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.

创伤性脑损伤（TBI）在初次机械性损伤后，其特征是继发性脑损伤的动态过程。 涉及慢性神经炎症并与长期认知和运动有关的损伤 损伤长期以来，人们已经认识到神经炎症是有害的，并且代表了治疗性的。 治疗TBI的目标。补体系统是炎症级联反应的中心组成部分， 越来越多的证据表明补体在TBI后的损伤传播中起重要作用， 补体还可有助于脑损伤后的稳态和修复机制。我们已经表明 短暂的损伤位点靶向补体抑制通过以下途径对TBI和中风具有保护作用： 慢性期，不干扰全身补体活性，不干扰修复和 再生机制我们还显示了持续和高水平的补体激活慢性， 这代表了预防持续炎症和损伤的治疗目标。该提案基于 这些发现。 补体激活有三种途径，并且有很强的实验和临床意义。 有证据表明，凝集素途径在激活补体和驾驶损伤后， 和TBI，尽管凝集素途径在TBI中的作用还不太清楚。我们的第一和第二个目标是 研究补体激活的凝集素途径在触发神经炎症中的作用， 促进脑外伤后的神经退化我们将在临床相关的范例中使用一种新的方法来实现这一点。 对凝集素途径特异的靶向抑制剂。我们将使用中度至重度对照的小鼠模型， 皮质撞击研究仅对凝集素途径具有特异性的抑制剂的治疗原理 如果有效，抑制单一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， 对补体如何驱动TBI后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丢失中的作用， 神经元和突触。根据我们目前的数据，我们将研究补充的假设- 依赖性的小胶质细胞活化和补体调理素介导的吞噬作用导致突触的丧失， 神经元，导致认知和运动恢复受损，这些影响可以通过 补体抑制