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
| Project/Area Number |
19J23450
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| Research Category |
Grant-in-Aid for JSPS Fellows
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| Allocation Type | Single-year Grants |
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| Section | 国内 |
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| Review Section |
Basic Section 49070:Immunology-related
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| Research Institution | Kyoto University |
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Principal Investigator |
Tse Ka Man Carman 京都大学, 医学研究科, 特別研究員(DC1)
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| Project Period (FY) |
2019-04-25 – 2022-03-31
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| Project Status |
Completed (Fiscal Year 2021)
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| Budget Amount *help |
¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 2021: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2020: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2019: ¥1,100,000 (Direct Cost: ¥1,100,000)
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| Keywords | Regnase-1 / mRNA stability / morpholino oligos / pulmonary diseases / autoimmune diseases / inflammation / antisense oligos |
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| Outline of Research at the Start |
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.
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| Outline of Annual Research Achievements |
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.
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| Research Progress Status |
令和3年度が最終年度であるため、記入しない。
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| Strategy for Future Research Activity |
令和3年度が最終年度であるため、記入しない。
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Report
(3 results)
Research Products
(8 results)
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[Journal Article] Enhancement of Regnase-1 expression with stem-loop-targeting antisense oligonucleotides alleviates inflammatory diseases2022
Author(s)
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
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Journal Title
Science Translational medicine
Volume: -
Related Report
Peer Reviewed
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[Presentation] Manipulation of Regnase-1 mRNA stability by morpholino-based antisense oligonucleotides alleviates inflammatory responses in pulmonary and autoimmune diseases2021
Author(s)
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
Organizer
The 22nd Annual Meeting of the RNA Society of Japan
Related Report
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[Presentation] Manipulating the expressions of Regnase-1 by stem-loop-targeting-antisense oligonucleotides to counteract inflammatory diseases2021
Author(s)
Ka Man Tse, Xiaotong Cui, Alexis Vandenbon, Takashi Mino, Takuya Uehata, Keioko Yasuda, Ayuko Sato, Tohru Tsujimura, Fabian Hia, Masanori Yoshinaga, Osamu Takeuchi
Organizer
The 44th Annual Meeting of the Molecular Biology Society of Japan
Related Report
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