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Enhancing the C. elegans animal resource through genome editing

通过基因组编辑增强线虫动物资源

基本信息

批准号：
10610879
负责人：
Ann E. Rougvie
金额：
$ 60.52万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10610879
关键词：
ATP phosphohydrolase Acceleration Address Alleles Animal Model Animals Area Attention Behavior Biology Biomedical Research CRISPR/Cas technology Caenorhabditis Caenorhabditis elegans Candidate Disease Gene Categories Clustered Regularly Interspaced Short Palindromic Repeats Code Collection Communities Databases Deposition Development Disease Dissection Event Funding G-Protein-Coupled Receptors Generations Genes Genetic Genome Goals Guide RNA Hand Health Human Human Biology Human Genetics Information Distribution Invertebrates Ion Channel Knock-in Knock-out Laboratories Lead MET gene Methods Microinjections Modeling Molecular Molecular Biology Molecular Genetics Monitor Mutation Neurons Oligonucleotides Orthologous Gene Pathway interactions Peptide Hydrolases Phase Phenotype Phosphotransferases Physiology Production Proteins Proteomics Quality Control Reagent Reproducibility Research Research Personnel Research Project Grants Research Support Resources Scientist Site Sorting United States National Institutes of Health Variant WormBase animal resource community center design gene conservation gene discovery gene function gene interaction genetic analysis genome editing genome resource human disease interest knockout gene loss of function loss of function mutation metabolomics model organism mutant programs screening transcriptome sequencing trend variant of unknown significance web site

项目摘要

Project Summary/Abstract The objective of this project is to extend the C. elegans genetic toolkit available to researchers by providing publicly available gene knockout (KO) mutations in genes of high value to those interested in human biology and disease. C. elegans is a proven model for discovery of gene function and for embedding genes into functional pathways, many of which were discovered in this transparent animal and are conserved in humans. Loss-of-function mutations are the gold-standard for genetic analysis and allow inferences of gene function and interaction. A relatively recent trend is that large-scale screens (e.g., RNA-seq, proteomics, natural variation studies) generate long candidate gene lists for researchers to sort through and functionally validate, requiring loss of function mutants in many genes to be examined. Having a community-driven resource generate KOs in such genes provides reproducibility and an economy of scale that benefits all. We have developed an efficient and high throughput CRISPR-Cas9 based gene knockout (KO) project to provide a set of precisely edited gene knockout strains to the communities of C. elegans researchers and human geneticists. We seek to continue the production phase of this project, thereby transformatively increasing the efficiency and impact of C. elegans molecular genetics. We employ a highly coordinated three-site production strategy to generate KOs. Each gene edit is carefully confirmed, and validated strains are grossly phenotyped and deposited into the Caenorhabditis Genetics Center (CGC) strain collection along with detailed strain information for distribution to the community. Strains are advertised through both the CGC and WormBase websites. We have generated over 1,000 KOs to date; these KOs have supported a variety of research projects – spanning from mechanistic studies of human variants to metabolomics – funded by at least 14 NIH Institutes and Centers, demonstrating the high impact of our resource. We propose to continue to use our established pipelines to target an additional 2500 C. elegans orthologs of human genes. We will prioritize known or suspected human disease genes, druggable gene classes, as well as understudied genes that are conserved to humans but that have no actionable information. This is a multi-PI project which includes the lead-PIs of the CGC and of WormBase and a subcontractor who maintains multiple community-centered databases, including a CRISPR guide RNA selection site.

项目总结/摘要该项目的目标是扩展C。elegans遗传工具包提供给研究人员，对人类生物学感兴趣的人具有高价值的基因中的公开可用的基因敲除（KO）突变和疾病C.线虫是发现基因功能和将基因嵌入功能途径，其中许多是在这种透明的动物中发现的，在人类中是保守的。功能丧失突变是遗传分析的金标准，可以推断基因功能，互动相对最近的趋势是大规模屏幕（例如，RNA-seq，蛋白质组学，自然变异研究）生成长的候选基因列表，供研究人员进行排序和功能验证，需要许多基因的功能缺失突变体有待研究。拥有社区驱动的资源，这些基因提供了可重复性和规模经济，使所有人受益。我们开发了一种高效的和基于CRISPR-Cas9的高通量基因敲除（KO）项目，以提供一组精确编辑的基因，敲除菌株对C.线虫研究者和人类遗传学家。我们寻求继续该项目的生产阶段，从而转型提高C. elegans 分子遗传学我们采用高度协调的三地生产策略来产生科斯。每个基因编辑被仔细确认，并且验证的菌株被粗略地表型化并被存放到小杆线虫遗传学中心（CGC）菌株采集沿着详细菌株信息，以分发至社会各界通过CGC和WormBase网站公布菌株。我们已经生成迄今为止，有超过1，000个科斯;这些科斯支持了各种研究项目--从机械代谢组学的人类变异研究-由至少14个NIH研究所和中心资助，证明我们资源的巨大影响。我们建议继续利用现有的管道， 2500摄氏度人类基因的直向同源物。我们将优先考虑已知或疑似的人类疾病基因，可药物化的基因类别，以及未充分研究的基因，这些基因在人类中是保守的，但没有可采取行动的信息。这是一个多PI项目，包括CGC和WormBase的主要PI，一个维护多个以社区为中心的数据库的分包商，包括CRISPR指导RNA 选择网站