CD47 Regulation of Leukocyte Integrins during Leukocyte Trafficking
白细胞贩运过程中 CD47 对白细胞整合素的调节
基本信息
- 批准号:9105867
- 负责人:
- 金额:$ 58.46万
- 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:2016-05-01 至 2020-03-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdhesionsAdhesivesAffectAffinityAlanineAnti-Inflammatory AgentsAnti-inflammatoryAntibodiesAntigen-Presenting CellsAntigensAtherosclerosisAutoimmune DiseasesBindingBiochemicalBiologicalBiological AssayBlood PlateletsC-terminalCD4 Positive T LymphocytesCD47 geneCardiovascular DiseasesCell Culture SystemCell physiologyCell surfaceCellsChronicClinical TrialsColitisCollaborationsComplexDataDefectDevelopmentDiabetes MellitusDiseaseEffector CellEmployee StrikesEndotheliumEpitopesEscherichia coliExperimental Autoimmune EncephalomyelitisExtracellular MatrixExtracellular Matrix ProteinsGenerationsGlycoproteinsGoalsGraft RejectionHaptensHomeostasisHomingHost DefenseHumanHuman Cell LineHypertensionImmigrationImmuneIn VitroInflammationInflammatoryInflammatory ResponseInjuryIntegrin alpha4beta1Integrin alphaVbeta3IntegrinsIntercellular adhesion molecule 1IschemiaJurkat CellsKidneyLeukocyte TraffickingLeukocytesLigandsLung InflammationLymphocyteLymphoid TissueMalignant NeoplasmsMass Spectrum AnalysisMeasuresMediatingMediator of activation proteinMetabolic syndromeModelingMolecularMolecular ConformationMusMutagenesisNeoplasm MetastasisPeptide FragmentsPeptidesPhage DisplayPharmaceutical PreparationsPhenotypePhysiologicalPlacentaPlayProcessProteinsPublicationsReactionReagentRegulationReperfusion TherapyReportingResearch PersonnelRoleSHPS-1 proteinSamplingScanningSignal PathwaySignal TransductionSignaling MoleculeSiteSkin graftStrokeSurfaceT cell regulationT-LymphocyteT-Lymphocyte SubsetsTNF geneTechnologyTh1 CellsTherapeuticThickThrombospondin 1TissuesVascular Cell Adhesion Molecule-1basecell typechemokinecremaster musclecytokinedesignin vitro Modelin vivoinnovationinsightmigrationnovelpublic health relevancetherapeutic targettrafficking
项目摘要
DESCRIPTION (provided by applicant): Inflammation is a significant contributor to cardiovascular disease and related pathophysiological processes including stroke, hypertension, atherosclerosis, diabetes-metabolic syndrome. The activation and recruitment of effector T cell subsets into tissues is a highly regulated process that is dependent upon adhesive interactions between T cell subsets and the endothelium lining the vascularture. Therefore, our overall goal is to gain a better understanding of the mechanisms that regulate CD4+ T cell subset recruitment to sites of immune-mediated inflammation. Based on our exciting preliminary data and recent publication, we hypothesize that CD47 plays an important role in leukocyte β1 and β2 integrin adhesive functions by regulating the expression of high affinity conformations. By virtue of its effect on LFA-1 and VLA-4 integrin adhesive function and its well-documented role in immune cell homeostasis, CD47 and its ligand SIRPα play a critical role in multiple steps (arrest and migration) in the inflammatory response. The specific aims will determine the molecular mechanisms and underlying structural basis of CD47 regulation of T cell LFA-1 and VLA-4 adhesive function and its role in T effector cell functions. We propose complementary and well-characterized in vitro cell culture systems and novel CyTOF mass spectroscopy technology to dissect the biochemical and molecular signaling pathways used by CD47 in human and murine immune cells to regulate integrin function. Specifically, Specific Aim 1 will employ recently developed single cell mass spectrometry (CyTOF mass spectrometry) and standard biochemical assays to interrogate intracellular signaling pathways in CD47-/- T cells to identify defects that cause impaired integrin activation in CD47-/- leukocytes. Up to 40 cell-surface molecules, intracellular signaling molecules and mediators (cytokines) can be measured in a single sample using CyTOF to provide much more information about cell phenotypes at a single-cell level. Specific Aim 2 will address whether in trans CD47 ligands, Signal Regulatory Protein (SIRP)α, and SIRPγ, and the secreted extracellular matrix protein, thrombospondin-1, affect CD47 in cis regulation of LFA-1 and VLA4 function during T cell recruitment. In Specific Aim 3 we propose to determine the residues in CD47 that interact with β2 integrins, which may provide guidance for designing novel and innovative therapeutic target(s), and identify biological reagents that impair these interactions. These approaches and our collaborations with established investigators will generate novel insights into CD47 regulation of integrin activation and adhesive functions in T cell trafficking.
