

      Journal of Biological Chemistry

      Volume: 296 Pages: 100346-100346

    • DOI

      10.1016/j.jbc.2021.100346

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] New vaccine production platforms used in developing SARS-CoV-2 vaccine candidates2021

    • Author(s)
      Ura Takehiro、Yamashita Akio、Mizuki Nobuhisa、Okuda Kenji、Shimada Masaru
    • Journal Title

      Vaccine

      Volume: 39 Issue: 2 Pages: 197-201

    • DOI

      10.1016/j.vaccine.2020.11.054

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] The human papillomavirus E6 protein targets apoptosis-inducing factor (AIF) for degradation2020

    • Author(s)
      Shimada M, Yamashita A, Saito M, Ichino M, Kinjo T, Mizuki N, Klinman DM, Okuda K
    • Journal Title

      Scientific Reports

      Volume: 10 Issue: 1 Pages: 1-14

    • DOI

      10.1038/s41598-020-71134-3

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Shank2 Binds to aPKC and Controls Tight Junction Formation with Rap1 Signaling during Establishment of Epithelial Cell Polarity2020

    • Author(s)
      Sasaki Kazunori、Kojitani Noriko、Hirose Hiroko、Yoshihama Yohei、Suzuki Hidefumi、Shimada Miho、Takayanagi Ayumi、Yamashita Akio、Nakaya Masa-aki、Hirano Hisashi、Takahashi Hidehisa、Ohno Shigeo
    • Journal Title

      Cell Reports

      Volume: 31 Issue: 1 Pages: 107407-107407

    • DOI

      10.1016/j.celrep.2020.02.088

    • Related Report
      2020 Research-status Report 2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Effects of Rikkunshito treatment on renal fibrosis/inflammation and body weight reduction in a unilateral ureteral obstruction model in mice2020

    • Author(s)
      Wakui H, Yamaji T, Azushima K, Uneda K, Haruhara K, Nakamura A, Ohki K, Kinguchi S, Kobayashi R, Urate S, Suzuki T, Kamimura D, Minegishi S, Ishigami T, Kanaoka T, Matsuo K, Miyazaki T, Fujikawa T, Yamashita A, Tamura K.
    • Journal Title

      Scientific Reports

      Volume: 10 Issue: 1 Pages: 1782-1782

    • DOI

      10.1038/s41598-020-58214-0

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Angiotensin II type 1 receptor-associated protein deficiency attenuates sirtuin1 expression in an immortalised human renal proximal tubule cell line2019

    • Author(s)
      Yamaji T, Yamashita A, Wakui H, Azushima K, Uneda K, Fujikawa Y, Haku S, Kobayashi R, Ohki K, Haruhara K, Kinguchi S, Ishii T, Yamada T, Urate S, Suzuki T, Abe E, Tanaka S, Kamimura D, Ishigami T, Toya Y, Takahashi H, Tamura K.
    • Journal Title

      Scientific Reports

      Volume: 9 Issue: 1 Pages: 16550-16550

    • DOI

      10.1038/s41598-019-52566-y

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Translation-dependent unwinding of stem?loops by UPF1 licenses Regnase-1 to degrade inflammatory mRNAs2019

    • Author(s)
      Mino Takashi、Iwai Noriki、Endo Masayuki、Inoue Kentaro、Akaki Kotaro、Hia Fabian、Uehata Takuya、Emura Tomoko、Hidaka Kumi、Suzuki Yutaka、Standley Daron M、Okada-Hatakeyama Mariko、Ohno Shigeo、Sugiyama Hiroshi、Yamashita Akio、Takeuchi Osamu
    • Journal Title

      Nucleic Acids Research

      Volume: 47 Pages: 8838-8859

    • DOI

      10.1093/nar/gkz628

    • NAID

      120006708220

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] N4BP1 restricts HIV-1 and its inactivation by MALT1 promotes viral reactivation.2019

    • Author(s)
      Yamasoba D, Sato K, Ichinose T, Imamura T, Koepke L, Joas S, Reith E, Hotter D, Misawa N, Akaki K, Uehata T, Mino T, Miyamoto S, Noda T, Yamashita A, Standley DM, Kirchhoff F, Sauter D, Koyanagi Y, Takeuchi O.
    • Journal Title

