Document text
Principal Investigator: Jason Knight
Organization: UNIVERSITY OF MICHIGAN AT ANN ARBOR
Fiscal Year: 2020
Award: $390,000
Funding agency: National Heart Lung and Blood Institute
ABSTRACT
This Coronavirus Disease 2019 (COVID-19) supplement will study the role of neutrophil extracellular traps
(NETs) as biomarkers and therapeutic targets in COVID-19. The supplement will preserve the parent project’s
focus on ectoenzymes and purinergic signaling as amplifiable counterpoints to neutrophil hyperactivity and
exaggerated NET release (NETosis). Indeed, elevated levels of blood neutrophils are an early indicator of
SARS-CoV-2 infection, where they predict severe COVID-19 respiratory disease.
Our group and others have recently revealed a critical role for NETs in various thrombo-inflammatory states
including sepsis, venous thrombosis, and respiratory failure. NETs are extracellular tangles of chromatin,
microbicidal proteins, and oxidant enzymes that are released by neutrophils to corral infections; however, when
not properly regulated, NETs have potential to amplify inflammation and thrombosis. In COVID-19, we
hypothesize that NETs will function as powerful biomarkers for predicting progression to respiratory failure.
With special relevance to this application, a recent study performed in China suggested potential efficacy of the
adenosine-receptor agonist, dipyridamole in severe cases of COVID-19. Dipyridamole is an FDA-approved
drug that our group recently discovered—through work on the parent project—to inhibit NETosis via activation
of adenosine A2A receptors (A2AR). The hypothesis here is that A2AR agonists such as dipyridamole will
compensate for virus-mediated deficiencies in the pulmonary ACE2 axis and thereby suppress NETosis.
This supplement requests funds to support three complementary Aims. Aim 1 will determine the extent to
which NET levels can be used as predictive biomarkers in COVID-19. Aim 2 will elucidate mechanisms by
which the ACE2/angiotensin-(1-7) axis regulates COVID-19 neutrophils. Finally, Aim 3 will determine the
extent to which adenosine receptor agonism prevents NETosis and macrophage activation in COVID-19.
Terms: <2019 novel coronavirus><2019-nCoV><21+ years old><3'5'-cyclic ester of AMP><A2AR><ADORA2><ADORA2A gene><ARDS><Acute Respiratory Distress><Acute Respiratory Distress Syndrome><Adenosine><Adenosine A(2A) Receptor><Adenosine A2A Receptor><Adenosine Cyclic 3',5'-Monophosphate><Adenosine Cyclic Monophosphate><Adenosine Cyclic Monophosphate-Dependent Protein Kinases><Adenosine Receptors><Adenosine, cyclic 3',5'-(hydrogen phosphate)><Adult><Adult ARDS><Adult Human><Adult RDS><Adult Respiratory Distress Syndrome><Agonist><Ang I (1-7)><Ang-2><Ang2><AngII><Angiopoietin-2><Angiotensin Converting Enzyme><Angiotensin I-Converting Enzyme><Angiotensin II><Angiotensin-Forming Enzyme><Angiotensinogenase><Angiotensins><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Antiinflammatories><Antiinflammatory Agents><Autoimmune><Autoimmune Process><B cell differentiation factor><B cell stimulating factor 2><B-Cell Differentiation Factor><B-Cell Differentiation Factor-2><B-Cell Stimulatory Factor-2><BCDF><BSF-2><BSF2><Beta Proprotein Interleukin 1><Biological Markers><Biology><Blood Circulation><Blood Neutrophil><Blood Plasma><Blood Platelet Count><Blood Platelet Number><Blood Polymorphonuclear Neutrophil><Blood Vessels><Blood leukocyte><Bloodstream><CD143 Antigens><COVID><COVID-19><COVID19><Carboxycathepsin><Cardiovascular><Cardiovascular Body System><Cardiovascular Organ System><Cardiovascular system><Cell Communication and Signaling><Cell Signaling><China><Chromatin><Circulation><Clinical><Co-culture><CoV disease><Cocultivation><Coculture><Coculture Techniques><Cyclic AMP><Cyclic AMP-Dependent Protein Kinases><D-dimer><D-dimer fibrin><D-dimer