Coagulation Factor XII Recruitment and Activation During Thrombus Formation
血栓形成过程中凝血因子 XII 的募集和激活
基本信息
- 批准号:10741964
- 负责人:
- 金额:$ 72.17万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-09-01 至 2028-06-30
- 项目状态:未结题
- 来源:
- 关键词:AffinityAnticoagulationBindingBinding SitesBiological AssayBlood Coagulation DisordersBlood PlateletsCell LineClinicalCo-ImmunoprecipitationsCoagulation ProcessCompetitive BindingComplexCryoelectron MicroscopyDataDeuteriumDevelopmentDisease susceptibilityDrug TargetingElectron MicroscopyEnzyme PrecursorsEventExhibitsFactor XIIFactor XII DeficiencyFactor XIIaFibrinolytic AgentsFlow CytometryFollow-Up StudiesGenerationsHemorrhageHemostatic functionHumanHydrogenIn VitroIntegrin BindingIntegrinsInterferometryKnockout MiceKringlesLigandsMapsMass Spectrum AnalysisMediatingMembrane ProteinsMolecularMolecular ConformationNegative StainingPathway interactionsPatientsPhasePhysiologicalPlasmaPlayPre-Clinical ModelProcessPropertyProteomicsRGD (sequence)ReagentRecombinant ProteinsRecombinantsReproducibilityResearch PersonnelRiskRoleSignal TransductionSiteSolidSurfaceTherapeuticThrombosisThrombusTreatment EfficacyWorkexperimental studyfactor Afollow-upin vivoinhibitorinsightinterestmicroscopic imagingmouse modelnovelnovel strategiesnovel therapeuticsparticlepreventreceptorreconstitutionrecruitstemtargeted agenttherapeutic targetthromboticvascular injury
项目摘要
PROJECT SUMMARY
An antithrombotic medication not associated with increased hemorrhage would be a transformative advance in
the treatment of coagulation disorders. Inhibiting coagulation factor XII (FXII) has emerged as a therapeutic
strategy that could “decouple” hemostasis from thrombosis to achieve antithrombotic efficacy without bleeding
complications. Enthusiasm for FXII as a therapeutic target stems from the observation that severe congenital
FXII deficiency is not associated with a bleeding diathesis while blockade or deletion of FXII in preclinical models
consistently protects against thrombosis. However, despite its potential clinical importance, the mechanisms
underlying platelet-dependent FXII activation in vivo remain unclear. Using a mass spectrometry-based
proteomic screen, we have identified integrin αIIbβ3 as the putative platelet receptor for FXII. These results have
been followed up with a number of additional studies reproducibly demonstrating the FXII-αIIbβ3 interaction and
localizing the integrin binding region to the kringle domain (KD) of the FXII heavy chain. Our central hypothesis
is that binding of FXII zymogen to platelet integrin αIIbβ3 potentiates FXII activation and is necessary and sufficient
for FXII-mediated coagulation. In Aim 1 of this proposal, we will map the region(s) of the FXII KD responsible
for binding to αIIbβ3 via competitive inhibition assays using recombinantly-generated fragments of the KD. We
will also evaluate the role of the FXII KD in a mouse model of thrombosis to determine if loss of the KD can
prevent thrombus formation in vivo. In Aim 2, we will work closely with our collaborators to conduct precision
structural studies of the FXII-αIIbβ3 complex. In Aim 3, we will focus on the mechanisms by which FXII binding
to αIIbβ3 leads to activation of FXII and downstream coagulation. The proposed work will provide important new
insights into the molecular mechanism of FXII recruitment, activation, and propagation at the platelet surface
and inform efforts to develop novel therapeutics based on inhibition of the FXII-αIIbβ3 complex.
项目总结
项目成果
期刊论文数量(0)
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Pavan Bendapudi其他文献
Pavan Bendapudi的其他文献
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{{ truncateString('Pavan Bendapudi', 18)}}的其他基金
Mechanisms of Coagulation Factor XII Recruitment and Activation at the Platelet Surface
血小板表面凝血因子 XII 招募和激活的机制
- 批准号:
10424806 - 财政年份:2022
- 资助金额:
$ 72.17万 - 项目类别:
Mechanisms of Coagulation Factor XII Recruitment and Activation at the Platelet Surface
血小板表面凝血因子 XII 招募和激活的机制
- 批准号:
10588194 - 财政年份:2022
- 资助金额:
$ 72.17万 - 项目类别:
Elucidating the Role of Inherited Complement System Defects in the Molecular Pathophysiology of Sepsis and Purpura Fulminans
阐明遗传性补体系统缺陷在败血症和暴发性紫癜分子病理生理学中的作用
- 批准号:
10044028 - 财政年份:2020
- 资助金额:
$ 72.17万 - 项目类别:
Elucidating the Role of Inherited Complement System Defects in the Molecular Pathophysiology of Sepsis and Purpura Fulminans
阐明遗传性补体系统缺陷在败血症和暴发性紫癜分子病理生理学中的作用
- 批准号:
10246412 - 财政年份:2020
- 资助金额:
$ 72.17万 - 项目类别:
The Role of Coagulation Factor XII in Hemostasis and Thrombosis
凝血因子 XII 在止血和血栓形成中的作用
- 批准号:
10194578 - 财政年份:2017
- 资助金额:
$ 72.17万 - 项目类别:
The Role of Coagulation Factor XII in Hemostasis and Thrombosis
凝血因子 XII 在止血和血栓形成中的作用
- 批准号:
9294310 - 财政年份:2017
- 资助金额:
$ 72.17万 - 项目类别:
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