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The Role of Brain Bile Acids in Neurological Diseases

Research Project

Project/Area Number 20K16497
Research Category

Grant-in-Aid for Early-Career Scientists

Allocation TypeMulti-year Fund
Review Section Basic Section 51030:Pathophysiologic neuroscience-related
Research InstitutionOsaka University

Principal Investigator

Sugiyama Shintaro  大阪大学, 大学院医学系研究科, 招へい教員 (50839636)

Project Period (FY) 2020-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywords肝-脳連関機構 / 脳梗塞 / Tight junction / Claudin3 / 胆汁酸 / Claudin5 / occludin / Tricellulin / Claudin 3 / 肝脳連関 / 上皮細胞間バリア
Outline of Research at the Start

肝性脳症の病態として肝障害で増加する血中アンモニアが脳の炎症を惹起すると考えられているが,血中アンモニア以外に脳機能を障害する未知の肝由来物質の存在が強く示唆され、肝-脳連関の制御機構に不明な点が多い。
肝臓上皮細胞間バリアの機能低下マウスにて胆汁酸などの肝由来物質が血中に漏出すると報告された。当該マウスの脳機能障害の可能性を検討し、脳炎症が惹起されることを見出した。
本研究では、肝臓上皮細胞間バリアの機能低下マウスを軸に肝-脳連関を伝達する未知の肝由来物質を同定し、メカニズムや神経病態への関与を明らかにする。肝性脳症等の原因不明の脳症や認知症に対する予防・診断・治療の開発につながると期待される。

Outline of Final Research Achievements

The purpose of this study was to identify novel transmitters of the liver-brain interface from the viewpoint of the epithelial cell barrier, and to elucidate the regulatory mechanism, physiological significance, and pathophysiological relationship of the liver-brain interface. Cldn3KO mice showed no increase in cerebral infarct volume. Cldn3, Cldn5 and occludin cooperated to regulate BBB in cerebral infarction. occludin KO mice showed decreased expression of Cldn5 and ZO-1, increased infarct volume and extravascular leakage after cerebral infarction, and induced BBB dysfunction from acute to chronic phase, angiogenesis was also suppressed, leading to neurological deterioration.

Academic Significance and Societal Importance of the Research Achievements

occludinは生体内で虚血性脳卒中後の急性期から慢性期にかけて重要な役割を果たすことが明らかになった。また、Cldn3KOマウス、Cldn2/3dKOマウス、occludin KOマウスを解析していく中で、Cldn3/2/5とMARVEL family のoccludin、Tricellulin及び裏打ち蛋白であるZO-1が、想定以上に、相互に強く連携しながらタイトジャンクションを形成していることが分かった。

Report

(5 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Research-status Report
  • 2021 Research-status Report
  • 2020 Research-status Report
  • Research Products

    (5 results)

All 2023 2022 2021

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

  • [Journal Article] The tight junction protein occludin modulates blood brain barrier integrity and neurological function after ischemic stroke in mice2023

    • Author(s)
      Sugiyama Shintaro、Sasaki Tsutomu、Tanaka Hiroo、Yan Haomin、Ikegami Takeshi、Kanki Hideaki、Nishiyama Kumiko、Beck Goichi、Gon Yasufumi、Okazaki Shuhei、Todo Kenichi、Tamura Atsushi、Tsukita Sachiko、Mochizuki Hideki
    • Journal Title

      Scientific Reports

      Volume: 13 Issue: 1 Pages: 2892-2892

    • DOI

      10.1038/s41598-023-29894-1

    • Related Report
      2023 Annual Research Report 2022 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] The effect of occludin deficiency in tight junction in blood brain barrier after stroke2022

    • Author(s)
      杉山慎太郎
    • Organizer
      第6回日本神経学会学術大会
    • Related Report
      2022 Research-status Report
  • [Presentation] The effect of occludin deficiency in tight junction in blood brain barrier after stroke2022

    • Author(s)
      杉山慎太郎
    • Organizer
      第63回日本神経学会学術大会
    • Related Report
      2021 Research-status Report
  • [Presentation] The role of occludin in Tight Junction in Blood Brain Barrier after stroke2021

    • Author(s)
      杉山慎太郎
    • Organizer
      第62回日本神経学会学術大会
    • Related Report
      2021 Research-status Report
  • [Presentation] The role of occludin in Tight Junction in Blood Brain Barrier after stroke2021

    • Author(s)
      Shintaro Sugiyama
    • Organizer
      第62回日本神経学会学術大会
    • Related Report
      2020 Research-status Report

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Published: 2020-04-28   Modified: 2025-01-30  

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