描述(由申请人提供):炎症是心血管疾病和相关病理生理过程(包括中风、高血压、动脉粥样硬化、糖尿病-代谢综合征)的重要促成因素。效应T细胞亚群的激活和募集到组织中是一个高度调节的过程,其依赖于T细胞亚群和血管内皮之间的粘附相互作用。因此,我们的总体目标是更好地了解调节CD 4 + T细胞亚群募集到免疫介导的炎症部位的机制。基于我们令人兴奋的初步数据和最近的出版物,我们假设CD 47通过调节高亲和力构象的表达在白细胞β1和β2整合素粘附功能中起重要作用。由于其对LFA-1和VLA-4整联蛋白粘附功能的影响及其在免疫细胞稳态中的作用得到充分证实,CD 47及其配体SIRPα在炎症反应的多个步骤(停滞和迁移)中发挥关键作用。具体的目标是确定CD 47调节T细胞LFA-1和VLA-4粘附功能的分子机制和潜在的结构基础及其在T效应细胞功能中的作用。我们提出了互补的和良好的特点,在体外细胞培养系统和新的CyTOF质谱技术,剖析的生化和分子信号转导途径,CD 47在人类和小鼠免疫细胞调节整合素功能。具体而言,具体目标1将采用最近开发的单细胞质谱法(CyTOF质谱法)和标准生化测定法来询问CD 47-/- T细胞中的细胞内信号传导途径,以鉴定导致CD 47-/-白细胞中整合素活化受损的缺陷。使用CyTOF可以在单个样品中测量多达40种细胞表面分子、细胞内信号传导分子和介体(细胞因子),从而在单细胞水平上提供更多有关细胞表型的信息。具体目标2将阐明反式CD 47配体、信号调节蛋白(SIRP)α和SIRPγ以及分泌的细胞外基质蛋白血小板反应蛋白-1是否影响T细胞募集期间CD 47顺式调节LFA-1和VLA 4功能。在具体目标3中,我们提出确定CD 47中与β2整合素相互作用的残基,这可能为设计新颖和创新的治疗靶点提供指导,并确定损害这些相互作用的生物试剂。这些方法以及我们与现有研究人员的合作将产生对CD 47调节T细胞运输中整合素活化和粘附功能的新见解。
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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FRANCIS W. LUSCINSKAS其他文献
FRANCIS W. LUSCINSKAS的其他文献
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{{ truncateString('FRANCIS W. LUSCINSKAS', 18)}}的其他基金
2014 Annual Meeting of the American Society for Investigative Pathology
2014年美国病理研究学会年会
- 批准号:
8716277 - 财政年份:2014
- 资助金额:
$ 58.46万 - 项目类别:
2013 Annual Meeting of the American Society for Investigative Pathology
2013年美国病理研究学会年会
- 批准号:
8527049 - 财政年份:2013
- 资助金额:
$ 58.46万 - 项目类别:
The Role of CD47 in Mononuclear Leukocyte Recruitment
CD47 在单核白细胞募集中的作用
- 批准号:
7753041 - 财政年份:2009
- 资助金额:
$ 58.46万 - 项目类别:
ENDOTHELIAL LATERAL JUNCTIONS AND LEUKOCYTE TRAFFICKING
内皮横向连接和白细胞运输
- 批准号:
6602438 - 财政年份:2002
- 资助金额:
$ 58.46万 - 项目类别:
ENDOTHELIAL LATERAL JUNCTIONS AND LEUKOCYTE TRAFFICKING
内皮横向连接和白细胞运输
- 批准号:
6469264 - 财政年份:2001
- 资助金额:
$ 58.46万 - 项目类别:
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