Targeting complement and chronic inflammation after traumatic brain injury
针对脑外伤后的补体和慢性炎症
基本信息
- 批准号:9235500
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AcuteAftercareAlternative Complement PathwayAntibodiesAreaBindingBinding SitesBrainBrain InjuriesCause of DeathCharacteristicsChronicChronic PhaseCognitiveComplementComplement 3d ReceptorsComplement ActivationComplement Factor HDataDepositionDevelopmentEncephalitisEnvironmentEpitopesHousingImmunoglobulin MImmunosuppressive AgentsImpaired cognitionInflammationInflammatoryInflammatory ResponseInjuryIschemic StrokeLeadLigandsLinkMaintenanceMechanicsMilitary PersonnelModelingMolecularMotorMusNeuronal PlasticityOutcomeOutcome MeasurePathogenesisPathologicPathway interactionsPatientsPatternPhasePilot ProjectsPlayProcessRecovery of FunctionRehabilitation therapyResearchRoleSiteSpecificityStagingStrokeSystemTherapeuticTherapeutic AgentsTraumatic Brain InjuryTreatment ProtocolsTreatment outcomeWorkactivation productbasecognitive recoverycognitive rehabilitationcomplement pathwaycontrolled cortical impactdisabilitydrug candidateexperienceimprovedinhibitor/antagonistinjury and repairmotor impairmentmotor recoverymotor rehabilitationmouse modelneuroinflammationnovel therapeuticspost strokepreclinical evaluationprimary outcomerehabilitation strategyresponsestandard of caretargeted treatmenttherapeutic target
项目摘要
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.
创伤性脑损伤(TBI)在最初的机械损伤后,其特征在于继发性脑损伤的动态过程。
涉及慢性神经炎症的损伤,涉及长期的认知和运动
损伤和影响功能恢复。补体激活是免疫系统的主要组成部分。
越来越多的证据表明,补体在传播损伤中起作用
至少在急性期。然而,补体也可以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一种神经保护机制。
最佳治疗靶点,因为它的抑制减少了补体激活的病理性放大,
不干扰被认为对维持稳态重要的其他补体途径
中枢神经系统的活性和修复机制。基于我们在中风模型中的工作和在一个
TBI模型,在这项初步研究中,我们将调查的特点,慢性炎症反应后,
小鼠TBI(控制皮质撞击,CCI),并研究长期给予替代治疗的效果。
补体途径抑制剂通过不同的策略特异性靶向脑损伤部位。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对
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
一个强有力的理由,并建立一个Merit建议的可行性,详细的机制研究的作用
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、修复和经验驱动的神经可塑性。这些研究也将为一个
更详细的临床前评估已确定的候选药物。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
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Stephen Tomlinson其他文献
Stephen Tomlinson的其他文献
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{{ truncateString('Stephen Tomlinson', 18)}}的其他基金
The role of complement in chronic neuroinflammation and cognitive decline after closed head brain injury
补体在闭合性脑损伤后慢性神经炎症和认知能力下降中的作用
- 批准号:
10641096 - 财政年份:2023
- 资助金额:
-- - 项目类别:
BLR&D Research Career Scientist Award Application for Dr. Stephen Tomlinson
BLR
- 批准号:
10618250 - 财政年份:2020
- 资助金额:
-- - 项目类别:
BLR&D Research Career Scientist Award Application for Dr. Stephen Tomlinson
BLR
- 批准号:
10451506 - 财政年份:2020
- 资助金额:
-- - 项目类别:
Cell survival in engineered skeletal muscle: The role of complement
工程骨骼肌中的细胞存活:补体的作用
- 批准号:
10189582 - 财政年份:2019
- 资助金额:
-- - 项目类别:
Cell survival in engineered skeletal muscle: The role of complement
工程骨骼肌中的细胞存活:补体的作用
- 批准号:
10017965 - 财政年份:2019
- 资助金额:
-- - 项目类别:
Cell survival in engineered skeletal muscle: The role of complement
工程骨骼肌中的细胞存活:补体的作用
- 批准号:
10449327 - 财政年份:2019
- 资助金额:
-- - 项目类别:
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