Developing organ-on-a-chip models of COVID-19

开发 COVID-19 的器官芯片模型

• 批准号: 555054-2020
• 负责人: Radisic, Milica
• 金额: $ 3.64万
• 依托单位: University of Toronto
• 依托单位国家: 加拿大
• 项目类别: Alliance Grants
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=705782
• 关键词: Developing; organ; chip; models; COVID

We propose the development of human organ-on-a-chip models to study SARS-CoV-2 infection. The virus binds to its receptor, angiotensin-converting enzyme 2 (ACE2), which is abundantly expressed in epithelial and endothelial cells. At the early stages, the innate immunity mounts a non-specific response to SARS-CoV-2 and directs the adaptive immune response to eliminate the virus and prevent disease progression to severe stages. It is currently impossible to predict who will experience a mild vs severe disease. Here, we will develop lung- and kidney-on-a-chip devices that enable studies of coronavirus infection to answer these questions. Uniquely, in organ-on-a-chip devices we can assess the earliest innate immunity responses that occur hours after the virus infection. Our goal is to place the devices on the market quickly so other academic and industry researchers can use them effectively. Currently, all organ-on-a-chip devices are produced by graduate students and post-docs manually at UofT. The partner organization, uFluidix, will develop a procedure for device scale-up and a conduit for device placement on the market. Dr. Radisic has a significant previous experience in studying immune cells such as monocytes and macrophages in a biomimetic environment under flow. In Aim 1, we will develop a human-cell based platform to study epithelial response to SARC-CoV-2. In Aim 2, a system to study macrophage and neutrophil extravasation in response to coronavirus infection of the lung will be established in our flow based systems, termed AngioTube. In Aim 3, model of SARS-CoV-2 infection of the kidney will be established using the Topomembrane platform. All models will first be developed with CL2 coronaviruses 229E and NL63 that Dr. Radisic has access to in her laboratory. Infection with a live SARS-CoV-2 will be performed by a skilled post-doc from the laboratory of Dr. Zhang in the CL3 facility at the UofT. Assurance of project success is the support of the leading Canadian microfluidic device manufacturer, uFluidix, who have manufactured devices for over 1000 customers over the past 10 years, enabling us to get the devices to the market in an extremely fast time frame.

我们建议开发人类器官芯片模型来研究SARS-CoV-2感染。该病毒与其受体血管紧张素转换酶2（ACE 2）结合，ACE 2在上皮细胞和内皮细胞中大量表达。在早期阶段，先天免疫对SARS-CoV-2产生非特异性反应，并指导适应性免疫反应以消除病毒并防止疾病进展到严重阶段。目前还无法预测谁将经历轻度或重度疾病。在这里，我们将开发肺和肾芯片设备，使冠状病毒感染的研究能够回答这些问题。独特的是，在器官芯片设备中，我们可以评估病毒感染后数小时发生的最早先天免疫反应。我们的目标是将这些设备迅速推向市场，以便其他学术和行业研究人员能够有效地使用它们。目前，所有的器官芯片设备都是由UofT的研究生和博士后手工生产的。 合作伙伴组织uFluidix将制定一个设备规模扩大的程序和一个设备投放市场的渠道。Radisic博士在流动下的仿生环境中研究免疫细胞（如单核细胞和巨噬细胞）方面具有重要的经验。在目标1中，我们将开发一个基于人细胞的平台来研究上皮对SARC-CoV-2的反应。在目标2中，将在我们的基于流动的系统中建立一个研究巨噬细胞和中性粒细胞外渗对肺部冠状病毒感染的反应的系统，称为AngioTube。在目标3中，将使用Topomembrane平台建立SARS-CoV-2肾脏感染模型。 所有模型将首先使用Radisic博士在其实验室中获得的CL 2冠状病毒229 E和NL 63进行开发。用活的SARS-CoV-2感染将由来自UofT CL 3设施的Zhang博士实验室的熟练博士后进行。项目成功的保证是加拿大领先的微流控设备制造商uFluidix的支持，他们在过去的10年里为1000多个客户制造了设备，使我们能够在极短的时间内将设备推向市场。