Document text
Principal Investigator: Cynthia Ann Derdeyn
Organization: EMORY UNIVERSITY
Fiscal Year: 2022
Award: $195,625
Funding agency: National Institute of Allergy and Infectious Diseases
SUMMARY
Clinical sequelae of COVID-19 patients include not only acute respiratory distress syndrome (ARDS), but also
often acute kidney injury and heart failure. These pathologies share endothelial activation as a common
underlying early response to injury, and endothelial cells express high levels of angiotensin converting enzyme
2 (ACE2), a functional receptor for SARS-CoV-2. Activated endothelium not only attracts and promotes
leukocyte infiltration into tissues and contributes to the cytokine storm resulting in capillary leakage and edema,
but is also prothrombotic. Together, these mechanisms result in tissue inflammation and ischemia, leading to
organ failure. Our laboratory discovered that polymerase delta interacting protein 2 (Poldip2) is a novel and
important regulator of inflammation, endothelial permeability and potentially coagulation in mice. Mice
heterozygous for Poldip2 are largely protected from lipopolysaccharide (LPS)- or P. aeruginosa-induced ARDS.
Here, we hypothesize that Poldip2 may be a novel target for treatment of SARS-CoV-2-infected individuals, as
downregulation of Poldip2 not only reduces ARDS complications such as edema and the cytokine storm, but
also potentially may inhibit thrombosis. To test this hypothesis, we propose to treat SARS-CoV-2-infected mice
with an anti-cancer agent undergoing clinical trials that we have recently shown to reduce Poldip2 levels and
restore endothelial barrier function. In the first Aim, we will use this agent to downregulate Poldip2 and test its
ability to preserve endothelial barrier function and reduce inflammation in response to SARS-CoV-2 infection in
mice. The second aim will focus on determining the effect of the anticancer agent and genetic ablation of Poldip2
on basal coagulation and that induced by SARS-CoV-2 infection. We anticipate that pharmacological
downregulation of Poldip2 will represent a promising new treatment for COVID-19 patients that can be rapidly
translated to the clinic.
Terms: <(TNF)-α><2019 novel corona virus><2019 novel coronavirus><2019-nCoV><72-kDa Gelatinase><72-kDa Type IV Collagenase><72kD type IV Collagenase><ACE2><ARDS><Ablation><Active Oxygen><Acute Renal Failure with Renal Papillary Necrosis><Acute Respiratory Distress><Acute Respiratory Distress Syndrome><Adhesion Plaques><Adult ARDS><Adult RDS><Adult Respiratory Distress Syndrome><Affect><Animal Model><Animal Models and Related Studies><Animals><Anti-Cancer Agents><Anticoagulation><Antineoplastic Agents><Antineoplastic Drugs><Antineoplastics><Antithrombin VI><Apoplexy><Arteries><Attenuated><BBB disruption><Binding><Biological Markers><Bleeding><Blood><Blood Clotting><Blood Neutrophil><Blood Polymorphonuclear Neutrophil><Blood Reticuloendothelial System><Blood capillaries><Blood coagulation><Blood leukocyte><Blood monocyte><Body Tissues><Brain Vascular Accident><CD154><CD40L><CD40LG><COVID associated ARDS><COVID associated acute respiratory distress syndrome><COVID induced ARDS><COVID induced acute respiratory distress syndrome><COVID infected patient><COVID patient><COVID positive patient><COVID related ARDS><COVID related acute respiratory distress syndrome><COVID-19><COVID-19 associated ARDS><COVID-19 associated acute respiratory distress syndrome><COVID-19 induced ARDS><COVID-19 induced acute respiratory distress syndrome><COVID-19 infected patient><COVID-19 infection><COVID-19 patient><COVID-19 positive patient><COVID-19 related ARDS><COVID-19 related acute respiratory distress syndrome><COVID-19 therapy><COVID-19 treatment><COVID-19 virus><COVID-19/ARDS><COVID-19/acute respiratory distress