The BCM Knockout Mouse Production and Phenotyping Project (BCM KOMP2)

BCM 敲除小鼠生产和表型项目 (BCM KOMP2)

基本信息

批准号：
10517774
负责人：
Mary E Dickinson
金额：
$ 278.57万
依托单位：
BAYLOR COLLEGE OF MEDICINE
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 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10517774
关键词：
Adopted Adult Alleles Anatomy Area Bioinformatics Biological Process Biology CRISPR/Cas technology Catalogs Clustered Regularly Interspaced Short Palindromic Repeats Code Collaborations Communities Cryopreservation Data Data Coordinating Center Defect Development Disease Embryo Ensure Essential Genes Exons Foundations Funding Future Generations Genes Genetic Goals Gold Human Image International Knockout Mice Machine Learning Mediating Medicine Methodology Mus Mutant Strains Mice Pathway interactions Phase Phenotype Procedures Production Program Development Proteins Quality Control Research Research Personnel Resources Role Site Standardization Techniques Technology Testing Time United States National Institutes of Health Work base behavior test college cost effective data quality design experience gene function genome editing human disease improved in vivo informatics infrastructure insight large scale production microCT mouse genome mutant novel novel strategies phenotypic data preclinical study repository research study technology development tool translational study

项目摘要

ABSTRACT The goal of the International Mouse Phenotyping Consortium (IMPC) is to develop a resource of null allele lines for every protein-coding gene in the mouse genome and, through standardized, broad-based phenotyping, catalog the biological function of each targeted gene. The NIH-funded Knockout Mouse Phenotyping Project (KOMP2) has supported two previous phases of null allele production and phenotyping, contributing to more than half of the null allele lines made and characterized by the IMPC. This application describes our plan for Baylor College of Medicine (BCM) to continue as a KOMP2 site during a third phase of funding. We propose to produce, cryopreserve, and phenotype null allele mouse lines for 600 protein coding genes. We have developed a bioinformatics approach to identify and prioritize genes with known or putative human disease associations but little-to-no in vivo functional annotation for null allele mouse line production. We will generate and validate null alleles using established CRISPR genome editing approaches and quality control procedures, cryopreserve all null allele lines using accepted techniques, and deliver germplasm to the MMRRC repositories for community- wide distribution. These null allele lines represent a gold standard resource for the scientific community and an important foundation for future research and translational studies. We will utilize our established pipelines to perform broad-based, standardized adult phenotyping on all mutant lines and assess homozygous lethal and subviable lines in an embryonic phenotyping pipeline. The phenotyping data we generate will provide fundamental new insights into mammalian biology as well as the genetic bases of human disease. All allele and phenotype data will be submitted in real time to the Data Coordination Center, ensuring the rapid dissemination of all BCM data to the wider biomedical scientific community. We will continue our production and phenotyping technology development programs, developing our own new approaches and adopting new methodologies from the community as they arise. The BCM KOMP2 team has the established expertise, experience, and resources to meet the proposed phase 3 goals in an efficient and cost-effective manner.

抽象的国际小鼠表型联盟 (IMPC) 的目标是开发无效等位基因系资源对于小鼠基因组中的每个蛋白质编码基因，通过标准化、广泛的表型分析，对每个目标基因的生物学功能进行分类。 NIH 资助的基因敲除小鼠表型分析项目（KOMP2）支持了无效等位基因产生和表型分析的前两个阶段，有助于更多超过一半的无效等位基因系是由 IMPC 制备和表征的。该应用程序描述了我们的计划贝勒医学院 (BCM) 在第三阶段资助期间继续作为 KOMP2 站点。我们建议生产、冷冻保存 600 个蛋白质编码基因的无效等位基因小鼠品系并进行表型分析。我们开发了一种生物信息学方法，用于识别和优先考虑与已知或假定的人类疾病相关的基因但对于空等位基因小鼠系生产几乎没有体内功能注释。我们将生成并验证使用已建立的 CRISPR 基因组编辑方法和质量控制程序、冷冻保存无效等位基因所有无效等位基因系均使用公认的技术，并将种质传送至 MMRRC 存储库以供社区使用分布广泛。这些无效等位基因系代表了科学界的黄金标准资源和为未来的研究和转化研究奠定了重要基础。我们将利用现有的管道对所有突变系进行基础广泛、标准化的成体表型分析，并评估纯合致死和胚胎表型分析管道中的亚存活系。我们生成的表型数据将提供对哺乳动物生物学以及人类疾病的遗传基础的基本新见解。所有等位基因和表型数据将实时提交至数据协调中心，保证快速传播将所有 BCM 数据提供给更广泛的生物医学科学界。我们将继续我们的生产和表型分析技术开发计划，开发我们自己的新方法并采用来自社区出现时。 BCM KOMP2 团队拥有成熟的专业知识、经验和资源以高效且具有成本效益的方式实现拟议的第三阶段目标。