Gene targeted rat resource for the study of complex disease

描述（由申请人提供）： 使用锌指核酸酶（ZFN）技术进行基因修饰或编辑，我们在两年内产生了101株。ZFN技术非常有效，不需要使用胚胎干细胞，因此任何大鼠品系都可以快速（3至6个月）进行修饰。 这项R24资源赠款使我们现有的基础设施：人员，基因编辑的专业知识， 通过表型分析，分销渠道导致规模经济，可以利用这些经济为更多的研究者产生新的和重要的大鼠模型。我们现有项目已经开发的独特大鼠模型已经证明：1）基础设施已经到位，以满足我们的目标; 2）这些基因修饰的菌株可用于验证数量性状基因座的基因，测试GWAS结果，后续研究以确定预测基因的功能，或开发模型以研究基因的生理学/机制; 3）我们的规模经济; 4）一个完整的分销系统到位;和5）超过十年的资源开发（数据，大鼠，遗传和基因组试剂）的大鼠。为了确保资源满足社区需求，我们将建立一个外部咨询委员会（EAB），评估我们的进展，并进行科学的价值审查过程，以选择科学界提名的R24的基因和资源的使用（目标1）。我们计划生成250个基因靶向大鼠模型（目标2），以提供可用但不需要的表型表征菜单（目标3），并冷冻保存来自每个品系的精子，沿着每个品系的组织和成纤维细胞原代培养库，以及将所有动物和试剂分发给社区（目标4）。 具体目标1-4预计将产生一个具有成本效益和功能强大的大鼠模型集合，用于 这将加速发现并增加该领域对复杂疾病机制的理解。科学界已经提名了超过343个基因，这表明R24中开发的资源对许多研究人员具有重要价值。EAB将确保透明度，并确保这些资源为社区服务。 (End摘要）

DESCRIPTION (provided by applicant): Using the zinc finger nucleases (ZFN) technology for making gene modification or edits we generated 101 strains within two years. The ZFN technology is extraordinarily efficient and does not require the use of embryonic stem cells, as a result any rat strain should be able to be rapidly (3 to 6 months) modified. This R24 resource grant enables our existing infrastructure: personnel, expertise in gene editing, high throughput phenotyping, distribution channels resulting in an economies of scale that can be leverage to generate novel and important rat models to more investigators. The unique rat models already developed by our existing program, have demonstrated: 1) that the infrastructure is already in place to meet our objectives; 2) these gene modified strains can be used to validate a gene underlying a quantitative trait locus, testing a GWAS result, follow-up studies to define function of a predicted gene, or developing a model to study the physiology/mechanisms of a gene; 3) our economy of scale; 4) a full distribution system in place; and 5) over a decade of resources development (data, rats, genetic and genomic reagents) for the rat. To assure the resource meets community needs, we will establish an External Advisory Board (EAB) that will assess our progress, and conduct a scientific merit review process to select the genes and use of the resources of the R24 nominated by the scientific community (Aim 1). We plan to generate 250 gene targeted rat models (Aim 2), to provide a menu of phenotypic characterization that are available, but not required (Aim 3), and cryopreserved sperm from each line, along with a tissue and fibroblast primary culture bank for each strain, as well as distribute all the animals and reagents to the community (Aim 4). Specific aims 1-4 are expected to generate a cost effective and powerful collection of rat models for the community that will accelerate discovery and increase the field's understanding ofthe mechanisms involved in complex diseases. The scientific community has already nominated more than 343 genes demonstrating that the resources developed in this R24 will be of significant value to many investigators. The EAB will assure transparency and that this resource serves the community. (End of Abstract)