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Principal Investigator: Wei Li
Organization: MARSHALL UNIVERSITY
Fiscal Year: 2022
Award: $444,000
Funding agency: National Heart Lung and Blood Institute
Project Summary/Abstract
Platelet activation and aggregation is a major component of thrombosis, an underlying cause of myocardial
infarction, ischemic stroke, and severe COVID-19, a new viral respiratory illness caused by severe acute
respiratory syndrome coronavirus-2 (SARS-CoV-2). Various antiplatelet drugs are used clinically to prevent
thrombosis. These drugs block platelet activation and aggregation systemically and, thus, have side effects
(e.g., thrombocytopenia and hemorrhage). Therefore, new molecular mechanism-mediated antiplatelet and
antithrombotic therapies are urgently needed. We recently discovered that thymidine phosphorylase (TYMP), a
highly expressed protein in platelet cytosol, facilitates multiple agonist-induced platelet activation. TYMP
haploinsufficiency or inhibition with its inhibitors significantly attenuates arterial thrombosis without disturbing
systemic hemostasis. Most importantly, TYMP is increased in COVID-19 patients in an acuity-dependent
manner. Increased plasma TYMP in COVID-19 patients occurs earlier than the increase in C-reactive protein,
a predictive factor for inflammation and future risk of cardiovascular events. Increased TYMP is also positively
associated with plasma D-dimer and lactate dehydrogenase levels and the presence of pulmonary symptoms.
These findings indicate that TYMP may play a critical role in the development of severe COVID-19, and
modulation of TYMP activity could potentially be a systemically safe therapy against COVID-19. To this end, it
is necessary to elucidate the detailed mechanistic pathways of TYMP in platelet activation and thrombosis. We
have clarified the role of TYMP in the platelet signaling pathway mediated by platelet glycoprotein VI (GPVI).
However, we still do not know how TYMP deficiency or inhibition attenuates G-protein coupled receptor
(GPCR)-mediated platelet activation and what TYMP’s role is in the hyperthrombotic milieu of severe COVID-
19. We will address these questions in the proposed specific aims. In Aim1, we will clarify the function of TYMP
in GPCR-mediated platelet activation using specific GPCR agonists and antagonists and test the hypothesis
that a combination of low-dose TYMP inhibitor and GPCR antagonist represents a new, safe dual antiplatelet
therapy. In Aim 2, we will determine whether the SARS-CoV-2 spike protein enhances TYMP expression and
subsequent microthrombi formation in the COVID-19 milieu. We will also investigate if TYMP deficiency or
inhibition attenuates SARS-CoV-2 spike protein-associated microthrombosis and reduces mortality in mice.
Our ongoing study suggest that pharmacological inhibition of TYMP with tipiracil, a selective TYMP inhibitor
and an FDA-approved medication, is a promising anti-thrombotic therapy without bleeding disorders.
Successful completion of this R15 renewal will pave the way for repurposing tipiracil as an antiplatelet
medication for patients with high thrombotic risks, especially COVID-19 patients.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV S protein><2019-nCoV spike glycoprotein><2019-nCoV spike protein><ACE2><ARDS><Accident and Emergency department><Acute Respiratory Distress><Acute Respiratory Distress Syndrome><Address><Adult ARDS><Adult RDS><Adult Respiratory Distress Syndrome><Agonist><Antiplatelet Agents><Antiplatelet Drugs><Antithrombotic Agents><Antithrombotic Drugs><Apoplexy><Atheroscleroses><Atherosclerosis><Atherosclerotic Cardiovascular Disease><Attenuated><Autocrine Systems><Biology><Bleeding><Blood Coagulation Disorders><Blood Plasma><Blood Platelets><Brain Vascular Accident><C-reactive protein><COVID infected patient><COVID patient><COVID positive patient><COVID-19><COVID-19 S protein><COVID-19 associated death><COVID-19 associated fatality><COVID-19 associated mortality><COVID-19 death><COVID-19 fatality><COVID-19 induced death><COVID-19 induced fatality><COVID-19 induced mortality><COVID-19 infected patient><COVID-19 infection><COVID-19 mortality><COVID-19 patient><COVID-19 positive><COVID-19 positive patient><COVID-19 positivity><COVID-19 related death><COVID-19 related fatality><COVID-19 related mortality><COVID-19 spike glycoprotein><COVID-19 