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

人肺先天免疫反应的机制模型，以了解 COVID-19 肺炎的个体间异质性

• 批准号: 10728396
• 负责人: REINHARD LAUBENBACHER
• 金额: $ 76.21万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10728396
• 关键词: 2019-nCoV; 3-Dimensional; ACE2; Affect; Animal Model; Biological; COVID-19; COVID-19 pneumonia; COVID-19 severity; Cell Death; Cells; Cessation of life; Complex; Computer Models; Confocal Microscopy; Cryopreservation; Data; Engineering; Epidemiologic Factors; Epithelial Cells; Event; FRAP1 gene; Flow Cytometry; Genetic Transcription; Goals; Grant; Heterogeneity; Human; Immune; Immune response; Immunity; Immunology; Individual; Infection; Innate Immune Response; Interferon Type I; Intervention; K-18 conjugate; Literature; Lung; Lung infections; Measurement; Mediating; Minor; Modeling; Molecular; Mus; Outcome; Pathway interactions; Persons; Phosphoproteins; Predictive Factor; Predisposition; Production; Protocols documentation; Public Health; Publishing; Reproducibility; Risk; Role; SARS-CoV-2 infection; Sampling; Severities; Signal Transduction; Structure of parenchyma of lung; Surgical Models; System; Testing; Time; Tissue Donors; Tissue Preservation; Tissues; Transgenic Mice; Transgenic Organisms; Viral; Virus; Work; alveolar epithelium; base; biobank; cohort; cytokine; digital twin; effective therapy; improved outcome; individual variation; innovation; mTOR inhibition; mathematical model; mouse model; multi-scale modeling; novel; outcome disparities; outcome prediction; pandemic disease; population based; receptor; response; severe COVID-19; therapeutic target; three dimensional cell culture; tool; virology

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.

项目概要/摘要 COVID-19 感染的一个关键特征是个体间存在巨大的异质性 感染的严重程度。这种变异性背后的复杂生物机制仍然存在 大多是晦涩难懂的。我们建议通过以下方式提供对这种敏感性的机械理解： 利用3个关键创新：首先，我们开发了3维肺培养系统 可以对 SARS-CoV-2 感染的早期事件进行详细询问。第二，我们 在人类 ACE2 转基因小鼠中建立了 COVID-19 动物模型 我们设施中的接收器。第三，我们建立了肺部感染的多尺度数学模型 COVID-19，我们现在寻求将其扩展到各个主机并对其进行个性化。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，使用公正的方法来识别和测试与易感性相关的假设 严重的 COVID-19，在目标 2 中，我们将测试有关机制的具体假设 观察到的 COVID-19 严重程度存在个体间异质性，即部分是， 由 I 型肺泡上皮细胞中 mTOR 通路的不同激活介导。如果 如果成功，该项目将确定免疫途径的生物学基础，从而导致 COVID-19 的异质性结果，为个性化、针对特定宿主的治疗铺平了道路 改善感染结果的干预措施。