权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Cellular effects of SARS-CoV-2 in mediating thrombotic susceptibility

SARS-CoV-2 在介导血栓易感性中的细胞作用

基本信息

批准号：
10467274
负责人：
Sanjana Dayal
金额：
$ 67.37万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-09 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10467274
关键词：
2019-nCoV ACE2 Acute Address Biological Markers Blood Blood Coagulation Disorders Blood Platelets Blood Vessels Blood coagulation COVID-19 COVID-19 complications COVID-19 impact COVID-19 patient Cause of Death Cells Clinical Coagulation Process Data Development Dose Endothelial Cells Enoxaparin Experimental Models Fibrin fragment D Future Galactose Galactose Binding Lectin Galectin 3 Generations Health Hematopoietic Histone H3 Histones Hospitalization Human IL6 gene Infection Inflammation Infusion procedures Interleukin-1 beta Iowa K-18 conjugate Lectin Link Literature Measures Mediating Mediator of activation protein Multiple Organ Failure Mus NF-kappa B Neutrophil Activation Outcome Pathway interactions Patients Phase Plasma Platelet Activation Pre-Clinical Model Predisposition Preventive Proteins Randomized Clinical Trials Randomized Controlled Trials Recovery Reporting Research Research Design Resources Role SARS-CoV-2 infection Sampling Severe Acute Respiratory Syndrome Signal Transduction TNF gene Thrombin Thrombosis Transgenic Mice Universities Venous Thrombosis Virus Diseases cohort cytokine cytokine release syndrome druggable target extracellular in vivo microvesicles mouse model neutrophil novel novel coronavirus pre-clinical prevent prophylactic receptor recruit response therapeutic target thrombogenesis thrombotic thrombotic complications translational approach trial comparing

项目摘要

Project Summary Infection with severe acute respiratory syndrome novel corona virus (SARS-CoV-2) causes COVID-19. In severe cases, COVID-19 leads to profound inflammation (“cytokine storm”) followed by coagulopathy and a prothrombotic-state with progression to multiple organ failure. Several cytokines, including IL6 are elevated. Further, a proinflammatory galectin, Galectin-3 (Gal-3) is also found elevated. Gal-3 upregulates IL6 and other cytokines, can directly activate platelets, neutrophils, and endothelial cells, and is known to mediate venous thrombosis via IL6 in a mouse model. A growing body of literature has implicated neutrophil, platelet and endothelial cell activation as potential drivers of thrombotic complications in COVID-19 patients. However, there are no direct mechanistic links established between inflammation, vascular cell activation, and thrombosis during SARS-CoV-2 infection. Our objective is to define the mediators that cause activation of neutrophils, platelets and/or endothelial cells during SARS-CoV-2 infection and their mechanistic roles in promoting thrombin generation and thrombosis. At the University of Iowa, we led a multicenter randomized clinical trial (RCT) comparing standard prophylactic dose to intermediate dose enoxaparin in hospitalized patients with COVID-19 (NCT04360824) and collected plasma samples for biomarkers and mechanistic studies. Given the upsurge in late thrombotic complications of COVID-19, we now propose to recruit additional patients to collect serial samples every week during hospitalization and thereafter every 3 months for up to 3 years. We hypothesize that thrombogenicity in COVID-19 is mediated by IL6- and Gal-3-driven activation of hematopoietic and endothelial cells and that the prothrombotic state persists even after recovery from viral infection. Our team has a unique combination of expertise and resources that will address the hypothesis in 2 well integrated but independent aims. In Aim 1, using serially collected patient’s samples, we will determine the mechanistic role of IL6, Gal-3, and NETs in mediating cellular activation and enhancing thrombin generation and thrombosis in COVID-19. Aim 2 will utilize a novel transgenic mouse model of SARS-CoV-2 infection to determine if targeting IL6, Gal-3, or NETs in vivo protects against cellular activation, thrombin generation and thrombosis. A strength of this proposal is in utilizing clinical samples and a novel preclinical model to identify critical mechanistic pathways for cellular activation, thrombin generation and in vivo thrombosis in COVID-19. Thus, the overall impact of the proposed research agenda is very high and is likely to provide therapeutic targets for decreasing thrombotic burden in COVID-19.

项目总结