Determinants of COVID19-induced venous thrombosis and targeted therapy assessed with bioengineered vein-chip

用生物工程静脉芯片评估新冠病毒引起的静脉血栓形成的决定因素和靶向治疗

• 批准号: 10199360
• 负责人: JOHN P COOKE
• 金额: $ 72.16万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10199360
• 关键词: 2019-nCoV; ACE2; Address; Adhesions; American; Anticoagulants; Anticoagulation; Apoptosis; Attention; Attenuated; Automobile Driving; Autopsy; Biological Assay; Biomedical Engineering; Blood; Blood Vessels; Blood coagulation; COVID-19; COVID-19 patient; COVID-19 treatment; Cells; Cessation of life; China; Clinical Research; Complex; Computational Biology; Data; Deep Vein Thrombosis; Development; Devices; Disease; Distal; Endothelial Cells; Endothelium; Enzyme Inhibitor Drugs; Exposure to; Geometry; Homeostasis; Human; Immune response; Infection; Inflammation; Inflammatory; Interdisciplinary Study; Kidney; Lead; Life; Lower Extremity; Lung; Mesentery; Modeling; Molecular Biology; Organ; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Physiological; Play; Pre-Clinical Model; Predisposition; Proteins; Proteomics; Research; Respiratory Failure; Role; SARS-CoV-2 infection; Savings; Signal Pathway; Stroke; Structure; Surgeon; Techniques; Technology; Therapeutic; Therapeutic Clinical Trial; Thrombosis; Triad Acrylic Resin; Veins; Venous; Venous Thrombosis; Viral; Virus; Virus Diseases; clinical phenotype; combinatorial; coronavirus disease; cytokine; design; differential expression; endothelial dysfunction; hemodynamics; improved; innovation; mechanotransduction; novel; novel coronavirus; organ on a chip; prevent; receptor; recruit; response; severe COVID-19; targeted treatment; thromboinflammation; transcriptome; transcriptome sequencing; venous thromboembolism

ABSTRACT Determinants of COVID19-induced venous thrombosis and targeted therapy assessed with bioengineered Vein-Chip Challenge: Increasing evidence shows that SARS-CoV-2, which is the novel coronavirus that causes COVID- 19, is able to trigger the formation of blood clots within the veins of patients. This ultimately manifests into strokes and other life-threatening complications, being observed even in younger people. Related to that, is emerging data that shows that the endothelial cells are dysfunctional across several organs other than the lungs of the most severe COVID19 patients. These cells express the angiotensin-converting enzyme 2 (ACE2) receptor, to which the virus attaches, using it as an entry point to infect cells. A recently created vein-on-a-chip (vein-chip) that is an endothelialized organ-on-a-chip model incorporating the unique hemodynamics of the venous valve cusp showed evidence that this model can be used to dissect the role of major determinants of venous thrombosis – endothelium; hemodynamics; and blood components – together known as the Virchow's triad. The central hypothesis in this proposal is that the venous thrombosis observed in COVID19 disease is due to the interaction of the three determinants of thrombosis (Virchow's triad) – endotheliitis; complex hemodynamics; and blood coagulability. There is an unmet need to understand the effects of the virus and/or blood-borne inflammatory cytokines on the endothelium; and the interaction of these effects with the uniquely complex venous hemodynamics (mechanotransduction); and to discover strategies to stabilize the endothelium that may be co-operatively therapeutic with anticoagulants. Proposal: The objective here is to deploy vein-chip technology to understand the determinants of SARS-CoV- 2 induced venous thrombosis; determine the roles of endothelial, hemodynamic and humoral alterations; and propose therapeutic strategies. This objective will be met through three specific aims: Aim 1: Characterize the SARS-CoV-2 induced endothelial dysfunction in the human Vein-Chip; Aim 2: Assess interplay of SARS-CoV-2 infection and hemodynamics in DVT with Vein-Chip, and Aim 3: Therapeutics-on-Chip: Assess combinatorial therapeutics in infection-led DVT with Vein-Chip. The team driving this proposal is composed of complementary expertise in vein-chip bioengineering and innovation (Jain); applying contemporary technology in the molecular and computational biology of endothelial function and fate (Cooke); together with techniques to define host response to coronaviral infection (Connor). Impact: Taken together, the outcomes of this proposal will directly improve our understanding of thrombosis in COVID-19 infection and make predictions that could potentially result in fast-tracking of therapeutic clinical trials.

抽象的 COVID19诱导的静脉血栓形成和针对性治疗的决定因素 生物工程静脉片 挑战：越来越多的证据表明，SARS-COV-2（这是新型的冠状病毒 19，能够触发患者静脉内血凝块的形成。这最终表现为中风 以及其他威胁生命的并发症，即使在年轻人中也被观察到。与之相关的是正在出现 数据表明内皮细胞在除肺以外的几个器官中功能失调 最严重的199例患者。这些细胞表达血管紧张素转化酶2（ACE2）受体， 病毒附着在该病毒中，将其作为感染细胞的入口点。最近创建的芯片静脉（静脉芯片） 这是一种芯片片的内皮化器官，编码静脉瓣的独特血流动力学 尖峰显示了该模型可用于剖析静脉主要决定剂的作用的证据 血栓形成 - 内皮；血液动力学；和血液成分 - 称为Virchow 三合会。该提议中的中心假设是，在Covid19疾病中观察到的静脉血栓形成应得 与血栓形成的三个决定者（Virchow的三合会） - 内皮炎相互作用；复杂的 血液动力学；和血液凝结性。有未满足的需要了解病毒的影响和/或 内皮上的血传播炎症细胞因子；这些影响与独特的效果的相互作用 复杂的静脉血流动力学（机械转导）；并发现稳定内皮的策略 这可能与抗凝剂合作治疗。 建议：这里的目的是部署静脉芯片技术来了解SARS-COV-的决定者 2诱导静脉血栓形成；确定内皮，血液动力学和体液变化的作用；和 建议理论策略。该目标将通过三个特定目的实现：目标1：表征 SARS-COV-2在人静脉芯片中引起的内皮功能障碍；目标2：评估SARS-COV-2的相互作用 DVT中的感染和血液动力学用静脉芯片和目标3：片上的治疗学：评估 与静脉芯片的感染主导DVT中的组合理论。驾驶此建议的团队由 在静脉芯片生物工程和创新方面完全专业知识（Jain）；应用当代技术 在内皮功能和命运的分子和计算生物学中（库克）；以及技术 定义宿主对冠状病毒感染（Connor）的反应。 影响：综上所述，该提案的结果将直接提高我们对血栓形成的理解 Covid-19感染并做出可能导致治疗性临床试验快速跟踪的预测。