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

基本信息

批准号：
10396569
负责人：
JOHN P COOKE
金额：
$ 66.53万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
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/10396569
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 Persons 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

项目摘要

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的决定因素和靶向治疗评估生物工程静脉芯片挑战：越来越多的证据表明，SARS-CoV-2（即导致新冠肺炎的新型冠状病毒） 19，能够引发患者静脉内血栓的形成，这最终会导致中风。甚至在年轻人中也观察到与此相关的其他危及生命的并发症。数据表明，除肺外的多个器官的内皮细胞功能失调最严重的 COVID19 患者这些细胞表达血管紧张素转换酶 2 (ACE2) 受体，病毒附着在其上，将其作为感染细胞的入口点。这是一种内皮化器官芯片模型，融合了静脉瓣膜独特的血流动力学 cusp 的证据表明，该模型可用于剖析静脉血流主要决定因素的作用。血栓形成 – 内皮细胞；和血液成分 – 统称为 Virchow 血流动力学该提案的中心假设是，在 COVID19 疾病中观察到的静脉血栓形成是由于血栓形成的三个决定因素（Virchow 三联征）的相互作用 - 内皮炎复合体；了解病毒和/或的影响的需求尚未得到满足。内皮上的血源性炎症细胞因子以及这些效应与独特的相互作用复杂的静脉血流动力学（机械传导）；并发现稳定内皮的策略；可能与抗凝剂协同治疗。建议：这里的目标是部署静脉芯片技术来了解 SARS-CoV-的决定因素 2 诱导静脉血栓形成；确定内皮、血流动力学和体液改变的作用；该目标将通过三个具体目标来实现：目标 1：表征 SARS-CoV-2 诱导人静脉芯片内皮功能障碍；目标 2：评估 SARS-CoV-2 的相互作用使用静脉芯片治疗 DVT 时的感染和血流动力学，目标 3：芯片治疗：评估使用 Vein-Chip 治疗感染导致的 DVT 的组合疗法推动该提案的团队由以下人员组成。静脉芯片生物工程和创新方面的互补专业知识（Jain）；内皮功能和命运的分子和计算生物学（库克）以及技术；定义宿主对冠状病毒感染的反应（Connor）。影响：总而言之，该提案的结果将直接提高我们对血栓形成的认识 COVID-19 感染并做出预测，这可能会导致治疗性临床试验的快速跟踪。