      Nat Microbiol

      Volume: 4 Issue: 9 Pages: 1532-1544

    • DOI

      10.1038/s41564-019-0460-3

    • NAID

      120006731123

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Effects of rikkunshito on renal fibrosis and inflammation in angiotensin II-infused mice2019

    • Author(s)
      Azushima Kengo、Uneda Kazushi、Wakui Hiromichi、Ohki Kohji、Haruhara Kotaro、Kobayashi Ryu、Haku Sona、Kinguchi Sho、Yamaji Takahiro、Minegishi Shintaro、Ishigami Tomoaki、Yamashita Akio、Tamura Kouichi
    • Journal Title

      Scientific Reports

      Volume: 9 Issue: 1 Pages: 6201-6201

    • DOI

      10.1038/s41598-019-42657-1

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Effects of ATRAP in Renal Proximal Tubules on Angiotensin‐Dependent Hypertension2019

    • Author(s)
      Kinguchi Sho、Wakui Hiromichi、Azushima Kengo、Haruhara Kotaro、Koguchi Tomoyuki、Ohki Kohji、Uneda Kazushi、Matsuda Miyuki、Haku Sona、Yamaji Takahiro、Yamada Takayuki、Kobayashi Ryu、Minegishi Shintaro、Ishigami Tomoaki、Yamashita Akio、Fujikawa Tetsuya、Tamura Kouichi
    • Journal Title

      Journal of the American Heart Association

      Volume: 8 Issue: 8

    • DOI

      10.1161/jaha.119.012395

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] mRNA翻訳による生命現象制御の新展開2021

    • Author(s)
      山下 暁朗、藤原 俊伸
    • Organizer
      第44回 日本分子生物学会年会
    • Related Report
      2021 Annual Research Report
  • [Presentation] mRNA監視機構制御因子SMG1キナーゼによる酸化ストレス応答制御機構2021

    • Author(s)
      山下 暁朗
    • Organizer
      第44回 日本分子生物学会年会
    • Related Report
      2021 Annual Research Report
  • [Presentation] mRNA監視機構制御因子SMG1キナーゼによる酸化ストレス応答制御機構2020

    • Author(s)
      山下暁朗
    • Organizer
      日本分子生物学会
    • Related Report
      2020 Research-status Report
  • [Presentation] 医学・生物学的観点からのmRNA翻訳制御の新展開2019

    • Author(s)
      藤原俊伸, 山下暁朗
    • Organizer
      第42回日本分子生物学会年会
    • Related Report
      2019 Research-status Report
  • [Presentation] PI3 kinase様タンパク質リン酸化酵素SMG1によるストレス応答統御機構2019

    • Author(s)
      山下暁朗
    • Organizer
      第42回日本分子生物学会年会
    • Related Report
      2019 Research-status Report
  • [Presentation] PI3 kinase様タンパク質リン酸化酵素SMG1による酸化ストレス依存的なNRF2活性制御機構の解析2019

    • Author(s)
      藤川由美子, 山下暁朗, 大貫 哲男, 鈴木香絵, 青柳杏子, 黒澤瞳, 廣瀬博子, 永井陽子, 上村博司, 吉田稔, 高橋秀尚, 大野 茂男
    • Organizer
      第42回日本分子生物学会年会
    • Related Report
      2019 Research-status Report
  • [Presentation] PI3 kinase様タンパク質リン酸化酵素SMG1によるアミノ酸飢餓応答依存的遺伝子発現制御2019

    • Author(s)
      山下暁朗
    • Organizer
      第21回日本RNA学会年会
    • Related Report
      2019 Research-status Report
  • [Book] 疾患原因遺伝子・タンパク質の 解析技術と創薬/診断技術への応用~エピゲノム、トランスクリプトーム、マルチオミクス、オープンデータベースの利活用~2022

    • Author(s)
      藤本明洋ら 86人
    • Total Pages
      530
    • Publisher
      技術情報協会
    • ISBN
      9784861048777
    • Related Report
      2021 Annual Research Report

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Published: 2019-07-04   Modified: 2023-01-30  

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