| Project/Area Number |
18K08380
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 54020:Connective tissue disease and allergy-related
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| Research Institution | Tokyo Medical and Dental University (2019-2020)
Hokkaido University (2018) |
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Principal Investigator |
Yasuda Shinsuke 東京医科歯科大学, 大学院医歯学総合研究科, 教授 (00374231)
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
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| Keywords | 関節リウマチ / 滑膜線維芽細胞 / RasGRP / 全身性エリテマトーデス / 細胞内シグナル / RasGRP1 / RasGRP4 |
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| Outline of Final Research Achievements |
In the joints of patients with rheumatoid arthritis (RA), abnormal growth of synovial fibroblasts and secretion of cytokines as well as proteases contribute to cartilage and bone destruction. Although treatment strategy in RA has been dramatically improved, still half of the patients achieve remission and unwanted infections are induced by immunosuppression. In the current research program, we aimed to search for novel treatment strategy targeting RA-synovial fibroblasts. We found abnormally high expression of RasGRP2 and RasGRP4 in synovial fibroblasts derived from some of RA patients, which are signal molecules restrictively expressed in platelets and bone-marrow derived cells in normal state, respectively. RasGRP2 and 4 coordinately induce cell migration, proliferation and cytokine/protease production. Moreover, inhibition of RasGRP2/4 ameliorated arthritis and joint destruction in animal arthritis model.
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| Academic Significance and Societal Importance of the Research Achievements |
RasGRPは1-4のファミリー分子からなるシグナル分子で、それぞれ血球の系統に比較的限局して発現する。関節リウマチの治療は飛躍的に進歩したが、寛解に至る患者は半数に過ぎず、免疫抑制に伴う感染症も避けがたい。本研究課題では、関節リウマチの本態とも言える増殖した滑膜においてRasGRP2,4が異所性発現すること、これらが共同して滑膜の病的な働きを促進すること、また関節炎動物モデルを用いてこれらが治療標的になり得ることを示した。これらは、RasGRP標的薬をリウマチの本態である滑膜にデリバリーする治療の開発に繋がる知見であるといえる。
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