Tissue Factor's Role in the Pathogenesis of Hypercoagulability in COVID-19

组织因子在 COVID-19 高凝状态发病机制中的作用

基本信息

批准号：
10448667
负责人：
Vijaya Mohan Rao Lella
金额：
$ 18.38万
依托单位：
UNIVERSITY OF TEXAS HLTH CTR AT TYLER
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：
2022-03-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10448667
关键词：
2019-nCoV Acute Respiratory Distress Syndrome Anticoagulants Attenuated Biological Models Blood Circulation Blood Coagulation Disorders COVID-19 COVID-19 pathogenesis COVID-19 patient Cell membrane Cell model Cell surface Cells Coagulation Process Complement Activation Critical Illness Data Desipramine Development Disease Disseminated Intravascular Coagulation Endothelial Cells Endothelium Enzymes Epithelial Cells FDA approved Fibrin fragment D Functional disorder Generations Goals Hemostatic Agents Human Hydrolysis Hypoxemic Respiratory Failure Imipramine Incidence Infection Inflammation Inflammatory Intervention Lentivirus Life Lung Metabolism Multiple Organ Failure Pathogenesis Pathologic Patients Phospholipids Platelet Activation Proteins Publications Receptor Cell Reporting Resources Role SARS-CoV-2 infection SARS-CoV-2 spike protein Small Interfering RNA Sphingomyelins Stimulus Technical Expertise Thromboembolism Thrombophilia Thromboplastin Thrombosis Transgenic Mice Tricyclic Antidepressive Agents Up-Regulation Venous Virus Diseases acid sphingomyelinase base cell type encryption experience extracellular extracellular vesicles improved in vivo inhibitor macrophage monocyte mortality mouse model neutrophil novel novel therapeutic intervention receptor response stem thrombotic complications tool

项目摘要

Emerging evidence indicates that the novel SARS-CoV-2 infection is associated with a high incidence of thrombotic complications. Thrombotic complications in COVID-19 patients are found to be life-threatening. Elevated D-dimers and disseminated intravascular coagulation (DIC) are strong predictors of mortality in hospitalized COVID-19 patients. Consistent with the major influence of coagulopathy in the pathogenesis of COVID-19, anticoagulant treatments were shown to improve the survival of critically ill COVID-19 patients. Although the association of coagulation abnormalities with COVID-19 is evident, the underlying mechanism for these abnormalities is unknown. Many diseases, including viral infections, induce tissue factor (TF) expression in monocytes/macrophages and endothelial cells and release TF+ extracellular vesicles (EVs) into circulation. Our recent studies suggest that alterations in sphingomyelin metabolism greatly influence TF activity by controlling TF encryption and decryption, and generation of TF+ EVs. We hypothesize that hypercoagulability associated with SARS-CoV-2 infection stems from increased TF activity and the release of TF+ EVs into the circulation following the infection. We further hypothesize that spike protein-induced activation of acid sphingomyelinase (ASMase) is responsible for increased TF activity via TF decryption and generation of TF+ EVs. We propose that treatment with ASMase functional inhibitors will attenuate coagulopathy associated with SARS-CoV-2 infection. The overall goal of the proposal is to obtain a proof of concept to the above hypothesis. Our aims are: (i) determine the mechanism by which the SARS-CoV-2 spike protein increases TF activity and generates TF+ EVs; (ii) define the role of SARS-CoV-2’s spike protein on activation of TF-induced coagulopathy and microvascular thrombosis in hACE2 transgenic mice and determine whether ASMase functional inhibitors attenuate SARS-CoV-2-induced coagulopathy. In the proposed studies, we will use both SARS-CoV-2 spike protein pseudovirus and authentic SARS-CoV-2 infections in cell model systems and a murine model system. Our proposed studies will identify potential mechanisms by which SARS-CoV2 infection induces hypercoagulability and thrombosis. They will also provide clues for the development of novel, targeted, and safe interventions to treat hypercoagulability in COVID-19 patients, which could help to reduce mortality. We have more than thirty years of experience working on TF and have all the tools and resources, and technical expertise to complete the proposed studies successfully.

新的证据表明，新型 SARS-CoV-2 感染与高发病率相关 COVID-19 患者的血栓并发症被发现危及生命。 D-二聚体升高和弥散性血管内凝血 (DIC) 是死亡率的有力预测因子住院的 COVID-19 患者与凝血功能障碍在发病机制中的主要影响一致。研究表明，针对 COVID-19 的抗凝治疗可提高重症 COVID-19 患者的生存率。尽管凝血异常与 COVID-19 的关联很明显，但其潜在机制这些异常的原因尚不清楚，包括病毒感染在内的许多疾病都会诱发组织因子 (TF)。在单核细胞/巨噬细胞和内皮细胞中表达，并将 TF+ 细胞外囊泡 (EV) 释放到我们最近的研究表明，鞘磷脂代谢的改变极大地影响 TF。通过控制 TF 加密和解密以及 TF+ EV 的生成来进行活动。与 SARS-CoV-2 感染相关的高凝状态源于 TF 活性增加和释放我们进一步追踪了感染后 TF+ EV 进入循环的情况。酸性鞘磷脂酶 (ASMase) 的激活通过 TF 解密和我们建议使用 ASMase 功能抑制剂治疗会减弱 TF+ EV 的产生。该提案的总体目标是获得与 SARS-CoV-2 感染相关的凝血病的证据。我们的目标是：(i) 确定 SARS-CoV-2 峰值的机制。蛋白增加 TF 活性并产生 TF+ EV；(ii) 定义 SARS-CoV-2 刺突蛋白在 hACE2 转基因小鼠中 TF 诱导的凝血病和微血管血栓形成的激活确定 ASMase 功能抑制剂是否可以减轻 SARS-CoV-2 诱导的凝血病。拟议的研究中，我们将使用 SARS-CoV-2 刺突蛋白假病毒和真实的 SARS-CoV-2 我们提出的研究将确定细胞模型系统和小鼠模型系统中的潜在感染。 SARS-CoV2 感染引起高凝状态和血栓形成的机制。为开发新颖、有针对性且安全的干预措施来治疗高凝状态提供线索 COVID-19 患者，这可能有助于降低死亡率，我们拥有三十多年的经验。致力于 TF 并拥有完成拟议研究的所有工具和资源以及技术专长成功地。