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Principal Investigator: Laurent Olivier Mosnier
Organization: SCRIPPS RESEARCH INSTITUTE, THE
Fiscal Year: 2024
Award: $452,500
Funding agency: National Heart Lung and Blood Institute
Project Summary
This application seeks to improve basic understanding of the molecular mechanisms that mediate cytoprotective
actions of coagulation proteases on cells and will test novel approaches for the potential treatment of thrombo-
inflammatory disease. Despite recent advances, major gaps in knowledge remain about the physiological and
pathophysiological mechanisms that are affected when vascular, inflammatory, and coagulation pathways
intertwine during bacterial or viral infection, and how unbalanced regulation of these pathways can fuel a vicious
cycle of vascular dysfunction, immunocoagulopathy, and thromboinflammation. Endogenous and pharmacologic
activated protein C (APC) has multiple beneficial effects in a diverse collection of preclinical animal injury models
where unbalanced regulation of vascular, inflammatory, and coagulation pathways contribute to pathogenesis.
These beneficial effects of APC are primarily mediated by the cytoprotective activities of APC that involve the
endothelial protein C receptor (EPCR) and non-canonical activation of PAR1 at Arg46 and of PAR3 at Arg41,
which induce biased signaling pathways contributing to rebalancing tissue homeostasis and host defense
systems. A major focus of Aim 1 will be on the regulation of EPCR function during thromboinflammation. We
have identified a novel mechanism for the functional regulation of EPCR on cell surfaces and have discovered
an EPCR stabilizing antibody that greatly enhances the beneficial effects of the endogenous protein C system.
In vitro and in vivo studies will characterize the mechanism for the antibody’s augmentation of APC’s
cytoprotective effects and its translational potential in thromboinflammation. Aim 2 focusses on synthetic APC-
mimetic peptides derived from non-canonical PAR1 and PAR3 activation. These APC-mimetic peptides do not
require EPCR to provide anti-inflammatory and endothelial stabilizing activities and may provide critical vascular
protective effects when EPCR is disabled by inflammatory mediators during thromboinflammatory disease. Aim
2 studies will provide highly innovative knowledge on the structure-function of biased PAR1 and PAR3 signaling.
The emerging knowledge of the pathobiology of COVID-19 caused by SARS-CoV-2 infection suggests a striking
dysregulation of host defense immune and blood coagulation systems, based on excessive levels of
cytokines/chemokines and D-dimer circulating in blood of severely ill patients. We hypothesize that EPCR
dysfunction, induced by the excessive cytokines/chemokines release in the circulation, contributes to vascular
dysfunction and impairments of the endogenous cytoprotective effects of APC in severely ill COVID-19 patients.
Aim 3 will characterize the contribution of EPCR in the pathogenesis of COVID 19 in SARS-CoV-2-infected mice
expressing human ACE2. Experimental treatments with our EPCR stabilizing antibody and our second-
generation PAR-sequence-derived peptide with improved APC-mimetic activities will be tested for efficacy to
mitigate the serious effects of murine COVID-19. These studies will improve our knowledge on the regulation of
EPCR function in thromboinflammation and may advance therapies for COVID-19 patients.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><ACE2><APC receptor><Affect><Agonist><Animals><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Antibodies><Anticoagulant Agents><Anticoagulant Drugs><Anticoagulants><Antiinflammatory Effect><Apoplexy><Autoregulation><Bacterial Infections><Basic Research><Basic Science><Biological Agent><Biological Products><Blood><Blood Clotting><Blood Plasma><Blood Reticuloendothelial System><Blood Vessels><Blood coagulation><Body Tissues><Brain><Brain Nervous System><Brain Vascular Accident><CF2R><COVID complications><COVID infected patient><COVID patient><COVID positive patient><COVID related complications><COVID-19><COVID-19 complications><COVID-19 infected patient><COVID-19 infection><COVID-19 pathogenesis><COVID-19 patient><COVID-19 positive patient><COVID-19 related complications><COVID-19 therapy><COVID-19 treatment><COVID-19 virus><COVID-19 virus infection><COVID19 infection><COVID19 pathogenesis><COVID19 patient><COVID19 positive patient><COVID19 virus><CV-19><Cardiac infarction><Cell Body><Cell Communication and Signaling><Cell Protection><Cell Signaling><Cell surface><Cells><Cellular biology><Cerebral Stroke><Cerebrovascular Apoplexy><Cerebrovascular Stroke><Chemotactic Cytokines><Circulation><Clinical Trials><Clotting><CoV-2><CoV2><Coagulants><Coagulation><Coagulation Factor II Receptor><Coagulation Process><Collection><Coronavirus Infectious Disease 2019><Cytoprotection><D-dimer><D-dimer fibrin><D-dimer fragments><Death Rate><Defense Mechanisms><Development><Diagnostic><Disease><Disorder><Dysfunction><EPCR><EPCR gene><Encephalon><Endopeptidase-Activated Receptors><Endothelial protein C receptor><Endothelium><Engineering><Epithelium><Equilibrium><Esteroproteases><F2R><F2R gene><Feedback><Fibrin fragment D><Functional disorder><Funding><Generations><Goals><Homeostasis><Homologous Chemotactic Cytokines><Host Defense><Human><Immune><Immunes><Impairment><In Vitro><Inflammation Mediators><Inflammatory><Injury><Intercrines><Intracellular Communication and Signaling><Ischemic Stroke><Kidney><Kidney Urinary System><Knowledge><Life><Liver><Lung><Lung Respiratory System><Mediating><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Murine><Mus><Myocardial Infarct><Myocardial