CEREBRAL ISCHEMIA AND EXPRESSION OF STRESS GENES

脑缺血和应激基因的表达

• 批准号: 2702992
• 负责人: FRANK A WELSH
• 金额: $ 30.48万
• 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/2702992
• 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：脑缺血诱导压力的选择性综合 蛋白质，包括72,000热激蛋白（HSPT2）。 我们有 证明大脑皮层中HSP72的局灶性诱导是 与神经元对A的耐受性的大幅提高相关 缺血的随后发作。 本提议的目的 是确定有助于这种神经保护的机制。 我们的中心假设是HSPT2是缺血性的主要因素 宽容。 另外，我们假设诱导神经营养 因素也可能对神经保护作用重要。 这些 假设将使用焦点预处理进行检验 大脑皮层，然后是短暂的前脑缺血 鼠。 皮质将通过短暂（20分钟）的闭塞进行预处理 大脑远端动脉或KCl刺激扩散 抑郁（SD）。 SD诱导脑衍生的神经营养因子（BDNF）， 但不是HSPT2。 为了检测缺血性耐受性的改变， 前脑被置换为10分钟，而神经元损伤 将预处理的皮质与对侧皮层中的皮质进行比较。 为了研究神经保护的机制 在前脑缺血期间ate衰落的前进将是 决定。 在。补充，我们将确定是否进行预处理 改变HSPT2 -A的表达或蛋白质合成的恢复 遵循前脑缺血。 最后，我们将确定是否 反义寡脱氧核苷酸可以特异性地阻止 HSP72以及是否可以使用携带Hsp72基因的病毒载体 以局部过表达HSP72。