Visualization and regulation of ischemia-induced stress response in brain.

大脑缺血引起的应激反应的可视化和调节。

• 批准号: 10480215
• 负责人: OGAWA Satoshi
• 金额: $ 4.16万
• 依托单位: Kanazawa University (1999-2000)Osaka University (1998)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B).
• 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/en/grant/KAKENHI-PROJECT-10480215/
• 关键词: Heat shock protein; Energy metabolism; Stress response; Transgenic mice; Stress reporter; Gene therapy

An integral component of the cellular response to environmental challenge is expression, usually by de novo protein synthesis, of stress-associated polypeptides, such as heat shock proteins (induced by high temperature), glucose-regulated proteins (GRPs ; induced by glucose deprivation), and oxygen-regulated proteins (induced by oxygen deprivation). These biosynthetic responses are well preserved from prokaryotes to mammals, and have been hypothesized to contribute importantly to maintenance of cellular homeostasis as cellular adaptation to altered environmental conditions is under way.Astrocytes are strategically positioned to exert cytoprotective effects on neurons, the latter known for their vulnerability to changes in the local environment. Such neuro-protective and even neuro-trophic properties of astrocytes have been suggested in the setting of trauma, inflammation, and ischemic insults. To analyze specific mechanisms through which astrocytes mediate these effects, we analyzed po … More lypeptides made by astrocytes exposed to hypoxia, an important component of the ischemic milieu. Our studies have identified a novel 150 kDa protein, ORP150. This endoplasmic reticulum (ER)-associated chaperone has been shown to contribute importantly to the viability of several cultured cell lines under conditions of oxygen deprivation.In view of the susceptibility of neurons to ischemic stress, we hypothesized that such vulnerability might be due, at least in part, to limited expression of ORP15O.In contrast, the resistance of astrocytes to ischemic stress might result from abundant ORP150 expression.Oxygen-regulated protein 150 kDa (ORP150) is a novel endoplasmic reticulum-associated chaperone induced by oxygen deprivation/ischemia. Although ORP15O was modestly upregulated in neurons from human brain undergoing ischemic stress, there was robust induction in astrocytes. Cultured neurons overexpressing ORP150 were resistant to hypoxemic stress, whereas astrocytes with inhibited ORP15O expression were more vulnerable. Mice with targeted neuronal overexpression of ORP150 displayed smaller strokes compared with controls. Neurons with increased ORP150 demonstrated suppressed caspase-3-like activity and enhanced elaboration of neurotrophic BDNF under hypoxia. These data indicate that ORP150 is an integral participant in ischemic cytoprotective pathways. Less

对环境挑战的细胞应答的一个组成部分是应激相关多肽的表达，通常通过从头蛋白质合成，例如热休克蛋白（由高温诱导）、葡萄糖调节蛋白（GRP;由葡萄糖剥夺诱导）和氧调节蛋白（由氧剥夺诱导）。从原核生物到哺乳动物，这些生物合成反应都得到了很好的保存，并且已经被假设为对维持细胞内稳态有重要贡献，因为细胞对改变的环境条件的适应正在进行中。星形胶质细胞被战略性地定位为对神经元发挥细胞保护作用，后者因其对局部环境变化的脆弱性而闻名。星形胶质细胞的这种神经保护甚至神经营养特性已经被认为是在创伤、炎症和缺血性损伤的情况下。为了分析星形胶质细胞介导这些作用的具体机制，我们分析了星形胶质细胞的表达。 ...更多信息 由暴露于缺氧的星形胶质细胞产生的糖肽，缺氧是缺血环境的重要组成部分。我们的研究已经确定了一个新的150 kDa的蛋白质，ORP 150。这种内质网（ER）相关的伴侣蛋白已被证明对缺氧条件下几种培养细胞系的活力有重要贡献。鉴于神经元对缺血应激的敏感性，我们假设这种脆弱性可能至少部分是由于ORP 15 O的有限表达。氧调节蛋白150（Oxygen-regulated protein 150，ORP 150）是一种新型的内质网相关分子伴侣，在缺氧/缺血条件下可诱导表达。虽然ORP 15 O在经历缺血应激的人脑神经元中适度上调，但在星形胶质细胞中有强烈的诱导。培养的神经元过表达ORP 150耐低氧应激，而星形胶质细胞与抑制ORP 15 O表达更脆弱。与对照组相比，具有靶向神经元过表达ORP 150的小鼠显示出较小的中风。神经元与增加的ORP 150表现出抑制caspase-3样活性和增强的神经营养性BDNF在缺氧下的阐述。这些数据表明，ORP 150是缺血性细胞保护途径中不可或缺的参与者。少

项目成果

Bando Y. ほか: "The 150 kDa Oxygen Regulated Protein (ORP150) functions as a novel molecular chaperone in the protein transport of the MDCK cells."Am.J.Physiol. (Cell Physiol.). 278. C1172-1182 (2000)

Bando Y. 等人：“150 kDa 氧调节蛋白 (ORP150) 在 MDCK 细胞的蛋白质转运中发挥新型分子伴侣的作用。”(Am.J.Physiol.)。 (2000)

Tamatani M, et al.: "Tumor necrosis factor induces Bcl-2 and Bcl-x expression through NFkappaB activation in primary hippocampal neurons."J.Biol.Chem.. 274. 8531-8538 (1999)

Tamatani M 等人：“肿瘤坏死因子通过初级海马神经元中的 NFkappaB 激活诱导 Bcl-2 和 Bcl-x 表达。”J.Biol.Chem.. 274. 8531-8538 (1999)

Yan S.D.et al.: "Role of ERAB/L-3 Hydroxyacyl-coenzyme A dehydrogenase type II activity in Ab-induced cytotoxicity."J.Biol.Chem.. 274. 2145-2156 (1999)

Yan S.D.等人：“ERAB/L-3 羟酰辅酶 A 脱氢酶 II 型活性在 Ab 诱导的细胞毒性中的作用。”J.Biol.Chem.. 274. 2145-2156 (1999)

Yamaguchi A, et al.: "Stress-associated endoplasmic reticulum protein 1 (SERP1)/Ribosome-associated membrane protein 4 (RAMP4) stabilizes membrane proteins during stress and facilitates subsequent glycosylation."J.Cell Biol.. 147. 1195-1204 (1999)

Yamaguchi A 等人：“应激相关内质网蛋白 1 (SERP1)/核糖体相关膜蛋白 4 (RAMP4) 在应激期间稳定膜蛋白并促进随后的糖基化。”J.Cell Biol.. 147. 1195-1204

Niitsu Y. et al.: "Exposure of cultured primary rat astrocytes to hypoxia results in intracellular glucose depletion and induction of glycolytic enzymes."Mol. Brain Res.. 74. 26-34 (1999)

Niitsu Y. 等人：“将培养的原代大鼠星形胶质细胞暴露于缺氧会导致细胞内葡萄糖消耗并诱导糖酵解酶。”