Elucidation of the role of ATM kinase pathway in cerebral ischemia-reperfusion injury and its application to new cerebral infarction therapy
| Project/Area Number |
18K08994
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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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| Review Section |
Basic Section 56010:Neurosurgery-related
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| Research Institution | Kobe University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
篠山 隆司 神戸大学, 医学部附属病院, 教授 (10379399)
甲村 英二 神戸大学, 医学研究科, 名誉教授 (30225388)
篠原 正和 神戸大学, 医学研究科, 准教授 (80437483)
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| Project Period (FY) |
2018-04-01 – 2022-03-31
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| Project Status |
Completed (Fiscal Year 2021)
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| Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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| Keywords | 脳虚血 / メタボロミクス / ペントースリン酸 / 熱ショック蛋白 / 虚血再灌流障害 / 熱ショックタンパク質 / NADPH / ischemia reperfusion / stroke / metabolomics / heat shock protein / geranylgeranylacetone / Geranylgeranylacetone / 脳虚血再灌流 / ペントースリン酸経路 / 熱ショックタンパク / 脳梗塞 / 脳虚血再灌流障害 / ATMキナーゼ / 治療薬 |
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| Outline of Final Research Achievements |
Using a rat middle cerebral artery occlusion model, we confirmed that cerebral ischemia-reperfusion → increased heat shock protein 27 (HSP27) phosphorylation → increased G6PD activity → increased NADPH/NADP+ ratio during cerebral ischemia-reperfusion, indicating the existence of an endogenous antioxidant system that deals with reactive oxygen species via HSP27 phosphorylation by Ataxia telangiectasia mutated(ATM) kinase (HSP27 phosphatase). Next, we investigated the neuroprotective effects of Geranylgeranylacetone (GGA), an HSP27 inducer, in rat ischemia-reperfusion model by intracerebroventricular administration of GGA. The results suggest that GGA may be applicable to the treatment of ischemia-reperfusion injury.
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| Academic Significance and Societal Importance of the Research Achievements |
申請者らはオミクス手法による包括的解析により，脳虚血再灌流時のATMKからHSP27リン酸化を介したG6PD活性化という内因性抗酸化機構とMAPK経路の亢進を見い出した．オミクスによる脳虚血再灌流障害の包括的解析に基づいて特定したATMKの下流経路を新たな脳梗塞治療の標的としたことが本研究の特色であり，この点に着目した研究は国際的に見てもほとんど行われていないのが現状である．ATMKの下流経路は短期的ならびに長期的に神経組織に影響を与えるため脳梗塞治療の時間軸を広げる可能性がある点も重要である．
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Report
(5 results)
Research Products
(14 results)
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[Journal Article] Geranylgeranylacetone attenuates cerebral ischemia-reperfusion injury in rats through the augmentation of HSP 27 phosphorylation: a preliminary study2021
Author(s)
Matsuo, Kazuya and Hosoda, Kohkichi and Tanaka, Jun and Yamamoto, Yusuke and Imahori, Taichiro and Nakai, Tomoaki and Irino, Yasuhiro and Shinohara, Masakazu and Sasayama, Takashi and Kohmura, Eiji
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Journal Title
BMC Neuroscience
Volume: 22
Issue: 1
Pages: 9-19
DOI
NAID
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Presentation] Phosphorylation of Heat Shock Protein 27 Leads to Activation of Pentose Phosphate Pathway and Protection from Cerebral Ischemia-Reperfusion Injury2019
Author(s)
3.Matsuo K, Hosoda K, Tanaka J, Yamamoto Y, Imahori T, Nakai T, Irino Y, Shinohara M, Sasayama T, Kohmura E
Organizer
Brain & Brain PET 2019, Yokohama (Japan)
Related Report
Int'l Joint Research
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