Mechanistic modeling of the innate immune responses of the human lung to understand the inter-individual heterogeneity of COVID-19 pneumonia

项目摘要/摘要 新冠肺炎感染的一个关键特征是 感染的严重程度。这种变化背后的复杂生物机制仍然存在。 大部分是默默无闻的。我们建议通过以下方式提供对这种易感性的机械性理解 利用三个关键创新：第一，我们开发了三维肺培养系统 这使得对SARS-CoV-2感染早期事件的详细询问成为可能。第二，我们 建立了转人血管紧张素转换酶2基因的小鼠新冠肺炎动物模型 接收器在我们的设施中。第三，我们建立了肺部感染的多尺度数学模型。 新冠肺炎，我们现在寻求对个人主持人进行扩展和个性化。我们有两个目标 在这个项目中：在目标1中，我们将验证、扩展和个性化我们现有的多尺度 模型，使用无偏见的方法来识别和测试与易感性有关的假设 严重的新冠肺炎，在目标2中，我们将检验一个关于糖尿病发病机制的特定假说 观察到的新冠肺炎严重程度的个体间异质性，即它在一定程度上是 由I型肺泡上皮细胞mTOR通路的差异激活所介导。如果 成功后，该项目将确定免疫途径的生物学基础，从而导致 新冠肺炎的异质成果，为个性化、主办方特定铺平了道路 改善感染结局的干预措施。

PROJECT SUMMARY/ABSTRACT A key feature of the COVID-19 infection is the vast inter-individual heterogeneity in the severity of the infection. The complex biological mechanisms that underlie this variability remain mostly obscure. We propose to provide a mechanistic understanding of this susceptibility by leveraging 3 key innovations: First, we have developed a 3-dimensional lung culture system that allows for detailed interrogation of the early events in SARS-CoV-2 infection. Second, we have established an animal model of COVID-19 in mice transgenic for the human ACE2 receptor in our facility. Third, we have built a multi-scale mathematical model of lung infection in COVID-19, that we now seek to expand and personalize to individual hosts. We have two Aims in this project: In Aim 1, we will validate, expand, and personalize our existing multi-scale model, using an unbiased approach to identify and test hypotheses relating to susceptibility to severe COVID-19, and in Aim 2 we will test a specific hypothesis regarding the mechanism of the observed inter-individual heterogeneity in COVID-19 severity, namely that it is, in part, mediated by divergent activation of the mTOR pathway in type I alveolar epithelial cells. If successful, this project will identify the biological basis of the immune pathways that result in heterogeneous outcome of COVID-19, paving the way for personalized, host-specific interventions to improve the outcome of the infection.