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Development of a novel therapeutic approach for fibropolycystic liver disease focusing on cellular senescence of cholangiocytes

Research Project

Project/Area Number 19K07458
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 49020:Human pathology-related
Research InstitutionKanazawa University

Principal Investigator

Sato Yasunori  金沢大学, 医学系, 准教授 (30324073)

Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Keywords人体病理学 / 肝臓 / 胆管細胞 / 肝線維嚢胞性疾患 / 病理
Outline of Research at the Start

本研究は,代表的な肝線維性多嚢胞性疾患であるCaroli病と先天性肝線維症の新たな治療法の開発を目的とする.Caroli病と先天性肝線維症の動物モデルとして確立されたpolycystic kidney(PCK)ラットを用い,特に胆管細胞の細胞老化に着目して,肝内胆管拡張と肝線維化を同時に抑制しうる効率的な方策を見出すことを目指す.

Outline of Final Research Achievements

This study revealed that activation of the Notch-Hes1 signaling pathway was critically involved in biliary cystogenesis of Caroli disease with congenital hepatic fibrosis (CHF) as well as the polycystic kidney (PCK) rat, an animal model of Caroli disease with CHF. In vitro experiments using PCK cholangiocytes showed that administration of Notch inhibitor (FLI-06) significantly inhibited cell proliferative activity. The inhibition was accompanied by the induction of apoptosis, but not cellular senescence. These results indicate that inhibition of the Notch signaling represents a potential target of therapy for Caroli disease with congenital hepatic fibrosis.

Academic Significance and Societal Importance of the Research Achievements

Caroli病は肝内胆管の進行性の拡張を来す先天性疾患で,多くの症例は先天性肝線維症を合併する。Caroli病 + 先天性肝線維症の患者予後を規定する臨床因子として,胆管拡張に起因する胆管炎と先天性肝線維症による門脈圧亢進症が重要であるが,現在の治療は対症療法が主体で重症例には肝移植が行われている。本研究は胆管細胞におけるNotchシグナル伝達系を阻害することで,Caroli病の胆管拡張を抑制しうることを示した。一連の研究成果は新たな治療法の開発に繋がる可能性を有している。

Report

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

    (3 results)

All 2021

All Journal Article (2 results) (of which Peer Reviewed: 2 results,  Open Access: 1 results) Presentation (1 results)

  • [Journal Article] Notch‐Hes1 signaling activation in Caroli disease and polycystic liver disease2021

    • Author(s)
      Takahashi Kenta、Sato Yasunori、Yamamura Minako、Nakada Satoko、Tamano Yuko、Sasaki Motoko、Harada Kenichi
    • Journal Title

      Pathology International

      Volume: 71 Issue: 8 Pages: 521-529

    • DOI

      10.1111/pin.13130

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Metformin slows liver cyst formation and fibrosis in experimental model of polycystic liver disease2021

    • Author(s)
      Sato Yoichi、Qiu Jiahe、Hirose Takuo、Miura Takahiro、Sato Yasunori、Kohzuki Masahiro、Ito Osamu
    • Journal Title

      American Journal of Physiology-Gastrointestinal and Liver Physiology

      Volume: 320 Issue: 4 Pages: G464-G473

    • DOI

      10.1152/ajpgi.00120.2020

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] Caroli病と多発性肝嚢胞におけるNotch-Hes1シグナルの活性化2021

    • Author(s)
      髙橋健太,佐藤保則,山村美奈子,中田聡子,玉野裕子,原田憲一
    • Organizer
      第53回日本臨床分子形態学会総会・学術集会
    • Related Report
      2021 Annual Research Report

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Published: 2019-04-18   Modified: 2023-01-30  

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