fragments><Da Nang Lung><Dipeptidyl Peptidase A><Dipyramidole><Dipyridamole><Disease><Disorder><Drugs><Enzyme Gene><Enzymes><Epithelial><Epithelial Cells><Epithelium><Epithelium Part><FDA approved><Fibrin fragment D><Funding><G Protein-Complex Receptor><G Protein-Coupled Receptor Genes><G-Protein-Coupled Receptors><GPCR><Goals><Grippe><HPGF><Heart Vascular><Hepatocyte-Stimulating Factor><Hybridoma Growth Factor><Hyperactive behavior><Hyperactivity><Hyperkinesia><Hyperkinesis><Hyperkinetic Movements><IFN-beta 2><IFNB2><IL-1 beta><IL-1 β><IL-1-b><IL-1β><IL-6><IL1-Beta><IL1-β><IL1B Protein><IL1F2><IL1β><IL6 Protein><Individual><Infection><Inflammation><Inflammatory><Influenza><Inpatients><Interleukin 1beta><Interleukin-1 beta><Interleukin-1β><Interleukin-6><Intracellular Communication and Signaling><Kininase A><Kininase II><Leukocytes><Leukocytes Reticuloendothelial System><Life><Lung><Lung Respiratory System><Lung diseases><MGI-2><Macrophage Activation><Mainland China><Marrow Neutrophil><Marrow leukocyte><Mediating><Medication><Medicine><Michigan><Modeling><Motor Hyperactivity><Myeloid Differentiation-Inducing Protein><Neurofibrillary Tangles><Neutrophil Activation><Neutrophilic Granulocyte><Neutrophilic Leukocyte><O element><O2 element><Oxidants><Oxidizing Agents><Oxygen><P1 Purinoceptors><PKA><Pathway interactions><Patients><Peptidyl-Dipeptidase A><Persantin><Persantine><Personalized medical approach><Pharmaceutic Preparations><Pharmaceutical Preparations><Phenotype><Phlebothrombosis><Plasma><Plasma Serum><Plasmacytoma Growth Factor><Platelet Count><Platelet Count measurement><Platelet Number><Polymorphonuclear Cell><Polymorphonuclear Leukocytes><Polymorphonuclear Neutrophils><Position><Positioning Attribute><Preinterleukin 1 Beta><Production><Protein Kinase A><Proteins><Pulmonary Diseases><Pulmonary Disorder><Purinergic P1 Receptors><RDC8><Regulation><Renin><Research><Research Specimen><Respiratory Disease><Respiratory Failure><Respiratory System Disease><Respiratory System Disorder><Reticuloendothelial System, Serum, Plasma><Role><SARS-CoV-2><SARS-CoV2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related coronavirus 2><Sepsis><Severe acute respiratory syndrome coronavirus 2><Shock Lung><Signal Transduction><Signal Transduction Systems><Signaling><Specimen><Stiff lung><Surface><Swab><Symptoms><Testing><Thrombosis><Venous Thrombosis><Virus><White Blood Cells><White Cell><Work><Wuhan coronavirus><adenosine 3'5' monophosphate><adenosine receptor activation><adulthood><angiotensin I (1-7)><angiotensin-(1-7)><antiinflammatory><bio-markers><biologic marker><biological signal transduction><biomarker><blood infection><bloodstream infection><cAMP><cAMP-Dependent Protein Kinases><circulatory system><corona virus disease><corona virus disease 2019><coronavirus disease><coronavirus disease 2019><cytokine><disease of the lung><disorder of the lung><drug/agent><electron acceptor><experiment><experimental research><experimental study><extracellular><fibrin fragment D-dimer><fibrin fragment D1 dimer><fibrin fragment DD><flu infection><improved><individualized approach><influenza infection><interferon beta 2><lung disorder><macrophage><microbicidal><microbicide><neurofibrillary degeneration><neurofibrillary lesion><neurofibrillary pathology><neutrophil><parent project><pathway><personalized approach><precision approach><predictive biomarkers><predictive marker><predictive molecular biomarker><preservation><pressure><prevent><preventing><primary end point><primary endpoint><pulmonary><pulmonary failure><respiratory><respiratory insufficiency/failure><response><social role><study population><tailored approach><tangle><therapeutic target><thromboinflammation><thromboinflammatory><thrombotic disease><thrombotic disorder><trend><vascular><wet lung><white blood cell><white blood corpuscle>