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The role of protease activated receptors on platelets

蛋白酶激活受体对血小板的作用

基本信息

批准号：
10319016
负责人：
Marvin Thomas Nieman
金额：
$ 47.5万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-15 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10319016
关键词：
Affect Alleles Animal Model Binding Sites Biological Biophysics Blood Blood Platelets Blood flow Collaborations Complex Complication Data Development Disease Endothelium Generations Genetic Polymorphism Goals Health Human Individual Injury Lead Ligand Binding Meta-Analysis Microfluidic Microchips Mission Molecular Multicellular Process Mutate Mutation Pathologic Pathway interactions Persons Pharmacology Physiological Process Proteinase-Activated Receptors Public Health Pulmonary Embolism Relative Risks Research Risk Factors Risk Reduction Role Serine Signal Pathway Signal Transduction Single Nucleotide Polymorphism Structure Testing Thrombin Thrombosis Thrombus Translating Triad Acrylic Resin United States National Institutes of Health Variant Venous Venous Thrombosis antagonist base drug development endothelial dysfunction experience extracellular genome wide association study in vivo in vivo Model inhibitor innovation insight mouse model mouse protease-activated receptor 4 neutrophil platelet function prevent programs protease-activated receptor 3 protease-activated receptor 4 therapeutic target venous thromboembolism

项目摘要

PROJECT SUMMARY/ABSTRACT Venous thrombosis (VT) and its major complication, pulmonary embolism (PE), are often grouped together and called venous thromboembolism (VTE). VTE is a major health problem that affect nearly 600,000 people each year. The historical drivers of VTE are blood stasis, endothelial dysfunction, and hypercoagulation (Virchow’s triad). It is now recognized that platelets and neutrophils have a critical initiating role. The molecular mechanisms are only being uncovered. Given that hypercoagulation is a risk factor and thrombin activated protease activated receptor 4 (PAR4) promotes procoagulant platelets, phosphatidyl serine (PS) exposure and subsequent thrombin generation, we propose that PAR4 is an important contributor to VTE. The long-term goals of this research program are to uncover the mechanisms of PAR4 activation at the molecular level and test these mechanism in vivo to inform disease processes and potential drug development. The scientific premise of this proposal is based our preliminary data showing that extracellular loop 3 (ECL3) of PAR4 coordinates with the ligand binding site (LBS) during PAR4 activation. Further, mutations in either ECL3 or the LBS disrupt PAR4 signaling to the same degree. This points to an essential role for ECL3 in PAR4 activation. The overall objective of this proposal is to 1) to determine how PAR4 contributes to the initiation and propagation of venous thrombosis using mouse models, 2) conduct proof-of-concept studies using PAR4 antagonist to treat VT, 3) to translate our recent structural insights on the PAR4 activation mechanism to PAR4 function in vivo. We will do this by taking advantage a PAR4 variant in human platelets and a new mouse model. Our overall hypothesis is that the sustained signaling from PAR4 on platelets is a driver of VTE and reduced PAR4 signaling from hypo-reactive variants or pharmacological inhibitors will lead to protection from VTE. Our innovative approach will take advantage of a new mouse model that recreates a polymorphism in ECL3 and will allow us to determine the mechanism of how this polymorphism contributes to platelet function and thrombosis. The completion of the proposed studies will accomplish two major advances. 1) we will be the first to specifically examine the role of PAR4 in venous thrombosis. 2) we will continue to push our basic understanding of PAR activation mechanisms by testing the observations from our structural studies in vivo to determine how these mechanisms operate in physiological and pathophysiological contexts.

项目总结/文摘