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Targeting Blood-Brain Barrier Protection to Develop Therapeutic Agents for Central Nervous System Diseases

Research Project

Project/Area Number 18K08973
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 56010:Neurosurgery-related
Research InstitutionNagasaki University

Principal Investigator

Izumo Tsuyoshi  長崎大学, 医歯薬学総合研究科(医学系), 准教授 (40343347)

Co-Investigator(Kenkyū-buntansha) 諸藤 陽一  長崎大学, 病院(医学系), 講師 (40437869)
藤本 隆史  長崎大学, 医歯薬学総合研究科(医学系), 客員研究員 (00712085)
Project Period (FY) 2018-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2020: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Keywords血液脳関門 / 脳梗塞 / 転移性脳腫瘍 / ドラッグリポジショニング / blood brain barrier / drug repositioning / fasudil hydorochloride / metastatic brain tumor / pericyte / metastasis / brain / tight junction protein / 3次元モデル / 中枢神経疾患 / 治療薬
Outline of Final Research Achievements

In this study, we used multiple co-cultured in vitro BBB models combining all cells of the blood-brain barrier (BBB), such as brain capillary endothelial cells, pericytes, and astrocytes, to create pathological models (ischemia, inflammation, cancer brain metastasis), and developed a perfusion-type 3D BBB model to investigate cell-cell interactions in the neurovascular unit. We also developed a perfused 3D BBB model and investigated cell-cell interactions in the neurovascular unit. In addition, we investigated the effects of drugs currently used in clinical practice on the BBB and their mechanisms of action. By elucidating these mechanisms, we have been conducting research with the aim of developing therapeutic agents for central nervous system diseases and, ultimately, a completely new concept of drug discovery, "BBB-protective drugs".

Academic Significance and Societal Importance of the Research Achievements

BBBの機能構築には基本構成単位である脳毛細血管内皮細胞、ペリサイト、及びアストロサイト間のクロストークが不可欠であり、このクロストーク不全が中枢神経疾患の発生に繋がることが明らかとなりつつある。本研究では、転移性脳腫瘍・造影剤脳症そして脳血管攣縮治療薬のBBBにおける作用機序とクロストークについて明らかにしてきた。BBB機能の制御またそのメカニズムを解明することにより、中枢神経疾患全般における、更なる病態解明、治療薬の発見と開発につながると考える。

Report

(6 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Research-status Report
  • 2020 Research-status Report
  • 2019 Research-status Report
  • 2018 Research-status Report
  • Research Products

    (21 results)

All 2022 2021 2020 2019 Other

All Int'l Joint Research (10 results) Journal Article (4 results) (of which Int'l Joint Research: 4 results,  Peer Reviewed: 4 results,  Open Access: 3 results) Presentation (6 results) (of which Int'l Joint Research: 5 results,  Invited: 1 results) Funded Workshop (1 results)

  • [Int'l Joint Research] Institute of Biophysics/Biological Research Centre/Hungarian Academy of Science(ハンガリー)

    • Related Report
      2022 Annual Research Report
  • [Int'l Joint Research] Division of Gerontology & Geriatric Med./Department of Internal Medicine/University of Washington(米国)

    • Related Report
      2022 Annual Research Report
  • [Int'l Joint Research] Institute of Biophysics/Biological Research Centre/Hungarian Academy of Science(ハンガリー)

    • Related Report
      2021 Research-status Report
  • [Int'l Joint Research] Division of Gerontology & Geriatric Med./Department of Internal Medicine/University of Washington(米国)

    • Related Report
      2021 Research-status Report
  • [Int'l Joint Research] Institute of Biophysics/Biological Research Centre/Hungarian Academy of Science(ハンガリー)

    • Related Report
      2020 Research-status Report
  • [Int'l Joint Research] Division of Gerontology & Geriatric Med./Department of Internal Medicine/University of Washington(米国)

    • Related Report
      2020 Research-status Report
  • [Int'l Joint Research] Institute of Biophysics/Biological Research Centre/Hungarian Academy of Sciences(ハンガリー)

    • Related Report
      2019 Research-status Report
  • [Int'l Joint Research] Division of Gerontology & Geriatric Med./Department of Internal Medicine/University of Washington(米国)

    • Related Report
      2019 Research-status Report
  • [Int'l Joint Research] Veterans Affairs/Puget Sound Health Care System/University of Washington(米国)

    • Related Report
      2018 Research-status Report
  • [Int'l Joint Research] Hungarian Academy of Scineces(ハンガリー)

    • Related Report
      2018 Research-status Report
  • [Journal Article] Effects of fasudil on blood?brain barrier integrity2022

