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

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

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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.

抽象的迄今为止，大多数使用鼠标模型进行covid-19的研究已使用转基因完成由角蛋白-18（K18）启动子驱动的小鼠模型表达高水平的人ACE2Gene。尽管该模型非常有用，但它具有一些明显的局限性：疾病的进展是在一周内迅速且总是致命的，大脑的感染率异常高。这些特征限制了其用于研究与感染的急性阶段有关的生物学的用途，留下了在模型中的差距更准确地反映了ACE2受体的表达模式和水平，并且这将疾病病程扩展到了急性感染阶段。我们将利用人类最近发表的敲门模型采用精致的遗传策略 ACE2 cDNA进入小鼠ACE2基因座。通过将这些HACE2敲入小鼠与近交生协作交叉（CC）创始人应变，并通过表征产生的人性化响应 F1后代通过与与研究人员建立的伙伴关系来实现SARS-COV-2感染特鲁多研究所（Trudeau Institute 在具有自然调节ACE2的小鼠中更准确地建模和表型表征在可变遗传背景上的表达。与MMRRC父授予的目的一致，以识别和分配鼠标模型生物医学界，该提案旨在迅速向研究社区提供紧急向研究社区提供将COVID-19疾病结局变异性与潜在宿主遗传联系起来的可变性所需的资源特征，以及开发用于后感染后遗症的精确模型。