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The pathogenesis of S1PR1 reduction via miR223-3p in Lupus T cells.

Research Project

Project/Area Number 20K17442
Research Category

Grant-in-Aid for Early-Career Scientists

Allocation TypeMulti-year Fund
Review Section Basic Section 54020:Connective tissue disease and allergy-related
Research InstitutionKawasaki Medical School

Principal Investigator

Sumie Asano  川崎医科大学, 医学部, 講師 (80816497)

Project Period (FY) 2020-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2021: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Fiscal Year 2020: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
KeywordsSLE / S1PR1 / microRNA / エピジェネティクス / miR223 / T細胞
Outline of Research at the Start

全身性ループスエリテマトーデス(SLE)の末梢血単核細胞ではスフィンゴシン1リン酸受容体1 (S1PR1)の発現低下が報告され、SIP-SIPR1シグナルの病態への関与が考えられている。我々はSLEモデルMRL/lprマウスの脾臓CD4+T細胞の網羅的エピゲノムライブラリーを作成し解析した。その結果、S1pr1の発現低下とともに、その遺伝子を標的とするmicro RNA 223-3pの発現亢進を見いだした。本研究では、miR223を介したS1PR1発現制御による病態関与を解明するため、miR223欠損MRL/lprマウスを作成し、疾患活動性の変化が得られるか表現型の差異を解析する。

Outline of Final Research Achievements

The micro RNAs (miRNAs) and their target mRNAs in CD4+ cells in systemic lupus erythematosus patients were suggested to play a key role in the pathogenesis. To identify new miRNAs related genes, we integrated mRNA and miRNA profiling data in CD4+ cells of MRL/lpr (MRL) and C57BL6/J (B6) mice. We identified downregulation of sphingosine-1-phosphate receptor 1 (S1pr1) and upregulation of Mir223 in MRL compared with B6 mice.We generated the B6-Mir223-/-Faslpr/lpr mice and the lupus phenotypes were analyzed. In B6-Mir223-/-Faslpr/lpr mice, S1PR1+CD4+ T cells in the spleen was significantly increased compared with that in B6-Mir223+/+Faslpr/lpr mice by flow cytometry. B6-Mir223-/-Faslpr/lpr mice demonstrated the elevation of glomerular and renal vascular scores associated with enhanced intraglomerular infiltration of S1PR1+CD4+ T cells.
The deletion of Mir223 exacerbated the lupus phenotypes.

Academic Significance and Societal Importance of the Research Achievements

SLEの新規治療薬を見いだすため、その発症機序に着目し、後天的遺伝子制御に関与するmiRNAとそのターゲットmRNAを探索した。SLEのCD4陽性T細胞で、miR223の発現を代償的に亢進させることにより標的遺伝子であるスフィンゴシン1-リン酸受容体 (S1pr1)の発現を低下させ、脾臓CD4陽性T細胞の増加とその糸球体への浸潤を抑制し、尿蛋白および糸球体スコアの増悪を抑制していることを確認した。ループス腎炎においてMir223の発現亢進は代償的にループス腎炎悪化を抑制する役割を果たすことが示唆された。Mir223 がSLEの病態解明や新規治療ターゲットになりうることが期待される。

Report

(3 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • Research Products

    (7 results)

All 2022 2021 2020

All Journal Article (1 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 1 results,  Open Access: 1 results) Presentation (6 results) (of which Int'l Joint Research: 2 results)

  • [Journal Article] Deletion of Mir223 Exacerbates Lupus Nephritis by Targeting S1pr1 in Faslpr/lpr Mice2021

    • Author(s)
      Hiramatsu-Asano Sumie、Sunahori-Watanabe Katsue、Zeggar Sonia、Katsuyama Eri、Mukai Tomoyuki、Morita Yoshitaka、Wada Jun
    • Journal Title

      Frontiers in Immunology

      Volume: 11 Pages: 616141-616141

    • DOI

      10.3389/fimmu.2020.616141

    • Related Report
      2021 Annual Research Report 2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Deletion of Mir223 exacerbates lupus nephritis by targeting S1pr1 in Faslpr/lpr mice2022

    • Author(s)
      Sumie Asano
    • Organizer
      第66回日本リウマチ学会総会・学術集会
    • Related Report
      2021 Annual Research Report
  • [Presentation] Deletion of Mir223 Exacerbates Lupus Nephritis by Targeting S1pr1 in Fas lpr/lpr Mice2020

    • Author(s)
      Sumie Asano, Tomoyuki Mukai , Yoshitaka Morita, Jun Wada
    • Organizer
      第43回日本分子生物学会年会
    • Related Report
      2020 Research-status Report
  • [Presentation] Deletion of miR-223 exacerbates lupus nephritis by targeting S1pr1 in Faslpr/lpr mice2020

    • Author(s)
      Sumie Hiramatsu-Asano, Tomoyuki Mukai, Yoshitaka Morita, Jun Wada
    • Organizer
      2020 American College of Rheumatology(ACR) Annual Meeting
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research
  • [Presentation] Deletion of miR-223 exacerbates lupus nephritis by targeting S1pr1 in Faslpr/lpr mice2020

    • Author(s)
      Sumie Hiramatsu-Asano, Tomoyuki Mukai, Yoshitaka Morita, Jun Wada
    • Organizer
      The 22nd Asia Pacific League of Associations for Rheumatology (APLAR 2020)
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research
  • [Presentation] miR223を介したS1PR1発現制御によるSLE病態への関与2020

    • Author(s)
      浅野澄恵, 向井知之, 守田吉孝, 和田淳
    • Organizer
      第48回日本臨床免疫学会総会
    • Related Report
      2020 Research-status Report
  • [Presentation] The reduction of S1pr1 by miR223-3p and their roles in the pathogenesis of SLE2020

    • Author(s)
      Sumie Asano, Katsue Watanabe, Jun Wada
    • Organizer
      第64回日本リウマチ学会総会・学術集会
    • Related Report
      2020 Research-status Report

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Published: 2020-04-28   Modified: 2023-01-30  

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