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The role of alternative autophagy-related ubiquitin ligase in the pathogenesis of colitis

Research Project

Project/Area Number 21K15968
Research Category

Grant-in-Aid for Early-Career Scientists

Allocation TypeMulti-year Fund
Review Section Basic Section 53010:Gastroenterology-related
Research InstitutionTokyo Medical and Dental University

Principal Investigator

Nibe Yoichi  東京医科歯科大学, 難治疾患研究所, 助教 (30793351)

Project Period (FY) 2021-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2022: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2021: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
Keywords炎症性腸疾患 / ユビキチン / 新規オートファジー / GOMED / ユビキチンリガーゼ / サイトカイン / オートファジー / 腸炎
Outline of Research at the Start

オートファジーは細胞内小器官などの自己構成成分を分解するシステムで、炎症性腸疾患との関連が注目されている。一方、申請者のグループは通常の経路と異なる、Atg5非依存的なオートファジー経路(新規オートファジー)を発見した。申請者は、様々な基質の分解シグナルであるユビキチン分子の新規オートファジーにおける役割に注目し、新規オートファジーの変調から炎症性腸疾患の発症に関与するメカニズムを明らかにする。

Outline of Final Research Achievements

We analyzed the functions of ubiquitin ligases related to alternative autophagy in the gastrointestinal tract. When the ubiquitin ligase Trim31 was abnormal, exacerbation of inflammation was observed in the DSS enteritis model. We also found that the combination of a special ubiquitin chain, K33, and an adapter protein is important for substrate recognition by novel autophagy.
Through the analysis of IBD patients with defects in alternative autophagy, we have identified several cytokines as substrates degraded by de novo autophagy. In the future, we will analyze whether the regulation of novel autophagy contributes to the improvement of pathology.

Academic Significance and Societal Importance of the Research Achievements

新規オートファジーは申請者らの研究室から提唱された新しい概念であり、世界に主導的な立場で、様々な解析系・ツールを用いた解析を進めている。ユビキチンを介して、新規オートファジーとその疾患における役割を解明しようとする試みは、独自のユビキチン解析系と、新規オートファジー解析系を同時に有する申請者にのみ遂行可能な研究であり、この標識機構の解明は今後の病態への関与の解明に資する。また、この研究は、ユビキチン化の関与する部位を特定することで同部位をターゲットとした創薬への応用など、新規オートファジーの機能解析として、ベッドサイドに直結する新たな側面の提供が期待される。

Report

(3 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Research-status Report
  • Research Products

    (3 results)

All 2022 2020

All Journal Article (3 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 3 results,  Open Access: 2 results)

  • [Journal Article] Nickel particles are present in Crohn's disease tissue and exacerbate intestinal inflammation in IBD susceptible mice.2022

    • Author(s)
      Hiroki Matsuda, Yoichi Nibe-Shirakihara, Akiko Tamura, Emi Aonuma, Satoko Arakawa, Kana Otsubo, Yasuhiro Nemoto, Takashi Nagaishi, Kiichiro Tsuchiya, Shigeomi Shimizu, Averil Ma, Mamoru Watanabe, Motohiro Uo, Ryuichi Okamoto, Shigeru Oshima.
    • Journal Title

      Biochemical and Biophysical Research Communications.

      Volume: 592 Pages: 74-80

    • DOI

      10.1016/j.bbrc.2021.12.111

    • Related Report
      2022 Annual Research Report 2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Zranb1-mutant mice display abnormal colonic mucus production and exacerbation of DSS-induced colitis.2022

    • Author(s)
      Tamura A, Ito G, Matsuda H, Nibe-Shirakihara Y, Hiraoka Y, Kitagawa S, Hiraguri Y, Nagata S, Aonuma E, Otsubo K, Nemoto Y, Nagaishi T, Watanabe M, Okamoto R, Oshima S.
    • Journal Title

      Biochem Biophys Res Commun.

      Volume: 628 Pages: 147-154

    • DOI

      10.1016/j.bbrc.2022.08.046

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Nickel ions attenuate autophagy flux and induce transglutaminase 2 (TG2) mediated post-translational modification of SQSTM1/p62.2020

    • Author(s)
      Emi Aonuma, Akiko Tamura, Hiroki Matsuda, Takehito Asakawa, Yuriko Sakamaki, Kana Otsubo, Yoichi Nibe, Michio Onizawa, Yasuhiro Nemoto, Takashi Nagaishi, Kiichiro Tsuchiya, Tetsuya Nakamura, Motohiro Uo, Mamoru Watanabe, Ryuichi Okamoto, Shigeru Oshima.
    • Journal Title

      Biochem Biophys Res Commun.

      Volume: 542 Pages: 17-23

    • DOI

      10.1016/j.bbrc.2021.01.023

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access

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Published: 2021-04-28   Modified: 2024-01-30  

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