Targeting complement and chronic inflammation after traumatic brain injury

针对脑外伤后的补体和慢性炎症

• 批准号: 9235500
• 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: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9235500
• 关键词: Acute; Aftercare; Alternative Complement Pathway; Antibodies; Area; Binding; Binding Sites; Brain; Brain Injuries; Cause of Death; Characteristics; Chronic; Chronic Phase; Cognitive; Complement; Complement 3d Receptors; Complement Activation; Complement Factor H; Data; Deposition; Development; Encephalitis; Environment; Epitopes; Housing; Immunoglobulin M; Immunosuppressive Agents; Impaired cognition; Inflammation; Inflammatory; Inflammatory Response; Injury; Ischemic Stroke; Lead; Ligands; Link; Maintenance; Mechanics; Military Personnel; Modeling; Molecular; Motor; Mus; Neuronal Plasticity; Outcome; Outcome Measure; Pathogenesis; Pathologic; Pathway interactions; Patients; Pattern; Phase; Pilot Projects; Play; Process; Recovery of Function; Rehabilitation therapy; Research; Role; Site; Specificity; Staging; Stroke; System; Therapeutic; Therapeutic Agents; Traumatic Brain Injury; Treatment Protocols; Treatment outcome; Work; activation product; base; cognitive recovery; cognitive rehabilitation; complement pathway; controlled cortical impact; disability; drug candidate; experience; improved; inhibitor/antagonist; injury and repair; motor impairment; motor recovery; motor rehabilitation; mouse model; neuroinflammation; novel therapeutics; post stroke; preclinical evaluation; primary outcome; rehabilitation strategy; response; standard of care; targeted treatment; therapeutic target

After initial mechanical insult, Traumatic Brain Injury (TBI) is characterized by a dynamic process of secondary injury that involves chronic neuroinflammation which is implicated in long-term cognitive and motor impairments and impacts recovery of function. Complement activation is a major component of the inflammatory cascade, and there is increasing evidence that complement plays a role in propagating injury after TBI, at least in the acute phase. However, complement can also contribute to homeostatic and reparative mechanisms after brain injury, and we have demonstrated in a stroke model that the alternative pathway is an optimal target for therapy because its inhibition reduces pathologic amplification of complement activation, but does not interfere with other complement pathways thought to be important for maintenance of homeostatic activity and reparative mechanisms in the CNS. Based on our work in stroke models and preliminary data in a TBI model, in this pilot study we will investigate the characteristics of the chronic inflammatory response after murine TBI (controlled cortical impact, CCI) and investigate the effects of chronically administered alternative complement pathway inhibitors that are specifically targeted to the site of brain injury by different strategies. In addition, based on our data showing a cooperative effect of complement inhibition and rehabilitation therapy, we will determine the effects of combining site-targeted complement modulation and rehabilitation therapy on long-term cognitive and motor recovery after murine CCI. Successful accomplishment of our aims will provide a strong rationale and establish the feasibility for a Merit proposal for detailed mechanistic studies into the role of C in the chronic neuroinflammatory response after TBI, and the role of the neuroinflammatory response in brain injury, repair and experience-driven (rehab) neural plasticity. These studies will also set the stage for a more detailed preclinical evaluation of an identified candidate drug.

在最初的机械损伤之后，创伤性脑损伤 (TBI) 的特点是继发性机械损伤的动态过程。 涉及慢性神经炎症的损伤，与长期认知和运动有关 损伤并影响功能恢复。补体激活是补体的主要组成部分 炎症级联反应，并且越来越多的证据表明补体在传播损伤中发挥作用 TBI 后，至少在急性期。然而，补体也有助于体内平衡和修复 脑损伤后的机制，我们已经在中风模型中证明了替代途径是 治疗的最佳目标，因为它的抑制减少了补体激活的病理放大，但是 不干扰其他被认为对维持体内平衡很重要的补体途径 中枢神经系统的活动和修复机制。基于我们在中风模型方面的工作和初步数据 TBI模型，在这项初步研究中我们将研究TBI模型后慢性炎症反应的特征 小鼠 TBI（受控皮质冲击，CCI）并研究长期施用替代疗法的效果 通过不同策略专门针对脑损伤部位的补体途径抑制剂。在 此外，根据我们的数据显示补体抑制和康复治疗的协同作用， 我们将确定结合位点靶向补体调节和康复治疗的效果 小鼠 CCI 后的长期认知和运动恢复。成功实现我们的目标将提供 强有力的理由，并为对该作用进行详细机制研究的优点提案建立可行性 C在TBI后慢性神经炎症反应中的作用，以及神经炎症反应在TBI后慢性神经炎症反应中的作用 脑损伤、修复和经验驱动（康复）神经可塑性。这些研究也将为 对已确定的候选药物进行更详细的临床前评估。