Role of complement in TBI

补体在 TBI 中的作用

• 批准号: 10436780
• 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/10436780
• 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; 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.

初次机械损伤后，创伤性脑损伤 (TBI) 的特点是继发性机械损伤的动态过程。 涉及慢性神经炎症并与长期认知和运动有关的损伤 损伤。人们很早就认识到神经炎症是有害的，并且是一种治疗方法 治疗 TBI 的目标。补体系统是炎症级联反应的核心组成部分，同时 越来越多的证据表明补体在 TBI 后损伤的传播中发挥着重要作用， 补体还有助于脑损伤后的体内平衡和修复机制。我们已经展示了 短暂损伤部位靶向补体抑制可通过以下途径预防 TBI 和中风 慢性期，不干扰全身补体活性，也不干扰修复和 再生机制。我们还长期显示出持续的高水平补体激活， 这代表了预防持续炎症和损伤的治疗目标。该提案建立在 这些发现。 补体激活有3条途径，有较强的实验和临床依据 有证据表明，凝集素途径在两次中风后激活补体和驱动损伤中发挥关键作用 和 TBI，尽管凝集素途径在 TBI 中的作用尚不明确。我们的第一个和第二个目标是 研究补体激活的凝集素途径在触发神经炎症中的作用 促进 TBI 后的神经退行性变。我们将使用一种新颖的临床相关范例来实现这一目标 凝集素途径特异性的靶向抑制剂。我们将使用中度至重度控制的小鼠模型 皮质影响。研究仅针对凝集素途径的抑制剂的治疗原理 是如果有效的话，抑制单一途径而不是所有途径将是有利的，因为有 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 后驱动继发性损伤进行更详细的机制分析。 具体来说，我们将研究补体-小胶质细胞轴在神经退行性丧失中的作用 神经元和突触。根据我们当前的数据，我们将研究以下假设： 依赖的微胶质激活和补体调理素引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，并且这些影响可以通过 补体抑制。