Consortium for Broad Based Disease Phenotyping of Knockout Mice

描述（由申请人提供）：所有基因的综合功能注释是哺乳动物系统和生物医学科学未来研究的关键目标。我们已经建立了一个财团的大规模表型小鼠突变体，这是根本的基因功能的调查。得克萨斯州休斯敦贝勒医学院（Baylor College of Medicine）的BaSH财团、联合王国欣克斯顿的威康信托桑格研究所小鼠遗传学方案和医学研究理事会Harwell，（哺乳动物遗传学单位和玛丽里昂中心），联合王国，将每年对300个IKMC小鼠品系进行广泛的表型分析，生理和生化途径，将指导实验人员发展假说驱动的研究疾病系统。我们的目标是：1）完成C57 BL/6 N遗传背景下超过1500系突变小鼠的广泛疾病表型分析，2）验证优化和增强的广泛表型分析管道，以检测各种疾病表型并提高通量，以及3）将表型数据提交给指定的数据协调中心，确保与更广泛的生物医学科学界建立联系，为人类遗传研究提供信息。我们的方法是建立在我们在小鼠表型分析方面的独特专业知识和EUCOMM和KOMP突变体小鼠表型分析的主要试点项目的成功运作的基础上，提供具有战略广度的表型分析管道，以满足医学界的需求。我们的管道设计旨在提供关键治疗相关领域的小鼠模型-例如心血管、代谢、神经、呼吸和免疫系统。使用我们的表型分析管道对小鼠突变体进行评估将发现具有治疗重要性的新型临床前模型，包括许多占发达国家疾病发病率最高的疾病。 相关性：一个人的大多数基因都是正常的，但我们也携带了数百个受损的基因。虽然一些受损的基因可能导致严重的疾病，如囊性纤维化或癌症，但其他基因几乎没有任何后果，或者只有在压力下才能发挥作用。目前，我们对人类三分之一基因的功能有一定的了解。如果我们要充分了解人类的健康和疾病，我们必须利用小鼠等模式生物将基因功能的知识扩展到我们所有的基因。

DESCRIPTION (provided by applicant): A comprehensive functional annotation of all genes is a key goal for the future investigation of mammalian systems and biomedical sciences. We have established a consortium for the large-scale phenotyping of mouse mutants, which is fundamental to the investigation of gene function. The BaSH consortium, Baylor College of Medicine (BCM), Houston, Texas, the Wellcome Trust Sanger Institute Mouse Genetics Programme, Hinxton, United Kingdom, and the Medical Research Council Harwell, (Mammalian Genetics Unit and Mary Lyon Centre), United Kingdom, will undertake broad-based phenotype analysis of 300 IKMC mouse lines per year with the aim of identifying perturbations on developmental, physiological and biochemical pathways that will guide experimenters to develop hypothesis-driven research into disease systems. Our aims are to 1) complete the broad-based disease phenotyping of over 1500 lines of mutant mice in the C57BL/6N genetic background, 2) validate an optimized and enhanced broad-based phenotyping pipeline that will detect a variety of disease phenotypes and increase throughput, and 3) submit phenotypic data to the designated data coordination center, ensuring an interface with the wider biomedical scientific community that will inform human genetic studies. Our approach is to build on our unique expertise in mouse phenotyping and the successful operation of major pilot projects for mouse phenotyping of EUCOMM and KOMP mutants to deliver a phenotyping pipeline with strategic breadth that serves the needs of the medical community. Our pipeline design aims to deliver mouse models in key therapeutically relevant areas - for example in Cardiovascular, Metabolic, Neurological, Respiratory and Immunological Systems. Assessment of mouse mutants using our phenotyping pipeline will discover novel preclinical models of therapeutic importance, encompassing many of the diseases that account for the highest rates of disease morbidity throughout the developed world. RELEVANCE: Most of the genes in a person are normal, but we also carry several hundred broken ones. While some broken genes can cause severe disease such as cystic fibrosis or cancer, others have little of no consequence, or function only under stress. Currently, we have some understanding of the function of just one third of human genes. If we are to fully understand human health and disease we must expand knowledge of gene function to all of our genes using model organisms such as the mouse.