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

• Project/Area Number: 18K08973
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 56010:Neurosurgery-related
• Research Institution: Nagasaki 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: ¥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。

Research Products

• [Int'l Joint Research] Institute of Biophysics/Biological Research Centre/Hungarian Academy of Science(ハンガリー)
• [Int'l Joint Research] Division of Gerontology & Geriatric Med./Department of Internal Medicine/University of Washington(米国)
• [Int'l Joint Research] Institute of Biophysics/Biological Research Centre/Hungarian Academy of Science(ハンガリー)
• [Int'l Joint Research] Division of Gerontology & Geriatric Med./Department of Internal Medicine/University of Washington(米国)
• [Int'l Joint Research] Institute of Biophysics/Biological Research Centre/Hungarian Academy of Science(ハンガリー)
• [Int'l Joint Research] Division of Gerontology & Geriatric Med./Department of Internal Medicine/University of Washington(米国)
• [Int'l Joint Research] Institute of Biophysics/Biological Research Centre/Hungarian Academy of Sciences(ハンガリー)
• [Int'l Joint Research] Division of Gerontology & Geriatric Med./Department of Internal Medicine/University of Washington(米国)
• [Int'l Joint Research] Veterans Affairs/Puget Sound Health Care System/University of Washington(米国)
• [Int'l Joint Research] Hungarian Academy of Scineces(ハンガリー)
• [Journal Article] Effects of fasudil on blood?brain barrier integrity (2022)
  • 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
  • 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 Disruption (2021)
  • 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
  • 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 barrier (2020)
  • 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
  • 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
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Interaction between Pericytes and brain metastasis (2021)
  • Author(s): Takashi Fujimoto
  • Organizer: 3rd Mini symposium on the blood brain barrier From basic to clinical research
  • Int'l Joint Research
• [Presentation] Intraarterial therapy of Rho-kinase inhibitor for acute ischemic stroke (2021)
  • Author(s): Yoichi Morofuji
  • Organizer: 3rd Mini symposium on the blood brain barrier From basic to clinical research
  • 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
  • Invited
• [Presentation] Role of pericytes in brain metastasis formation (2019)
  • 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
  • Int'l Joint Research
• [Presentation] The current trends in the treatment for brain metastasis (2019)
  • 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
  • Int'l Joint Research
• [Presentation] Rho-kinase inhibitor fasudil protcts blood brain barrier from ischemia/prefusion injury (2019)
  • 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
  • Int'l Joint Research
• [Funded Workshop] 1st Mini-symposium on the Blood Brain Barrier from Basic to research (2019)