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

• 批准号: 10580840
• 负责人: Vijaya Mohan Rao Lella
• 金额: $ 22.05万
• 依托单位: UNIVERSITY OF TEXAS HLTH CTR AT TYLER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10580840
• 关键词: 2019-nCoV; Acute Respiratory Distress Syndrome; Anticoagulants; Attenuated; Biological Models; Blood Coagulation Disorders; Blood Vessels; COVID-19; COVID-19 pathogenesis; COVID-19 patient; Cell membrane; Cell model; Cell surface; Cells; Circulation; 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; Hospitalization; Human; Hydrolysis; Hypoxemic Respiratory Failure; Imipramine; Incidence; Infection; Inflammation; Inflammatory; Intervention; Lentivirus; Life; Lung; Macrophage; 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; cell type; encryption; experience; extracellular; extracellular vesicles; improved; in vivo; inhibitor; monocyte; mortality; mouse model; neutrophil; novel; novel therapeutic intervention; receptor; response; stem; thrombotic complications; tool

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.

新出现的证据表明，新的SARS-CoV-2感染与高发的 血栓并发症。新冠肺炎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)是急性心肌梗死患者死亡的有力预测因素 住院的新冠肺炎患者。与凝血障碍在发病机制中的主要影响是一致的 在新冠肺炎，抗凝治疗被证明可以提高重症新冠肺炎患者的存活率。 虽然凝血功能异常与新冠肺炎的关联是显而易见的，但其潜在的机制 因为这些反常现象是未知的。许多疾病，包括病毒感染，都会诱导组织因子(TF) 在单核/巨噬细胞和内皮细胞中表达并释放Tf+胞外小泡(EVS) 发行量。我们最近的研究表明，鞘磷脂代谢的改变对转铁蛋白有很大影响。 通过控制TF加密和解密以及TF+EV的生成来实现活动。我们假设 与SARS-CoV-2感染相关的高凝状态源于TF活性增加和释放 Tf+EVS在感染后进入循环。我们进一步假设，Spike蛋白诱导 酸性鞘磷脂酶(ASMase)的激活通过TF解密和 Tf+电动汽车的产生。我们建议用ASMase功能抑制剂治疗会减弱 与SARS-CoV-2感染相关的凝血障碍。该提案的总体目标是获得以下证据 对上述假说的概念。我们的目标是：(I)确定SARS-CoV-2病毒尖峰的机制 蛋白质增加TF活性并产生TF+EV；(Ii)确定SARS-CoV-2‘S刺突蛋白在 HACE2转基因小鼠TF诱导的凝血障碍和微血管血栓的激活 确定ASMase功能抑制剂是否减轻SARS-CoV-2诱导的凝血障碍。在 建议的研究，我们将使用SARS-CoV-2刺突蛋白假病毒和真正的SARS-CoV-2 细胞模型系统和小鼠模型系统中的感染。我们提议的研究将确定潜在的 SARS-CoV2感染导致高凝状态和血栓形成的机制他们还将 为开发新的、有针对性的、安全的干预措施治疗高凝状态提供线索 新冠肺炎患者，这可能有助于降低死亡率。我们有三十多年的经验 从事工作组的工作，并拥有完成拟议研究的所有工具和资源以及技术专业知识 成功了。