Vascular Protection in Acute Ischemic Stroke

描述（由申请人提供）：再灌注治疗重新开放闭塞的脑动脉是缺血性卒中患者完全康复的最佳机会。尽管如此，每年60多万患者中只有不到5%接受治疗。广泛使用的主要障碍之一是担心严重脑出血的风险增加10倍，这可能是致命的。迫切需要制定减少这种风险的战略。很明显，缺血会损害脑血管，在某些情况下，这会导致脑出血。这项研究的目的是确定为什么脑出血后再灌注和评估方法，以提供血管保护的实验性中风模型。我们推测，组织来源的基质金属蛋白酶（MMPs）和血液中性粒细胞是必要的血管损伤，导致出血，有时，恶化的结果。我们计划通过研究以下两个具体目标来检验这一假设：1）确定中性粒细胞和组织MMPs对暂时性脑缺血后脑中微血管完整性破坏的贡献。2)评价血管保护策略对暂时性脑缺血的治疗效果。将使用大鼠再灌注出血模型实现这些特定目标，其中将严格评价中性粒细胞耗竭、MMP抑制、MMP酶谱和对比增强磁共振成像（MRI），以评估出血发展中的致病机制。将在三年内对总共189只动物进行研究。在完成上述实验时，我们期望充分了解中性粒细胞和组织来源的基质蛋白酶对脑血管破坏的相对贡献，以及可能具有血管保护作用并有助于改善结果的策略。总的来说，本提案中总结的研究的成功完成有望有助于开发使再灌注更安全的方法，从而使人类中风患者更容易获得再灌注。

DESCRIPTION (provided by applicant): Reperfusion therapy to reopen an occluded cerebral artery is the best chance that ischemic stroke patients have of making a full recovery. Despite this less than 5% of the more than 600,000 annual patients receive the therapy. One of the main barriers to the wide spread use is the fear of the 10X increase risk of severe brain hemorrhage, which can be fatal. There is an urgent need to develop strategies to reduce this risk. It is clear that ischemia damages brain blood vessels and, in some cases, this leads to brain hemorrhage. The objective of this research is to determine why the brain bleeds upon reperfusion and to evaluate ways to provide vascular protection in an experimental stroke model. We hypothesize that both tissue-derived matrix metalloproteinases (MMPs) and blood neutrophils are necessary for the blood vessel damage that leads to hemorrhage and sometimes, worsened outcome. We plan to test this hypothesis by investigating the following two specific aims: 1) Determine the contribution of neutrophils and tissue MMPs to the disruption of microvascular integrity in the brain following temporary cerebral ischemia. 2) Evaluate the therapeutic efficacy of vascular protection strategies for temporary cerebral ischemia. These specific aims will be achieved using a rat model of reperfusion hemorrhage in which neutrophil depletion, MMP inhibition, MMP zymography and contrast-enhanced magnetic resonance imaging (MRI) will be critically evaluated to assess pathogenic mechanisms operative in the development of hemorrhage. A total of 189 animals will be studied over a three year period. At the completion of the above experiments, we expect to have a full understanding of the relative contributions of neutrophils and tissue-derived matrix proteases to the destruction of the cerebral blood vessel and the strategies that are likely to be vascular protective and contribute to improved outcome. Collectively, the successful completion of the research summarized in this proposal can be expected to contribute to the development of methods to make reperfusion safer, and therefore more accessible, to human stroke patients.