Targeting synovial fibroblasts for the treatment of rheumatoid arthritis by CDK4/6 inhibition
Project/Area Number |
19K17884
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Research Category |
Grant-in-Aid for Early-Career Scientists
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Allocation Type | Multi-year Fund |
Review Section |
Basic Section 54020:Connective tissue disease and allergy-related
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Research Institution | Tokyo Medical and Dental University |
Principal Investigator |
Hosoya Tadashi 東京医科歯科大学, 大学院医歯学総合研究科, 講師 (60737104)
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Project Period (FY) |
2019-04-01 – 2021-03-31
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Project Status |
Completed (Fiscal Year 2020)
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Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2020: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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Keywords | 滑膜線維芽細胞 / CDK4/6 / 関節リウマチ / AP-1 / RNA-Seq |
Outline of Research at the Start |
本研究では、CDK4/6阻害が細胞増殖抑制作用、抗炎症作用に細胞種特異性をもたらすメカニズムを解析する。これまでの解析で、CDKIが抑制するサイトカイン群はプロモーター領域に転写因子AP-1を共有していた。細胞種間AP-1構成因子の制御メカニズムの違いがもたらす生理学的意義を以下の3つの仮説に基づいて検証し、候補分子の同定後はノックダウンによる表現型の変化をCHIPシークエンスを行いpathway解析する。
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Outline of Final Research Achievements |
We identified that a small part of inflammatory gene transcription, including was impaired in the absence of CDK4/6 activity by attenuating the AP-1 transcriptional activity. Since the target AP-1 component was protected from ubiquitine-proteasome dependent degradation when CDK4/6 were active, the inhibition of CDK4/6 resulted in the down-regulation of the baseline expression and its induction in RASFs. We hypothesized that the inhibition of CDK4/6 attenuated cytokine responsiveness in the RASFs by enhancing degradation. Furthermore, we confirmed that the inhibition of CDK4/6 resulted in selective gene suppression sharing specific AP-1 motifs in their promoter by the RNA-seq analysis.
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Academic Significance and Societal Importance of the Research Achievements |
関節リウマチ(RA)は代表的な炎症性疾患であり、炎症を標的にした治療は患者の予後を大きく改善するに至ったが、関節炎を完全にコントロールできる患者は一部で感染症などの合併症が問題になる。 滑膜線維芽細胞を標的としたいくつかの治療戦略は現在のRA治療を補補完と期待され、臨床応用が現在試みられているが、本研究で注目したCDK4/6はリウマチ関節の滑膜線維芽細胞の特徴である過剰な細胞増殖とサイトカイン産生という両面を抑制する、理想的な治療になりうる。
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Report
(4 results)
Research Products
(13 results)
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[Journal Article] Chondroprotective effects of CDK4/6 inhibition via enhanced ubiquitin-dependent degradation of JUN in synovial fibroblasts.2021
Author(s)
Hosoya T, Saito T, Baba H, Tanaka N, Noda S, Komiya Y, Tagawa Y, Yamamoto A, Mizoguchi F, Kawahata K, Miyasaka N, Kohsaka H, Yasuda S
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Journal Title
Rheumatology (Oxford).
Volume: 61
Issue: 8
Pages: 3427-3438
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Identification of Compounds With Glucocorticoid Sparing Effects on Suppression of Chemokine and Cytokine Production by Rheumatoid Arthritis Fibroblast-Like Synoviocytes2020
Author(s)
Tadashi Hosoya, Nikunj M Shukla, Yuya Fujita, Shiyin Yao, Fitzgerald S Lao, Hiroyuki Baba, Shinsuke Yasuda, Howard B Cottam, Dennis A Carson, Tomoko Hayashi, Maripat Corr
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Journal Title
Frontiers in Pharmacology
Volume: -
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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