Role of complement in TBI

创伤性脑损伤（TBI）是发展神经系统疾病的主要危险因素。 对退伍军人进行临床随访的累积证据表明， 与匹配的非TBI退伍军人相比，痴呆和认知能力下降的风险更高。的 目前针对TBI后痴呆症的干预措施有限，而且目前还没有治疗方法， 已经证明可以预防、阻止或逆转经历过以下任一情况的患者的认知能力下降： 轻度或重度TBI。越来越多的证据表明，慢性神经免疫/炎症 TBI诱导的反应在神经退行性疾病的病理生理学中起着重要作用， 紊乱然而，这种反应在不同类型的脑损伤之间差异很大， 在受伤后的不同阶段有所不同。我们建议研究神经免疫/炎症 严重局灶性挫伤与轻度弥漫性挫伤相比， 震荡性损伤补体系统是炎症的关键介质，并且补体系统的焦点是炎症。 该建议是补体在慢性神经免疫应答中的作用， 在这些不同类型的脑损伤后发生的神经变性。理解 TBI后神经免疫反应的差异以及区域差异将允许 根据规定，设计适当定制的疗法，包括补体抑制疗法 受伤的类型和阶段总的来说，本提案的目的是调查 在挫伤与震荡性损伤后的病理生理学区域反应中的补充， 比较挫伤与脑震荡损伤后的神经行为结果， 与创伤后神经炎症和病理学的关系，最后研究 中枢神经系统衍生补体与外周补体以及免疫细胞补体的作用 受体在挫伤或震荡损伤后慢性病理中的作用。

Traumatic brain injury (TBI) is a major risk factor for developing neurological disorders. Cumulative evidence from clinical follow-up of returning Veterans demonstrate at least 2-4 times higher risk of dementia and cognitive decline compared to matched non-TBI Veterans. The current interventions for post-TBI dementia are limited, and there are currently no therapies that have shown to prevent, stop, or reverse cognitive decline in patients who have experienced either mild or severe TBI. There is increasing evidence that a chronic neuroimmune/inflammatory response induced by TBI plays a central role in the pathophysiology of neurodegenerative disorders. However, this response can vary greatly between different types of brain injury and can vary at different stages after injury. We propose to investigate the neuroimmune/inflammatory response that occurs and develops chronically after severe focal contusion injury vs. mild diffuse concussive injury. The complement system is a key mediator of inflammation, and the focus of this proposal is the role of complement in chronic neuroimmune responses and neurodegeneration that occurs after these different types of brain insults. Understanding differences in post-TBI neuroimmune responses, as well as regional differences, will permit the design of appropriately tailored therapies, including complement inhibitory therapies, according to the type and stage of injury. Overall, the aims of this proposal are to investigate the role of complement in pathophysiological regional responses after contusion versus concussive injuries, to compare neurobehavioral outcomes after contusion versus concussive injuries and determine associations with post-traumatic neuroinflammation and pathology, and finally to investigate the role of CNS derived complement vs. peripheral complement, as well as immune cell complement receptors in chronic pathology after either contusion or concussive injuries.