| Project/Area Number |
16390252
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Neurology
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| Research Institution | HIROSHIMA UNIVERSITY |
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Principal Investigator |
MATSUMOTO Masayasu Hiroshima University, Graduate School of Biomedical Sciences, Professor, 大学院・医歯薬学総合研究科, 教授 (20192346)
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| Co-Investigator(Kenkyū-buntansha) |
YAMASHITA Hiroshi Hiroshima University, Graduate School of Biomedical Sciences, Assistant, 大学院・医歯薬学総合研究科, 助手 (20311813)
KAWAKAMI Hideshi Hiroshima University, Hospital, Assistant Professor, 病院・講師 (70253060)
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| Project Period (FY) |
2004 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥11,600,000 (Direct Cost: ¥11,600,000)
Fiscal Year 2005: ¥5,500,000 (Direct Cost: ¥5,500,000)
Fiscal Year 2004: ¥6,100,000 (Direct Cost: ¥6,100,000)
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| Keywords | neurogenesis / ischemia / neural stem cell / ischemic stroke / cerebral infarction / 脳虚血 / 神経幹細胞 / Neurogenesis / 脳梗塞 / 海馬 / シクロオキシゲナーゼ / ノックアウトマウス |
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| Research Abstract |
In the subgranular zone (SGZ) of the dentate gyrus (DG) of the hippocampus and subventricular zone (SVZ) of the lateral ventricles, progenitor cells generate new neurons throughout adulthood. Ischemic insults to the brain have been shown to promote hippocampal neurogenesis in adult gerbils and rats. However, the molecular mechanism underlying increased neurogenesis after ischemia remains unclear. The present study investigated optimal regulation of neurogenesis and neural stem cells for the treatment of ischemic stroke. Proliferation of progenitor cells occurred at least a week after ischemic insult suggests that the stimulus was not an ischemic insult to progenitor cells. Msi1 and nestin were induced in the reactive astrocytes in the adult rat hippocampus after transient forebrain ischemia, suggesting that reactive astrocytes might have immature characteristics. Cyclooxygenase (COX)-2 modulates inflammation, glutamate-mediated cytotoxicity, and synaptic plasticity. Delayed treatment w
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ith different classes of COX inhibitor significantly blunted enhancement of DG proliferation of neural progenitor cells after ischemia. COX-2 immunoreactivity was observed in both neurons and astrocytes in the DG, but not in neural progenitor cells in the SGZ. Moreover, in the postischemic DG of heterozygous and homozygous COX-2 knockout mice, proliferating BrdU-positive cells were significantly fewer than in wild-type littermates. These results demonstrate that COX-2 is an important modulator in enhancement of proliferation of neural progenitor cells after ischemia. Efficient differentiation of mouse embryonic stem (ES) cells into neural stem cells was attempted with induction of Nurr1 and retinoic acid treatment. The ES cell-derived neural stem cells were efficiently differentiated into neurons and oligodendrocytes. The ES cell-derived neural stem cells were subjected to the treatment of the rat brain after transient focal ischemia, and the restorative effect of neurological damage was investigated. The role of Rho-kinase, that inhibits neuroregeneration, was also investigated. Expression of Rho-kinase as well as its activator RhoA were increased after ischemic insult to rat brain, suggesting that increased Rho-kinase might negatively regulate neurogenesis after ischemia. Less
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