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Regulation of membrane-anchored serine protease activities and its significance in epithelial pathophysiology

Research Project

Project/Area Number 18K06964
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 49010:Pathological biochemistry-related
Research InstitutionUniversity of Miyazaki

Principal Investigator

Kawaguchi Makiko  宮崎大学, 医学部, 助教 (90405598)

Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
KeywordsHAI-2 / matriptase / prostasin / EpCAM / SPINT2 / tufting enteropathyy / SPINT-2 / 膜結合型セリンプロテアーゼ / 腸管上皮
Outline of Final Research Achievements

In this study, we generated conditional Spint2 knockout mouse model based on the Cre recombinase and LoxP system. We found that spint2 knockout mouse showed severe epithelial damage in the whole intestinal tracts. The intestinal epithelium showed enhanced exfoliation, villous atrophy, enterocyte tufts and elongated crypts. Organoid crypt culture indicated that Spint2 ablation induced Epcam cleavage with decreased claudin-7 levels and resulted in organoid rupture. These organoid changes could be rescued by addition of serine protease inhibitors and matriptase selective inhibitor as well as by co-deletion of prostasin. These results indicate that HAI-2 is an essential cellular inhibitor for maintaining intestinal epithelium architecture.

Academic Significance and Societal Importance of the Research Achievements

本研究では、HAI-2コンディショナルKOマウスを作製し、HAI-2をコードするSPINT2遺伝子の変異が原因であるヒトの先天性ナトリウム下痢症と類似の表現型を呈することを明らかにした。また、HAI-2 KOマウスやマウスから樹立したHAI-2欠損オルガノイドは、この疾患の病態の解明や新たな治療法開発やスクリーニングのツールとしても有用であることを示した。

Report

(4 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Research-status Report
  • 2018 Research-status Report
  • Research Products

    (14 results)

All 2020 2019 2018 Other

All Int'l Joint Research (3 results) Journal Article (4 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 3 results,  Open Access: 3 results) Presentation (7 results) (of which Int'l Joint Research: 1 results)

  • [Int'l Joint Research] Washington University School of Medicine/National Institutes of Health(米国)

    • Related Report
      2020 Annual Research Report
  • [Int'l Joint Research] Washington University School of Medicine/National Institutes of Health(米国)

    • Related Report
      2019 Research-status Report
  • [Int'l Joint Research] Washington University School of Medicine(米国)

    • Related Report
      2018 Research-status Report
  • [Journal Article] Protease‐activated receptor‐2 accelerates intestinal tumor formation through activation of nuclear factor‐κB signaling and tumor angiogenesis in Apc Min/+ mice2020

    • Author(s)
      Kawaguchi Makiko、Yamamoto Koji、Kataoka Hiroaki、Izumi Aya、Yamashita Fumiki、Kiwaki Takumi、Nishida Takahiro、Camerer Eric、Fukushima Tsuyoshi
    • Journal Title

      Cancer Science

      Volume: 111 Issue: 4 Pages: 1193-1202

    • DOI

      10.1111/cas.14335

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Hepatocyte growth factor activator inhibitor-2 stabilizes Epcam and maintains epithelial organization in the mouse intestine2019

    • Author(s)
      Kawaguchi Makiko、Yamamoto Koji、Takeda Naoki、Fukushima Tsuyoshi、Yamashita Fumiki、Sato Katsuaki、Kitamura Kenichiro、Hippo Yoshitaka、Janetka James W.、Kataoka Hiroaki
    • Journal Title

      Communications Biology

      Volume: 2 Issue: 1 Pages: 11-11

    • DOI

      10.1038/s42003-018-0255-8

    • Related Report
      2019 Research-status Report 2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] 腸上皮の正常性維持に不可欠な細胞膜結合セリンプロテアーゼ制御機構2019

    • Author(s)
      山本晃士、川口真紀子、片岡寛章
    • Journal Title

      メディカルサイエンスダイジェスト

      Volume: 45 Pages: 622-625

    • Related Report
      2019 Research-status Report
  • [Journal Article] Aberrant methylation and silencing of the SPINT2 gene in high-grade gliomas.2018

    • Author(s)
      Fukushima T, Kawaguchi M, Yamamoto K, Yamashita F, Izumi A, Kaieda T, Takezaki Y, Itoh H, Takeshima H, Kataoka H
    • Journal Title

      Cancer Science

      Volume: 109 Issue: 9 Pages: 2970-2979

    • DOI

      10.1111/cas.13732

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] HAI-2 (SPINT2 ) はEpCAM/Claudin-7複合体を安定化し、腸上皮完全性を維持する2020

    • Author(s)
      川口真紀子、山本晃士、山下文希、福島剛、片岡寛章
    • Organizer
      第109回 日本病理学会総会
    • Related Report
      2020 Annual Research Report
  • [Presentation] HAI-1 deficient ApcMin+mice increased tumor formation through promoting tumor angiogenesis by PAR-2 signaling2019

    • Author(s)
      Kawaguchi M, Yamamoto K, FukushimaT, Kataoka H
    • Organizer
      第78回日本癌学会学術総会
    • Related Report
      2019 Research-status Report
  • [Presentation] Protease-activated receptor 2 promotes intestinal tumorigenesis through activation of NF-κB signaling and tumor angiogenesis in ApcMin/+mice2019

    • Author(s)
      Kawaguchi M, Yamamoto K, Kiwaki T, FukushimaT, Camerer E, Kataoka H
    • Organizer
      ASBMB Special Symposia Series; Serine Proteases in Pericellular Proteolysis and Signaling
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] HAI-2欠損マウスは腸管上皮の破綻を来たし早期に致死となる2019

    • Author(s)
      川口真紀子、山本晃士、山下文希、福島剛、片岡寛章
    • Organizer
      第24回 日本病態プロテアーゼ学会
    • Related Report
      2019 Research-status Report
  • [Presentation] HAI-1欠損によるDSS誘発大腸炎の感受性亢進と腸粘膜上皮の修復再生過程におけるPAR-2活性化の意義に関する研究2018

    • Author(s)
      川口 真紀子、山本 晃士、福島 剛、片岡 寛章
    • Organizer
      第41回日本分子生物学会年会
    • Related Report
      2018 Research-status Report
  • [Presentation] Concomitant deletion of PAR-2 abrogated the increased tumor formation in HAI-1 deficient ApcMin+ mice2018

    • Author(s)
      Kawaguchi M, Yamamoto K, Fukushima T, Kataoka H
    • Organizer
      第77回日本癌学会学術総会
    • Related Report
      2018 Research-status Report
  • [Presentation] HAIによる標的プロテアーゼ活性調節を介した上皮完全性の制御2018

    • Author(s)
      川口真紀子、山本晃士、田中弘之、福島剛、片岡 寛章
    • Organizer
      第23回 日本病態プロテアーゼ学会
    • Related Report
      2018 Research-status Report

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Published: 2018-04-23   Modified: 2022-01-27  

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