COMPLEMENT-MEDIATED NEURONAL INJURY IN STROKE

描述(申请人提供)：相当大的兴趣集中在阐明卒中后进行性细胞死亡的发病机制上，最近还集中在确定组织修复/恢复的机制上，希望确定相关的治疗靶点。一个受到越来越多关注的潜在目标是补充级联。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，但随后对缺失突变的小鼠和非人类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，再加上人们对补体，尤其是补体C3，在清除死亡/死亡细胞以及内源性神经发生方面发挥的重要作用的日益认识，使我们假设：(1)C3激活在中风后几个小时内会导致进行性组织损伤，但最终其在细胞清除和神经发生中的作用可能会对功能结局产生积极影响，(2)精心定制和高度特异的抗C3策略最终将被证明比非特异性策略更安全和有效，尤其是当与常规使用的抗血小板、抗血栓和纤溶药物一起使用时。为了解决这些假说，为了开发临床相关的治疗方法，实验将：(1)研究C3阻断的神经保护作用是否主要通过C3a-C3a受体介导，以及(2)检查C3阻断在何种程度和条件下改变：(A)凋亡/坏死细胞清除，(B)炎症消退，以及(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.