Mechanisms of cellular and intracellular functions in brain-immune qnetwork.

脑免疫q网络中细胞和细胞内功能的机制。

• 批准号: 10307055
• 负责人: NOMURA Yasuyuki
• 金额: $ 23.81万
• 依托单位: HOKKAIDO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A).
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10307055/
• 关键词: 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

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.

我们研究了1）缺血诱导的神经元细胞死亡和2）神经胶质细胞获得对缺血应激耐受的机制。缺氧是一种缺血性应激，通过线粒体释放细胞色素c和caspase激活诱导神经元凋亡。另一方面，这种应激上调了一些应激蛋白，如70 kDa热休克蛋白（HSP 70）和78 kDa葡萄糖调节蛋白（GRP 78）。此外，我们发现HSP 70的诱导对SB 203580敏感，这表明p38 MAP激酶积极参与了这种表达。我们进一步试图确定一种应激蛋白，这种蛋白在神经胶质细胞中被缺氧或脑缺血增强或诱导。我们分离到一种蛋白质二硫键异构酶（PDI）作为候选蛋白质，该蛋白质在缺血脑的胶质细胞中确实被诱导。PDI在体外和体内的过表达分别导致神经母细胞瘤SK-N-MC细胞中细胞活力丧失的衰减和脑缺血大鼠海马CA 1区DNA片段化细胞数量的减少。因此，上调的PDI可能在抵抗缺血性损伤中起关键作用。

项目成果

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田中，S.

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