Establishment of treatment for acute ischemic stroke focusing on TRPV4
| Project/Area Number |
19K21303
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| Project/Area Number (Other) |
18H06198 (2018)
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| Research Category |
Grant-in-Aid for Research Activity Start-up
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| Allocation Type | Multi-year Fund (2019)
Single-year Grants (2018) |
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| Review Section |
0902:General internal medicine and related fields
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| Research Institution | Kyushu University |
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Principal Investigator |
Tanaka Koji 九州大学, 大学病院, 医員 (50722344)
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| Project Period (FY) |
2018-08-24 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
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| Keywords | TRPV4 / ノックアウトマウス / 脳梗塞 / アストロサイト / 脳浮腫 / 脳血管障害 / 浮腫 |
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| Outline of Research at the Start |
虚血性脳血管障害の急性期には血液脳関門を構成するアストロサイトの足突起の浮腫が生じ、次第に細胞性浮腫、血管性浮腫に移行する。アストロサイトの浮腫には足突起にAQP4水チャネルとともに共発現している陽イオンチャネルであるTRPV4が関与している。
TRPV4を標的とした急性期虚血性脳血管障害の治療法の開発のため、本研究ではTPRV4阻害薬を用いたマウス脳梗塞モデル、培養細胞での血液脳関門構築モデルを用いた実験を行う。
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| Outline of Final Research Achievements |
In the acute phase of ischemia-reperfusion, hypoperfusion associated with ischemia and reperfusion in microvascular regions and disruption of the blood brain barrier (BBB) contribute to post-ischemic brain injury. We aimed to clarify whether brain injury following transient middle cerebral artery occlusion (tMCAO) is ameliorated in Transient Receptor Potential Vanilloid 4 (TRPV4) knockout (Trpv4-/-) mice.
Compared with WT mice, Trpv4-/- mice showed reduced ischemia-induced lesion volume and reduced water content and Evans blue leakage in the ipsilateral hemisphere alongside milder neurological symptoms after the tMCAO. The loss of zonula occludens-1 and occludin proteins in the ipsilateral hemisphere after the tMCAO was attenuated in Trpv4-/- mice. Transmission electron microscopy revealed that parenchymal microvessels in the ischemic lesion were compressed and narrowed by the swollen endfeet of astrocytes in WT mice, but these effects were markedly ameliorated in Trpv4-/- mice.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究結果から、急性期にTransient Receptor Potential Vanilloid 4 (TRPV4)を抑制することは再灌流直後のアストロサイト足突起の浮腫を軽減しblood brain barrierを保持することで脳保護的に働くと推察された。
主幹動脈閉塞を伴う急性期脳梗塞に対する急性期再開通療法の進歩が著しい近年において、虚血再灌流後の脳損傷に対する脳保護効果を示した本研究結果の意義は大きいと考えられる。
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Report
(3 results)
Research Products
(5 results)
