Mechanisms of microvascular thrombosis in inflammation

炎症中微血管血栓形成的机制

• 批准号: 10382358
• 负责人: ROLANDO E RUMBAUT
• 金额: --
• 依托单位: MICHAEL E DEBAKEY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10382358
• 关键词: 2019-nCoV; Acute; Admission activity; Adult; Animal Model; Blood Coagulation Disorders; Blood Vessels; Blood coagulation; COVID-19; Cause of Death; Cell surface; Cells; Coronavirus; Critical Care; Critical Illness; Data; Diagnosis; Disease; Economic Burden; Endothelial Cells; Endotoxemia; Fibrin; Functional disorder; Future; Goals; Healthcare Systems; Individual; Infection; Inflammation; Inflammatory; Intensive Care; Intensive Care Units; Knowledge; Laboratories; Life; Link; Mediating; Mediator of activation protein; Medical center; Medicine; Modeling; Morbidity - disease rate; Mus; Organ; Patients; Phosphorylation; Plasma; Play; Post-Translational Protein Processing; Proteins; Research; Role; Sepsis; Severities; Sickle Cell Anemia; System; Techniques; Therapeutic; Thrombin; Thrombosis; Thrombotic Thrombocytopenic Purpura; Thrombus; Tissue Model; United States; Veterans; Vimentin; Work; airway inflammation; animal data; cell type; clinically significant; effective therapy; experimental study; extracellular; glycosylation; improved outcome; interest; military veteran; mortality; mouse model; new therapeutic target; novel; polymerization; polymicrobial sepsis; prevent; programs; response; systemic inflammatory response; thromboinflammation; wound healing

Thrombosis and inflammation (or thromboinflammation) are interrelated in a variety of illnesses including sepsis or the body’s dysregulated response to an infection, and the novel Coronavirus 2019 (COVID-19). Sepsis is typically the most common individual admission diagnosis in intensive care units in the VA system, although during certain weeks in 2020, COVID-19 was by far the leading acute medicine admission diagnosis at our VA Medical Center and others in the VA system. Despite advances in critical care medicine, sepsis and COVID-19 remain as life-threatening conditions resulting in significant morbidity, mortality, and a high economic burden in Veterans and non-Veterans worldwide. Both COVID-19 and sepsis are associated with microvascular thrombosis and coagulopathy and in both conditions, the severity of coagulopathy is associated with increased mortality rates. Thus, understanding the mechanisms of microvascular thrombosis in systemic inflammation such as sepsis and COVID-19, has major clinical significance to the VA health care system. Recent work from our laboratory demonstrate that an extracellular form of a cytoplasmic intermediate protein circulating in plasma, vimentin, plays important roles in experimental thrombosis, and mediates fibrin polymerization in COVID-19 and in sepsis-induced coagulopathy. This application aims to understand the role of plasma vimentin in thrombosis and fibrin polymerization in systemic inflammation. Our central hypothesis is that plasma vimentin mediates microvascular thrombosis in sepsis and COVID-19 via enhancing thrombin-induced fibrin polymerization. Two aims are proposed: Aim 1 will determine the role of plasma vimentin on microvascular thrombosis in mice and on fibrin polymerization in Veterans with COVID-19- and sepsis-induced coagulopathy. Aim 2 will define the role of post-translational modifications of vimentin and its cell- specific origin on microvascular thrombosis. Completion of the proposed experiments will broaden our understanding of the links between inflammation and microvascular thrombosis in sepsis and COVID-19, and will provide the basis for future work aimed at preventing microvascular thrombosis in systemic inflammation. The long-term goal is to develop optimal therapeutic approaches for patients with sepsis, COVID-19, and other diseases associated with thromboinflammation.

血栓形成和炎症（或血栓炎症）在多种疾病中相互关联 包括败血症或身体对感染的失调反应，以及新型冠状病毒 2019（COVID-19）脓毒症通常是最常见的个人入院诊断。 VA 系统的重症监护病房，尽管在 2020 年的某些周内，COVID-19 迄今为止，我们 VA 医疗中心和其他中心领先的急性医学入院诊断 尽管重症监护医学取得了进步，败血症和 COVID-19 仍然存在。 作为危及生命的情况，导致显着的发病率、死亡率和高发病率 COVID-19 和脓毒症都是全球退伍军人和非退伍军人的经济负担。 与微血管血栓形成和凝血病有关，在这两种情况下， 凝血功能障碍的严重程度与死亡率增加有关。 脓毒症等全身炎症中微血管血栓形成的机制 和 COVID-19，对 VA 医疗保健系统的近期工作具有重大临床意义。 我们实验室的研究表明，细胞质中间蛋白的细胞外形式 波形蛋白在血浆中循环，在实验性血栓形成中起重要作用，并介导 COVID-19 和脓毒症引起的凝血病中的纤维蛋白聚合该应用的目的是。 了解血浆波形蛋白在全身血栓形成和纤维蛋白聚合中的作用 我们的中心假设是血浆波形蛋白介导微血管。 通过增强凝血酶诱导的纤维蛋白聚合来预防脓毒症和 COVID-19 中的血栓形成。 提出了两个目标： 目标 1 将确定血浆波形蛋白对微血管的作用 小鼠血栓形成以及 COVID-19 和脓毒症引起的退伍军人纤维蛋白聚合 目标 2 将定义波形蛋白及其细胞的翻译后修饰的作用。 完成所提出的实验将拓宽微血管血栓形成的具体起源。 我们对脓毒症炎症和微血管血栓形成之间联系的理解 COVID-19，并将为未来旨在预防微血管的工作奠定基础 长期目标是开发最佳治疗方法。 针对脓毒症、COVID-19 和其他相关疾病患者的治疗方法 血栓炎症。