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免疫疾患におけるRNA分解酵素Regnase-1調節機構解明とその操作法の開発

研究課題

研究課題/領域番号 19J23450
研究種目

特別研究員奨励費

配分区分補助金
応募区分国内
審査区分 小区分49070:免疫学関連
研究機関京都大学

研究代表者

Tse Ka Man Carman  京都大学, 医学研究科, 特別研究員(DC1)

研究期間 (年度) 2019-04-25 – 2022-03-31
研究課題ステータス 完了 (2021年度)
配分額 *注記
3,100千円 (直接経費: 3,100千円)
2021年度: 1,000千円 (直接経費: 1,000千円)
2020年度: 1,000千円 (直接経費: 1,000千円)
2019年度: 1,100千円 (直接経費: 1,100千円)
キーワードRegnase-1 / mRNA stability / morpholino oligos / pulmonary diseases / autoimmune diseases / inflammation / antisense oligos
研究開始時の研究の概要

The discovery that IL17 producing CD4 T cells were major drivers for development of autoimmune diseases positioned IL17-Th17 pathway as a promising therapeutic target. Recent studies on how post-transcriptional mechanisms control immunity has attracted enormous attention. Being an essential ribonuclease controlling T cell activation, Regnase-1 was shown to have a negative effect on IL17 signaling. In this study we aim to elucidate the role of Regnase-1 in the development of autoimmune diseases, and whether enhancing the action of Regnase-1 is beneficial for the treatment process.

研究実績の概要

Regnase-1 is a negative regulator of inflammation. It restricts immune responses by limiting the stability of inflammatory mRNAs (Il6, Il1b, Regnase-1, etc) through recognition of stem-loop (SL) structures in 3'untranslated regions (UTRs). In this project, we aimed to develop a therapeutic strategy to suppress inflammations through manipulating Regnase-1 availability. We achieved this by modulating the binding interaction between Regnase-1 and its SL structures, which was enabled by the simultaneous use of two antisense phosphorodiamidate morpholino oligonucleotides (MOs) targeting the right arms of the SL structure.

Blocking Regnase-1 self-regulation by MOs successfully enhanced Regnase-1 expression in macrophages, which in turn decreased the expression of inflammatory transcripts targeted by Regnase-1. In addition, we observed that tissue-targeted delivery of Regnase-1-targeting-MOs attenuated inflammation and immune cell infiltration to disease sites in mouse models of acute respiratory distress syndrome, bleomycin-induced pulmonary fibrosis, and experimental autoimmune encephalomyelitis. At last, we found that Regnase-1 expression was inversely correlated with the disease severity of patients with multiple sclerosis, whereas MO treatment against human Regnase-1 SL structures successfully blunted their expression of pro-inflammatory genes upon LPS stimulation. Overall, our findings highlight that MO-mediated enhancement of Regnase-1 expression could serve as a novel therapeutic strategy to restrict inflammation and improve disease outcomes in mouse and human.

現在までの達成度 (段落)

令和3年度が最終年度であるため、記入しない。

今後の研究の推進方策

令和3年度が最終年度であるため、記入しない。

報告書

(3件)
  • 2021 実績報告書
  • 2020 実績報告書
  • 2019 実績報告書
  • 研究成果

    (8件)

すべて 2022 2021 2020

すべて 雑誌論文 (2件) (うち査読あり 2件、 オープンアクセス 1件) 学会発表 (6件) (うち国際学会 2件)

  • [雑誌論文] Enhancement of Regnase-1 expression with stem-loop-targeting antisense oligonucleotides alleviates inflammatory diseases2022

    • 著者名/発表者名
      Ka Man Tse, Alexis Vandenbon, Xiaotong Cui, Takashi Mino, Takuya Uehata, Keiko Yasuda, Ayuko Sato, Tohru Tsujimura, Fabian Hia, Masanori Yoshinaga, Makoto Kinoshita, Tatsusada Okuno, Osamu Takeuchi
    • 雑誌名

      Science Translational medicine

      巻: -

    • 関連する報告書
      2021 実績報告書
    • 査読あり
  • [雑誌論文] IRAK1-dependent Regnase-1-14-3-3 complex formation controls Regnase-1-mediated mRNA decay2021

    • 著者名/発表者名
      Akaki Kotaro、Ogata Kosuke、Yamauchi Yuhei、Iwai Noriki、Tse Ka Man、Hia Fabian、Mochizuki Atsushi、Ishihama Yasushi、Mino Takashi、Takeuchi Osamu
    • 雑誌名

      eLife

      巻: 10

    • DOI

      10.7554/elife.71966

    • NAID

      120007166024

    • 関連する報告書
      2021 実績報告書
    • 査読あり / オープンアクセス
  • [学会発表] Manipulation of Regnase-1 mRNA stability by antisense oligonucleotides alleviates inflammatory responses in pulmonary and autoimmune diseases2021

    • 著者名/発表者名
      Ka Man Tse, Xiaotong Cui, Osamu Takeuchi
    • 学会等名
      The Korean Association of Immunologists International Meeting 2021
    • 関連する報告書
      2021 実績報告書
    • 国際学会
  • [学会発表] Manipulation of Regnase-1 mRNA stability by morpholino-based antisense oligonucleotides alleviates inflammatory responses in pulmonary and autoimmune diseases2021

    • 著者名/発表者名
      Ka Man Tse, Xiaotong Cui, Alexis Vandenbon, Keiko Yasuda, Takuya Uehata, Ayuko Sato, Tohru, Tsujimura, Takashi Mino, Masanori Yoshinaga, Tatsusada Okuno, Yoshinari Nakatsuka, Osamu Takeuchi
    • 学会等名
      The 22nd Annual Meeting of the RNA Society of Japan
    • 関連する報告書
      2021 実績報告書
  • [学会発表] Manipulating the expressions of Regnase-1 by stem-loop-targeting-antisense oligonucleotides to counteract inflammatory diseases2021

    • 著者名/発表者名
      Ka Man Tse, Xiaotong Cui, Alexis Vandenbon, Takashi Mino, Takuya Uehata, Keioko Yasuda, Ayuko Sato, Tohru Tsujimura, Fabian Hia, Masanori Yoshinaga, Osamu Takeuchi
    • 学会等名
      The 44th Annual Meeting of the Molecular Biology Society of Japan
    • 関連する報告書
      2021 実績報告書
  • [学会発表] Manipulating the expression of Regnase-1 by antisense oligonucleotides to counteract inflammatory diseases2021

    • 著者名/発表者名
      Ka Man Tse, Takashi Mino, Takuya Uehata, Keiko Yasuda, Masanori Yoshinaga, Osamu Takeuchi
    • 学会等名
      The 50th Annual Meeting of the Japanese Society for Immunology
    • 関連する報告書
      2021 実績報告書
  • [学会発表] Manipulation of Regnase-1 mRNA stability alleviates inflammatory responses in diseased models2020

    • 著者名/発表者名
      Ka Man Tse, Xiaotong Cui, Takuya Uehata, Osamu Takeuchi.
    • 学会等名
      The 25th Annual Meeting of the RNA society
    • 関連する報告書
      2020 実績報告書
    • 国際学会
  • [学会発表] Manipulation of Regnase-1 mRNA stability alleviates inflammatory responses in diseased models2020

    • 著者名/発表者名
      Ka Man Tse, Xiaotong Cui, Takuya Uehata, Osamu Takeuchi.
    • 学会等名
      Conference of the Molecular Biology Society of Japan
    • 関連する報告書
      2020 実績報告書

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公開日: 2019-05-29   更新日: 2024-03-26  

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