| 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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