Mac-1 (CR3) and Fc gamma receptors in immune-mediated neutrophil cytotoxicity
Mac-1 (CR3) 和 Fc gamma 受体在免疫介导的中性粒细胞细胞毒性中的作用
基本信息
- 批准号:8209095
- 负责人:
- 金额:$ 37.83万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2003
- 资助国家:美国
- 起止时间:2003-09-30 至 2013-12-31
- 项目状态:已结题
- 来源:
- 关键词:4-ethoxymethylene-2-phenyl-2-oxazoline-5-oneAdhesivesAntibodiesAntigen-Antibody ComplexAttenuatedAutoimmune DiseasesAutoimmune ProcessAutoimmune hemolytic anemiaBindingBiochemicalBiological AssayBullous PemphigoidC3biClinical TrialsComplementCoupledCutaneous InvolvementDataDepositionDermalDiseaseEnsureErythrocytesExhibitsFamilyFamily memberFundingGenerationsGlomerulonephritisGlucansGoalsGrantGuanineGuanine Nucleotide Exchange FactorsGuanosine Triphosphate PhosphohydrolasesHemolytic AnemiaHemorrhagic VasculitisHost DefenseHost Defense MechanismITAMIgG ReceptorsImmuneImmunityImmunocompromised HostImmunoglobulin GImmunosuppressionIn VitroInfectionInflammatoryInflammatory ResponseInjuryIntegrinsLeadLeukocyte ElastaseLinkMacrophage-1 AntigenMediatingModelingMolecularMycosesMyelogenousNADPH OxidaseNeutrophil InfiltrationOrganPTK2 genePathologyPathway interactionsPhagocytesPhagocytosisPhagosomesPharmaceutical PreparationsPhospholipase CPhospholipase DPhosphorylationPhosphotransferasesPhysiologicalPlayPredispositionProcessProtein FamilyProtein Kinase CProtein Tyrosine KinaseProteinsProteomicsReactive Oxygen SpeciesRegulationRelative (related person)Respiratory BurstRheumatismRoleShwartzman PhenomenonSignal PathwaySignal TransductionSignaling MoleculeTherapeuticTissuesTransducersTreatment EfficacyVariantVasculitisbasecombatcomparativecytotoxiccytotoxicitydectin 1designglomerular basement membranehuman SYK proteinhuman diseasein vitro Assayin vivoin vivo Modelinterestmacrophagemicrobialnatalizumabneutrophilneutrophil cytosol factor 40Kopsonin receptorparticleprotein functionpublic health relevancerac GTP-Binding Proteinsreceptorresponserhorho GTP-Binding Proteinsskin disordersrc-Family Kinasestherapeutic developmenttherapeutic targettooltraffickinguptake
项目摘要
DESCRIPTION (provided by applicant): Phagocytic functions of neutrophils and macrophages are essential for immunity to microbial infection, but can also contribute to tissue injury during inflammatory responses and autoimmune pathologies. The overall goal of this application is to continue to extend our understanding of the molecular basis of phagocyte cytotoxicity focusing on two major opsonic receptors on phagocytes, Fc?Rs (receptors for IgG immune complex) and the ¿2 integrin Mac-1 (receptor for complement fragment iC3b). Major accomplishments of the past 4 years were to 1) demonstrate that Vav proteins, exchange factor for Rho GTPase family members are required for several Mac-1 and Fc?R mediated adhesive functions in neutrophils, 2) identify Vav proteins as the major signal transducers of NADPH oxidase activation following Fc?R engagement, through regulation of Rac GTPases and phosphorylation of the NADPH oxidase p40phox, 3) present in vivo evidence that neutrophil Fc?R dependent but not complement dependent tissue injury requires Vav and Rac proteins, 4) define a role for Mac-1 in triggering neutrophil elastase release and subsequent hemorrhagic vasculitis in vivo, through activation of the src and syk kinases, and 5) demonstrate a critical role for Mac-1 on neutrophils in two additional complement dependent models, bullous pemphigoid and thrombotic glomerulonephritis. The current application builds on these discoveries. The objective of Aim I is to delineate mechanisms of neutrophil phagocytosis that are relevant for complement C3 mediated tissue injury and host defense. In particular we will examine both signals that lead to Mac-1 binding of its target and those that link Mac-1 to downstream effector functions. In Aim II, we will further delineate mechanisms of Vav mediated regulation of the NADPH oxidase following Fc?R engagement in neutrophils and macrophages. We will also clarify the role of Vav and Rac in IgG or complement mediated phagocytosis in macrophages in models of autoimmune hemolytic anemia. We anticipate that the completion of our aims should lead to a better understanding of signaling pathways that link opsonic receptors to specific phagocyte cytotoxic functions. This may aid in the design of therapeutics to selectively target pathways responsible for tissue damage in inflammatory and autoimmune disorders while minimizing effects on host defense.
PUBLIC HEALTH RELEVANCE: The objective of this proposal is to understand the neutrophil dependent mechanisms that mediate injury to the dermal microvasculature, a well-recognized target of autoimmune damage that contributes to end organ/skin disease. For example, the inflammatory destruction of the vessel wall, vasculitis, is observed in autoimmune rheumatic diseases with cutaneous involvement being the most common, and neutrophil accumulation being a common feature. Drugs such as natalizumab, which interferes with neutrophil trafficking have demonstrated marked therapeutic efficacy in autoimmune diseases, but also exhibited potentially fatal immunosuppression. In this application we propose to delineate signaling pathways that potentially promote microvascular tissue damage, but are not required for neutrophil recruitment. This could lead to the identification of targeted therapeutic strategies that attenuate organ injury while minimally immunocompromising the host.
