Cerebral ischemia and expression of stress genes

描述（由申请人提供）：目前治疗人类中风的方法疗效有限。最近的研究表明，大脑中存在保护机制，可以通过预处理刺激激活。这些机制的确定可能为人类中风提供新的治疗靶点。这一提议的中心假设是，预处理上调炎症抑制剂，保护大脑免受缺血。增强脑卒中后炎症抑制剂的表达是一种减轻缺血性损伤的新策略。中心假设将在四个具体目标中得到检验。首先，在预处理后测量选定的炎症抑制剂的时间进程和区域表达。其次，这些抑制剂与神经保护之间的因果关系将通过确定其表达的衰减是否会消除对缺血耐受的诱导来评估。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对缺血的耐受。最后，我们将确定神经营养因子（已知通过预处理而上调）本身是否会增加炎症抑制剂的表达，以及这种表达的拮抗是否会减弱神经营养因子对缺血的保护作用。这些研究将测试炎症抑制剂的上调是否是促进缺血耐受的主要机制。增强抑制炎症的内源性途径是治疗人类中风的一种创新和有前途的策略。

DESCRIPTION (provided by applicant): 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 inhibitors of 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.