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

摘要 COVID19诱导的静脉血栓形成的决定因素和靶向治疗 生物工程静脉芯片 挑战：越来越多的证据表明，引起COVID的新型冠状病毒SARS-CoV-2- 19，能够在患者的静脉内触发血栓的形成。这最终表现为中风。 和其他危及生命的并发症，即使在年轻人身上也能观察到。与此相关的，正在兴起 数据表明，除了肺之外，内皮细胞在几个器官中都功能失调 最严重的冠状病毒感染者19例。这些细胞表达血管紧张素转换酶2(ACE2)受体 病毒附着的细胞，用它作为感染细胞的入口点。一种最近制造的芯片上的静脉(VINE-CHIP) 这是一个内皮化的单芯片器官模型，包含了静脉瓣膜独特的血流动力学。 Cusp提供的证据表明，该模型可以用来剖析静脉血主要决定因素的作用。 血栓形成--内皮；血流动力学；和血液成分--统称为Virchow‘s 三合会。这项建议的中心假设是，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‘s Triad)--内皮炎的相互作用；复合体 血液动力学；和血液凝固性。了解病毒和/或病毒的影响的需求尚未得到满足 血管内皮细胞上的血源性炎性细胞因子；以及这些效应与独特的 复杂的静脉血流动力学(机械转导)；以及寻找稳定内皮的策略 这可能与抗凝剂协同治疗。 建议：这里的目标是利用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；以及 提出治疗策略。这一目标将通过三个具体目标来实现：目标1：确定 SARS-CoV-2诱导的人静脉内皮细胞功能障碍；目的2：评估SARS-CoV-2的相互作用 静脉芯片治疗DVT的感染和血流动力学，目标3：芯片上治疗：评估 静脉芯片治疗感染性深静脉血栓形成的综合治疗推动这项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)；应用现代技术 在内皮功能和命运的分子和计算生物学(库克)；与技术一起 定义宿主对冠状病毒感染的反应(Connor)。 影响：综上所述，这项建议的结果将直接提高我们对血栓形成的理解 并做出可能导致快速追踪治疗临床试验的预测。

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.