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The Mutant Mouse Resource and Research Center at The Jackson Laboratory

杰克逊实验室突变小鼠资源和研究中心

基本信息

批准号：
10400428
负责人：
Cathleen M Lutz
金额：
$ 49.19万
依托单位：
JACKSON LABORATORY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10400428
关键词：
2019-nCoV ACE2 Acute Animal Model Animals Basic Science Biology Biomedical Research Body Weight decreased Brain Breeding COVID-19 COVID-19 patient Catalogs Clinical Communities Complementary DNA Complex DNA Sequence Alteration DNA sequencing Data Disease Disease Outcome Disease Progression Dose Engineering Ensure Feedback Future Genes Genetic Genetic Engineering Genetic Transcription Genome Heterogeneity Histologic Human Inbred Strain Inbreeding Infection Institutes Keratin Knock-in Knock-in Mouse Laboratory mice Leadership Light Link Measures Modeling Monitor Mus Mutant Strains Mice Outcome Pattern Phase Phenotype Physiology Predisposition Process Publishing Reproducibility Research Research Personnel Resources Role SARS-CoV-2 infection Sampling Scientist Ships Specificity Speed Technology Testing The Jackson Laboratory Tissue Sample Tissues Transgenic Mice Variant Viral base biobank cohort drug testing experience genetic approach genetic variant human model infection rate model development mouse genetics mouse model parent grant patient response pre-clinical promoter receptor research and development response tool transcriptome transcriptome sequencing transcriptomics viral genomics

项目摘要

Abstract To date, most of the research using mouse models for COVID-19 has been done using a transgenic mouse model expressing high levels of the human ACE2gene driven by the Keratin-18(K18) promoter. While this model has been extremely useful, it has some notable limitations: disease progression is rapid and invariably fatal within one week, with an uncharacteristically high infection rate in the brain. These features restrict its use to study the biology related to the acute phase of the infection, leaving a gap in models that more accurately reflect the expression patterns and levels of the ACE2 receptor, and that extend the disease course beyond the acute phase of infection. We will employ a refined genetic strategy utilizing a recently published knock-in model of the human ACE2 cDNA into the mouse Ace2 locus. By crossing these hACE2 knock-in mice with inbred Collaborative Cross (CC) founder strains, and by characterizing the response of resulting humanized F1 progeny to live SARS-CoV-2 infection through an established partnership with researchers at the Trudeau Institute, we will test the hypothesis that clinical variation in COVID-19 patient response can be more accurately modelled and phenotypically characterized in mice with naturally regulated ACE2 expression on variable genetic backgrounds. Consistent with the aims of MMRRC parent grant to identify and distribute mouse models to the biomedical community, this proposal aims to rapidly provide the research community with an urgently needed resource for linking the variability in COVID-19 disease outcome with underlying host genetic features, and for developing precision models for post infection sequelae.

摘要到目前为止，大多数使用COVID-19小鼠模型的研究都是使用转基因技术完成的。表达高水平的由角蛋白-18（K18）启动子驱动的人ACE2基因的小鼠模型。虽然这种模型非常有用，但它有一些明显的局限性：疾病进展是在一周内迅速和总是致命的，在大脑中具有异常高的感染率。这些特征限制了其用于研究与感染急性期相关的生物学，更准确地反映ACE2受体表达模式和水平的模型中的差距，以及使病程延长到感染的急性期之后。我们将采用一种精细的遗传策略，利用最近发表的人类基因敲入模型，将ACE2 cDNA插入小鼠Ace2基因座。通过将这些hACE 2基因敲入小鼠与近交系小鼠杂交，协同交叉（CC）创始者菌株，并通过表征所得人源化 F1后代通过与研究人员建立伙伴关系，特鲁多研究所，我们将测试的假设，即临床变异的COVID-19患者的反应，在具有天然调节的ACE2的小鼠中更准确地建模和表型表征不同遗传背景下的表达。与MMRRC父母补助金的目的一致，以确定和分发小鼠模型，生物医学界，这项建议的目的是迅速提供一个迫切的研究社区将COVID-19疾病结果的变异性与潜在宿主遗传联系起来所需的资源功能，并为感染后后遗症开发精确模型。