| Project/Area Number |
17K10821
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Neurosurgery
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| Research Institution | Kanazawa University |
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Principal Investigator |
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
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| Keywords | くも膜下出血 / 脳血管攣縮 / 免疫細胞 / 好中球 / RAGE / 早期脳障害 / 損傷関連分子 |
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| Outline of Final Research Achievements |
Subarachnoid hemorrhage (SAH) suddenly occurs predominantly by ruptured cerebral aneurysm. The severity of SAH is higher than other types of stroke such as cerebral ischemia and intracranial hemorrhage. It is critical to prevent disability after SAH by modulating its underlying molecular mechanism. Here, we identified a receptor for advanced glycation endproducts (RAGE) as an inducer molecule of cerebral vasospasm (CVS)/brain injury after SAH. In RAGE-deficient mice, neurological score and cerebral vasospasm was markedly improved compared with control mice. RAGE was expressed in endothelial cells of internal carotid artery after SAH. However, vascular specific RAGE-deficient mice did not show improvement of CVS after SAH. In stead, neutrophil-specific RAGE-deficient mice showed improvement of these phenotypes compared with control ones. Therefore, RAGE in neutrophil contributes to CVS after SAH. Indeed, neutrophils accumulated around cerebral artery after SAH in RAGE-dependent manner.
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| Academic Significance and Societal Importance of the Research Achievements |
これ迄は脳血管攣縮における内皮細胞による攣縮作用のみが着目され、これが内皮細胞の細胞骨格制御分子Rhoキナーゼに対する阻害剤（塩酸ファスジル）が臨床適用されている根拠となっている。しかし依然顕著な患者予後の改善に迄は至っていない。これに対して本研究は初めて末梢の好中球動員がSAH後病態の核心である事を解明するものである。また我々はSAHの後遺障害が重篤な患者では内在性RAGE阻害蛋白質であるRAGEデコイ受容体が血中で少ない事実を確認している（J Neurosurg 2019）。この臨床結果はRAGE阻害剤の臨床応用への有望性を強く示唆しており、これは本研究の学術的創造性に繋がるものと考える。
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