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Principal Investigator: Marvin Thomas Nieman
Organization: CASE WESTERN RESERVE UNIVERSITY
Fiscal Year: 2024
Award: $465,471
Funding agency: National Heart Lung and Blood Institute
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.
Terms: <Affect><Alleles><Allelomorphs><Animal Model><Animal Models and Related Studies><Binding Sites><Biological><Biophysics><Blood><Blood Neutrophil><Blood Platelets><Blood Polymorphonuclear Neutrophil><Blood Reticuloendothelial System><Blood flow><Cell Communication and Signaling><Cell Signaling><Collaborations><Combining Site><Complex><Complication><Data><Development><Disease><Disorder><Endopeptidase-Activated Receptors><Endothelium><F2RL3 protein><GWA study><GWAS><Generations><Genetic Alteration><Genetic Change><Genetic Polymorphism><Genetic defect><Goals><Health><Human><Individual><Injury><Intracellular Communication and Signaling><L-Serine><Learning><Ligand Binding><Marrow Neutrophil><Marrow platelet><Meta-Analysis><Microfluidic Device><Microfluidic Lab-On-A-Chip><Microfluidic Microchips><Mission><Modern Man><Molecular><Multicellular Process><Mutate><Mutation><NIH><National Institutes of Health><Neutrophilic Granulocyte><Neutrophilic Leukocyte><PAR3 protein><Pathologic><Pathway interactions><Persons><Phlebothrombosis><Physiologic><Physiological><Platelets><Polymorphonuclear Cell><Polymorphonuclear Leukocytes><Polymorphonuclear Neutrophils><Process><Protease-Activated Receptors><Proteinase-Activated Receptors><Public Health><Pulmonary Embolism><Qualifying><Reactive Site><Relative Risks><Research><Risk Factors><Risk Reduction><Role><Serine><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Single Base Polymorphism><Single Nucleotide Polymorphism><Structure><Testing><Thrombase><Thrombin><Thrombocytes><Thrombosis><Thrombus><Translating><United States National Institutes of Health><Variant><Variation><Venous><Venous Thrombosis><antagonism><antagonist><biologic><biological signal transduction><biophysical foundation><biophysical principles><biophysical sciences><coagulation factor II (thrombin) receptor-like 3 protein><developmental><drug development><endothelial dysfunction><experience><extracellular><fibrinogenase><genome mutation><genome wide association><genome wide association scan><genome wide association studies><genome wide association study><genomewide association scan><genomewide association studies><genomewide association study><in vivo><in vivo Model><inhibitor><injuries><innovate><innovation><innovative><insight><microfluidic chip><model of animal><mouse PAR-4 receptor><mouse model><mouse protease-activated receptor 4><murine model><neutrophil><pathway><pharmacologic><platelet function><polymorphism><prevent><preventing><programs><protease-activated receptor 3><protease-activated receptor 4><proteinase-activated receptor-3><reduce risk><reduce risks><reduce that risk><reduce the risk><reduce these risks><reduces risk><reduces the risk><reducing risk><reducing the risk><risk-reducing><single nucleotide variant><social role><therapeutic target><thrombotic disease><thrombotic disorder><validation studies><venous thromboembolism><whole genome association analysis><whole genome association studies><whole genome association study>