Pulmonary arteriole occlusion by platelet-neutrophil micro-emboli in Acute Chest Syndrome
急性胸部综合征中血小板-中性粒细胞微栓塞引起的肺动脉闭塞
基本信息
- 批准号:9273634
- 负责人:
- 金额:$ 37.35万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-08-15 至 2020-05-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdhesionsAdhesivesAffectAmericanBacterial InfectionsBacterial PneumoniaBindingBiophysical ProcessBiophysicsBloodBlood PlateletsBlood capillariesBlood flowCessation of lifeDevelopmentDiseaseEmbolismEndothelial CellsEndotheliumEpidemiologyEtiologyEventFluorescence MicroscopyHospitalizationHumanITGAM geneITGB2 geneIn SituIn VitroInfectionInheritedKnowledgeLinkLipopolysaccharidesLungMacrophage-1 AntigenMediatingMembraneMethodsMicrofluidicsMicroscopyMolecularMolecular TargetMorbidity - disease rateMusNatureP-SelectinP-selectin ligand proteinPainPatientsPhysiologicalPreventionProcessRaceResolutionRisk FactorsSickle Cell AnemiaTestingTherapeuticThrombusTimeTransgenic Organismsacute chest syndromearteriolebasecapillaryhuman diseaseimaging approachin vivoin vivo imaginglive cell imaginglung imaginglung injurymanmortalitymulti-photonneutrophilnovelpreventpublic health relevancesicklingtargeted treatmentvaso-occlusive pain
项目摘要
DESCRIPTION (provided by applicant): Acute chest syndrome (ACS) is a leading cause of morbidity among Sickle Cell Disease (SCD) patients. Therapies that can prevent ACS are highly warranted but the development of such treatments has been stalled by the lack of knowledge of the events that initiate ACS. Both infection and vaso-occlusion are believed to cause ACS; however, the cellular and molecular mechanism of ACS is not completely understood. We propose to use an integrative physiologic approach to test the hypothesis that ACS is caused by occlusion of the pulmonary arterioles by aggregates of neutrophils and platelets and this process of aggregation requires P-selectin and GPIba expressed on membrane extensions known as "slings" on platelets binding to P-selectin- glycoprotein-ligand-1 (PSGL)-1 and Mac-1, respectively on neutrophil slings. In Aim 1, we will use in vivo multi- photon excitation (MPE) imaging of the lung vasculature in live transgenic SCD mice to prove that intravascular (IV) administration of bacterial lipopolysaccharide (LPS) results in sequential steps of neutrophil accumulation in the pulmonary arteriole, platelet nucleation on accumulated neutrophils, formation of micro-thrombus, abrogation of blood flow and lung injury. The PI has shown previously that neutrophils form slings, which are long membrane extensions decorated with PSGL-1 and CD18. In Aim 2, we will flow blood drawn from SCD patients and race-matched control subjects through in vitro microfluidic channels cultured with human lung endothelial cells and use fluorescence microscopy to prove that platelet nucleation on neutrophils can be prevented by either blocking P-selectin on platelets or Mac-1 on neutrophils or preventing sling formation by neutrophils and platelets. In the Aim 3, we will show that chimeric SCD mice deficient in platelet P-selectin and neutrophil Mac-1 do not develop pulmonary arteriole occlusion and are protected from ACS following IV challenge with LPS. The successful completion of these Aims will demonstrate that ACS can be prevented by inhibiting platelet P-selectin and neutrophil Mac-1.
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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Prithu Sundd其他文献
Prithu Sundd的其他文献
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{{ truncateString('Prithu Sundd', 18)}}的其他基金
CD39-carrying extracellular vesicles regulate pulmonary thrombosis in Sickle Cell Disease
携带CD39的细胞外囊泡调节镰状细胞病中的肺血栓形成
- 批准号:
10736531 - 财政年份:2023
- 资助金额:
$ 37.35万 - 项目类别:
Pulmonary arteriole occlusion by platelet-neutrophil micro-emboli in Acute Chest Syndrome
急性胸部综合征中血小板-中性粒细胞微栓塞引起的肺动脉闭塞
- 批准号:
10625962 - 财政年份:2015
- 资助金额:
$ 37.35万 - 项目类别:
Pulmonary arteriole occlusion by platelet-neutrophil micro-emboli in Acute Chest Syndrome
急性胸部综合征中血小板-中性粒细胞微栓塞引起的肺动脉闭塞
- 批准号:
10205691 - 财政年份:2015
- 资助金额:
$ 37.35万 - 项目类别:
Pulmonary arteriole occlusion by platelet-neutrophil micro-emboli in Acute Chest Syndrome
急性胸部综合征中血小板-中性粒细胞微栓塞引起的肺动脉闭塞
- 批准号:
10390355 - 财政年份:2015
- 资助金额:
$ 37.35万 - 项目类别:
Pulmonary arteriole occlusion by platelet-neutrophil micro-emboli in Acute Chest Syndrome
急性胸部综合征中血小板-中性粒细胞微栓塞引起的肺动脉闭塞
- 批准号:
8939237 - 财政年份:2015
- 资助金额:
$ 37.35万 - 项目类别:
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