COMPLEMENT-MEDIATED NEURONAL INJURY IN STROKE

描述（由申请人提供）：相当大的兴趣集中在阐明中风后进行性细胞死亡的发病机制，以及最近确定负责组织修复/恢复的机制，以期确定相关的治疗靶点。一个受到越来越多关注的潜在靶点是补体级联。尽管最初的数据表明补体介导的脑损伤主要是通过C1q介导的，但随后对缺失突变小鼠和非人灵长类动物的研究表明，完全阻断C3对成年动物的神经保护至关重要。不幸的是，直到最近我们才能够产生特定的C3抑制剂。这些工具，加上对补体，特别是C3的越来越多的认识，在清除死亡/垂死细胞以及内源性神经发生中发挥着重要作用，使我们假设：(1) C3激活导致中风后数小时内进行性组织损伤，但其最终在细胞清除和神经发生中的作用可能对功能结果产生积极影响；(2)精心定制的、高度特异性的抗C3策略最终将被证明比非特异性策略更安全、更有效，尤其是在与常规抗血小板、抗血栓形成和纤溶药物一起使用时。为了解决这些假设，以开发临床相关疗法为目标，实验将：(1)研究C3阻断剂的神经保护作用是否主要通过C3a-C3a受体介导，(2)检查C3阻断剂在多大程度上以及在什么条件下改变：(a)凋亡/坏死细胞清除，(b)炎症消退，(c)内源性神经发生。

DESCRIPTION (provided by applicant): Considerable interest has been focused on elucidating the pathogenesis of progressive cell death following stroke, and more recently on identifying the mechanisms responsible for tissue repair/recovery, in hopes of identifying relevant therapeutic targets. One potential target that has received increasing attention is the complement cascade. Despite initial data suggesting that complement-mediated cerebral injury was principally mediated through C1q, subsequent studies in deletionally mutant mice and non-human primates suggest that complete C3 blockade is critical for neuroprotection in adult animals. Unfortunately, only recently have we been able to generate specific C3 inhibitors. These tools, together with an increasing appreciation that complement, and specifically C3, play an important role in the clearance of dead/dying cells, as well in endogenous neurogenesis, lead us to hypothesize: (1) that C3 activation results in progressive tissue injury in the hours following stroke, but that ultimately its role in cell clearance and neurogenesis may exert positive effects on functional outcome, and (2) that carefully tailored, and highly specific, anti-C3 strategies will ultimately prove safer and more efficacious than non-specific strategies especially when administered together with routinely utilized anti-platelet, anti-thrombotic and fibrinolytic medications. To address these hypotheses, with the goal of developing clinically relevant therapies, experiments will: (1) investigate whether the neuroprotective effect of C3 blockade is predominantly mediated through C3a-C3a receptor, and (2) examine to what degree, and under what conditions C3-blockade alters: (a) apoptotic/necrotic cell clearance, (b) the resolution of inflammation, and (c) endogenous neurogenesis.