Characterization of A Novel 65kDa E-selectin Ligand on G-CSF Mobilized Leukocytes
Characterization of A Novel 65kDa E-selectin Ligand on G-CSF Mobilized Leukocytes
批准号:
7460691
负责人:
ROBERT SACKSTEIN
金额:
$21.44万
依托单位国家:
美国
项目类别:
财政年份:
2007
资助国家:
美国
项目状态:
已结题
起止时间:
2007-07-01 至 2010-06-30
关键词:
AcuteAcute Lung InjuryAdhesionsAdhesivesAffinityAntigensArthritisBindingBiological AssayBiologyBlood VesselsBone MarrowBone Marrow CellsCarbohydratesCardiacCell Adhesion MoleculesCell surfaceCellsChimera organismClinicalConditionDoseE-SelectinElectrophoresisEpitopesExhibitsFlow CytometryGelGlycoproteinsGranulocyte Colony-Stimulating FactorHarvestHematopoieticHematopoietic Stem Cell MobilizationHematopoietic Stem Cell TransplantationHeterogeneityHumanIn VitroInflammatoryInflammatory ResponseIschemiaL-SelectinLeadLeukocytesLigandsLiquid substanceMass Spectrum AnalysisMediatingMembraneMembrane ProteinsMethodsModificationMolecularMyeloid CellsNewborn Respiratory Distress SyndromeP-selectin ligand proteinPathologicPeripheral Blood Stem CellPhasePhysiologicalPreparationProteinsRangeRelative (related person)SeriesSerumSourceTimeVascular EndotheliumWestern Blottingbaseclinically relevantcomparativeglycosylationglycosyltransferasein vivoinsightinterestleukocyte mediatornovelnovel strategiesperipheral bloodpreventprogenitorprotein Eresearch study
中文摘要
描述(由申请人提供):粒细胞集落刺激因子(G-CSF)动员的外周血(MPB)已取代传统的骨髓采集,成为造血干细胞移植的首选细胞来源。虽然一般认为G-CSF是收获的一种更安全的替代方法,但越来越多的观察结果表明,由于白细胞与血管内皮的粘附增强,G-CSF给药会导致血管和炎症并发症。白细胞-内皮粘附相互作用的主要介质是E-选择素,其是一种可诱导的内皮分子,可结合mAb HECA-452识别的唾液酸岩藻糖基化碳水化合物抗原。我们推断,血管和炎症并发症可能是由于G-CSF诱导的E-选择素配体在循环白细胞上的表达。我们发现P-选择素糖蛋白配体-1(P-selectin glycoprotein ligand-1,PSGL-1)和造血细胞E-和L-选择素配体(Hematopoietic Cell E-and L-selectin Ligand,HCELL)是G-CSF MPB白细胞上的E-选择素配体。重要的是,我们的研究还揭示了一种新的HECA-452反应性~ 65 kDa高亲和力E-选择素配体(下文称为“~ 65 kDa蛋白”)在G-CSF MPB白细胞上表达,但不在天然白细胞上表达,也不在正常人骨髓细胞上表达。这种~ 65 kDa的蛋白质表现出有效的Ca 2+依赖性E-选择素配体活性,如通过(i)与流体相E-选择素结合和(ii)在生理剪切流条件下E-选择素转染的细胞的亲和结合所证明的。在体外用药代动力学相关浓度的G-CSF处理正常人骨髓细胞可直接诱导该~ 65 kDa蛋白在髓样细胞上表达。我们推测,这种~ 65 kDa的E-选择素配体有助于G-CSF给药后的血管和炎症并发症。本提案的具体目的是:(1)鉴定作为G-CSF MPB白细胞上的E-选择素配体的~ 65 kDa蛋白;和(2)鉴定体内和体外给予G-CSF后表达该糖蛋白的人白细胞系细胞亚群。这种新的E-选择素配体的鉴定和表达的表征应该提供对E-选择素配体的生物学的见解,并大大增加我们对G-CSF MPB白细胞-内皮细胞相互作用的理解。预期所获得的结果将导致预防或减轻G-CSF诱导的血管和炎症并发症的新方法
英文摘要
DESCRIPTION (provided by applicant): Granulocyte-colony stimulating factor (G-CSF)-mobilized peripheral blood (MPB) has replaced traditional bone marrow harvest as the preferred source of cells for hematopoietic stem cell transplantation. Though generally considered to be a safer alternative to harvest, there are increasing observations that G-CSF administration causes vascular and inflammatory complications due to enhanced adhesion of leukocytes to vascular endothelium. A major mediator of leukocyte-endothelial adhesive interactions is E-selectin, an inducible endothelial molecule that binds sialofucosylated carbohydrate antigens recognized by the mAb HECA-452. We reasoned that vascular and inflammatory complications may result from G-CSF-induced expression of E-selectin ligands on circulating leukocytes. We have found that P-selectin glycoprotein ligand-1 (PSGL-1) and Hematopoietic Cell E-and L-selectin Ligand (HCELL) are E-selectin ligands on G- CSF MPB leukocytes. Importantly, our studies also reveal that a novel HECA-452-reactive ~65kDa high affinity E-selectin ligand (hereinafter called "~65kDa protein") is expressed on G-CSF MPB leukocytes but not on native leukocytes and not on normal human bone marrow cells. This ~65kDa protein exhibits potent Ca2+-dependent E-selectin ligand activity, as evidenced by (i) binding to fluid phase E-selectin and (ii) avid binding of E-selectin- transfected cells under physiological shear flow conditions. Treatment of normal human bone marrow cells with G-CSF at a pharmacokinetically-relevant concentration in vitro induces the expression of this ~65kDa protein directly on myeloid cells. We hypothesize that this ~65kDa E-selectin ligand contributes to vascular and inflammatory complications following G-CSF administration. The specific aims of this proposal are: (1) To identify the ~65kDa protein serving as an E-selectin ligand on G-CSF MPB leukocytes; and (2) To identify the subset(s) of human leukocyte-series cells that express this glycoprotein following G-CSF administration in vivo and in vitro. The identification and the characterization of expression of this novel E-selectin ligand should provide insights into the biology of E-selectin ligands and greatly increase our understanding of G-CSF MPB leukocyte-endothelial interactions. It is anticipated that the results obtained will lead to new approaches for preventing or alleviating G-CSF-induced vascular and inflammatory complications
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