Investigation of the Cellular and Molecular Mechanisms of Thrombocyte Integrin Signaling
血小板整合素信号传导的细胞和分子机制研究
基本信息
- 批准号:10616738
- 负责人:
- 金额:$ 39.66万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-05-05 至 2026-04-30
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalAdaptor Signaling ProteinAffinityAgonistArchitectureBindingBiochemicalBiological AssayBiologyBlood Coagulation DisordersBlood PlateletsCell Surface ReceptorsCell surfaceCellsCessation of lifeCholesterolClassificationClinicalComplexCryo-electron tomographyCryoelectron MicroscopyCytoskeletonDefectDetergentsDevelopmentDiseaseDoseDrug DesignDrug TargetingDrug usageEGF geneEquilibriumEventFamilyFeasibility StudiesFibrinogenFutureGoalsHematological DiseaseHemorrhageHourHumanHybridsImaging TechniquesImmunotherapyIn SituIn VitroInflammationIntegral Membrane ProteinIntegrinsInvestigationIonsKineticsLaboratoriesLengthLicensingLigandsLinkMacrophage-1 AntigenMalignant NeoplasmsMapsMembraneModelingMolecularMolecular ConformationMolecular ProbesMonoclonal AntibodiesMyocardial InfarctionPathologyPharmaceutical PreparationsPhysiologicalPlatelet ActivationPlatelet aggregationProcessPropertyProtein Structure InitiativeProteinsRegulationReportingResearchResolutionRoentgen RaysRoleShapesSignal TransductionSpecimenStrokeStructureSurfaceTechniquesTherapeuticThermodynamicsThickThigh structureThrombastheniaThrombocytopeniaThrombosisTimeVesicleVisualizationantagonistbiophysical techniquesclinical effectclinically relevanteffective therapyexperimental studyimprovedin situ imaginginhibitorinsightmicrovesiclesnanodisknanometer resolutionnovelparticleplatelet functionpre-clinicalreceptorreconstitutionskillssmall moleculestructural biologysuccesstargeted treatmenttherapeutic targetthrombotictomographyvon Willebrand Factor
项目摘要
Abstract
Platelet integrin αIIbβ3 is central to platelet activation, which occurs through highly complex molecular
interactions and structural alteration. Ultimately, αIIbβ3 matures its affinity for fibrinogen and von Willebrand
factor. Dysregulation in αIIbβ3 affinity maturation events causes Glanzmann's thrombasthenia or
thrombocytopenia. Therefore, fine-tuning these interactions through the αIIbβ3 receptor is a proven and effective
strategy for both therapeutic thrombotic pathology targeting and immunotherapy. Currently, there are no αIIbβ3
inhibitors for long-term clinical use, while current inhibitors for short-term use may cause serious
thrombocytopenia. The overall goal of our proposed research is to understand the molecular basis of the αIIbβ3
shapeshifting and the mechanochemistry of αIIbβ3 activation and inhibition by small molecules, including clinical-
drugs. Our guiding hypothesis is that multiple forms of αIIbβ3 exist in a dynamic conformational equilibrium that
is temporally and spatially regulated by cell signaling, association with the cytoskeleton, and interactions with
exocellular ligands. We will determine, for the first time, the single-particle cryoEM structure of intact αIIbβ3,
characterize structural transitions at the atomic level as they relate to physiological ligands (e.g., fibrinogen), and
determine the effects of clinically relevant antagonists on αIIbβ3 conformational equilibrium both in situ and in
vitro. All specific aims will elaborate integrin αIIbβ3 events at the molecular level pertaining to these objectives.
Aim 1 experiments will characterize shapeshifting structural changes of αIIbβ3 induced by ligands or clinical-
relevant drugs. We will investigate the kinetics of the conformational dynamics of the purified full-length αIIbβ3
using a single-particle cryoEM approach and wide-ranging biochemical techniques for the protein in solution.
Aim 2 experiments will study architectural changes in intact αIIbβ3 by probing its conformational states on the
cell surfaces using conformation-reporting mAbs and by directly solving in situ structures using cutting-edge
advanced cryoET imaging techniques. Collectively, our proposed studies will provide unique molecular insights
into structural and bidirectional signaling regulation of αIIbβ3, which will advance our understanding of integrin
biology and may identify new antagonists for modulating αIIbβ3 function.
摘要
项目成果
期刊论文数量(1)
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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Zhao Wang其他文献
Zhao Wang的其他文献
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{{ truncateString('Zhao Wang', 18)}}的其他基金
Role of de novo pyrimidine biosynthesis in pathological cardiac remodeling
从头嘧啶生物合成在病理性心脏重塑中的作用
- 批准号:
10579222 - 财政年份:2022
- 资助金额:
$ 39.66万 - 项目类别:
Investigation of the Cellular and Molecular Mechanisms of Thrombocyte Integrin Signaling
血小板整合素信号传导的细胞和分子机制研究
- 批准号:
10421216 - 财政年份:2022
- 资助金额:
$ 39.66万 - 项目类别:
Role of de novo pyrimidine biosynthesis in pathological cardiac remodeling
从头嘧啶生物合成在病理性心脏重塑中的作用
- 批准号:
10364407 - 财政年份:2022
- 资助金额:
$ 39.66万 - 项目类别:
Molecular mechanism of Androgen Receptor mediated transcription
雄激素受体介导转录的分子机制
- 批准号:
10810416 - 财政年份:2021
- 资助金额:
$ 39.66万 - 项目类别:
Molecular mechanism of Androgen Receptor mediated transcription
雄激素受体介导转录的分子机制
- 批准号:
10447691 - 财政年份:2021
- 资助金额:
$ 39.66万 - 项目类别:
Molecular mechanism of Androgen Receptor mediated transcription
雄激素受体介导转录的分子机制
- 批准号:
10279240 - 财政年份:2021
- 资助金额:
$ 39.66万 - 项目类别:
Molecular mechanism of Androgen Receptor mediated transcription
雄激素受体介导转录的分子机制
- 批准号:
10612440 - 财政年份:2021
- 资助金额:
$ 39.66万 - 项目类别:
Role of the Xbp1s/GFAT1 axis in pathological cardiac remodelling
Xbp1s/GFAT1 轴在病理性心脏重塑中的作用
- 批准号:
9362022 - 财政年份:2017
- 资助金额:
$ 39.66万 - 项目类别:
Role of the Xbp1s/GFAT1 axis in pathological cardiac remodelling
Xbp1s/GFAT1 轴在病理性心脏重塑中的作用
- 批准号:
10170415 - 财政年份:2017
- 资助金额:
$ 39.66万 - 项目类别:
Role of the Xbp1s/GFAT1 axis in pathological cardiac remodelling
Xbp1s/GFAT1 轴在病理性心脏重塑中的作用
- 批准号:
10584092 - 财政年份:2017
- 资助金额:
$ 39.66万 - 项目类别: