Development of novel treatment and prognostic prediction for acute brain injury after aneurysmal subarachnoid hemorrhage.

2019 Fiscal Year Annual Research Report

• Project/Area Number: 18K16566
• Research Institution: Yokohama City University
• Principal Investigator: 高瀬 創 横浜市立大学, 医学研究科, 客員研究員 (00549975)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Keywords: くも膜下出血 / 急性期脳損傷 / 分子メカニズム / 血管内皮 / 神経炎症 / ミクログリア / cell-cell interaction / translational study

Outline of Annual Research Achievements

血管内皮細胞の接着結合分子VE-cadherinは、BBBの恒常性維持という本来の役割だけでなく、全身性炎症性疾患において細胞外部分が遊離して新たな生物学的な機能を有することが近年示唆された。本研究では、炎症性メカニズムが大きく関与する中枢神経系の代表的疾患である「くも膜下出血」における同分子の役割について、臨床研究と基礎研究を用いたReverse-translational Studyの手法を用いて解析と考察を行った。臨床面では、くも膜下出血の急性期における髄液中可溶性VE-cadherin濃度が、長期的予後と負の相関を有することが示された。一方で、初代培養細胞とモデル動物を用いた基礎研究では、同分子がミクログリアの炎症性活性を惹起していることが示唆され、くも膜下出血における新たな炎症障害性メカニズムの存在が明らかとなった。この血管内皮細胞ーミクログリアの新たなcell-cell interactionの役割を追求することで、中枢神経系における新たな治療戦略を展開できる可能性がある。

Research Products

• [Int'l Joint Research] Massachusetts General Hospital/Harvard Medical School/Brigham and Women's Hospital(米国)
  • Country Name: U.S.A.
  • Counterpart Institution: Massachusetts General Hospital/Harvard Medical School/Brigham and Women's Hospital
• [Journal Article] Soluble vascular endothelial-cadherin in CSF after subarachnoid hemorrhage. (2020)
  • Author(s): Takase H, Chou SH, Hamanaka G, Ohtomo R, Islam MR, Lee JW, Hsu L, Mathew J, Reyes-Bricio E, Hayakawa K, Xing C, Ning MM, Wang X, Arai K, Lo EH, Lok J.
  • Journal Title: Neurology Volume: 94(12) Pages: e1281-e1293
  • DOI: 10.1212/WNL.0000000000008868.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Microglial responses after phagocytosis: Escherichia coli bioparticles, but not cell debris or amyloid beta, induce matrix metalloproteinase-9 secretion in cultured rat primary microglial cells. (2020)
  • Author(s): Hamanaka G, Kubo T, Ohtomo R, Takase H, Reyes-Bricio E, Oribe S, Osumi N, Lok J, Lo EH, Arai K.
  • Journal Title: Glia Volume: 68(7) Pages: 1435-1444
  • DOI: 10.1002/glia.23791.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Axonal regeneration and functional recovery driven by endogenous Nogo receptor antagonist LOTUS in a rat model of unilateral pyramidotomy. (2020)
  • Author(s): Ueno R, Takase H*, Suenaga J, Kishimoto M, Kurihara Y, Takei K, Kawahara N, Yamamoto T.
  • Journal Title: Experimental Neurology Volume: 323 Pages: 113068
  • DOI: 10.1016/j.expneurol.2019.113068.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Translating concepts of neural repair after stroke: Structural and functional targets for recovery. (2020)
  • Author(s): Regenhardt RW, Takase H, Lo EH, Lin DJ.
  • Journal Title: Restorative Neurology and Neuroscience Volume: 38(1) Pages: 67-92
  • DOI: 10.3233/RNN-190978.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Thiel's embalming method with additional intra-cerebral ventricular formalin injection (TEIF) for cadaver training of head and brain surgery. (2020)
  • Author(s): Miyake S, Suenaga J, Miyazaki R, Sasame J, Akimoto T, Tanaka T, Ohtake M, Takase H, Tateishi K, Shimizu N, Murata H, Funakoshi K, Yamamoto T.
  • Journal Title: Anatomical Science International Volume: N/A Pages: N/A
  • DOI: 10.1007/s12565-020-00545-z.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Treadmill Exercise Suppresses Cognitive Decline and Increases White Matter Oligodendrocyte Precursor Cells in a Mouse Model of Prolonged Cerebral Hypoperfusion. (2019)
  • Author(s): Ohtomo R, Kinoshita K, Ohtomo G, Takase H, Hamanaka G, Washida K, Islam MR, Wrann CD, Katsuki H, Iwata A, Lok J, Lo EH, Arai K.
  • Journal Title: Translational Stroke Research Volume: Oct 12 Pages: N/A
  • DOI: 10.1007/s12975-019-00734-7.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Oxidative stress-responsive apoptosis inducing protein (ORAIP) plays a critical role in cerebral ischemia/reperfusion injury. (2019)
  • Author(s): Kishimoto M, Suenaga J, Takase H, Araki K, Yao T, Fujimura T, Murayama K, Okumura K, Ueno R, Shimizu N, Kawahara N, Yamamoto T, Seko Y
  • Journal Title: Scientific Reports Volume: 9(1) Pages: 13512
  • DOI: 10.1038/s41598-019-50073-8.
  • Peer Reviewed / Int'l Joint Research
• [Presentation] White matter damage and microglial alterations after concussive brain injury. (2019)
  • Author(s): Takase H, Ohtomo R, Wang X, Lo EH, Chung JY, Whalen MJ, Arai K, Lok J
  • Organizer: BRAIN 2019
  • Int'l Joint Research
• [Presentation] Treadmill exercise suppresses cognitive decline and increases white matter oligodendrocyte precursor cells in a mouse model of prolonged cerebral hypoperfusion (2019)
  • Author(s): Ohtomo R, Ohtomo G, Takase H, Hamanaka G, Iwata A, Lok J, Lo EH, Arai K
  • Organizer: BRAIN 2019
  • Int'l Joint Research
• [Presentation] Biphasic roles of pentraxin 3 in cerebrovascular responses after white matter stroke (2019)
  • Author(s): Shindo A, Ohtomo R, Takase H, Hamanaka G, Maki T, Egawa N, Lok J, Tomimoto H, Lo EH, Arai K
  • Organizer: BRAIN 2019
  • Int'l Joint Research
• [Presentation] Microglial responses after phagocytosis: e. coli bioparticles, but not cell debris or amyloid beta, induce matrix metalloproteinase-9 secretion in vitro (2019)
  • Author(s): Hamanaka G, Ohtomo R, Takase H, Lok J, Lo EH, Arai K
  • Organizer: BRAIN 2019
  • Int'l Joint Research