Role of complement in TBI

创伤性脑损伤在最初的机械损伤后，表现为继发性损伤的动态过程。 涉及慢性神经炎的损伤，并与长期的认知和运动有关 减损。长期以来，人们一直认为神经炎是有害的，是一种治疗方法。 脑外伤的治疗靶点。补体系统是炎症级联反应的中心组成部分，虽然 越来越多的证据表明，补体在颅脑损伤后的传播性损伤中发挥了重要作用。 补体也有助于脑损伤后的体内平衡和修复机制。我们已经展示了 短暂性损伤部位靶向补体抑制对脑损伤和中风都有保护作用，这是通过 慢性期，不干扰系统补体活动，也不干扰修复性和 再生机制。我们还展示了慢性持续和高水平的补体激活， 这代表了预防持续炎症和损伤的治疗目标。这项建议的基础是 这些发现。 补体激活有三条途径，有很强的实验和临床依据 有证据表明凝集素途径在激活补体和两次中风后的驾驶损伤中起关键作用 和脑损伤，尽管凝集素途径在脑损伤中的作用还不是很清楚。我们的第一个和第二个目标是 探讨补体激活的凝集素途径在引发神经炎症和 促进脑外伤后神经退行性变。我们将在临床相关的范例中使用一种新的 凝集素途径的靶向抑制物。我们将使用一个中度到重度受控的小鼠模型 大脑皮层撞击。研究一种仅针对凝集素途径的抑制剂的治疗原理 如果有效，抑制单个途径而不是所有途径将是有利的，因为有 不太可能破坏正常的免疫动态平衡过程和宿主防御。在《目标3》中，我们将 对补体如何驱动颅脑损伤后继发性损伤进行更详细的机制分析。 具体地说，我们将研究补体-小胶质细胞轴在神经退行性变中的作用。 神经元和突触。基于我们目前的数据，我们将调查补体- 依赖的微血管激活和补体调理蛋白导向的吞噬作用导致突触和 神经元，这会导致认知和运动恢复受损，这些影响可以通过 补体抑制。

After initial mechanical insult, traumatic brain injury (TBI) is characterized by a dynamic process of secondary injury that involves chronic neuroinflammation and which is implicated in long-term cognitive and motor impairments. It has long been recognized that neuroinflammation is injurious and represents a therapeutic target for treating TBI. The complement system is a central component of the inflammatory cascade, and while there is increasing evidence that complement plays an important role in propagating injury after TBI, complement can also contribute to homeostatic and reparative mechanisms after brain injury. We have shown that transient injury site-targeted complement inhibition is protective against both TBI and stroke through the chronic phase, does not interfere with systemic complement activity, and does not interfere with reparative and regenerative mechanisms. We have also shown continued and high-level complement activation chronically, and this represents a therapeutic target to prevent ongoing inflammation and injury. This proposal builds on these findings. There are three pathways of complement activation, and there is strong experimental and clinical evidence that the lectin pathway plays a key role in activating complement and driving injury after both stroke and TBI, although the role of the lectin pathway in TBI is less well defined. Our first and second aims are to investigate the role of the lectin pathway of complement activation in triggering neuroinflammation and promoting neurodegeneration after TBI. We will accomplish this in a clinically relevant paradigm using a novel targeted inhibitor specific for the lectin pathway. We will use a murine model of moderate to severe controlled cortical impact. The therapeutic rationale for investigating an inhibitor that is specific for only the lectin pathway is that if effective, it will be advantageous to inhibit a single pathway rather than all pathways, since there is less likelihood of disrupting normal immune homeostatic processes and host defense. In aim 3 we will undertake a more detailed mechanistic analysis of how complement drives secondary injury after TBI. Specifically, we will investigate the role of a complement-microglial axis in the neurodegenerative loss of neurons and synapses. Based on our current data, we will investigate the hypothesis that complement- dependent microlgial activation and complement opsonin-directed phagocytosis results in loss of synapses and neurons, which results in impaired cognitive and motor recovery, and that these effects are reversed by complement inhibition.