Recognition of fibrinogen by leukocyte integrins
白细胞整合素对纤维蛋白原的识别
基本信息
- 批准号:7447379
- 负责人:
- 金额:$ 28.35万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1999
- 资助国家:美国
- 起止时间:1999-07-01 至 2010-11-30
- 项目状态:已结题
- 来源:
- 关键词:AccountingAdhesivenessAdhesivesAffectBindingBinding SitesBiologicalCD18 AntigensCell AdhesionCell Surface ReceptorsCell modelCellsChargeClassificationConsensusDataDendritic CellsDiseaseDoctor of PhilosophyEmigrationsEndothelial CellsEndotheliumExhibitsExtracellular MatrixExtracellular Matrix ProteinsFamilyFibrinogenFibronectinsFundingGoalsHost DefenseITGAM geneInflammationInflammatoryInflammatory ResponseIntegrinsKnowledgeLeadLeukocytesLigand BindingLigandsLocomotionLymphocyte SubsetMacrophage-1 AntigenMapsMediatingModelingMolecularMutationPeptide LibraryPeptide Phage Display LibraryPeptide ReceptorPeptidesPhage DisplayPhysiologicalPlayPoint MutationPropertyProteinsReactionResearch PersonnelRoleSignal TransductionSimulateSiteSpecificitySurfaceSystemTestingTherapeutic AgentsWorkadhesion receptorbasecell motilitycombinatorialdensitydesignin vivoinsightinterstitialmigrationmonocyteneutrophilnovel therapeuticsprogramsprototypereceptorresponsetherapeutic target
项目摘要
DESCRIPTION (provided by applicant): Integrin-alpha-M-beta-2 (CD11b/CD18, Mac-l) plays a pivotal role in the inflammatory response and host defense. By mediating critical adhesive reactions of neutrophils it participates in regulating neutrophil influx to the sites of inflammation and initiates numerous neutrophil responses. This receptor is also a potential therapeutic target in many diseases in which the inflammatory component plays an essential role. Alpha-M-beta-2 exerts its functions by binding a multitude of biologically diverse molecules. However, the mechanism which allows alpha-Mbeta-2 to exhibit broad specificity and the biological value of alpha-M-beta-2 ligand promiscuity are not known. Our long term goal is to understand the molecular basis for ligand recognition by alpha-M-beta-2, and to determine how alpha-M-beta-2 ligand promiscuity affects its adhesive functions. Studies over the past funding period have mapped the alpha-M-beta-2-binding site in the physiologically important ligand fibrinogen, and identified the recognition peptide that effectively disrupted alpha-M-beta-2-mediated cell adhesion not only to fibrinogen but also to many other ligands. Based on these findings, we have hypothesized that the fibrinogen recognition motif contains critical structural information required for alpha-M-beta-2 binding and that it may serve as a prototype adhesive signal in many alpha-M-beta-2 ligands. We will test this hypothesis by analyzing alpha-M-beta-2-binding sites in fibrinogen and in other physiological ligands using combinatorial peptide libraries and mutational analyses of fibrinogen domains. We will also use phage display to delineate the general principles that control alpha--beta-2 ligand recognition. Our data further indicated that a discrete region in the alpha-M-I-domain of alpha-M-beta-2 participates in binding of numerous ligands which has led us to propose the hypothesis that the unique region in the alpha-M-I-domain constitutes the consensus binding site for recognition of many ligands. Through the use of chimeric and point mutations between alpha-M-beta-2 and alpha-L-beta-2, the related beta-2 integrin with a different ligand specificity, we will determine the structural features required for the interaction of the consensus binding