    • Author(s)
      Sato Kei、Nakagawa Shinsuke、Morofuji Yoichi、Matsunaga Yuki、Fujimoto Takashi、Watanabe Daisuke、Izumo Tsuyoshi、Niwa Masami、Walter Fruzsina R.、Vigh Judit P.、Santa-Maria Ana Raquel、Deli Maria A.、Matsuo Takayuki
    • Journal Title

      Fluids and Barriers of the CNS

      Volume: 19 Issue: 1 Pages: 43-43

    • DOI

      10.1186/s12987-022-00336-w

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] MAP Kinase Pathways in Brain Endothelial Cells and Crosstalk with Pericytes and Astrocytes Mediate Contrast-Induced Blood-Brain Barrier Disruption2021

    • Author(s)
      Matsunaga Yuki、Nakagawa Shinsuke、Morofuji Yoichi、Dohgu Shinya、Watanabe Daisuke、Horie Nobutaka、Izumo Tsuyoshi、Niwa Masami、Walter Fruzsina R.、Santa-Maria Ana Raquel、Deli Maria A.、Matsuo Takayuki
    • Journal Title

      Pharmaceutics

      Volume: 13 Issue: 8 Pages: 1272-1272

    • DOI

      10.3390/pharmaceutics13081272

    • NAID

      120007172250

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Comparison of the rate of dedifferentiation with increasing passages among cell sources for an in vitro model of the blood?brain barrier2020

    • Author(s)
      Fujimoto Takashi、Morofuji Yoichi、Nakagawa Shinsuke、Kovac Andrej、Horie Nobutaka、Izumo Tsuyoshi、Niwa Masami、Matsuo Takayuki、Banks William A.
    • Journal Title

      Journal of Neural Transmission

      Volume: 127 Issue: 8 Pages: 1117-1124

    • DOI

      10.1007/s00702-020-02202-1

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Pericytes Suppress Brain Metastasis from Lung Cancer In Vitro.2019

    • Author(s)
      Fujimoto, T., Nakagawa, S., Morofuji, Y., Watanabe, D., Ujifuku, K., Horie, N., Izumo, T., Niwa, M., Banks, W. A., Deli, M. A., Matsuo, T.
    • Journal Title

      Cell Mol Neurobiol

      Volume: 40(1) Issue: 1 Pages: 113-121

    • DOI

      10.1007/s10571-019-00725-0

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Interaction between Pericytes and brain metastasis2021

    • Author(s)
      Takashi Fujimoto
    • Organizer
      3rd Mini symposium on the blood brain barrier From basic to clinical research
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research
  • [Presentation] Intraarterial therapy of Rho-kinase inhibitor for acute ischemic stroke2021

    • Author(s)
      Yoichi Morofuji
    • Organizer
      3rd Mini symposium on the blood brain barrier From basic to clinical research
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research
  • [Presentation] 灌流型in vitro血液脳関門モデル及び中枢神経疾患治療薬の開発2019

    • Author(s)
      諸藤陽一
    • Organizer
      日本脳神経外科学会第78回学術総会
    • Related Report
      2019 Research-status Report
    • Invited
  • [Presentation] Role of pericytes in brain metastasis formation2019

    • Author(s)
      Takashi Fujimoto, Yoichi Morofuji, Shinsuke Nakagawa, Nobutaka Horie, Tsuyoshi Izumo, Takeo Anda, Takayuki Matsuo
    • Organizer
      1st Mini-symposium on the Blood Brain Barrier from Basic to Research
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] The current trends in the treatment for brain metastasis2019

    • Author(s)
      Kei Sato, Yoichi Morofuji, Shinsuke Nakagawa, Takashi Fujimoto, Nobutaka Horie, Tsuyoshi Izumo, Takeo Anda, Takayuki Matsuo
    • Organizer
      1st Mini-symposium on the Blood Brain Barrier from Basic to Research
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] Rho-kinase inhibitor fasudil protcts blood brain barrier from ischemia/prefusion injury2019

    • Author(s)
      Yuki Matsunaga, Yoichi Morofuji, Shinsuke Nakagawa, Takashi Fujimoto, Nobutaka Horie, Tsuyoshi Izumo, Takeo Anda, Takayuki Matsuo
    • Organizer
      1st Mini-symposium on the Blood Brain Barrier from Basic to Research
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Funded Workshop] 1st Mini-symposium on the Blood Brain Barrier from Basic to research2019

    • Related Report
      2018 Research-status Report

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Published: 2018-04-23   Modified: 2024-01-30  

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