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Novel animal models to study organ-specific SARS-CoV-2-induced pathology

研究器官特异性 SARS-CoV-2 诱导病理学的新型动物模型

基本信息

批准号：
10576043
负责人：
Ekaterina Koroleva
金额：
$ 27.85万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-11-11 至 2024-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10576043
关键词：
2019-nCoV 3-Dimensional ACE2 Acute Respiratory Distress Syndrome Animal Model Automobile Driving Binding Brain COVID-19 COVID-19 complications COVID-19 monitoring COVID-19 patient COVID-19/ARDS Cells Colitis Communities Complex Consensus Data Development Disease Epithelial Cells Generations Goals Heart Immune Immune response Inflammation Intestinal Diseases Intestines K-18 conjugate Kidney Liver Luciferases Lung Mediating Morbidity - disease rate Mouse Strains Mus Organ Pathogenesis Pathologic Pathology Patients Public Health Pulmonary Pathology Recombinants Reporter Reporter Genes Research Role SARS-CoV-2 infection Structure of parenchyma of lung Testing Therapeutic Therapeutic Intervention Tissues Transgenic Mice Validation Viral Virus Visualization airway epithelium alveolar epithelium alveolar type II cell cell type chronic inflammatory disease cytokine release syndrome effective therapy gut inflammation immunopathology in vivo innovation insight intestinal epithelium lung injury mortality mouse model novel post-COVID-19 pre-clinical receptor severe COVID-19 therapeutic evaluation tool

项目摘要

Accumulating evidence suggest that SARS-CoV-2 infection induces tissue pathology in multiple organs in addition to the lung, including, among others, intestine, heart, liver, kidney, and brain. Furthermore, SARS- CoV-2 infection can exacerbate many chronic inflammatory diseases. However, mouse models that allow to study SARS-CoV-2-induced pathology in specific organs are currently lacking. Additionally, therapeutic strategies using the commercially available K18-hACE2 transgenic mouse model are limited due to ectopic hACE2 expression in the brain driving high lethality. To overcome these problems, we have generated mice with conditional tissue-specific hACE2 expression. The goal of this proposal is to characterize these novel mouse models and define the impact of SARS-CoV-2 specifically on lung immunopathology and intestinal disease. Our central hypothesis is that mice with conditional expression of hACE2 in Rosa26 locus represent a robust platform to study tissue-specific SARS-CoV-2-induced pathology. In Aim 1, we will test the hypothesis that hACE2 expression in type II alveolar epithelial cells and club cells is necessary and sufficient for SARS-CoV-2-induced lung immunopathology. We will analyze SARS-CoV-2 infection dynamics and lung immunopathology in mice with specific expression of hACE2 in type II alveolar epithelial cells and club cells, using our recently developed dual reporter- expressing mCherry-Nluc recombinant (r)SARS-CoV-2. In Aim 2, we will test the hypothesis that SARS-CoV-2 infection exacerbates intestinal inflammation using mice with specific expression of hACE2 in intestinal epithelial cells. This proposal is innovative and significant, as it will generate and characterize novel small animal models to study SARS- CoV-2 mediated organ-specific disease and provide insights into mechanisms of SARS-CoV-2-mediated lung and gut pathology. These mouse models will provide a robust platform to study and monitor SARS-CoV-2 infection in desired cell types and long-term complications of SARS-CoV-2 infection, and to perform therapeutic interventions.

越来越多的证据表明，SARS-CoV-2感染可引起小鼠多器官组织病理改变除肺外，还包括肠、心、肝、肾和脑。此外，SARS- CoV-2感染可加重许多慢性炎症性疾病。然而，鼠标模型允许目前还缺乏对SARS-CoV-2诱导的特定器官病理的研究。此外，还具有治疗作用由于异位，使用商业上可用的k18-hACE2转基因小鼠模型的策略受到限制 HACE2在驱动高致命性的大脑中的表达。为了克服这些问题，我们培育了小鼠具有条件性组织特异性hACE2表达。这项提议的目的是描述这些小说的特点建立小鼠SARS-CoV-2模型，明确SARS-CoV-2对小鼠肺免疫病理和肠道的影响疾病。我们的中心假设是在rosa26基因座有条件表达hACE2的小鼠为研究组织特异性SARS-CoV-2诱导的病理学提供了一个强大的平台。在目标1中，我们将测试假设hACE2在II型肺泡上皮细胞和俱乐部细胞中表达是必要的，并且足以对抗SARS-CoV-2诱导的肺免疫病理。我们将分析SARS-CoV-2感染情况肺泡II型上皮细胞hACE2特异性表达小鼠的动力学和肺免疫病理变化细胞和俱乐部细胞，使用我们最近开发的双重报告表达mCherry-Nluc重组 (R)SARS-CoV-2。在目标2中，我们将检验SARS-CoV-2感染会加剧肠道疾病的假设炎症利用小鼠肠道上皮细胞特异性表达hACE2。这项建议是创新和重大意义，因为它将产生和表征研究SARS的新的小动物模型- 冠状病毒-2介导的器官特异性疾病和SARS-CoV-2介导的肺的机制还有肠道病理学。这些小鼠模型将为研究和监测SARS-CoV-2提供一个强大的平台预期细胞类型的感染和SARS-CoV-2感染的长期并发症，并进行治疗性干预。