Development of novel therapeutic strategies targeting NR4A2 in Sjogren's syndrome.
| Project/Area Number |
18K16137
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 54020:Connective tissue disease and allergy-related
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| Research Institution | University of Tsukuba |
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Principal Investigator |
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| Project Period (FY) |
2018-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2019: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
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| Keywords | シェーグレン症候群 / T細胞 / RORγt |
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| Outline of Final Research Achievements |
Objective: To clarify the effectiveness of A213, a RORgt antagonist, and the role of Nr4a2 in the mechanism of action in T-cell-specific RORgt-transgenic mice under human CD2 promoter (RORgt-Tg mice) with Sjogren's syndrome (SS)-like sialadenitis. Methods: Six-week-old RORgt-Tg mice were administered orally of A213 or phosphate-buffered saline every three days for two weeks, and the saliva volume and the collected tissues were analyzed. Results: A213 significantly increased saliva volume and reduced mononuclear cell infiltration in salivary glands and whole population or both Foxp3+ and Foxp3- cells of CD4+CD25+ cells in cervical lymph nodes (CLNs). There was no difference of Nr4a2 in splenic CD4+ T cells between the two groups. A213 reduced CD4+CD8+ cells in thymus. Conclusion: A213 could improve SS-like sialadenitis via suppression of CD4+CD25+ cells in CLNs. Further investigations are needed to elucidate the in vivo role of Nr4a2 especially in the aspect of the central tolerance.
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| Academic Significance and Societal Importance of the Research Achievements |
我々が開発したSSモデルマウスであるRORγt-Tgを用い、その治療実験により、RORγtの唾液腺炎発症における役割と、唾液腺炎の制御において治療標的となる病因的な細胞集団を明らかにした。また、本研究代表者は、先行研究においてSS患者の病態とNr4a2の関連を初めて報告しており、本モデルマウスを用い、in vivoにおけるNr4a2の病因的役割を明らかにすることを目的とした。本研究では、本モデルマウスのin vivoにおける病態解析を深化させることができたことから、この成果をもとに、Nr4a2を基軸としたSSの病態解明を継続することで、SSの新規治療開発を目指すことができると考える。
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Report
(3 results)
Research Products
(10 results)
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[Presentation] RORγt antagonist suppressed spontaneous sialadenitis in RORγt transgenic mice via inhibition of IL-17 production with increase of regulatory T cells.2018
Author(s)
Ono Y, Tsuboi H, Moriyama M, Asashima H, Kudo H, Takahashi H, Kondo Y, Matsumoto I, Nakamura S, Sumida T.
Organizer
The 14th International Symposium on Sjogren’s syndrome (Washington DC, USA)
Related Report
Int'l Joint Research