site with multiple ligands. Finally, the impact of alpha-M-beta-2's multi-ligand binding potential on its adhesive functions will be studied. We hypothesize that the alpha-M-beta-2 ability to be upregulated to high density on the surface of neutrophils and its capacity to engage numerous ligands in the extracellular matrix may modulate general cell adhesiveness and, thus, stop neutrophil migration at the site of inflammation. We will test this hypothesis by manipulating alpha-M-beta-2 expression on the surface of neutrophils and will also use neutrophils with alpha-M-beta-2 deficiency. Together, these studies will provide important insights into the structural basis of alpha-m-beta-2 ligand binding and define the mechanism by which alpha-M-beta-2 binding promiscuity controls leukocyte adhesive functions. Thus, these studies may lead to an increased understanding of the principles that govern ligand recognition by integrins and will be useful in the design of novel therapeutic agents to specifically disrupt alpha-M-beta-2-ligand interactions
描述(申请人提供):整合素-α-M-β-2(CD11b/CD18,Mac-L)在炎症反应和宿主防御中发挥关键作用。通过介导中性粒细胞的关键黏附反应,它参与调节中性粒细胞流入炎症部位,并启动大量的中性粒细胞反应。这种受体也是许多疾病的潜在治疗靶点,在这些疾病中,炎症成分起着至关重要的作用。α-M-β-2通过结合多种不同的生物分子发挥其功能。然而,允许α-M-β-2表现出广泛的特异性和α-M-β-2配体混杂的生物学价值的机制尚不清楚。我们的长期目标是了解α-M-β-2识别配体的分子基础,并确定α-M-β-2配体的混杂如何影响其黏附功能。在过去的资助期内,研究已经绘制了生理上重要的配体纤维蛋白原中的α-M-β-2结合位点,并确定了有效地破坏α-M-β-2介导的细胞与纤维蛋白原以及许多其他配体的黏附的识别肽。基于这些发现,我们假设纤维蛋白原识别基序包含α-M-β-2结合所需的关键结构信息,并且它可能在许多α-M-β-2配体中作为原型黏附信号。我们将利用组合多肽库和纤维蛋白原域的突变分析,通过分析纤维蛋白原和其他生理配体中的α-M-β-2结合位点来检验这一假设。我们还将使用噬菌体展示来描述控制α-β-2配体识别的一般原则。我们的数据进一步表明,α-M-β-2的α-M-I结构域中的一个离散区域参与了众多配体的结合,这导致我们提出了这样的假设,即α-M-I结构域中的唯一区域构成了识别许多配体的共识结合部位。通过利用具有不同配体特异性的相关β-2整合素α-M-β-2和α-L-β-2之间的嵌合突变和点突变,我们将确定共识结合位点与多个配体相互作用所需的结构特征。最后,研究了α-M-β-2‘S多配体结合势对其黏附功能的影响。我们推测,中性粒细胞表面α-M-β-2上调至高密度的能力及其与细胞外基质中众多配体结合的能力可能调节细胞的一般粘附性,从而阻止中性粒细胞在炎症部位的迁移。我们将通过操纵中性粒细胞表面的α-M-β-2表达来检验这一假设,并将使用缺乏α-M-β-2的中性粒细胞。总之,这些研究将对α-m-β-2配体结合的结构基础提供重要的见解,并确定α-M-β-2结合紊乱控制白细胞黏附功能的机制。因此,这些研究可能会增加对整合素识别配体的原理的理解,并将有助于设计新的治疗剂来具体破坏α-M-β-2配体的相互作用
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)
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Tatiana P Ugarova其他文献
Tatiana P Ugarova的其他文献
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{{ truncateString('Tatiana P Ugarova', 18)}}的其他基金
RECOGNITION OF FIBRINOGEN BY LEUKOCYTE INTERGRINS
白细胞整合素对纤维蛋白原的识别
- 批准号:
6390461 - 财政年份:1999
- 资助金额:
$ 28.35万 - 项目类别:
Recognition of Fibrinogen by Leukocyte Integrins
白细胞整合素对纤维蛋白原的识别
- 批准号:
8197907 - 财政年份:1999
- 资助金额:
$ 28.35万 - 项目类别:
Recognition of Fibrinogen by Leukocyte Integrins
白细胞整合素对纤维蛋白原的识别
- 批准号:
8386971 - 财政年份:1999
- 资助金额:
$ 28.35万 - 项目类别:
The role of beta 2 integrins in macrophage fusion
β2整合素在巨噬细胞融合中的作用
- 批准号:
9888193 - 财政年份:1999
- 资助金额:
$ 28.35万 - 项目类别:
The role of beta 2 integrins in macrophage fusion
β2整合素在巨噬细胞融合中的作用
- 批准号:
10082459 - 财政年份:1999
- 资助金额:
$ 28.35万 - 项目类别:
RECOGNITION OF FIBRINOGEN BY LEUKOCYTE INTERGRINS
白细胞整合素对纤维蛋白原的识别
- 批准号:
6184837 - 财政年份:1999
- 资助金额:
$ 28.35万 - 项目类别:
RECOGNITION OF FIBRINOGEN BY LEUKOCYTE INTERGRINS
白细胞整合素对纤维蛋白原的识别
- 批准号:
6537649 - 财政年份:1999
- 资助金额:
$ 28.35万 - 项目类别:
Recognition of fibrinogen by leukocyte integrins
白细胞整合素对纤维蛋白原的识别
- 批准号:
6917095 - 财政年份:1999
- 资助金额:
$ 28.35万 - 项目类别:
Recognition of Fibrinogen by Leukocyte Integrins
白细胞整合素对纤维蛋白原的识别
- 批准号:
8039061 - 财政年份:1999
- 资助金额:
$ 28.35万 - 项目类别:
Recognition of fibrinogen by leukocyte integrins
白细胞整合素对纤维蛋白原的识别
- 批准号:
7260330 - 财政年份:1999
- 资助金额:
$ 28.35万 - 项目类别:
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