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.
Rats are the preferred model for the study of many human diseases. However, their use has been limited by the inability to genetically modify rats to delete specific genes that are important in disease-relevant regulatory pathways. Using a novel technology developed at our institution, we will develop a panel of genetically modified rats that will enable us to delete genes of interest in specific tissues in a highly targeted fashion, allowing us to model human disease in a way that was not previously possible.