描述(由申请人提供):中性粒细胞和巨噬细胞的吞噬功能对于对微生物感染的免疫是必不可少的,但在炎症反应和自身免疫病理过程中也可能导致组织损伤。这项应用的总体目标是继续扩大我们对吞噬细胞细胞毒性的分子基础的理解,重点放在吞噬细胞上的两个主要调理受体Fc?RS(免疫球蛋白免疫复合物受体)和整合素Mac-1(补体片段IC3b受体)。过去四年的主要成就是:1)证明了Rho GTP酶家族成员的交换因子Vav蛋白是几种Mac-1和Fc?R介导的中性粒细胞黏附功能所必需的;2)通过调节Rac GTP酶和NADPH氧化酶p40Phox的磷酸化,确定Vav蛋白是Fc?R参与后NADPH氧化酶激活的主要信号转导;3)体内证据表明,中性粒细胞Fc?R依赖而不是补体依赖的组织损伤需要Vav和Rac蛋白,4)Mac-1通过激活src和syk激酶,在体内确定了触发中性粒细胞弹性蛋白酶释放和随后的出血性血管炎的作用。5)在大疱性类天疱疮和血栓性肾小球肾炎这两种补体依赖模型中,Mac-1在中性粒细胞上发挥重要作用。当前的应用程序建立在这些发现的基础上。目的I的目的是描述与补体C3介导的组织损伤和宿主防御相关的中性粒细胞吞噬机制。特别是,我们将研究导致其靶标与Mac-1结合的信号以及那些将Mac-1与下游效应器功能联系起来的信号。在AIM II中,我们将进一步阐明Vav介导的Fc?R参与中性粒细胞和巨噬细胞后NADPH氧化酶的调节机制。我们还将在自身免疫性溶血性贫血模型中阐明Vav和Rac在免疫球蛋白或补体介导的巨噬细胞吞噬中的作用。我们预计,我们的目标的完成应该会导致更好地理解将光学受体与特定的吞噬细胞细胞毒功能联系起来的信号通路。这可能有助于治疗药物的设计,以选择性地针对炎症和自身免疫疾病中负责组织损伤的途径,同时将对宿主防御的影响降至最低。
公共卫生相关性:这项建议的目的是了解中性粒细胞依赖的机制,介导对真皮微血管的损伤,真皮微血管是公认的自体免疫损伤的目标,有助于最终器官/皮肤病。例如,在自身免疫性风湿病中观察到血管壁的炎性破坏,血管炎,最常见的是皮肤受累,中性粒细胞聚集是常见的特征。干扰中性粒细胞运输的药物,如Natalizumab,在自身免疫性疾病中已显示出显著的治疗效果,但也显示出潜在的致命免疫抑制。在这项应用中,我们建议描绘可能促进微血管组织损伤的信号通路,但不是中性粒细胞募集所必需的。这可能导致确定有针对性的治疗策略,以减轻器官损伤,同时最大限度地降低对宿主的免疫损害。
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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Tanya N Mayadas其他文献
Tanya N Mayadas的其他文献
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{{ truncateString('Tanya N Mayadas', 18)}}的其他基金
Neutrophil plasticity in autoimmune disease
自身免疫性疾病中的中性粒细胞可塑性
- 批准号:
10326852 - 财政年份:2020
- 资助金额:
$ 37.83万 - 项目类别:
Neutrophil plasticity in autoimmune disease
自身免疫性疾病中的中性粒细胞可塑性
- 批准号:
10569637 - 财政年份:2020
- 资助金额:
$ 37.83万 - 项目类别:
TNFR2 Regulation of Leukocyte Recruitment in Glomerulonephritis
肾小球肾炎中白细胞募集的 TNFR2 调节
- 批准号:
8821615 - 财政年份:2014
- 资助金额:
$ 37.83万 - 项目类别:
TNFR2 Regulation of Leukocyte Recruitment in Glomerulonephritis
肾小球肾炎中白细胞募集的 TNFR2 调节
- 批准号:
9456733 - 财政年份:2014
- 资助金额:
$ 37.83万 - 项目类别:
cAMP Control of Endothelial Barrier and T Cell Migration
cAMP 控制内皮屏障和 T 细胞迁移
- 批准号:
7753048 - 财政年份:2009
- 资助金额:
$ 37.83万 - 项目类别:
Endothelia mechanisms of leukocyte accumulation in glomerulonephritis
肾小球肾炎白细胞积聚的内皮机制
- 批准号:
7903751 - 财政年份:2009
- 资助金额:
$ 37.83万 - 项目类别:
Endothelia mechanisms of leukocyte accumulation in glomerulonephritis
肾小球肾炎白细胞积聚的内皮机制
- 批准号:
7620123 - 财政年份:2007
- 资助金额:
$ 37.83万 - 项目类别:
Endothelia mechanisms of leukocyte accumulation in glomerulonephritis
肾小球肾炎白细胞积聚的内皮机制
- 批准号:
7322748 - 财政年份:2007
- 资助金额:
$ 37.83万 - 项目类别:
MAC-1(CR3) IN IMMUNE-MEDIATED NEUTROPHIL CYTOTOXICITY
MAC-1(CR3) 在免疫介导的中性粒细胞细胞毒性中的作用
- 批准号:
6734495 - 财政年份:2003
- 资助金额:
$ 37.83万 - 项目类别:
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