Complement inhibition as sepsis therapy
补体抑制作为败血症治疗
基本信息
- 批准号:8466739
- 负责人:
- 金额:$ 50.28万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-08-02 至 2015-04-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAdverse effectsAnimal ModelAnimalsAntibiotic TherapyAntibioticsAntibodiesAttenuatedBacteremiaBacteriaBasic ScienceBedsBiochemicalBiological PreservationBlood PressureCD14 geneCessation of lifeClinicClinicalClinical ResearchCoagulation ProcessCombined Modality TherapyComplementComplement 3 ConvertaseComplement ActivationComplement InactivatorsDefense MechanismsDiseaseDisease ProgressionDisease modelDoseElectron MicroscopyEquilibriumEscherichia coliEventFamily suidaeFunctional disorderGenomicsGoalsHistonesHumanImaging TechniquesImmune responseIn VitroInflammationInflammatoryInflammatory ResponseInfusion proceduresInvadedIschemiaKidneyLeadLectinLifeLiverLungModelingMorbidity - disease rateMultiple Organ FailureOrganOrgan failureOutcomePapioPathogenesisPathologyPathway interactionsPatientsPerfusionPlayProcessRecombinantsRecoveryRegimenReperfusion InjuryReperfusion TherapyResearchRodentRoleSepsisSeptic ShockSeriesStagingSystemTestingTherapeutic EffectThrombocytopeniaThrombomodulinTimeTissuesToxic effectTranslationsWhole BloodWorkactivation productbasecDNA Arrayscomplement systemcompstatineffective therapyextracellularhuman diseaseimmunocytochemistryimprovedinhibitor/antagonistmicrobialmortalitynovel therapeuticspathogenpreventprotective effectresponse
项目摘要
DESCRIPTION (provided by applicant): Severe sepsis leads to systemic inflammation, wherein coagulation and complement activation play critical roles. Evidence from patients and animal models suggest that sepsis is a multi-stage, multi-factorial disease in which the early fulminate inflammatory response to the invading bacteria leads to hypo-perfusion and ischemia-reperfusion (IR) injury that evolves to multiple organ failure (MOF) and ultimately to death. Work from our lab has demonstrated that severe sepsis induced in animals by using sublethal doses of E. coli develops as two-stage series of events, each stage being driven by different pathophysiologies. First stage events are caused by the direct effects of the pathogen, whereas the second stage occurs as result of an aberrant host recovery after IR. The objectives of this proposal are to investigate whether inhibition of complement activation alone or as combination therapies could prevent MOF and improve the outcome of sepsis. Aim 1 will use a C3 convertase inhibitor to determine the role of complement during each of the two stages of sepsis, assess complement activation as a potential cause of thrombocytopenia in sepsis and identify organ- specific protective effects of complement inhibition during sepsis progression. This research will employ cDNA microarray, immunocytochemistry, electron microscopy and biochemical analysis of vital organs to identify the effect of complement activation products on the dominant pathophysiologic processes controlling the progression of sepsis. Aim 2 will determine if, and through what mechanisms, complement inhibition by the recombinant lectin-like domain of thrombomodulin (TM-LLD) could prevent organ failure and improve outcome in our sepsis model. Aim 3 will determine whether combining complement blockade with immunological inhibition of CD14 or extracellular histones could provide superior/additional effects therapeutic effects on E. coli sepsis as compared to complement inhibition alone. This project has potential to advance our understanding of the role of complement activation in sepsis progression and to test whether complement inhibition could be used as effective therapy for sepsis-induced organ failure. )
描述(由申请方提供):严重脓毒症导致全身性炎症,其中凝血和补体激活起关键作用。来自患者和动物模型的证据表明,脓毒症是一种多阶段、多因素的疾病,其中对入侵细菌的早期暴发性炎症反应导致低灌注和缺血再灌注(IR)损伤,其演变为多器官衰竭(MOF)并最终导致死亡。本实验室的工作已经证明,用亚致死剂量的E.大肠杆菌作为两阶段系列事件发展,每个阶段由不同的病理生理学驱动。第一阶段的事件是由病原体的直接影响,而第二阶段发生的结果异常主机恢复后IR。本建议的目的是调查是否抑制补体激活单独或联合治疗可以防止MOF和改善脓毒症的结果。 目的1将使用C3转化酶抑制剂来确定补体在脓毒症的两个阶段中的每一个阶段中的作用,评估补体活化作为脓毒症中血小板减少症的潜在原因,并鉴定脓毒症进展期间补体抑制的器官特异性保护作用。本研究将采用基因芯片,免疫细胞化学,电子显微镜和生化分析的重要器官,以确定补体激活产物的影响,占主导地位的病理生理过程控制脓毒症的进展。目的2将确定重组凝血调节蛋白凝集素样结构域(TM-LLD)的补体抑制作用是否以及通过何种机制可以预防脓毒症模型中的器官衰竭并改善结局。目的3将确定将补体阻断与CD 14或细胞外组蛋白的免疫抑制相结合是否可以对大肠杆菌提供上级/额外的效果。大肠杆菌脓毒症与单独的补体抑制相比。该项目有可能促进我们对补体激活在脓毒症进展中的作用的理解,并测试补体抑制是否可用作脓毒症诱导的器官衰竭的有效治疗。)
项目成果
期刊论文数量(0)
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{{ truncateString('JOHN D LAMBRIS', 18)}}的其他基金
Complement in AMD: Mechanisms and Therapeutic Intervention
AMD 中的补体:机制和治疗干预
- 批准号:
8039646 - 财政年份:2011
- 资助金额:
$ 50.28万 - 项目类别:
Complement in AMD: Mechanisms and Therapeutic Intervention
AMD 中的补体:机制和治疗干预
- 批准号:
8215666 - 财政年份:2011
- 资助金额:
$ 50.28万 - 项目类别:
Complement in AMD: Mechanisms and Therapeutic Intervention
AMD 中的补体:机制和治疗干预
- 批准号:
8420509 - 财政年份:2011
- 资助金额:
$ 50.28万 - 项目类别:
Complement in Cell Proliferation and Injury-Therapeutic Interventions
细胞增殖和损伤治疗干预中的补充
- 批准号:
7298797 - 财政年份:2007
- 资助金额:
$ 50.28万 - 项目类别:
Complement in inflammatory diseases: mechanisms & therapeutic modulation
炎症性疾病中的补体:机制
- 批准号:
8850372 - 财政年份:2007
- 资助金额:
$ 50.28万 - 项目类别:
Thermodynamic and structural studies on the formation of the C3 convertase
C3转化酶形成的热力学和结构研究
- 批准号:
7628975 - 财政年份:2007
- 资助金额:
$ 50.28万 - 项目类别:
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