Cerebral ischemia and expression of stress genes

目前治疗人类中风的方法疗效有限。最近的研究表明，有保护作用 驻留在大脑中的机制，可以使用预适应刺激来激活。身份识别 这些机制可能为人类中风提供新的治疗靶点。这一点的中心假设是 建议是，预适应上调炎症抑制物，从而保护大脑免受缺血。 增强卒中后炎症抑制物的表达是减轻缺血的新策略 损坏。核心假设将在四个具体目标上得到检验。第一，时间进程和地区性 在预适应后，将测量选定的炎症抑制因子的表达。第二， 这些抑制剂和神经保护之间的因果关系将通过确定 它们表达的减弱取消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因子并诱导 对缺血的耐受。最后，我们将确定已知被上调的神经营养因子是否 预适应，本身增加了炎症抑制因子的表达，是否具有拮抗作用 这种表达减弱了神经营养因子对缺血的保护作用。这些研究将 检测炎症抑制物上调是否是导致缺血的主要机制 宽容。增强抑制炎症的内源性途径是一种创新和 治疗人类中风的有希望的策略。

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.