Immune regulation through vesicle trafficking regulator Arf family proteins
| Project/Area Number |
20K07555
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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 49070:Immunology-related
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| Research Institution | Kansai Medical University |
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Principal Investigator |
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| Project Period (FY) |
2020-04-01 – 2023-03-31
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| Project Status |
Completed (Fiscal Year 2022)
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| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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| Keywords | ADP-ribosylation factor / 自己免疫疾患 / 小胞輸送制御因子 / 免疫制御 / 小胞輸送 / mTORC1 / Arf1 / T細胞 / 細胞内シグナル伝達 |
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| Outline of Research at the Start |
ADP-ribosylation factor (Arf)は、小胞輸送を制御する低分子量Gタンパク質である。Arf阻害剤であるBrefeldin Aはin vitroでT細胞からのサイトカイン分泌阻害に用いられるが、生理的にArf経路が果たす役割は不明である。本研究では、免疫系特異的Arf欠損マウスの解析と、Arf経路の活性制御機構の同定を通じて、Arf経路が免疫系で果たす役割解明に取り組む。
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| Outline of Final Research Achievements |
ADP-ribosylation factor (Arf) family, consisting of six family members Arf1-Arf6, regulates vesicle trafficking. However, their physiological roles remain elusive. We therefore established mice lacking Arf1 and/or Arf6 in the immune cells, and investigated their physiological roles in the immune system. The lack of Arf1 in mast cells resulted in the defect in cell proliferation due to the impaired activation of mTORC1 while B cells lacking Arf1 failed to differentiate to germinal center B cells upon IL-4 stimulation. Although, unlike mast cells or B cells, loss of Arf1 alone had no impact in T cell function, we found that the lack of both Arf1 and Arf6 alleviates autoimmune diseases like colitis and experimental autoimmune encephalomyelitis which are mediated by Th17, whereas immune responses through Th1 or Th2 are seemingly normal. Our findings reveal an unexpected role for the Arf pathway as a therapeutic target in the autoimmune diseases.
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| Academic Significance and Societal Importance of the Research Achievements |
低分子量Gタンパク質であるADP-ribosylation factor (Arf)は、細胞の恒常性維持に必須な小胞輸送を制御することが示唆されているが、高次生命現象への関わりについては不明な点が多い。本研究を通じて、Arf１がマスト細胞の増殖過程ならびにB細胞の機能分化過程でそれぞれ必須の役割を担うことが明らかとなり、さらにArf1/Arf6の二重欠損によりTh17依存性の自己免疫病態のみがほぼ完全に抑制されることが明らかとなった。以上の結果は、Arf経路を標的とした治療法の開発が、これまで困難とされてきた自己免疫病態治療時の日和見感染症の問題の解決に繋がることを強く示唆する。
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Report
(4 results)
Research Products
(12 results)
