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

细胞对环境挑战的反应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来表达，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（由缺氧诱导）。星形胶质细胞的战略定位是对神经元发挥细胞保护作用，众所周知，后者容易受到局部环境变化的影响，星形胶质细胞的这种神经保护甚至神经营养特性已在创伤、炎症和神经损伤的情况下被提出。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暴露于缺氧时产生的肽，这是缺血环境的重要组成部分。 150 kDa 蛋白 ORP150 已被证明对几种培养细胞系在缺氧条件下的生存能力有重要贡献。鉴于神经元对缺血应激的敏感性，我们担心这种情况。脆弱性可能至少部分归因于 ORP15O 的有限表达。相反，星形胶质细胞对缺血应激的抵抗可能来自丰富的 ORP150氧调节蛋白 150 kDa (ORP150) 是一种由缺氧/缺血诱导的新型内质网相关伴侣，尽管 ORP15O 在遭受缺血应激的人脑神经元中适度上调，但在培养的神经元中过度表达。 ORP150 对低氧应激具有抵抗力，而 ORP15O 表达受到抑制的星形胶质细胞则更容易受到伤害。与对照组相比，ORP150 的靶向神经元过度表达显示出较小的中风，这些数据表明 ORP150 是缺血性细胞保护途径的一个组成部分。

项目成果

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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)

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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)

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)

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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。”