Role of complement in TBI

补体在 TBI 中的作用

• 批准号: 10084230
• 负责人: Stephen Tomlinson
• 金额: --
• 依托单位: RALPH H JOHNSON VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10084230
• 关键词: Acute; Affect; Automobile Driving; Behavioral; Biological Availability; Brain; Brain Diseases; Brain Injuries; Cause of Death; Cells; Chronic; Chronic Phase; Clinical; Coculture Techniques; Cognitive; Complement; Complement 3; Complement 3d; Complement 3d Receptors; Complement Activation; Complement Inactivators; Complement Receptor; Cytometry; Data; Data Analyses; Deposition; Development; Disease; Gene Expression Profiling; Genes; Goals; Host Defense; Human; Immune; Impaired cognition; In Vitro; Inflammation; Inflammatory; Injury; Lead; Lectin; Lectin Inhibitor; Link; Macrophage-1 Antigen; Mechanics; Microglia; Microscopy; Military Personnel; Mus; Nerve Degeneration; Neurons; Opsonin; Outcome; Pathway interactions; Patients; Pattern; Phagocytosis; Phase; Phenotype; Play; Presynaptic Terminals; Process; Progress Reports; Recovery; Recovery of Function; Role; Site; Stroke; Synapses; Therapeutic; Therapeutic Agents; Time; Traumatic Brain Injury; Treatment outcome; Work; activation product; base; clinically relevant; cognitive recovery; complement pathway; complement system; controlled cortical impact; disability; high risk; improved; in vivo; infection risk; inhibitor/antagonist; injury and repair; macrophage; motor impairment; motor recovery; mouse model; nano-string; neuroinflammation; neuron loss; neuronal cell body; novel; novel therapeutics; post stroke; prevent; receptor; regenerative; spatiotemporal; stroke model; therapeutic target; therapeutically effective; tool

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.

初始机械侮辱后，创伤性脑损伤（TBI）的特征是次要的动态过程 涉及慢性神经炎症的损伤，与长期认知和运动有关 障碍。长期以来人们已经认识到，神经炎症是有害的，代表了一种治疗性 治疗TBI的目标。补体系统是炎症级联的核心组成部分，而 越来越多的证据表明补体在TBI后传播损伤方面起着重要作用， 补体还可以导致脑损伤后的稳态和修复机制。我们已经显示了 暂时性损伤部位的补体抑制是针对TBI和中风的保护 慢性阶段，不会干扰全身补体活动，也不会干扰修复和 再生机制。我们还显示了持续和高级补体激活长期激活， 这代表了防止持续炎症和伤害的治疗靶标。该提议建立在 这些发现。 补体激活有三种途径，并且有强大的实验和临床 凝集素途径在双中风后激活补体和驾驶伤害中起关键作用的证据 和TBI，尽管凝集素途径在TBI中的作用不太明确。我们的第一个和第二个目标是 研究补体激活凝集素途径在触发神经炎症和 TBI后促进神经变性。我们将使用小说在临床上相关的范式中实现这一目标 针对凝集素途径的靶向抑制剂。我们将使用中度至重度控制的鼠模型 皮质影响。研究仅针对凝集素途径的抑制剂的治疗原理 是，如果有效，抑制单个途径而不是所有途径将是有利的，因为 破坏正常免疫稳态过程和宿主防御的可能性较小。在目标3中，我们将 对补体如何在TBI之后驱动继发性伤害进行更详细的机械分析。 具体而言，我们将研究补体神经轴在神经退行性损失中的作用 神经元和突触。根据我们当前的数据，我们将研究以下假设。 依赖的微观激活和补体Opsonin指导的吞噬作用导致突触丧失和 神经元，这会导致认知和运动恢复受损，并且这些作用被逆转 补体抑制作用。