Infarction><Organ><Outcome><PAR-1 Receptor><PAR1><PAR1 Receptor><Pathogenesis><Pathway interactions><Patients><Peptidases><Peptide Hydrolases><Peptide Signal Sequences><Peptides><Physiologic><Physiological><Physiological Homeostasis><Physiopathology><Plasma><Plasma Serum><Process><Protease Gene><Protease-Activated Receptor 1><Protease-Activated Receptors><Proteases><Protein C><Proteinase-Activated Receptor 1><Proteinase-Activated Receptors><Proteinases><Proteolytic Enzymes><Reaction><Receptor Protein><Receptor Signaling><Regulation><Resistance><Reticuloendothelial System, Serum, Plasma><Role><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 infected patient><SARS-CoV-2 infection><SARS-CoV-2 patient><SARS-CoV-2 positive patient><SARS-CoV-2 therapy><SARS-CoV-2 treatment><SARS-CoV2><SARS-CoV2 infection><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><SIS cytokines><Sepsis><Serine Endopeptidases><Serine Protease><Serine Protein Hydrolases><Serine Proteinases><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome related corona virus 2><Signal Pathway><Signal Peptide><Signal Sequences><Signal Transduction><Signal Transduction Systems><Signaling><Stroke><Structure><Structure-Activity Relationship><Symptoms><System><Testing><Therapeutic><Therapeutic Effect><Thrombosis><Tissues><Translational Research><Translational Science><Translations><Treatment Efficacy><Variant><Variation><Vascular Diseases><Vascular Disorder><Viral Diseases><Virus Diseases><Wuhan coronavirus><activated Protein C><activated protein C receptor><angiotensin converting enzyme 2><angiotensin converting enzyme II><anti-inflammatory effect><bacteria infection><bacterial disease><balance><balance function><biological signal transduction><biologics><biopharmaceutical><biotherapeutic agent><blood infection><blood thinner><blood vessel disorder><bloodstream infection><brain attack><cardiac infarct><cell biology><cell type><cerebral vascular accident><cerebrovascular accident><chemical structure function><chemoattractant cytokine><chemokine><complications due to COVID-19><coronary attack><coronary infarct><coronary infarction><coronavirus disease 2019><coronavirus disease 2019 infected patient><coronavirus disease 2019 infection><coronavirus disease 2019 pathogenesis><coronavirus disease 2019 patient><coronavirus disease 2019 positive patient><coronavirus disease 2019 therapy><coronavirus disease 2019 treatment><coronavirus disease 2019 virus><coronavirus disease infected patient><coronavirus disease patient><coronavirus disease positive patient><coronavirus disease-19><coronavirus disease-19 pathogenesis><coronavirus disease-19 patient><coronavirus disease-19 virus><coronavirus infectious disease-19><coronavirus patient><cytokine><cytoprotective><design><designing><developmental><disabled><disease model><disorder model><efficacy testing><encryption><endothelial cell protein C receptor><fibrin fragment D-dimer><fibrin fragment D1 dimer><fibrin fragment DD><hCoV19><heart attack><heart infarct><heart infarction><hepatic body system><hepatic organ system><improved><in vivo><infected with COVID-19><infected with COVID19><infected with SARS-CoV-2><infected with SARS-CoV2><infected with coronavirus disease 2019><infected with severe acute respiratory syndrome coronavirus 2><inflammatory mediator><injuries><innovate><innovation><innovative><insight><intervention efficacy><life-threatening COVID><life-threatening COVID-19><life-threatening SARS-CoV-2><life-threatening coronavirus disease><life-threatening coronavirus disease 2019><life-threatening severe acute respiratory syndrome coronavirus 2><mimetics><mortality rate><mortality ratio><mutant><nCoV2><new approaches><novel><novel approaches><novel strategies><novel strategy><pathophysiology><pathway><patient infected with COVID><patient infected with COVID-19><patient infected with SARS-CoV-2><patient infected with coronavirus disease><patient infected with coronavirus disease 2019><patient infected with severe acute respiratory syndrome coronavirus 2><patient with COVID><patient with COVID-19><patient with COVID19><patient with SARS-CoV-2><patient with coronavirus disease><patient with coronavirus disease 2019><patient with severe acute respiratory distress syndrome coronavirus 2><peptide mimetic><peptide mimic><peptidomimetics><pharmacologic><pre-clinical><preclinical><protective effect><protein signal sequence><psychological defense mechanism><pulmonary><receptor><receptor function><renal><resistant><serious COVID><serious COVID-19><serious SARS-CoV-2><serious coronavirus disease><serious coronavirus disease 2019><serious severe acute respiratory syndrome coronavirus 2><severe COVID><severe COVID-19><severe COVID19><severe SARS-CoV-2><severe acute respiratory syndrome coronavirus 2 infected patient><severe acute respiratory syndrome coronavirus 2 patient><severe acute respiratory syndrome coronavirus 2 positive patient><severe acute respiratory syndrome coronavirus 2 therapy><severe acute respiratory syndrome coronavirus 2 treatment><severe coronavirus disease><severe coronavirus disease 19><severe coronavirus disease 2019><severe severe acute respiratory syndrome coronavirus 2><social role><stroked><strokes><structure function relationship><therapeutic efficacy><therapy efficacy><thromboinflammation><thromboinflammatory><thrombopoiesis inhibitor><thrombotic disease><thrombotic disorder><translation><translation research><translational investigation><translational opportunities><translational potential><treat COVID-19><treat SARS-CoV-2><treat coronavirus disease 2019><treat severe acute respiratory syndrome coronavirus 2><vascular><vascular dysfunction><vasculopathy><viral infection><virus infection><virus-induced disease>