The Role of PPAR Agonists in Inflammation and stroke

超出所提供的空间。中风是一种毁灭性的疾病。我们迫切需要了解缺血性中风后损伤和恢复的机制，以便设计出限制缺血性损伤和促进恢复的治疗方法。炎症加重缺血性损伤，并可能在中风后的重塑和恢复中发挥作用。我们的长期目标是阐明炎症在急性和慢性脑缺血中的作用。为了实现这一目标，我们建议使用一类新的药物，具有抗炎特性的PPARgamma激动剂。曲格列酮是一种PPARgamma激动剂，可减少促炎细胞因子和其他炎症分子的表达。初步数据显示，曲格列酮可减少大鼠局灶性缺血后的梗死面积，并降低对促炎细胞因子的免疫反应性。此外，我们发现脑缺血后PPARgamma表达增加。这种增加在数小时内出现，并持续至少一周。实验旨在使用额外的PPARgamma激动剂和拮抗剂来测试PPARgamma激活在神经保护中的作用。将检查激活必须发生的时间段。我们建议采用Western blotting，定量rt-PCR和免疫细胞化学相结合的方法来分析炎症对观察到的神经保护的贡献。我们将特别研究促炎细胞因子的作用，方法是将阻断细胞因子、白细胞介素- β和肿瘤坏死因子α的化合物与曲格列酮一起给予大脑中动脉闭塞的动物。我们建议进一步研究PPARgamma在缺血脑中的表达，并探讨PPARgamma激动剂对其表达的影响。最后探讨了PPARgamma激动剂在确定梗死体积后调节功能结果的能力。初步数据表明，在局灶性中风后24小时和4天给予曲格列酮可改善预后。此时给药时，曲格列酮不能减小梗死面积。这些初步数据将通过更多的大鼠和额外的行为分析得到证实。Western blotting、rt-PCR和免疫细胞化学将用于检测曲格列酮对促炎细胞因子和生长因子的影响，这些因子可能是调节脑缺血后恢复的候选因子。网站性能 ======================================== 节结束 ===========================================

EXCEED THE SPACE PROVIDED. Stroke is a devastating disease. We desparately need to understand mechanisms of injury and recovery following ischemic stroke in order to design treatments that will limit ischemic injury and promote recovery. Inflammation exacerbates ischemic injury and may play a role in remodeling and recovery following stroke. Our long term objective is to clarify the role of inflammation in cerebral ischemia both in the acute and chronic time frames. To accomplish this, we propose to use a new class of drugs, PPARgamma agonists, that have anti-inflammatory properties. Troglitazone, a PPARgamma agonist, reduces the expression of the proinflammatory cytokines and other inflammatory molecules. Preliminary data show that troglitazone reduces infarct size following focal ischemia in rats and that immunoreactivity against proinflammatory cytokines is reduced in the same animals. Furthermore, we show that PPARgamma expression is increased following cerebral ischemia. This increase is present within hours and persists for least one week. Experiments are designed to test the role of PPARgamma activation in neuroprotection using additional PPARgamma agonists and antagonists. The time period in which the activation must occur will be examined. We propose to use a combination of Western blotting, quantitative rt-PCR and immunocytochemistry to assay the contribution of inflammation to the observed neuroprotection. We will specifically examine the role played by proinflammatory cytokines by administering compounds that block the cytokines, interleukin-lbeta and tumor necrosis factor alpha along with troglitazone to animals undergoing middle cerebral artery occlusion. We propose to further examine the expression of PPARgamma in ischemic brain and explore the effects of PPARgamma agonists on this expression. Finally the ability of PPARgamma agonists to modulate functional outcome after the time when infarct volume has been determined is explored. Preliminary data that suggests that troglitazone may improve outcome when administered twenty-four hours and four days after focal stroke. When administered at this time, troglitazone does not reduce infarct size. These preliminary data will be confirmed with a larger number of rats and additional behavioral analysis. Western blotting, rt-PCR and immunocytochemistry will be used to assay the effects of troglitazone on proinflammatory cytokines and growth factors that are likely candidates for modulating recovery followng cerebral ischemia. PERFORMANCE SITE ========================================Section End===========================================