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Development of lymphocyte trafficking regulation using single-molecule measurement

Research Project

Project/Area Number 17K19574
Research Category

Grant-in-Aid for Challenging Research (Exploratory)

Allocation TypeMulti-year Fund
Research Field Pathology, Infection/Immunology, and related fields
Research InstitutionKansai Medical University

Principal Investigator

KINASHI Tatsuo  関西医科大学, 医学部, 教授 (30202039)

Research Collaborator UEDA Yoshihiro  
KAMIOKA Yuji  
KONDO Naoyuki  
Project Period (FY) 2017-06-30 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
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)
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
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.

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。

Report

(3 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Research-status Report
  • Research Products

    (11 results)

All 2018 2017

All Journal Article (3 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 2 results,  Open Access: 2 results) Presentation (8 results) (of which Int'l Joint Research: 2 results,  Invited: 2 results)

  • [Journal Article] Essential Role of Canonical NF-κB Activity in the Development of Stromal Cell Subsets in Secondary Lymphoid Organs2018

    • Author(s)
      Bogdanova Dana、Takeuchi Arata、Ozawa Madoka、Kanda Yasuhiro、Rahman M. Azizur、Ludewig Burkhard、Kinashi Tatsuo、Katakai Tomoya
    • Journal Title

      The Journal of Immunology

      Volume: 201 Issue: 12 Pages: 3580-3586

    • DOI

      10.4049/jimmunol.1800539

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] 自己免疫疾患のイメージング:自己寛容の成立と維持における細胞間相互作用の可視化2018

    • Author(s)
      植田祥啓、近藤直幸、木梨達雄
    • Journal Title

      臨床免疫・アレルギー科

      Volume: 69(4) Pages: 318-325

    • Related Report
      2018 Annual Research Report
  • [Journal Article] Mode of Tolerance Induction and Requirement for Aire Are Governed by the Cell Types That Express Self-Antigen and Those That Present Antigen.2017

    • Author(s)
      Mouri Y, Ueda Y, Yamano T, Matsumoto M, Tsuneyama K, Kinashi T, and Matsumoto M.
    • Journal Title

      The Journal of Immunology

      Volume: 199 Issue: 12 Pages: 3959-3971

    • DOI

      10.4049/jimmunol.1700892

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Rap1 signaling to NDR1 kinase regulate immune synapse formation and cell polarity.2018

    • Author(s)
      T Kinashi, N Kondo, Y Ueda, Y Kamioka
    • Organizer
      The 9th Xiamen Winter Symposium Nov.2-5 2018. Xiamen. China.
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Roles of Rap1 signaling in immunodeficiency and autoimmunity.2018

    • Author(s)
      T Kinashi
    • Organizer
      The 9th Asian Congress of Pediatric Infectious Diseases (ACPID) Dec 2nd. 2018.Fukuoka.
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] LFA-1を介したリンパ球細胞接着の一分子解析2018

    • Author(s)
      N Kondo, T Kinashi
    • Organizer
      分子生物学会, 2018 . Nov. 28-30 Yokohama
    • Related Report
      2018 Annual Research Report
  • [Presentation] W747 talin1 binding site in cytoplasmic domain of the integrin beta2 subunit is crucial for Tcell migration and activatio2018

    • Author(s)
      Y Ueda, N Kondo, Y Kamioka, T Kinashi
    • Organizer
      The 41th Annual Meeting of the Molecular Biology Society of Japan. Fukuoka
    • Related Report
      2018 Annual Research Report
  • [Presentation] Roles of Rap1, Talin-1 and Kindlin-3 in lymphocyte homing to peripheral and mucosal lymph nodes.2018

    • Author(s)
      Y Kamioka, Y Ueda, N Kondo, T Kinashi
    • Organizer
      The 41th Annual Meeting of the Molecular Biology Society of Japan. Fukuoka
    • Related Report
      2018 Annual Research Report
  • [Presentation] NDR1 acts as a molecular hub for the organization of immunological synapse2017

    • Author(s)
      Kondo N, Ueda Y, Kinashi T
    • Organizer
      The 46th Annual Meeting of the Japanese Society for Immunology
    • Related Report
      2017 Research-status Report
  • [Presentation] Roles of Rap1 and Kindlin-3 in lymphocyte homing to peripheral lymph nodes2017

    • Author(s)
      Kamioka Y, Ueda Y, Kondo N, Kinashi T
    • Organizer
      The 46th Annual Meeting of the Japanese Society for Immunology
    • Related Report
      2017 Research-status Report
  • [Presentation] Regulation of cell polarization by Rap1 via NDR/Rab8 axis upon chemokine stimulation2017

    • Author(s)
      Ueda Y, Kondo N, Kamioka Y, Kinashi T
    • Organizer
      The 46th Annual Meeting of the Japanese Society for Immunology
    • Related Report
      2017 Research-status Report

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Published: 2017-07-21   Modified: 2020-03-30  

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