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.

积累的证据表明，SARS-COV-2感染在多个器官中诱导组织病理除肺部外，包括肠道，心脏，肝脏，肾脏和大脑。此外，SARS- COV-2感染会加剧许多慢性炎症性疾病。但是，允许的鼠标模型目前缺乏研究特定器官中SARS-COV-2诱导的病理。另外，治疗性使用市售K18-HACE2转基因鼠标模型的策略受到异位的限制 HACE2在大脑中的表达驱动高致死性。为了克服这些问题，我们已经产生了小鼠带有条件组织特异性HACE2表达。该提议的目的是描述这些小说鼠标模型并定义SARS-COV-2专门对肺免疫病理和肠道的影响疾病。我们的中心假设是rosa26基因座中有条件表达HACE2的小鼠代表了研究组织特异性SARS-COV-2诱导的病理的强大平台。在AIM 1中，我们将测试 II型肺泡上皮细胞和俱乐部细胞中HACE2表达是必要的，这是必要的，并且足够用于SARS-COV-2诱导的肺免疫病理学。我们将分析SARS-COV-2感染在II型肺泡上皮中HACE2特异性表达的小鼠中的动力学和肺免疫病理学细胞和俱乐部细胞，使用我们最近开发的双重报道器表达MCHERRY-NLUC重组（R）SARS-COV-2。在AIM 2中，我们将检验以下假设：SARS-COV-2感染加剧了肠道使用小鼠在肠上皮细胞中使用HACE2特异性表达的小鼠炎症。该提议是创新且重要的是，它将产生和表征新型的小动物模型来研究SAR COV-2介导的器官特异性疾病，并提供有关SARS-COV-2介导的肺机制的见解和肠道病理。这些鼠标模型将为研究和监视SARS-COV-2提供一个强大的平台所需细胞类型的感染和SARS-COV-2感染的长期并发症，并进行治疗干预措施。