| 研究課題/領域番号 |
19J21942
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| 研究種目 |
特別研究員奨励費
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| 配分区分 | 補助金 |
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| 応募区分 | 国内 |
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| 審査区分 |
小区分49030:実験病理学関連
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| 研究機関 | 東京大学 |
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研究代表者 |
顔 明露 東京大学, 大学院医学系研究科, 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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| 研究課題ステータス |
完了 (2021年度)
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| 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)
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| キーワード | Rheumatoid arthritis / RANKL / tissue destruction / Bone destruction / Synovial fibroblasts / osteoclastogenesis |
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| 研究開始時の研究の概要 |
Rheumatoid arthritis is a chronic inflammatory disease leading to the joint destruction and disability. The novel therapeutic strategy that targeting the osteoclastogenetic cell subset would possibilily prevent bone destruction and repair the damaged bone, thus restore the joint homeostasis.
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| 研究実績の概要 |
Rheumatoid arthritis (RA) is one of the most common autoimmune diseases characterized by inflammation and joint destruction. Joint destruction in RA patients is usually irreversible, which often leads to the permanent loss of joint function and subsequent disability. In this study we aimed to investigate the molecular mechanisms underlying the arthritic joint damage. We performed scRNA-seq analysis of synovial cells of the inflamed joints of arthritis. Unsupervised clustering of synovial cells revealed several cell types, of which the fibroblasts specifically highly express the joint destructive genes such as TNFSF11 and MMPs (encoding RANKL and MMPs, respectively). Focusing on the fibroblast population, we found these destructive genes are specifically enriched in one fibroblast cluster, we subsequently named the fibroblast population as "tissue-destructive fibroblast". Chromatin analysis of the arthritic fibroblasts further identified the distal regulatory elements located upstream of the RANKL and MMPs gene loci. A small molecule inhibitor of active enhancers called bromodomain protein 4 (BRD4) substantially inhibited the expression of RANKL and MMPs. Thus, the epigenetic mechanisms inducing the abnormal RANKL and MMPs contribute to RA joint damage.
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| 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。
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| 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。
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