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Mechanisms linking the plasminogen/fibrinogen axis to the pathogenesis of COVID-19

纤溶酶原/纤维蛋白原轴与 COVID-19 发病机制的联系机制

基本信息

批准号：
10471424
负责人：
MATTHEW J FLICK
金额：
$ 55.17万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10471424
关键词：
2019-nCoV ACE2 Acute Respiratory Distress Syndrome Alveolar Automobile Driving Autopsy Blood Blood Coagulation Disorders Blood Coagulation Factor Blood Vessels Blood coagulation C-reactive protein COVID-19 COVID-19 morbidity COVID-19 mortality COVID-19 pandemic COVID-19 pathogenesis COVID-19 patient COVID-19 treatment Capsid Proteins Cell surface Cessation of life Clinical Clinical Management Coagulation Process Coronavirus Coronavirus Infections Coupling Data Deposition Disease Engineering Fibrin Fibrin fragment D Fibrinogen Fibrosis Fostering Functional disorder Goals Healthcare Systems Hematology Hemorrhage Hemostatic Agents Human Hypoxia Immune response Immunologics Individual Infection Inflammatory Inflammatory Response Integration Host Factors Interleukin-6 Knowledge Lead Leukocytes Link Lung Mediating Modeling Molecular Morbidity - disease rate Mus Mutation Organ Organ failure Outcome Pathogenicity Pathology Patient-Focused Outcomes Patients Persons Plasminogen Public Health Pulmonary Edema Pulmonary Inflammation Reporting Research Structure of parenchyma of lung Surface Symptoms System Testing Thrombophilia Thrombosis Tissues Translations Viral Proteins Virus body system coronavirus disease coronavirus receptor cost cytokine release syndrome experience human coronavirus improved inflammatory marker insight mortality novel patient response programs severe COVID-19 systemic inflammatory response tool trigger point

项目摘要

SUMMARY Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2; CoV2) is the first highly pathogenic and highly transmissible human coronavirus that is the causative agent for the worldwide COVID-19 pandemic. As of November 2020, 50 million cases of CoV2 infection worldwide and 1.25 million deaths have been reported. The U.S. accounts for the majority of cases, 9.7 million (20%) and deaths 235,000 (19%), and COVID-19 is expected to add an $8 trillion burden to the U.S. health care system. A particularly challenging aspect of clinical management is the variable patient response to CoV2 infection. Some infected individuals report few symptoms whereas others display severe disease characterized by hypoxia, acute respiratory distress syndrome, and multi-organ involvement that can lead to death. A pro-inflammatory ‘cytokine storm’ in COVID- 19 patients promotes derangements in vascular function and blood composition. Elevated fibrinogen and D- dimer (the breakdown product of fibrin clots) track with significant elevations inflammatory markers (e.g., IL-6, C-reactive protein), which significantly and positively correlate with poor patient outcomes. Autopsy studies of COVID-19 patients have revealed intravascular and extravascular fibrin deposits in lung tissue and other organ systems. A current critical knowledge gap is the molecular basis of how persistent fibrin deposits develop and whether they are functionally linked to the pathophysiology of severe COVID-19 disease. Our central hypothesis that an insufficiency in the plasminogen activation (PA) system is a trigger point for transition of COVID-19 from mild to severe disease due accumulating, proinflammatory, and tissue-damaging fibrin deposits within the lung and other organ systems. To test this hypothesis, our research team developed a mouse-adapted CoV2 virus that replicates key immunological and hematological aspects of COVID-19 in humans. This unique tool will be used in conjunction with mice carrying single or combined deficiencies or functional mutations in fibrinogen or PA system components to define the natural course of hemostatic changes following infection and elucidate functional contributions of coagulation and fibrinolytic factors to the host response. Specifically, we will determine (i) the differences in local and systemic activity of host factors that control fibrin(ogen) deposition, stabilization, and dissolution following mild vs. severe CoV2 infection; (ii) how PA deficiency promotes severe disease following CoV2 infection characterized by exacerbation of local and systemic inflammatory, organ damage, and host mortality; and (iii) the mechanisms linking fibrin(ogen) to exacerbation of host inflammatory responses and induction of severe disease following CoV2 infection. The proposed studies will provide novel insights into the contribution of the plasminogen/fibrinogen axis to the CoV2 pathobiology, illuminate key mechanisms coupling deficiencies in PA system components to CoV2- mediated thrombophilia, tissue damage, and loss of organ function, and provide essential proof-of-principle data to facilitate translation of findings into new treatments for COVID-19.

总结