Consortium for large-scale production and phenotyping of knockout mice (UM1)

基因敲除小鼠（UM 1）的大规模生产和表型鉴定联盟 摘要： 国际基因敲除小鼠联盟（IKMC）的长期目标是开发一种 研究人员在小鼠中对哺乳动物基因组中的每一个蛋白质编码基因进行了靶向突变， 社区可以用来阐明基因在人类生物学和疾病中的功能。我们成立了一个财团， 两个研究所（贝勒医学院和MRC哈维尔）。此应用程序描述了我们的计划， 使用CRISPR/RGN基因组编辑技术对1500个小鼠基因进行无效等位基因，并使用 建立QC程序。我们将冷冻保存所有突变菌株，并将种质送到MMRRC 储存库。这些突变等位基因代表了更广泛的突变等位基因的黄金标准资源。 社区，并为未来的研究和转化研究使用小鼠模型的重要基础 创造我们将对所有突变株系进行广泛的成体表型分析，并首次将 一个老化组件的显着比例的突变体，后者涉及一个额外的测试组件 从12个月开始。我们还将评估胚胎中的纯合致死和亚存活品系， 表型分析管道，很明显，小鼠致死（必需）和亚存活基因之间存在关系， 与人类疾病基因座相关所有等位基因和表型数据将真实的提交给数据协调员 中心，确保所有的BasH数据传播到更广泛的生物医学科学界。我们将 继续我们的研发计划，以引入适当的方法和技术发展， 生产到表型分析。BasH将继续对Cas9 RGN进行试点改进，以生产更多 复杂的等位基因，并在平行确保发展低温保存方法在贝勒和 Harwell被整合到生产管道中。我们亦会继续进行各项主要工程， 丰富成人和胚胎表型管道，专注于代谢组学，行为， 表型分析和饲养笼监测，目的是提供更复杂的纵向数据。贝勒 医学院和MRC Harwell拥有既定的专业知识，经验和资源， 并以经济高效的方式实现这一目标。

Consortium for large-scale production and phenotyping of knockout mice (UM1) ABSTRACT: The long-term goal of the International Knockout Mouse Consortium (IKMC) is to develop a resource of targeted mutations in mice for every protein-coding gene in the mammalian genome that the research community can use to elucidate gene function in human biology and disease. We have formed a consortium of two Institutes (Baylor College of Medicine and MRC Harwell). This application describes our plan to generate null alleles for 1500 mouse genes using CRISPR/RGN genome editing technology and validate each line using established QC procedures. We will cryopreserve all mutant strains and deliver germplasm to the MMRRC repositories. These mutant alleles represent a gold standard resource of mutant alleles for the wider community, and an important foundation for future research and translational studies using the mouse models created. We will perform broad-based adult phenotyping on all mutant lines, and for the first time incorporate an ageing component for a significant fraction of mutants, the latter involving an additional testing component from 12 months onwards. We will also assess homozygous lethal and subviable lines in an embryonic phenotyping pipeline, It is apparent that there is a relationship of mouse lethal (essential) and subviable genes with human disease loci. All allele and phenotype data will be submitted in real time to the Data Coordination Center, ensuring that all of the BasH data is disseminated to the wider biomedical scientific community. We will continue our R&D program to introduce appropriate methodological and technological developments from production to phenotyping. BasH will continue to pilot improvements in Cas9 RGN for the production of more sophisticated alleles, and in parallel ensure that developments in cryopreservation approaches at Baylor and Harwell are integrated into the production pipeline. We will also continue our major projects in improving and enriching the adult and embryo phenotyping pipelines, focusing on areas such as metabolomics, behavioral phenotyping and home cage monitoring, with the aim of providing more complex and longitudinal data. Baylor College of Medicine and MRC Harwell have the established expertise, experience, and resources to efficiently and cost-effectively meet this goal.