Analysis of Complement Activation and Regulation by Mass Cytometry
通过质谱流式细胞术分析补体激活和调节
基本信息
- 批准号:9235239
- 负责人:
- 金额:$ 20.51万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-03-15 至 2019-02-28
- 项目状态:已结题
- 来源:
- 关键词:AddressAdjuvantAge related macular degenerationAlpha CellAnaphylatoxinsAntibodiesAntibody FormationAntigen-Antibody ComplexAutoimmunityB-Cell ActivationBinding ProteinsCD4 Positive T LymphocytesCell DeathCell Differentiation processCell LineCell SurvivalCellsClinicalCollectionComplementComplement 3 ConvertaseComplement ActivationComplement Membrane Attack ComplexComputer softwareCytolysisCytometryDangerousnessDevelopmentDiagnosticDiseaseDisease ProgressionEffector CellEmerging TechnologiesEpithelial CellsFailureFeedbackFlow CytometryGenerationsGenomicsGoalsHeavy MetalsHemolytic-Uremic SyndromeHumanImmune systemIndividualInfectious AgentInflammatoryInflammatory ResponseInjuryInstructionInvestigationIsotope LabelingIsotopesLupusMass Spectrum AnalysisMeasuresMediatingMembraneMethodsNatureOnset of illnessOpsoninPathway interactionsPhenotypePlayProteinsReagentRecruitment ActivityRegulationReporterResistanceRoleSignal TransductionSiteStructure of retinal pigment epitheliumSurfaceT-LymphocyteTherapeutic AgentsTherapeutic InterventionTimeTissuesWorkantibody conjugatebasecell typedesignhuman diseaseimmune clearanceinflammatory milieumembrane assemblynew technologynovelnovel diagnosticsnovel therapeutic interventionpathogenpublic health relevanceresponsetool
项目摘要
DESCRIPTION (provided by applicant): Analysis of complement activation and regulation by mass cytometry SUMMARY Complement (C) is a collection of 50-60 soluble and membrane-bound proteins that constitutes the first line of defense of the intravascular space. Complement marks infectious agents for immune clearance or lysis, promotes the local inflammatory response, and facilitates B cell activation and antibody production (i.e. nature's adjuvant) as wel as T cell effector responses. Complement is also a principal cause of tissue damage: Complement-related disease and injury states can be traced to inappropriate complement activation (humoral autoimmunity), inadequate complement regulation (PNH, atypical hemolytic uremic syndrome, age-related macular degeneration), or a failure to effectively clear immune-complexes and/or cell debris (lupus). Therapeutic agents have begun to emerge in the clinical setting to inhibit systemic complement activity. The three complement activation pathways converge with the assembly of C3 convertases on a target surface. C3 convertase generates opsonins that promote target clearance, release anaphylatoxins that activate and recruit inflammatory cells, initiate the assembly of the membrane attack complex (MAC, C5b-9), and, importantly, engage a positive feedback mechanism that amplifies all of these activities. The MAC forms a pore that compromises membrane integrity and commonly leads to pathogen lysis. Host cells are protected from complement activity by surface regulators that inhibit convertase formation, compromise convertase stability and obstruct MAC assembly and function. Nucleated cells respond to complement attack by engaging intracellular pathways that further determine cell survival, cell differentiation or cell death. Mass cytometry (MC) is an emerging technology that provides the unique ability to measure >40 proteins on a single cell basis. We propose to use MC to profile the complement activators, regulators, and intracellular responses as a cell undergoes complement attack. We have selected two vastly different cell types of translational significance for hypothesis driven analyses, retinal pigment epithelial (RPE) cells and T cells, and propose the following Specific Aims: 1. To construct and validate a panel of complement-specific heavy isotope-labeled reporter antibodies; 2. To profile by mass cytometry the responses of a human RPE cell line to sublytic C attack, and compare to those findings to the responses of other epithelial cell types; 3. To profile by mass cytometry the responses of CD4+ T cells undergoing C activation. We anticipate the proposed work will generate a set of novel, unique and critical tools to delineate in unprecedented detail the activation and regulation of complement at the membrane and intracellular levels and to define the impact that intracellular responses play on comlement-dependent disease. Further, the reagents/methods we propose to generate/establish will facilitate the development of a new generation of C-based diagnostics in subsequent investigations and likely drive a paradigm shift in C-based therapeutic intervention.
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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DENNIS EMIL HOURCADE其他文献
DENNIS EMIL HOURCADE的其他文献
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{{ truncateString('DENNIS EMIL HOURCADE', 18)}}的其他基金
Cellular Models of a Monogenic Small Vessel Disease of the Brain
脑单基因小血管疾病的细胞模型
- 批准号:
10307638 - 财政年份:2020
- 资助金额:
$ 20.51万 - 项目类别:
Characterization/bioinformatics-modeling of nanoparticle:complement interactions
纳米粒子的表征/生物信息学建模:补体相互作用
- 批准号:
8323416 - 财政年份:2010
- 资助金额:
$ 20.51万 - 项目类别:
Characterization/bioinformatics-modeling of nanoparticle:complement interactions
纳米粒子的表征/生物信息学建模:补体相互作用
- 批准号:
8068114 - 财政年份:2010
- 资助金额:
$ 20.51万 - 项目类别:
Characterization/bioinformatics-modeling of nanoparticle:complement interactions
纳米粒子的表征/生物信息学建模:补体相互作用
- 批准号:
8150949 - 财政年份:2010
- 资助金额:
$ 20.51万 - 项目类别:
Complement Convertase: Assembly, Function and Regulation
补体转化酶:组装、功能和调节
- 批准号:
8070077 - 财政年份:2010
- 资助金额:
$ 20.51万 - 项目类别:
Complement Convertase: Assembly, Function and Regulation
补体转化酶:组装、功能和调节
- 批准号:
6616462 - 财政年份:2003
- 资助金额:
$ 20.51万 - 项目类别:
COMPLEMENT CONVERTASE: ASSEMBLY, FUNCTION AND REGULATION
补充转化酶:组装、功能和调节
- 批准号:
8437634 - 财政年份:2003
- 资助金额:
$ 20.51万 - 项目类别:
COMPLEMENT CONVERTASE: ASSEMBLY, FUNCTION AND REGULATION
补充转化酶:组装、功能和调节
- 批准号:
8897952 - 财政年份:2003
- 资助金额:
$ 20.51万 - 项目类别:
Complement Convertase: Assembly, Function and Regulation
补体转化酶:组装、功能和调节
- 批准号:
8055493 - 财政年份:2003
- 资助金额:
$ 20.51万 - 项目类别:
Complement Convertase: Assembly, Function and Regulation
补体转化酶:组装、功能和调节
- 批准号:
7800882 - 财政年份:2003
- 资助金额:
$ 20.51万 - 项目类别:
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