| Project/Area Number |
10307055
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| Research Category |
Grant-in-Aid for Scientific Research (A).
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Biological pharmacy
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| Research Institution | HOKKAIDO UNIVERSITY |
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Principal Investigator |
NOMURA Yasuyuki Hokkaido Univ., Grad.Sch.of Pharma.Sci., Professor, 大学院・薬学研究科, 教授 (00034041)
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| Co-Investigator(Kenkyū-buntansha) |
MURAYAMA Toshihiko Chiba Univ., Professor, 薬学部, 教授 (90174317)
UEHARA Takashi Hokkaido Univ., Associate Professor, 大学院・薬学研究科, 助教授 (00261321)
OKUMA Yasunobu Hokkaido Univ., Associate Professor, 大学院・薬学研究科, 助教授 (20127939)
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| Project Period (FY) |
1998 – 2000
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| Project Status |
Completed (Fiscal Year 2000)
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| Budget Amount *help |
¥37,200,000 (Direct Cost: ¥37,200,000)
Fiscal Year 2000: ¥8,400,000 (Direct Cost: ¥8,400,000)
Fiscal Year 1999: ¥8,600,000 (Direct Cost: ¥8,600,000)
Fiscal Year 1998: ¥20,200,000 (Direct Cost: ¥20,200,000)
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| Keywords | brain / glia / ischemia / apoptosis / stress protein / chaperon / caspase / nitric oxide / ニューロン / アストログリア / 一酸化窒素 / 一酸化窒素合成酵素 / カスパーゼ / DNA断片化 / HSP70 |
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| Research Abstract |
We investigated the mechanisms of 1) ischemia-induced neuronal cell death and 2) acquisition of tolerance against ischemic stress in glial cells. Hypoxia, an ischemic stress, induced neuronal apoptosis via cytochrome c release from mitochondria and following caspase activation. On the other hand, this stress up-regulated some stress proteins such as a 70 kDa heat-shock protein (HSP70) and a 78 kDa glucose-regulated protein (GRP78). In addition, we found that HSP70 induction was sensitive to SB203580, suggesting that p38 MAP kinase was positively involved in this expression. We further attempted to identify a stress protein that was enhanced or induced by hypoxia or brain ischemia in glial cells. We isolated protein-disulfide isomerase (PDI) as a candidate protein and this protein certainly induced in glial cells of ischemic brain. Overexpression of PDI in vitro and in vivo resulted in attenuation of the loss of cell viability in neuroblastoma SK-N-MC cells and a reduction in the number of DNA-fragmented cells in the CA1 subfield of the hippocampus in brain ischemic rats, respectively. Thus, up-regulated PDI may play a critical role in resistance to ichemic damage.
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