Consortium for large-scale production and cryopreservation of knockout mice

基因敲除小鼠大规模生产和冷冻保存联盟

• 批准号: 8325929
• 负责人: MONICA J. JUSTICE
• 金额: $ 413.3万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8325929
• 关键词: Address; Adult; Alleles; Animals; Archives; Behavior; Biochemical Pathway; Biological; Biological Assay; Breeding; Cell physiology; Chimera organism; Code; Communities; Cryopreservation; Cystic Fibrosis; Data; Data Coordinating Center; Deposition; Development; Disease; Embryo; Embryonic Development; Female; Fertility; Fertility Study; Freezing; Functional RNA; Funding; Gene Targeting; Genes; Genome; Germ Lines; Glean; Health; Homozygote; House mice; Human; Human Genome; Image; Individual; Infertility; Institutes; International; Knock-out; Knockout Mice; Knowledge; LacZ Genes; Malignant Neoplasms; Mammalian Genetics; Medical Research; Medicine; Metabolic; Mus; Mutant Strains Mice; Mutation; Organism; Output; Pattern; Persons; Phenotype; Physiological; Physiology; Production; Proteins; Quality Control; Research; Resources; Role; Route; Staging; Stress; System; Time; Tissues; Trust; United States National Institutes of Health; Variant; Work; base; body system; college; cost; embryonic stem cell; experience; gene function; genetic resource; genome-wide; large scale production; loss of function; male; member; mouse development; mutant; new technology; programs; promoter; repository; sperm cell; stem cell technology

DESCRIPTION (provided by applicant): Annotation of the reference human genome has identified approximately 20,000 protein coding genes as well as 3,000 non-coding RNAs. Together these genes orchestrate the development of the organism, supporting all aspects of the function of cells, tissues, organ systems as well physiology and behavior. The l000 genomes project has revealed extraordinary levels of diversity in human genomes, yet for most genes neither the function of normal version nor the disease consequence of loss-of-function variants is known. The mouse provides a route to understand the function of genes and their variants. Mice share developmental, physiological, anatomical and metabolic parallels with humans, which are evident in healthy as well as diseased states. These reflect similarities of the genes in both species. Mutant mice generated using ES cell technology are a sensitive biological assay system from which a deep understanding of function can be gleaned and they also provide a long lasting biological resource for further study. The objective of this proposal is to generate mutant mice from a resource of ES cells with conditionally targeted, lacZ-tagged alleles generated under previous NIH (KOMP) and EU (EUCOMM) funded programs. We and others will use these mice to discover the function of genes. We are proposing to carry out this work at scale and have formed a consortium of three Institutes (Baylor College of Medicine, the Sanger Institute and MRC Harwell) to work together as equal partners to achieve this objective. We will generate mice corresponding to 1500 mutant genes from ES cells distributed by the Sanger Institute. We will characterize the adult and embryonic expression pattern of the each targeted gene and by breeding determine the requirement of each for embryonic development and fertility, if any. All of the alleles will be cryo-preserved and placed in a repository and all of the data will be deposited in a centralized data coordination center to support further studies. RELEVANCE: Most of the 20,000 genes in a typical person are normal but we also have several hundred broken ones. While some broken genes can cause severe disease such as cystic fibrosis or cancer, others have little or 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.

描述（由申请人提供）：参考人类基因组的注释已鉴定出约20，000个蛋白质编码基因以及3，000个非编码RNA。这些基因共同协调有机体的发育，支持细胞，组织，器官系统以及生理和行为功能的各个方面。1000个基因组计划已经揭示了人类基因组的非凡多样性，但对于大多数基因来说，既不知道正常版本的功能，也不知道功能丧失变体的疾病后果。小鼠为理解基因及其变体的功能提供了一条途径。小鼠在发育、生理、解剖和代谢方面与人类相似，这在健康和患病状态下都很明显。这反映了两个物种基因的相似性。使用ES细胞技术产生的突变小鼠是一种灵敏的生物测定系统，从中可以深入了解功能，并且它们也为进一步研究提供了持久的生物资源。该提案的目的是从具有条件靶向的、lacZ标记的等位基因的ES细胞资源中产生突变小鼠，所述等位基因是根据先前NIH（KOMP）和EU（EUCOMM）资助的计划产生的。我们和其他人将用这些老鼠来发现基因的功能。我们建议大规模开展这项工作，并成立了一个由三个研究所（贝勒医学院、桑格研究所和MRC哈维尔）组成的联合体，作为平等的伙伴共同努力实现这一目标。我们将从桑格研究所分发的ES细胞中产生对应于1500个突变基因的小鼠。我们将描述每个靶基因的成体和胚胎表达模式，并通过育种确定每个基因对胚胎发育和生育力的要求（如果有的话）。所有的等位基因将被冷冻保存并放置在一个储存库中，所有的数据将被存放在一个集中的数据协调中心，以支持进一步的研究。 相关性： 在一个典型的人身上，20,000个基因中的大多数都是正常的，但我们也有几百个基因被破坏了。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或根本没有后果，或者只在压力下发挥作用。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，我们必须将基因功能的知识扩展到我们所有的基因。