| Project/Area Number |
21592302
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Emergency medicine
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| Research Institution | Yamagata University |
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Principal Investigator |
ISEKI Ken 山形大学, 医学部, 准教授 (70332921)
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| Co-Investigator(Kenkyū-buntansha) |
GOTO Kaoru 山形大学, 医学部, 教授 (30234975)
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| Project Period (FY) |
2009 – 2011
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| Project Status |
Completed (Fiscal Year 2011)
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| Budget Amount *help |
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2011: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2010: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2009: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
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| Keywords | 生体ストレス応答 / OGD酸素グルコース欠乏 / 海馬神経細胞 / 核内脂質代謝酵素 / 細胞死 / 低酸素 / 脳 / グリア細胞 / 神経細胞 / ストレス応答 |
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| Research Abstract |
Diacylglycerol kinase (DGK) plays a key role in pathophysiological cellular responses by regulating the levels of a lipid messenger diacylglycerol. Of DGK isozymes, DGKζ localizes to the nucleus in various cells such as neurons. We previously reported that DGKζ translocates from the nucleus to the cytoplasm in hippocampal CA1 pyramidal neurons after 20 min of transient forebrain ischemia. In this study, we examined the underlying mechanism of DGKζ translocation using hippocampal slices exposed to oxygen-glucose deprivation (OGD) to simulate an ischemic model of the brain. DGKζ-immunoreactivity gradually changed from the nucleus to the cytoplasm in CA1 pyramidal neurons after 20 min of OGD and was never detected in the nucleus after reoxygenation. Intriguingly, DGKζ was detected in the nucleus at 10 min OGD whereas the following 60 min reoxygenation induced complete cytoplasmic translocation of DGKζ. Morphometric analysis revealed that DGKζ cytoplasmic translocation correlated with nuclear shrinkage indicative of an early process of neuronal degeneration. The translocation under OGD conditions was blocked by NMDA receptor (NMDAR) inhibitor, and was induced by activation of NMDAR. Chelation of the extracellular Ca(2+) blocked the translocation under OGD conditions. These results show that DGKζ cytoplasmic translocation is triggered by activation of NMDAR with subsequent extracellular Ca(2+) influx. Furthermore, inhibition of PKC activity under OGD conditions led to nuclear retention of DGKζ in about one-third of the neurons, suggesting that PKC activity partially regulates DGKζ cytoplasmic translocation. These findings provide clues to guide further investigation of glutamate excitotoxicity mechanisms in hippocampal neurons.
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