MMP-12 and post-stroke brain damage

项目摘要/摘要 目前，组织型纤溶酶原激活剂(TPA)是FDA批准的唯一一种治疗中风的药物。TPA确立 血栓溶栓再通，但只有一小部分患者有资格接受tPA治疗。此外， TPA治疗前后的脑损伤仍是临床上尚未满足的需求。确定新的 治疗靶点有助于开发新的和有效的药物来减少中风后的继发性脑损伤。 我们最近的研究表明，在再灌注过程中，基质金属蛋白酶-12(MMP12)的升高 啮齿类动物短暂性局灶性脑缺血可导致血脑屏障损伤、细胞凋亡和脑梗塞。我们 目前的假设是，基质金属蛋白酶-12的诱导有助于卒中后的病理生理和 会影响神经系统的结果。目的1是研究基质金属蛋白酶-12在卒中后脑中的作用 男性和女性以及第二个物种的损伤和神经恢复。目标2是 揭开基质金属蛋白酶-12的来源，阐明基质金属蛋白酶-12诱导脑损伤的分子机制 中风后的损伤。目的3探讨老年患者脑缺血后抑制基质金属蛋白酶-12的疗效 动物和患有高血压的动物。我们将使用最先进的技术，包括shRNA介导的 纳米粒载体介导的靶基因敲除，大脑中动脉缝合模型 闭塞程序，流式细胞仪分析，和透射电子显微镜来执行建议的 实验。该项目的长期目标是开发中风后疗法，调节基质金属蛋白酶-12以 预防继发性脑损伤，促进神经功能恢复。

Project Summary/Abstract At present, tissue-type plasminogen activator (tPA) is the only FDA approved stroke therapy. tPA establishes reperfusion by thrombolysis of clots, but only a small subset of patients is eligible for tPA therapy. Moreover, the brain damage that occurs before and after tPA therapy is still an unmet clinical need. Identifying new therapeutic targets helps in developing novel and potent drugs to curtail post-stroke secondary brain damage. Our recent studies have shown that elevation of matrix metalloproteinase-12 (MMP-12) during reperfusion following transient focal ischemia in rodents contributes to BBB damage, apoptosis, and brain infarction. We currently hypothesize that the induction of MMP-12 contributes to post-stroke pathophysiology and compromises the neurologic outcome. Aim 1 is to characterize the role of MMP-12 in post-stroke brain damage and neurological recovery in both males and females as well as in a second species. Aim 2 is to unravel the source of MMP-12 and elucidate the molecular mechanisms underlying MMP-12-induced brain damage after stroke. Aim 3 is to investigate the efficacy of post-ischemic MMP-12 suppression in aged animals and animals with hypertension. We will use state of the art techniques including the shRNA-mediated knockdown of target genes by nanoparticle-mediated delivery of plasmids, suture model middle cerebral artery occlusion procedure, FACS analysis, and transmission electron microscopy to execute the proposed experiments. The long-term goal of this project is to develop post-stroke therapies that modulate MMP-12 to prevent secondary brain damage and promote neurological recovery.