Cerebral ischemia and expression of stress genes

目前人类中风的治疗方法疗效有限。最近的研究表明， 存在于大脑内的机制，可以使用预处理刺激激活。鉴定 这些机制可能为人类中风提供新的治疗靶点。这个问题的核心假设是 提出预处理上调炎症抑制剂，保护脑免受缺血。 增强卒中后炎症抑制因子的表达是减轻缺血性脑卒中的新策略。 损害中心假设将在四个具体目标中得到检验。第一，国际和区域合作的时间进程 在预处理后测量所选炎症因子的表达。二是 这些抑制剂和神经保护之间的因果关系将通过确定是否 其表达的减弱消除了对缺血耐受性的诱导。第三，我们将确定 特异性激活Toll样受体的药物是否上调炎症抑制剂并诱导 缺血耐受性。最后，我们将确定是否神经营养因子，已知是上调的， 预处理，本身增加炎症抑制因子的表达，是否拮抗 这种表达减弱了神经营养素对缺血的保护作用。这些研究将 测试炎症抑制剂的上调是否是导致缺血性心脏病的主要机制。 宽容增强抑制炎症的内源性途径是一种创新的， 治疗人类中风的有前途的策略。

Current therapies for human stroke have limited efficacy. Recent studies indicate that there are protective mechanisms residing within the brain that can be activated using preconditioning stimuli. Identification of these mechanisms may provide new therapeutic targets for stroke in humans. The central hypothesis of this proposal is that preconditioning upregulates inhibitors of inflammation that protect the brain against ischemia. Enhancing the expression of inflammatory inhibitors after stroke is a novel strategy to attenuate ischemic damage. The central hypothesis will be tested in four specific aims. First, the timecourse of and regional expression of selected inhibitorsof inflammation will be measured after preconditioning. Second, the causative relationship between these inhibitors and neuroprotection will be assessed by determining whether attenuation of their expression abrogates the induction of tolerance to ischemia. Third, we will determine whether agents that specifically activate Toll-like receptors upregulate inhibitors of inflammation and induce tolerance to ischemia. Finally, we will determine whether neurotrophic factors, known to be upregulated by preconditioning, themselves increase the expression of inhibitors of inflammation and whether antagonism of this expression attenuates the protective effects of the neurotrophins against ischemia. These studies will test whether upregulation of inhibitors of inflammation is a major mechanism contributing to ischemic tolerance. Enhancement of endogenous pathways that suppress inflammation is an innovative and promising strategy for the treatment of stroke in humans.