Novel therpeautic interventions to treat ischemic stroke

项目摘要 中风造成巨大的健康和经济负担。目前改善卒中结局的策略是 使用组织纤溶酶原激活剂和机械血栓切除术（包括 缺血区域的再灌注。然而，越来越多的证据表明，脑再灌注是 通常伴有氧化应激、血栓形成和血管炎症， 在缺血半暗带死亡。目前还没有有效的干预措施来保护大脑 再灌注治疗后的损伤。临床研究表明， 再灌注后中性粒细胞的大量流入和损伤的严重程度。整合素α 9 β 1是高度 在中性粒细胞上表达（相对于单核细胞），在活化和迁移时上调， 已知与α 2 β 1整联蛋白协同作用稳定中性粒细胞粘附于活化的内皮。的 α 9 β 1在中风结果中的机械作用还没有研究。利用新的突变菌株，中试 研究中，我们发现α 9 β 1通过调节血栓形成和血管生成， 炎症根据更新的卒中治疗学术行业圆桌会议（STAIR）临床前 指南和令人信服的试点数据，我们建议测试创新的假设，整合素α 9 β 1 在伴有合并症和治疗靶向的卒中模型中导致缺血性卒中加重 α 9 β 1将通过限制血栓形成和炎症来改善中风结果。为了做到这一点，我们 将利用互补的遗传学和药理学方法，最先进的活体显微镜， 磁共振成像、激光散斑成像，并遵循当前的STAIR/RIGOR指南。老化和 生物学性别是影响卒中结局的关键决定因素。我们将决定是否针对 α 9 β 1将在生物性别和衰老的背景下改善卒中结局， 效果可以推广到更广泛的背景。该项目可能具有重要的临床意义， 了解中性粒细胞在卒中模型中促进再灌注损伤的机制， 合并症可能为缺血性卒中的治疗提供新的干预措施。

Project Summary Stroke results in immense health and economic burden. Current strategies to improve stroke outcome is fibrinolysis of the clot with tissue plasminogen activator and mechanical thrombectomy, which involves reperfusion of the ischemic region. However, accumulating evidence suggests that cerebral reperfusion is often accompanied by oxidative stress, thrombosis, and vascular inflammation, which exacerbates neuronal death in the ischemic penumbra. There is currently no effective intervention available to protect the brain damage following reperfusion therapy. Clinical studies have shown a positive correlation between the massive influx of neutrophils and severity of injury following reperfusion. Integrin alpha9beta1 is highly expressed on neutrophils (relative to monocytes), upregulated upon activation and transmigration, and is known to stabilize neutrophil adhesion to activated endothelium in synergy with alpha2beta1 integrin. The mechanistic role of alpha9beta1 in stroke outcome is not explored yet. Utilizing novel mutant strains, in pilot studies, we found that alpha9beta1 exacerbates stroke outcome by modulating thrombosis and vascular inflammation. Following updated Stroke Therapy Academic Industry Roundtable (STAIR) pre-clinical guidelines and compelling pilot data, we propose to test the innovative hypothesis that integrin alpha9beta1 contributes to ischemic stroke exacerbation in stroke models with comorbidities and therapeutic targeting alpha9beta1 will improve stroke outcome by limiting thrombosis and inflammation. To accomplish this, we will utilize complementary genetic and pharmacological approaches, state-of-the-art intravital microscopy, magnetic resonance imaging, laser speckle imaging and follow current STAIR/RIGOR guidelines. Aging and biological sex are key determinants that influence stroke outcome. We will determine whether targeting alpha9beta1 will improve stroke outcome in the context of biological sex and aging so that the observed effect is generalizable to the broader context. This project may have significant clinical implications since understanding the mechanisms by which neutrophils contribute to reperfusion injury in stroke models with comorbidities may provide new therapeutic interventions to treat ischemic stroke.