spike protein><COVID-19 therapy><COVID-19 treatment><COVID-19 virus><COVID19><COVID19 S protein><COVID19 associated death><COVID19 associated fatality><COVID19 associated mortality><COVID19 death><COVID19 fatality><COVID19 induced death><COVID19 induced fatality><COVID19 induced mortality><COVID19 infection><COVID19 mortality><COVID19 patient><COVID19 positive><COVID19 positive patient><COVID19 positivity><COVID19 related death><COVID19 related fatality><COVID19 related mortality><COVID19 spike glycoprotein><COVID19 spike protein><COVID19 therapy><COVID19 treatment><COVID19 virus><CV-19><CV19><Cancers><Cardiac infarction><Cell Communication and Signaling><Cell Signaling><Cerebral Stroke><Cerebrovascular Apoplexy><Cerebrovascular Stroke><Chemicals><Clinical><CoV-2><CoV2><Coagulation Disorder><Coagulopathy><Collagen><Complex><Complication><Consumption Coagulopathy><Cytoplasm><Cytoplasmic Protein><Cytosol><D-dimer><D-dimer fibrin><D-dimer fragments><Da Nang Lung><Data><Development><Diabetes Mellitus><Dimerization><Disease><Disorder><Disseminated Intravascular Coagulation><Dose><Drug usage><Drugs><EC 1.1.1.27><Emergency Department><Emergency room><Event><FDA approved><Fibrin fragment D><Fibrinolytic Agents><Fibrinolytic Drugs><Future><G Protein-Complex Receptor><G Protein-Coupled Receptor Genes><G Protein-Coupled Receptor Signaling><G-Protein-Coupled Receptors><G-Proteins><GPCR><GPCR Signaling><GTP-Binding Proteins><GTP-Regulatory Proteins><General Hospitals><Gliostatin><Goals><Guanine Nucleotide Coupling Protein><Guanine Nucleotide Regulatory Proteins><Hemorrhage><Hemostasis><Hemostatic function><Human><Individual><Inflammation><Inflammatory><Intracellular Communication and Signaling><Ischemic Stroke><L-Lactate Dehydrogenase><L-Lactic Acid Dehydrogenase><Lactate Dehydrogenase><Lead><Lentivirinae><Lentivirus><Life><Lung><Lung Respiratory System><MOF syndrome><Malignant Neoplasms><Malignant Tumor><Marrow platelet><Massachusetts><Mediating><Medication><Mice><Mice Mammals><Modern Man><Molecular><Multiple Organ Dysfunction Syndrome><Multiple Organ Failure><Murine><Mus><Myocardial Infarct><Myocardial Infarction><NAD-Lactate Dehydrogenase><PD-ECGF><Pathway interactions><Patients><Pb element><Pharmaceutic Preparations><Pharmaceutical Preparations><Pharmacology><Phosphorylase a><Plasma><Plasma Serum><Platelet Activation><Platelet Glycoproteins><Platelet aggregation><Platelet-Derived Endothelial Cell Growth Factor><Platelets><Play><Predictive Factor><Process><Protein Dimerization><Proteins><Proteins, specific or class, C-reactive><Reticuloendothelial System, Serum, Plasma><Risk><Role><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 S protein><SARS-CoV-2 associated death><SARS-CoV-2 associated fatality><SARS-CoV-2 associated mortality><SARS-CoV-2 death><SARS-CoV-2 fatality><SARS-CoV-2 induced death><SARS-CoV-2 induced fatality><SARS-CoV-2 induced mortality><SARS-CoV-2 infected patient><SARS-CoV-2 infection><SARS-CoV-2 mortality><SARS-CoV-2 patient><SARS-CoV-2 positive><SARS-CoV-2 positive patient><SARS-CoV-2 positivity><SARS-CoV-2 related death><SARS-CoV-2 related fatality><SARS-CoV-2 related mortality><SARS-CoV-2 spike glycoprotein><SARS-CoV-2 spike protein><SARS-CoV-2 therapy><SARS-CoV-2 treatment><SARS-CoV2><SARS-CoV2 S protein><SARS-CoV2 infection><SARS-CoV2 spike glycoprotein><SARS-CoV2 spike protein><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><SH3 Domains><SRC Homology Region 3 Domain><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 corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 S protein><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome coronavirus 2 positive><Severe acute respiratory syndrome coronavirus 2 positivity><Severe acute respiratory syndrome coronavirus 2 spike glycoprotein><Severe acute respiratory syndrome coronavirus 2 spike protein><Severe acute respiratory syndrome related corona virus 2><Severity of illness><Shock Lung><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Stiff lung><Stroke><Systemic disease><TdRPase><Testing><Thrombase><Thrombin><Thrombocytes><Thrombocytopenia><Thrombolytic Agents><Thrombolytic Drugs><Thrombopenia><Thrombosis><Thrombus><Thymidine Phosphorylase><Transgenic Organisms><Viral><Virus><Virus-Lenti><Wuhan coronavirus><angiotensin converting enzyme 2><angiotensin converting enzyme II><antagonist><antithrombotic