| Project/Area Number |
17K19574
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| Research Category |
Grant-in-Aid for Challenging Research (Exploratory)
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| Allocation Type | Multi-year Fund |
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| Research Field |
Pathology, Infection/Immunology, and related fields
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| Research Institution | Kansai Medical University |
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Principal Investigator |
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| Research Collaborator |
UEDA Yoshihiro
KAMIOKA Yuji
KONDO Naoyuki
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| Project Period (FY) |
2017-06-30 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2017: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
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| Keywords | 免疫学 / インテグリン / 一分子計測 / Rap1 / talin / kindlin3 / 免疫シナプス / ケモタキシス |
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| Outline of Final Research Achievements |
Lymphocyte trafficking is dynamically regulated by modulating adhesiveness of leukocyte integrin LFA-1 to ligand ICAM-1. Small GTPase Rap1 and integrin-associated molecules, talin1 and kindlin3 play essential roles during this process. By establishment of single-molecule imaging of Rap1, talin1, and kindlin-3, we found that talin1 binding kinetics with LFA-1 determined LFA-1 binding kinetics to ICAM-1. Rap1 was required for talin1 recruitment to LFA-1, but did not affect binding lifetime of talin1. Our study revealed that simultaneous bidirectional signals of inside-out and outside-in amplified Rap1 activation, which was a critical checkpoint for adhesion. Furthermore, kindlin3 was required for high-affinity binding to ICAM-1, but did not affect talin1 binding kinetics. Instead, Rho signaling regulate talin1 binding lifetime.
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| Academic Significance and Societal Importance of the Research Achievements |
リンパ球は生体内を移動しながら病原微生物などの異物の侵入を監視し、生体防御を行っている。白血球インテグリンはリンパ球の接着因子として活発な移動や異物の排除に重要な役割をはたしているが、その調節機構について不明な点がおおく、過剰なリンパ球が集積することが特徴である慢性炎症やアレルギーの薬剤開発が困難である。本研究は接着過程に重要な分子としてRap1、talin1, kindlin3が接着過程の重要なチェックポイントとして機能しているメカニズムを発見した。この発見によって白血球インテグリンの制御法が開発されることが期待される。
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