• Search Research Projects
  • Search Researchers
  • How to Use
  1. Back to previous page

Mechanisms of the development of colitis in T cell-specific Rap1-deficient mice

Research Project

Project/Area Number 19K07612
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 49070:Immunology-related
Research InstitutionThe University of Tokyo (2022)
Kitasato University (2019-2021)

Principal Investigator

Koko Katagiri  東京大学, 大学院総合文化研究科, 特任研究員 (00322157)

Project Period (FY) 2019-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2022: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2021: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2020: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Keywordscolitis / Rap1 / TCR / regulatory T cells / microRNA / lymphopenia / proliferation / IBD / T cells / Treg / Actin foci / alpha4beta7 / microbiota / miRNA / Th17 / helper T cells / integrin
Outline of Research at the Start

独自に開発した大腸炎・がん自然発症モデルマウスを用いて、1)T細胞におけるRap1欠損が大腸炎発症につながる新規メカニズムを明らかにする。2)活性型alpha4beta7を特異的に認識するモノクローナル抗体を作成し、その大腸炎治療効果を検討する。また、Rap1がalpha4beta7の構造変化を抑制する分子機講を解明する。3)大腸炎から大腸がんへの進行に関与する因子をプロテオミクス解析及びメタボローム解析により特定する。さらに、4)モデルマウスを用いて明らかになった大腸炎・がん原因分子に関して、ヒトIBD患者T細胞を用いた解析を行い、IBDの原因因子の可能性を検討する。

Outline of Final Research Achievements

T-cell-specific Rap1 deletion causes spontaneous colitis in mice. In the large intestinal lamina propria of these mice, RORgammat+Treg cells were scarcely induced by 4 weeks of age. The expression of CTLA-4 on Rap1-deficient Treg cells was impaired. Rap1-deficient T cells exhibited the defective nuclear translocation of NFAT and actin foci in response to TCR engagement, which is critical for Treg-mediated control of colitogenic Th17 responses. Integrin activation is associated with conformational regulation. We generated two kinds of mAbs that recognized Mn2+-dependent epitopes of β7. Using these mAbs, we found that the conversion of Rap1-GDP to GTP exerts two distinct effects stepwise on the conformation of α4β7. Colitogenic CD4+ T cells demonstrated the increased expression of miR-150. MiR-150 silencing completely inhibited the expansion of pathogenic Th17 cells and the development of colitis in Rap1KO mice. MiR-150 is a potential therapeutic target of IBD.

Academic Significance and Societal Importance of the Research Achievements

Rap1シグナルがTCR distal signalに重要な役割を果たすこと及びRap1-GDPがインテグリンalpah4beta7の活性型構造を抑制していることを初めて明らかにした。また、miR-150の阻害は、リンパ節におけるLIP(lymphopenia-induced proliferation)を抑制し、大腸炎の発症を抑制することから、miR-150阻害剤はIBDなどの自己免疫疾患治療薬として有望であることを見出した。

Report

(5 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Research-status Report
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (15 results)

All 2023 2022 2021 2020 2019

All Journal Article (10 results) (of which Int'l Joint Research: 4 results,  Peer Reviewed: 10 results,  Open Access: 9 results) Presentation (3 results) Patent(Industrial Property Rights) (2 results)

  • [Journal Article] Deletion of miR-150 Prevents Spontaneous T Cell Proliferation and the Development of Colitis2023

    • Author(s)
      Ishihara S*, Sato M*, Miyazaki H, Saito H, Sato T, Fujikado N, Sawai S, Kotani A, Katagiri K.
    • Journal Title

      Gastro Hep Advances

      Volume: 2 Issue: 4 Pages: 487-496

    • DOI

      10.1016/j.gastha.2023.01.021

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Rap1 prevents colitogenic Th17 cell expansion and facilitates Treg cell differentiation and distal TCR signaling2022

    • Author(s)
      Ishihara Sayaka、Sato Tsuyoshi、Fujikado Noriyuki、Miyazaki Haruka、Yoshimoto Takayuki、Yamamoto Hiromitsu、Fukuda Shinji、Katagiri Koko
    • Journal Title

      Communications Biology

      Volume: 5 Issue: 1 Pages: 206-223

    • DOI

      10.1038/s42003-022-03129-x

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Rap1 is essential for B-cell locomotion, germinal center formation and normal B-1a cell population.2021

    • Author(s)
      Ishihara S, Sato T, Sugioka R, Miwa R, Saito H, Sato R, Fukuyama H, Nakajima A, Sawai S, Kotani A, Katagiri K.
    • Journal Title

      Front Immunol.

