Animal Model Production Section

动物模型制作科

• 批准号: 10450129
• 负责人: Stephen A Murray
• 金额: $ 4.43万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-18 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10450129
• 关键词: Acute; Alleles; Alzheimer' s Disease; Alzheimer' s disease model; Animal Model; CRISPR/Cas technology; Cells; Clinic; Collaborations; Credentialing; Development; Disease; Engineering; Evaluation; Event; Foundations; Future; Generations; Genes; Genetic Engineering; Goals; In Situ; Knockout Mice; Laboratories; Light; Mediating; Modeling; Modification; Molecular; Molecular Analysis; Mus; Nature; Nonhomologous DNA End Joining; Outcome; Phenotype; Process; Production; Reporter; Research; Research Personnel; Resolution; Science; Services; Somatic Cell; Specificity; System; Technology; Testing; The Jackson Laboratory; Tissues; Translations; United States National Institutes of Health; Visualization; Work; base; base editing; cell type; clinical application; design; experience; gene therapy; genetic resource; genome editing; homologous recombination; human disease; improved; in vivo; insertion/deletion mutation; member; model design; mouse model; next generation; novel; precision genetics; programs; recombinase-mediated cassette exchange; serial imaging; somatic cell gene editing; tool

PROJECT SUMMARY ANIMAL MODEL PRODUCTION CORE The overall goal of the Somatic Cell Editing Consortium (SCGE) is to create a novel, integrated set of genome editing tools to accelerate translation of these approaches to the clinic. The goal of the JAX Gene Editing Mouse Testing Center (JAX-GEMTC) is to provide a robust, scalable platform for the optimization and credentialing of new editing machinery. Reporter models designed to detect different types of specific and non- specific genome-editing activity are essential for the systematic and efficient evaluation of a variety of novel delivery approaches designed to target a diverse array of disease-relevant cells and tissues. The specific goals of the Animal Model Production component of this Center are to generate and validate a suite of genome- editing reporter mouse lines that will illustrate the efficiency, specificity, and nature of editing modifications with single-cell resolution, and to develop a platform for future reporter line development to serve the goals of SCGE consortium members. Building on our existing reporter model, we will create a panel of reporter lines that support analysis of multiple editors, editing outcomes, and off-target activity. Through the colony management and distribution effort of the RESOURCE CORE, these models will serve to support the goals of the TESTING CORE. Our goals will be achieved through three Specific Aims: 1) We will generate mouse reporter lines designed to test somatic cell editing efficiency and specificity for multiple types of editing activity, including NHEJ-mediated indels, HR, base editing, and off-target activity; We will assess the function of each reporter line in vivo to assure its utility as a test platform for new delivery technologies; 3) To develop and deploy platforms and models to support future collaborations with the SCGE consortium. To accomplish this, we will validate and implement a novel recombinase-mediated cassette exchange (RMCE) platform to improve the efficiency of targeting of large reporter constructs, and will work with the SCGE to develop reporter models that assess novel editor functions not captured by the panel of lines produced in Aim 1.

项目概要 动物模型制作核心 体细胞编辑联盟 (SCGE) 的总体目标是创建一套新颖的、集成的基因组 编辑工具可加速将这些方法转化为临床。 JAX 基因编辑的目标 鼠标测试中心 (JAX-GEMTC) 旨在提供一个强大的、可扩展的平台，用于优化和 新编辑机制的认证。报告模型旨在检测不同类型的特定和非 特定的基因组编辑活动对于系统有效地评估各种新颖的基因组编辑活动至关重要 旨在针对多种疾病相关细胞和组织的递送方法。具体目标 该中心动物模型制作部分的任务是生成并验证一套基因组- 编辑报告小鼠系，将说明编辑修饰的效率、特异性和性质 单细胞分辨率，并为未来报告系开发开发一个平台，以服务于以下目标： SCGE 联盟成员。在我们现有的记者模型的基础上，我们将创建一个记者线路面板 支持对多个编辑器、编辑结果和脱靶活动的分析。通过殖民地 资源核心的管理和分配工作，这些模型将有助于支持以下目标： 测试核心。我们的目标将通过三个具体目标来实现：1）我们将生成鼠标 报告系设计用于测试体细胞编辑效率和多种类型编辑活动的特异性， 包括 NHEJ 介导的插入缺失、HR、碱基编辑和脱靶活动；我们将评估每个功能 体内报告线，以确保其作为新递送技术测试平台的实用性； 3) 开发和 部署平台和模型以支持未来与 SCGE 联盟的合作。为了实现这一目标， 我们将验证并实施一种新型重组酶介导的盒式交换（RMCE）平台，以改进 大型报告构建体的靶向效率，并将与 SCGE 合作开发报告模型 评估目标 1 中生成的行面板未捕获的新颖编辑器功能。