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

• 批准号: 10569568
• 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
• 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/10569568
• 关键词: 2019-nCoV; ACE2; Acute; 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; Deterioration; 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; Inflammatory; Infusion procedures; Interleukin-1 beta; Iowa; K-18 conjugate; Lectin; Link; Literature; Measures; Mediating; Mediator; Multiple Organ Failure; Mus; NF-kappa B; Neutrophil Activation; Outcome; Pathway interactions; Patients; Phase; Plasma; Platelet Activation; Pre-Clinical Model; Predisposition; Preventive; Proteins; 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; poor health outcome; pre-clinical; prevent; prophylactic; randomized, clinical trials; receptor; recruit; response; therapeutic target; thrombogenesis; thrombotic; thrombotic complications; translational approach; trial comparing

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.

项目摘要 严重急性呼吸综合症的感染新型电晕病毒（SARS-COV-2）导致COVID-19。在 严重的病例，Covid-19导致深刻感染（“细胞因子风暴”），其次是凝血病和A 促血栓形成态，发展为多器官衰竭。包括IL6在内的几种细胞因子升高。 此外，还发现促炎乳糖素3（GAL-3）升高。 GAL-3上调IL6和其他 细胞因子可以直接激活血小板，中性粒细胞和内皮细胞，已知可以介导静脉 小鼠模型中通过IL6通过IL6的血栓形成。越来越多的文献实施了中性粒细胞，血小板和 内皮细胞激活是199例患者血栓形成并发症的潜在驱动因素。然而， 在炎症，血管细胞激活和 SARS-COV-2感染期间的血栓形成。我们的目标是定义引起激活的调解人 SARS-COV-2感染期间的中性粒细胞，血小板和/或内皮细胞及其在机械作用中 促进凝血酶产生和血栓形成。在爱荷华大学，我们领导了一个多中心随机分组 将标准预防剂量与中间剂量的依诺沙司蛋白进行比较的临床试验（RCT） COVID-19（NCT04360824）的患者并收集了用于生物标志物和机械的血浆样品 研究。鉴于Covid-19的晚期血栓形成并发症的激增，我们现在建议招募更多 患者每周在住院期间收集连续样品，此后每3个月最多3个月 年。我们假设Covid-19中的血栓形成性是由IL6和GAL-3驱动的激活介导的 造血和内皮细胞，即使从病毒中恢复 感染。我们的团队具有专业知识和资源的独特组合，可以解决2中的假设 整合但独立的目标。在AIM 1中，使用串行收集的患者的样本，我们将确定 IL6，GAL-3和网的机械作用在介导细胞激活和增强凝血酶中的机械作用 COVID-19中的产生和血栓形成。 AIM 2将利用SARS-COV-2的新型转基因小鼠模型 感染以确定靶向IL6，GAL-3或净体内的网络可预防细胞激活，凝血酶 产生和血栓形成。该建议的优势在于利用临床样本和新型临床前 识别细胞激活，凝血酶产生和体内临界机械途径的模型 COVID-19中的血栓形成。这就是拟议的研究议程的总体影响很高，很可能 提供热目标，以减少Covid-19中的血栓形成伯嫩。