medication><antithrombotics><arrestin B><atheromatosis><atherosclerotic disease><atherosclerotic vascular disease><autocrine><beta-arrestin><biological signal transduction><bleeding disorder><blood loss><brain attack><cardiac infarct><cardiovascular risk><cardiovascular risk factor><cerebral vascular accident><cerebrovascular accident><clotting disorder><cohort><corona virus disease 2019><coronary attack><coronary infarct><coronary infarction><coronavirus disease 2019><coronavirus disease 2019 S protein><coronavirus disease 2019 associated death><coronavirus disease 2019 associated fatality><coronavirus disease 2019 associated mortality><coronavirus disease 2019 death><coronavirus disease 2019 fatality><coronavirus disease 2019 induced death><coronavirus disease 2019 induced fatality><coronavirus disease 2019 induced mortality><coronavirus disease 2019 infected patient><coronavirus disease 2019 infection><coronavirus disease 2019 mortality><coronavirus disease 2019 patient><coronavirus disease 2019 positive><coronavirus disease 2019 positive patient><coronavirus disease 2019 positivity><coronavirus disease 2019 related death><coronavirus disease 2019 related fatality><coronavirus disease 2019 related mortality><coronavirus disease 2019 spike glycoprotein><coronavirus disease 2019 spike protein><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 mortality><coronavirus disease-19 patient><coronavirus disease-19 virus><coronavirus infectious disease-19><coronavirus patient><cremaster muscle><cytokine release syndrome><cytokine storm><death due to COVID-19><death due to COVID19><death due to SARS-CoV-2><death due to coronavirus disease 2019><death due to severe acute respiratory syndrome coronavirus 2><death in COVID><death in COVID-19><death in SARS-CoV-2><death in coronavirus disease><death in coronavirus disease 2019><death in severe acute respiratory syndrome coronavirus 2><desensitization><developmental><diabetes><disease severity><drug use><drug/agent><fatality due to COVID-19><fatality due to COVID19><fatality due to SARS-CoV-2><fatality due to coronavirus disease 2019><fatality due to severe acute respiratory syndrome coronavirus 2><fibrin fragment D-dimer><fibrin fragment D1 dimer><fibrin fragment DD><fibrinogenase><hCoV19><heart attack><heart infarct><heart infarction><heavy metal Pb><heavy metal lead><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><inhibitor><insight><lactic acid dehydrogenase><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><malignancy><mortality><mortality due to COVID-19><mortality due to COVID19><mortality due to SARS-CoV-2><mortality due to coronavirus disease 2019><mortality due to severe acute respiratory syndrome coronavirus 2><mouse model><multiorgan failure><multiple organ system failure><murine model><nCoV2><neoplasm/cancer><novel><pandemic><pandemic disease><paracrine><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><platelet function><prevent><preventing><pulmonary><pulmonary symptom><recruit><respiratory><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 associated death><severe acute respiratory syndrome coronavirus 2 associated fatality><severe acute respiratory syndrome coronavirus 2 associated mortality><severe acute respiratory syndrome coronavirus 2 death><severe acute respiratory syndrome coronavirus 2 fatality><severe acute respiratory syndrome coronavirus 2 induced death><severe acute respiratory syndrome coronavirus 2 induced fatality><severe acute respiratory syndrome coronavirus 2 induced mortality><severe acute respiratory syndrome coronavirus 2 infected patient><severe acute respiratory syndrome coronavirus 2 mortality><severe acute respiratory syndrome coronavirus 2 patient><severe acute respiratory syndrome coronavirus 2 positive patient><severe acute respiratory syndrome coronavirus 2 related death><severe acute respiratory syndrome coronavirus 2 related fatality><severe acute respiratory syndrome coronavirus 2 related mortality><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><side effect><social role><src Kinases><src Protein-Tyrosine Kinases><src Tyrosine Kinases><src-Family Kinases><src-Family Tyrosine Kinases><thrombotic><thrombotic disease><thrombotic disorder><transgenic><treat COVID-19><treat COVID19><treat SARS-CoV-2><treat coronavirus disease 2019><treat severe acute respiratory syndrome coronavirus 2><wet lung><β-arrestin>