Generation of Cre/lox rats

摘要 这项R24资源提案旨在促进广泛和具有成本效益的使用大鼠模型， 和一组流行的Cre/lox敲入大鼠的分布。长期以来，老鼠一直被用作模型， 复制人类生理学和病理生理学比小鼠，是研究的首选模型， 许多人类疾病。然而，直到最近，使用大鼠来模拟人类疾病一直受到限制， 不能产生具有生殖能力的大鼠胚胎干（ES）细胞，从而妨碍了基于ES细胞的 产生条件性/诱导性敲除大鼠的方法。2010年，我们培育出了第一只基因敲除的老鼠 通过在ES细胞中基于同源重组的基因靶向。最近，我们已经生成了一个面板， 包括基因敲除、点突变敲入、报告基因敲入、Cre 司机和被鞭打的老鼠ES细胞方法的一个主要优势是结合Cre/lox 技术，以产生其中基因在特定时间和/或在特定组织中失活的大鼠， 机关我们已经召集了一个强大的调查小组，他们具有互补的专业知识， 通用Cre/lox报告基因大鼠（Aim 1）、细胞特异性和诱导性Cre大鼠（Aim 2）和floxed大鼠（其中 感兴趣的特定基因的侧翼是loxP位点（Aim 3）。这些Cre/lox大鼠将使研究人员能够 在原位可视化特定的细胞类型，也可以作为产生条件性/诱导性 被击倒的老鼠本项目产生的Cre/lox大鼠将通过密苏里州大鼠资源中心分发， 研究中心（RRRC）（目标4）。这些大鼠的可用性将结合联合收割机的重要生物学特性 老鼠的遗传温顺性，为研究人员提供了一个高度相关的， 体内模型，研究特定基因和途径对许多疾病发病机制的贡献， 重要的人类疾病。

ABSTRACT This R24 resource proposal seeks to promote broad and cost-effective usage of rat models through generation and distribution of a panel of popular Cre/lox knockin rats. Rats have long been used as models that better replicate human physiology and pathophysiology than do mice and are the preferred model for the study of many human diseases. Use of rats to model human disease, however, has been limited until recently by the inability to generate germline-competent rat embryonic stem (ES) cells, precluding the use of ES-cell based approaches to produce conditional/inducible knockout rats. In 2010, we generated the first gene knockout rats by homologous recombination-based gene targeting in ES cells. More recently, we have generated a panel of genetically modified rat lines including gene knockout, knockin of point mutation, knockin of reporters, Cre drivers, and floxed rats. A major strength of the ES cell approach is the ability, in conjunction with Cre/lox technology, to generate rats in which genes are inactivated at specific times and/or in specific tissues or organs. We have assembled a strong group of investigators with complementary expertise to develop a panel of universal Cre/lox reporter rats (Aim 1), cell-specific and inducible Cre rats (Aim 2), and floxed rats in which specific genes of interest are flanked by loxP sites (Aim 3). These Cre/lox rats will allow investigators to visualize specific cell types in situ and can also serve as the basis for the generation of conditional/inducible knockout rats. Cre/lox rats generated in this project will be distributed through the Missouri Rat Resource and Research Center (RRRC) (Aim 4). Availability of these rats would combine the significant biological advantages of the rat with the genetic tractability of the mouse, providing investigators with a highly relevant in vivo model with which to study the contributions of specific genes and pathways to pathogenesis of a number of important human diseases.