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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：
Pavan Bendapudi
金额：
$ 72.17万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
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：
https://reporter.nih.gov/project-details/10741964
关键词：
Affinity Anticoagulation Binding Binding Sites Biological Assay Blood Coagulation Disorders Blood Platelets Cell Line Clinical Co-Immunoprecipitations Coagulation Process Competitive Binding Complex Cryoelectron Microscopy Data Deuterium Development Disease susceptibility Drug Targeting Electron Microscopy Enzyme Precursors Event Exhibits Factor XII Factor XII Deficiency Factor XIIa Fibrinolytic Agents Flow Cytometry Follow-Up Studies Generations Hemorrhage Hemostatic function Human Hydrogen In Vitro Integrin Binding Integrins Interferometry Knockout Mice Kringles Ligands Maps Mass Spectrum Analysis Mediating Membrane Proteins Molecular Molecular Conformation Negative Staining Pathway interactions Patients Phase Physiological Plasma Play Pre-Clinical Model Process Property Proteomics RGD (sequence)Reagent Recombinant Proteins Recombinants Reproducibility Research Personnel Risk Role Signal Transduction Site Solid Surface Therapeutic Thrombosis Thrombus Treatment Efficacy Work experimental study factor A follow-up in vivo inhibitor insight interest microscopic imaging mouse model novel novel strategies novel therapeutics particle prevent receptor reconstitution recruit stem targeted agent therapeutic target thrombotic vascular 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