syndrome><COVID/ARDS><COVID/acute respiratory distress syndrome><COVID19><COVID19 associated ARDS><COVID19 associated acute respiratory distress syndrome><COVID19 induced ARDS><COVID19 induced acute respiratory distress syndrome><COVID19 infection><COVID19 patient><COVID19 positive patient><COVID19 related ARDS><COVID19 related acute respiratory distress syndrome><COVID19 therapy><COVID19 treatment><COVID19 virus><COVID19/ARDS><COVID19/acute respiratory distress syndrome><CV-19><CV19><Cachectin><Cancer Drug><Cancers><Cell Body><Cell Cycle Control><Cell Cycle Regulation><Cell Nucleus><Cell membrane><Cell-Extracellular Matrix><Cell-Matrix Adherens Junctions><Cells><Cerebral Stroke><Cerebrovascular Apoplexy><Cerebrovascular Stroke><Clinic><Clinical><Clinical Treatment><Clinical Trials><Clotting><CoV-2><CoV2><Coagulation><Coagulation Process><Cytoplasmic Membrane><Cytoskeletal Modeling><Cytoskeletal Organization><Cytoskeletal Organization Process><Cytoskeletal Reorganization><D-dimer><D-dimer fibrin><D-dimer fragments><DNA Damage Repair><DNA Repair><Da Nang Lung><Data><Depressed mood><Disease><Disorder><Down-Regulation><Downregulation><Dropsy><Drug Targeting><Dysfunction><ECM><Edema><Endothelial Cells><Endothelium><Exhibits><Extracellular Matrix><Extravasation><Fibrin Degradation Products><Fibrin Fibrinogen Degradation Products><Fibrin Fibrinogen Split Products><Fibrin fragment D><Fibrin split products><Focal Adhesions><Focal Contacts><Functional disorder><Gelatinase A><Gelatinase Neutrophil><Genetic><Heart failure><Hemorrhage><Hydrops><Impairment><In Vitro><Individual><Infiltration><Inflammation><Inflammatory><Inflammatory Response><Injections><Investigation><Ischemia><Ischemic Stroke><Laboratories><Leakage><Leukocytes><Leukocytes Reticuloendothelial System><Lipopolysaccharides><Liquid substance><LoxP-flanked allele><Lung><Lung Parenchyma><Lung Respiratory System><Lung Tissue><Lung damage><MMP-2><MMPs><MOF syndrome><Macrophage-Derived TNF><Maintenance><Malignant Neoplasms><Malignant Tumor><Marrow Neutrophil><Marrow leukocyte><Marrow monocyte><Matrix Metalloproteinase-2><Matrix Metalloproteinases><Metabolic><Mice><Mice Mammals><Middle Cerebral Artery Occlusion><Mitochondria><Molecular Interaction><Monocyte-Derived TNF><Multiple Organ Dysfunction Syndrome><Multiple Organ Failure><Murine><Mus><NADPH Oxidase><Neoplastic Disease Chemotherapeutic Agents><Neutrophilic Granulocyte><Neutrophilic Leukocyte><Nucleus><Organ failure><Outcome><Oxygen Radicals><P aeruginosa><P. aeruginosa><Pathology><Pathway interactions><Patients><Permeability><Pharmacology><Physiopathology><Plasma Membrane><Polymerase><Polymorphonuclear Cell><Polymorphonuclear Leukocytes><Polymorphonuclear Neutrophils><Pro-Oxidants><Production><Proteins><Pseudomonas aeruginosa><Pseudomonas pyocyanea><Reactive Oxygen Species><Receptor Protein><Respiratory distress><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 associated ARDS><SARS-CoV-2 associated acute respiratory distress syndrome><SARS-CoV-2 induced ARDS><SARS-CoV-2 induced acute respiratory distress syndrome><SARS-CoV-2 infected patient><SARS-CoV-2 infection><SARS-CoV-2 patient><SARS-CoV-2 positive patient><SARS-CoV-2 related ARDS><SARS-CoV-2 related acute respiratory distress syndrome><SARS-CoV-2 therapy><SARS-CoV-2 treatment><SARS-CoV-2/ARDS><SARS-CoV-2/acute respiratory distress syndrome><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><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 infection><Severe acute respiratory syndrome related corona virus 2><Shock Lung><Spillage><Stiff lung><Stroke><Structure of parenchyma of lung><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFSF5><TNFSF5 gene><TNFα><TRAP Gene><Tail><Testing><Thrombosis><Thrombus><Tissues><Toxic