研究課題/領域番号 |
19J23450
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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)
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研究期間 (年度) |
2019-04-25 – 2022-03-31
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キーワード | Regnase-1 / autoimmune diseases / mRNA stability |
研究実績の概要 |
The landmark discovery that IL-17 producing CD4 T cells were the major drivers of autoimmune diseases positioned IL-17-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 the activation and differentiation of CD4 T cells, and the expression of inflammatory cytokines upon TLR stimulation in macrophages, Regnase-1 was shown to have an important role in the suppression of autoimmunity in mice. However, the exact role of Regnase-1 plays in the development of autoimmune diseases was not known. In this study, we found that Regnase-1 is actively down-regulated in several autoimmune murine models and interfering with the structured RNA motifs of Regnase-1 can be a new strategy to influence autoimmune and inflammatory responses in a therapeutic setting.
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現在までの達成度 (区分) |
現在までの達成度 (区分)
2: おおむね順調に進展している
理由
We have evaluated the role of Regnase-1 in the development of autoimmune diseases from several different view points: (1) using the spontaneous EAE model (2D2 TCR transgenic mouse), we found that the deficiency of Reg1 in CD4+ T cells renders mice to develop EAE more often than WT counterparts, suggesting down-regulation of Regnase-1 can exacerbate the progression of EAE; (2) it was also found that Reg1 expression (mRNA and protein) is significantly reduced in the PBMCs in patients with autoimmune diseases, compared to healthy controls; (3) we found that administrating antisense oligonucleotides targeting Regnase-1 stem-loop structures in the brain of EAE mice postponed and relived the EAE symptoms and allowed better weight recovery. This was associated with a significant reduction in spinal cord/brain-infiltrating immune cells.
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今後の研究の推進方策 |
To investigate the potential mechanism by which Regnase-1 is degraded in the PBMCs (especially CD4 T cells) in patients with autoimmune diseases, different protein degradation inhibitors and antibodies will be screened in vitro, and RNA sequencing will be performed. To better understand the function of Regnase-1 in certain cell(s) during EAE development, flow cytometry will be performed to analyze the Regnase-1 expression in various kinds of cell in the CNS after intracranial administration of PBS or antisense oligonucleotides, taking advantage of the flag-tag Regnase-1 knock-in mouse. In addition, in order to reveal the mechanistic details of how antisense oligonucleotides ameliorates the EAE symptoms, we will perform single cell RNA sequencing to identify the set(s) of gene and pathway are altered when Regnase-1 is stabilized.
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