      Volume: 12 Pages: 624419-624419

    • DOI

      10.3389/fimmu.2021.624419

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Comparative mapping of crawling-cell morphodynamics in deep learning-based feature space2021

    • Author(s)
      Imoto, D., Saito, N., Nakajima, A., Honda, G., Ishida, M., Sugita, T., Ishihara, S., Katagiri, K., Okimura, C., Iwadate, Y. and Sawai, S.
    • Journal Title

      PLoS Computational Biology

      Volume: 17(8) Issue: 8 Pages: 1009237-1009267

    • DOI

      10.1371/journal.pcbi.1009237

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Phosphatidic acid-dependent localization and basal de-phosphorylation of RA-GEFs regulate lymphocyte trafficking2020

    • Author(s)
      Ishihara Sayaka、Sato Tsuyoshi、Du Guangwei、Guardavaccaro Daniele、Nakajima Akihiko、Sawai Satoshi、Kataoka Tohru、Katagiri Koko
    • Journal Title

      BMC Biology

      Volume: 18 Issue: 1 Pages: 75-75

    • DOI

      10.1186/s12915-020-00809-0

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Overexpression of miR-669m inhibits erythroblast differentiation2020

    • Author(s)
      Kotaki R., et.al. Kawashima M, Yamaguchi A, Suzuki N, Koyama-Nasu R, Ogiya D, Okuyama K, Yamamoto Y, Takamatsu M, Kurosaki N, Ando K, Murata A, Ohtsuka M, Nakagawa S, Katagiri K, Kotani A.
    • Journal Title

      Sci Rep.

      Volume: 10 Issue: 1 Pages: 13554-13554

    • DOI

      10.1038/s41598-020-70442-y

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Dissection of α 4 β 7 integrin regulation by Rap1 using novel conformation-specific monoclonal anti-β 7 antibodies.2020

    • Author(s)
      Sato T, Ishihara S, Marui R, Takagi J, Katagiri K
    • Journal Title

      Sci Rep.

      Volume: 10 Issue: 1 Pages: 13221-13221

    • DOI

      10.1038/s41598-020-70111-0

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Phosphatidic acid regulates subcellular distribution of RA-GEFs critical for chemokine-dependent migration2020

    • Author(s)
      Momoi Yasuyuki、Nishikimi Akihiko、Du Guangwei、Kataoka Tohru、Katagiri Koko
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 524 Issue: 2 Pages: 325-331

    • DOI

      10.1016/j.bbrc.2020.01.080

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] PD-L1/L2 protein levels rapidly increase on monocytes via trogocytosis from tumor cells in classical Hodgkin lymphoma2020

    • Author(s)
      Kawashima M, Carreras J, Higuchi H, Kotaki R, Hoshina T, Okuyama K, Suzuki N, Kakizaki M, Miyatake Y, Ando K, Nakayama M, Umezu S, Horie R, Higuchi Y, Katagiri K, Goyama S, Kitamura T, Chamoto K, Yano S,Nakamura N, and A Kotani
    • Journal Title

      Leukemia

      Volume: - Issue: 9 Pages: 2405-2417

    • DOI

      10.1038/s41375-020-0737-9

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] HIV Reactivation in Latently Infected Cells With Virological Synapse-Like Cell Contact2020

    • Author(s)
      Okutomi T, Minakawa S, Hirota R, Katagiri K and Morikawa Y.
    • Journal Title

      Viruese

      Volume: - Issue: 4 Pages: 417-417

    • DOI

      10.3390/v12040417

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] Role of Rap1 in preventing colitogenic Th17 cell expansion and in Treg cell differentiation.2021

    • Author(s)
      Haruka Miyazaki, Sayaka Ishihara, Tsuyoshi Sato, Noriyuki Fujikado, Takayuki Yoshimoto, Shinji Fukuda, Koko Katagiri
    • Organizer
      日本免疫学会
    • Related Report
      2021 Research-status Report
  • [Presentation] Regulation of TCR signaling by Rap12019

    • Author(s)
      Kageyama T, Mamiyoda M, Ishihara S, and Katagiri K.
    • Organizer
      第48回日本免疫学会
    • Related Report
      2019 Research-status Report
  • [Presentation] IL-17 plays critical role in the development of spontaneous colitis of T cell-specific Rap1-knockout mice.2019

    • Author(s)
      Hashimoto H, Yoshimoto T, Kodera Y, Ishihara S, and Katagiri K.
    • Organizer
      第48回日本免疫学会
    • Related Report
      2019 Research-status Report
  • [Patent(Industrial Property Rights)] 炎症性腸疾患の予防又は治療剤2022

    • Inventor(s)
      片桐 晃子
    • Industrial Property Rights Holder
      片桐 晃子
    • Industrial Property Rights Type
      特許
    • Filing Date
      2022
    • Related Report
      2022 Annual Research Report
  • [Patent(Industrial Property Rights)] 炎症性腸疾患の予防又は治療剤2022

    • Inventor(s)
      片桐 晃子
    • Industrial Property Rights Holder
      片桐 晃子
    • Industrial Property Rights Type
      特許
    • Filing Date
      2022
    • Related Report
      2021 Research-status Report

URL: 

Published: 2019-04-18   Modified: 2024-01-30  

Information User Guide FAQ News Terms of Use Attribution of KAKENHI

Powered by NII kakenhi