effect><Toxicities><Translating><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><Tumor-Specific Treatment Agents><Unscheduled DNA Synthesis><White Blood Cells><White Cell><Wuhan coronavirus><acute kidney injury><angiotensin converting enzyme 2><angiotensin converting enzyme II><anti-cancer drug><anticancer agent><anticancer drug><bio-markers><biologic marker><biomarker><blood loss><blood-brain barrier disruption><bloodbrain barrier disruption><brain attack><capillary><cardiac failure><cerebral vascular accident><cerebrovascular accident><corona virus disease 2019><coronavirus disease 2019><coronavirus disease 2019 associated ARDS><coronavirus disease 2019 associated acute respiratory distress syndrome><coronavirus disease 2019 induced ARDS><coronavirus disease 2019 induced acute respiratory distress syndrome><coronavirus disease 2019 infected patient><coronavirus disease 2019 infection><coronavirus disease 2019 patient><coronavirus disease 2019 positive patient><coronavirus disease 2019 related ARDS><coronavirus disease 2019 related acute respiratory distress syndrome><coronavirus disease 2019 therapy><coronavirus disease 2019 treatment><coronavirus disease 2019 virus><coronavirus disease 2019/ARDS><coronavirus disease 2019/acute respiratory distress syndrome><coronavirus disease associated ARDS><coronavirus disease associated acute respiratory distress syndrome><coronavirus disease induced ARDS><coronavirus disease induced acute respiratory distress syndrome><coronavirus disease infected patient><coronavirus disease patient><coronavirus disease positive patient><coronavirus disease related ARDS><coronavirus disease related acute respiratory distress syndrome><coronavirus disease-19><coronavirus disease-19 patient><coronavirus disease-19 virus><coronavirus disease/ARDS><coronavirus disease/acute respiratory distress syndrome><coronavirus infectious disease-19><coronavirus patient><cytokine><cytokine release syndrome><cytokine storm><depressed><fibrin fragment D-dimer><fibrin fragment D1 dimer><fibrin fragment DD><floxed><floxed allele><fluid><hCoV19><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><injury response><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><liquid><lung injury><malignancy><mitochondrial><model of animal><model organism><monocyte><mouse model><multiorgan failure><multiple organ system failure><murine model><nCoV2><neoplasm/cancer><neutrophil><novel><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><plasmalemma><preservation><prevent><preventing><pulmonary><pulmonary damage><pulmonary injury><pulmonary tissue damage><pulmonary tissue injury><receptor><recruit><response><response to injury><sadness><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 ARDS><severe acute respiratory syndrome coronavirus 2 associated acute respiratory distress syndrome><severe acute respiratory syndrome coronavirus 2 induced ARDS><severe acute respiratory syndrome coronavirus 2 induced acute respiratory distress syndrome><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 related ARDS><severe acute respiratory syndrome coronavirus 2 related acute respiratory distress syndrome><severe acute respiratory syndrome coronavirus 2 therapy><severe acute respiratory syndrome coronavirus 2 treatment><severe acute respiratory syndrome coronavirus 2/ARDS><severe acute respiratory syndrome coronavirus 2/acute respiratory distress syndrome><severe coronavirus disease><severe coronavirus disease 19><severe coronavirus disease 2019><severe severe acute respiratory syndrome coronavirus 2><therapeutic target><thrombotic disease><thrombotic disorder><treat COVID-19><treat COVID19><treat SARS-CoV-2><treat coronavirus disease 2019><treat severe acute respiratory syndrome coronavirus 2><trial regimen><trial treatment><wet lung><white blood cell><white blood corpuscle>