CEREBRAL ISCHEMIA AND EXPRESSION OF STRESS GENES

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(Hspt2)。我们有 证明HSP72在大脑皮层的局灶性诱导 与神经元耐力的显著提高有关 随后的缺血发作。本提案的目标是 就是确定有助于这种神经保护的机制。 我们的中心假设是hspt2是缺血的一个主要因素。 宽容。此外，我们假设神经营养的诱导 这些因素也可能对神经保护起到重要作用。这些 假设将使用焦点预适应策略进行检验。 在短暂性前脑缺血后的大脑皮层 老鼠。皮层将用短暂的(20分钟)阻断进行预处理 大脑中动脉远端或有氯化钾刺激的扩张 抑郁(SD)。SD诱导脑源性神经营养因子(BDNF)， 但不是hspt2。为了检测缺血耐受性的变化， 前脑缺血10分钟-，神经元损伤 将预处理皮层与对侧皮质进行比较。 为探讨神经保护的作用机制，本实验研究了黄连素的神经保护作用 对前脑缺血时ATE下降的预适应 下定决心。在……里面。此外，我们将确定预适应是否 改变hspt2-A的表达或蛋白质合成的恢复 在前脑缺血后。最后，我们将确定是否 反义寡核苷酸可特异性阻断血管内皮生长因子的表达 热休克蛋白72及携带热休克蛋白72基因的病毒载体能否使用 靶向过表达HSP72。

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.