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The Jackson Laboratory Knockout Mouse Production and Phenotyping Project (JAX KOMP2)

杰克逊实验室基因敲除小鼠生产和表型项目 (JAX KOMP2)

基本信息

批准号：
10683282
负责人：
ROBERT E BRAUN
金额：
$ 233.95万
依托单位：
JACKSON LABORATORY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-16 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10683282
关键词：
Adult Age Alleles Archives Award Behavior Biological Biological Models Biology Body Composition Body Weight Breeding CRISPR/Cas technology Cardiovascular system Catalogs Collection Communities Complement Complex Coupled Cryopreservation Data Data Coordinating Center Databases Deposition Development Disease Disease model Drug Screening Embryo Encyclopedias Engineering Ensure Faculty Fertility Future Generations Genes Genetic Genotype Goals Guide RNA Health Human Infertility Infrastructure Institution International Internet Knock-out Knockout Mice Knowledge Laboratories Leadership Link Metabolic Methods Mission Mus Mutant Strains Mice Orthologous Gene Partner in relationship Pathway interactions Phase Phenotype Physiological Production Protocols documentation Public Health Publications Recording of previous events Reproducibility Research Research Personnel Resources Role Services Standardization Technology Testing The Jackson Laboratory Time United States National Institutes of Health Work aged animal data animal resource cohort cost cost effective endonuclease experience fortification gene function genome-wide human disease human model imaging modality improved innovation meetings member mouse genetics mouse genome mouse model multidisciplinary mutant new technology novel novel strategies nuclease offspring preclinical study programs repository sex skills social media tool transmission process young adult

项目摘要

ABSTRACT Mice and humans share approximately 20,000 genes. To date, little data exists for more than a quarter of these genes and nearly one third have no functional annotation. Because of the high degree of similarity between the mouse and human gene set, genetic data generated in mice can often be extrapolated to human gene function. Mouse models of genes with common functionality between mice and humans can lead to new models of disease, which are useful for drug screening, preclinical studies, and deeper understanding of biological and disease mechanism. The goal of the Knockout Mouse Phenotyping Program (KOMP2) is to generate lines of mice that carry knockouts (KOs) for a genome-wide collection of mouse genes and subject the mice to broad based phenotyping. JAX KOMP2 phase 3 proposes to use cutting-edge and cost-effective Cas9 RNA-guided nuclease (Cas9 RGN, also called CRISPR/Cas9) technology to generate, breed, cryopreserve and phenotype 600 lines of mice during the project period. Continued effort will be made to improve the Cas9 RGN technology so as to reduce costs, increase targeting efficiency, and create more complex mutant alleles. Genes will be selected in coordination with our KOMP2 and IMPC partners and will focus on those that; have human orthologs, have not been previously knocked out, have no or poor annotation, have significant community demand and integrate with other NIH-support programs, or are predicted to function in select pathways. To guarantee ready access to the community, we will ship mice to outside investigators while they are alive on the shelf and deposit the lines into the Mouse Mutant Regional Resource Center (MMRRC) repositories for future use. Broad based phenotyping on young adult mice up to 17 weeks of age will be performed on all 600 lines of mice using International Mouse Phenotyping Consortium (IMPC)-required and JAX-specific protocols. We will assess body weight and composition, and behavior, cardiovascular, metabolic, ocular and physiological parameters. Based on data generated from the current phase of KOMP2, we expect about 30% of lines to be non-viable. We will characterize the non-viable mutants using high-throughput imaging modalities at three embryonic time points. Based on previous data we also expect approximately 7% of the lines to be infertile. Direct fertility testing to assess the fertility of each sex will be performed on all lines that fail to generate offspring from homozygous by homozygous matings. All data generated from embryonic and adult mice will be rapidly deposited into the Data Coordination Center (DCC) that supports KOMP2 and the IMPC. Lastly, JAX will work collaboratively with the KOMP2 Regional Network and with member organizations of the IMPC to share protocols, innovation, and new technology and to broadly and openly disseminate our findings to the international community through publication, presentations at meetings, web activities, and social media.

摘要老鼠和人类有大约20,000个基因。到目前为止，其中超过四分之一的数据很少基因和近三分之一没有功能注释。因为它们之间的高度相似在小鼠和人类的基因集合中，小鼠产生的遗传数据往往可以推断出人类的基因功能。具有老鼠和人类共同功能的基因的小鼠模型可能会导致新的疾病，这对药物筛选、临床前研究和加深对生物学和疾病机制。Knokout鼠标表型程序(KOMP2)的目标是生成携带全基因组小鼠基因集合的敲除(KO)的小鼠，并使小鼠受到广泛的基于表型的。 JAX KOMP2阶段3建议使用尖端且经济高效的Cas9 RNA引导核酸酶(Cas9 RGN，也称为CRISPR/CAS9)技术，用于产生、繁殖、冷冻保存和表型为600的小鼠项目期。将继续努力改进Cas9 RGN技术，以降低成本，提高靶向效率，创造更复杂的突变等位基因。基因将在协调中进行选择与我们的KOMP2和IMPC合作伙伴，并将专注于那些；有人类同源基因，还没有以前被淘汰，没有注释或注释不佳，有显著的社区需求，并与其他 NIH支持计划，或预计将在选定的途径中发挥作用。以确保可以随时访问社区，我们将把老鼠送到外面的调查人员那里，当它们还活着的时候，把线放到小鼠突变区域资源中心(MMRRC)资源库，以备将来使用。将在所有600个品系的小鼠上对17周龄以下的年轻成年小鼠进行广泛的表型鉴定使用国际小鼠表型鉴定联盟(IMPC)要求的和JAX特定的协议。我们将评估体重和成分，以及行为、心血管、代谢、眼睛和生理参数。根据KOMP2当前阶段产生的数据，我们预计大约30%的线路不可行。我们将在三个胚胎时间点使用高通量成像方式来表征不能存活的突变体。根据以前的数据，我们还预计大约7%的品系是不育的。将生育测试直接发送到对所有不能从纯合子中产生后代的品系进行每一性别的育性评估，方法是纯合子配对。所有从胚胎和成年小鼠产生的数据都将被快速存储到数据中支持KOMP2和IMPC的协调中心(DCC)。最后，日本宇宙航空研究开发机构将与KOMP2区域网络和 IMPC分享协议、创新和新技术，并广泛和公开地将我们的发现传播给通过出版物、在会议上的发言、网络活动和社交媒体向国际社会宣传。