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株菌株。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应该能够快速(3至6个月)进行修改。 这笔R24资源赠款支持我们现有的基础设施：人员、基因编辑专业知识、高 吞吐量表型，分销渠道，产生规模经济，可以被用来为更多的研究人员产生新的和重要的老鼠模型。我们现有计划已经开发的独特的大鼠模型已经证明：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下的基因，测试GWAS结果，进行后续研究以确定预测基因的功能，或开发模型来研究基因的生理/机制；3)规模经济；4)全面的分配系统；以及5)大鼠十多年的资源开发(数据、大鼠、遗传和基因组试剂)。为了确保资源满足社区的需求，我们将建立一个外部咨询委员会(EAB)来评估我们的进展，并进行科学的功绩审查程序，以选择由科学界提名的R24的基因和资源的使用(目标1)。我们计划建立250个基因靶向的大鼠模型(目标2)，提供现有的但不是必需的表型特征菜单(目标3)，以及来自每个品系的冷冻保存的精子，以及每个品系的组织和成纤维细胞原代培养库，以及向社区分发所有动物和试剂(目标4)。 特定的目标1-4预计将产生具有成本效益和强大的大鼠模型集合 这将加速发现并增加该领域对复杂疾病涉及的机制的了解。科学界已经提名了超过343个基因，这表明在R24中开发的资源将对许多研究人员具有重要价值。选管会将确保透明度，并确保这些资源为社会服务。 (摘要结束)

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)