CEREBRAL ISCHEMIA AND EXPRESSION OF STRESS GENES

脑缺血和应激基因的表达

• 批准号: 2267523
• 负责人: FRANK A WELSH
• 金额: $ 27.55万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-05-01 至 2000-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2267523
• 关键词: antisense nucleic acid; cell death; cerebral cortex; cerebral ischemia /hypoxia; cerebrovascular occlusions; gene expression; gene induction /repression; laboratory rat; messenger RNA; neuroprotectants; neurotrophic factors; spreading cortical depression; stress proteins; transfection

DESCRIPTION: Cerebral ischemia induces the selective synthesis of stress proteins, including the 72,000 heat-shock protein (hspt2). We have demonstrated that focal induction of hsp72 in the cerebral cortex is associated with a profound increase in the tolerance of neurons to a subsequent episode of ischemia. The objective of the present proposal is to identify the mechanisms that contribute to this neuroprotection. Our central hypothesis is that hspt2 is'a major factor in ischemic tolerance. In addition, we hypothesize that induction of neurotrophic factors may also contribute importantly to the neuroprotection. These hypotheses will be tested using the strategy of focal preconditioning of the cerebral cortex followed by transient forebrain ischemia in the rat. The cortex will be preconditioned with brief (20 min) occlusion of the distal middle cerebral artery or with KCl- stimulated spreading depression (SD). SD induces brain-derived neurotrophic factor (BDNF), but not hspt2. To detect alterations in ischemic tolerance, the forebrain is rendered ischemic for 10 min-, and neuronal injury in the preconditioned cortex is compared with that in the contralateral cortex. To investigate the mechanism of neuroprotection, the effect of preconditioning on the decline of ATE during forebrain ischemia will be determined. In. addition, we will determine whether preconditioning alters the expression of hspt2 -A or recovery of protein synthesis following forebrain ischemia. Finally, we will determine whether antisense oligodeoxynucleotides can specifically block expression of hsp72 and whether viral vectors carrying the hsp72 gene can be --used to focally overexpress hsp72.

描述：脑缺血诱导应激的选择性合成 蛋白质，包括72，000热休克蛋白（hspt 2）。 我们有 表明大脑皮层中hsp 72的局灶性诱导是 这与神经元对一种神经刺激的耐受性的显著增加有关。 随后缺血发作。 本提案的目的是 就是找出这种神经保护的机制。 我们的中心假设是hspt 2是缺血性心脏病的主要因素， 宽容 此外，我们假设，诱导神经营养 这些因素也可能对神经保护有重要贡献。 这些 假设将使用局灶预处理策略进行检验 大脑皮层的缺血，随后是短暂的前脑缺血， 大鼠 皮质将通过短暂（20分钟）闭塞进行预处理 大脑中动脉远端或KCl刺激的扩散 抑郁症（SD）。 SD诱导脑源性神经营养因子（BDNF）， 而不是HSPT 2。 为了检测缺血耐受性的改变， 使前脑缺血10分钟，并且在脑中神经元损伤。 将预处理皮层与对侧皮层中的预处理皮层进行比较。 为探讨神经保护作用的机制， 预处理对前脑缺血时ATE下降的影响将是 测定 In.此外，我们将确定是否预处理 改变hspt 2-A的表达或蛋白质合成的恢复 导致前脑缺血 最后，我们将确定 反义寡脱氧核苷酸可以特异性地阻断 hsp 72以及是否可以使用携带hsp 72基因的病毒载体 局部过表达HSP 72。