Role of complement in TBI

补体在 TBI 中的作用

• 批准号: 10589488
• 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 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10589488
• 关键词: Acute; Affect; Affective; Alzheimer' s Disease; Amygdaloid structure; Anatomy; Anti-Inflammatory Agents; Astrocytes; Automobile Driving; Brain; Brain Concussion; Brain Injuries; Brain region; CD11c Antigens; Cause of Death; Cells; Cerebrum; Characteristics; Chronic; Chronic Phase; Clinical; Closed head injuries; Cognitive; Cognitive deficits; Complement; Complement Receptor; Contusions; Cytometry; Data; Dementia; Diffuse; Disease; Functional disorder; Gender; Genetic Transcription; Growth Factor; Hippocampus; Immune; Immunologics; Impaired cognition; Inflammation; Inflammation Mediators; Inflammatory Response; Injury; Knockout Mice; Ligands; Link; Magnetic Resonance Imaging; Mediating; Microglia; Military Personnel; Modeling; Molecular; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neuroimmune; Neurologic; Neurons; Outcome; Pathologic; Pathology; Pathway interactions; Patients; Performance; Peripheral; Phagocytosis; Play; Prefrontal Cortex; Production; Proteins; Reporting; Risk Factors; Risk Reduction; Role; Serum; Source; Synapses; Synaptic plasticity; System; Therapeutic; Time; Transgenic Mice; Traumatic Brain Injury; Veterans; Work; age related; blood-brain barrier function; burden of illness; cell type; chronic traumatic encephalopathy; clinically relevant; complement system; controlled cortical impact; dementia risk; design; disability; early onset; executive function; experience; follow-up; high risk; imaging study; immune cell infiltrate; immunomodulatory therapies; improved; individualized medicine; nervous system disorder; neurobehavioral; neurobehavioral test; neuroinflammation; neuron loss; novel; post intervention; prevent; receptor; regional difference; response; tau Proteins; therapy design; treatment strategy

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.

创伤性脑损伤(TBI)是导致神经系统疾病的主要危险因素。 对归来的退伍军人进行临床随访的累积证据表明，至少有2-4次 与匹配的非颅脑损伤退伍军人相比，患痴呆症和认知能力下降的风险更高。这个 目前对脑外伤后痴呆的干预措施有限，目前还没有治疗方法 已被证明可以预防、阻止或逆转经历过以下情况的患者的认知能力下降 轻度或重度颅脑损伤。越来越多的证据表明，慢性神经免疫/炎症 颅脑损伤诱导的反应在神经退行性变的病理生理学中起核心作用 精神错乱。然而，这种反应在不同类型的脑损伤之间可能有很大的差异，并且可以 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损伤后慢性发生和发展的反应 脑震荡损伤。补体系统是炎症的关键介质，而补体系统是 这一建议是补体在慢性神经免疫反应和 在这些不同类型的大脑侮辱后发生的神经退化。理解 脑外伤后神经免疫反应的差异，以及地区差异，将使 设计适当定制的疗法，包括补体抑制疗法，根据 与受伤的类型和阶段有关。总体而言，这项提案的目的是调查 与脑震荡损伤相比，挫伤后病理生理区域反应中的补体 比较挫伤和脑震荡损伤后的神经行为结果，并确定 与创伤后神经炎和病理学的关系，最后调查 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 挫伤或脑震荡损伤后慢性病理中的受体。

项目成果

Complement Component 5 (C5) Deficiency Improves Cognitive Outcome After Traumatic Brain Injury and Enhances Treatment Effects of Complement Inhibitors C1-Inh and CR2-Crry in a Mouse Model.

• DOI: 10.1089/neur.2023.0024
• 发表时间: 2023
• 期刊: NEUROTRAUMA REPORTS
• 影响因子: 2.4
• 作者: Chen, Min;Edwards, Stephen R.;Maskey, Dhiraj;Woodruff, Trent M.;Tomlinson, Stephen;Reutens, David
• 通讯作者: Reutens, David