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 difficulty in modifying rat genes to mimic human conditions. The main goal of this project was to produce rat models of heart failure, diabetes, and amyotrophic lateral sclerosis. The embryonic stem cell-based gene-targeting technology was used for the generation of these rat models. First, we introduced targeted genetic mutations into rat embryonic stem cells. Next, we produced rats from these gene-targeted embryonic stem cells. Several genetically modified rats that are essential for the generation of rat disease models mentioned above have been generated. We are still in the process of generating the remaining genetically modified rats that are also essential for the production of the three rat disease models. Once generated, we will use these rat models to assess the safety and therapeutic potential of cells derived from human pluripotent stem cells. These rats models are highly valuable to many investigators in California and across the world with diverse research interests. We will distribute the rat models produced in this project to investigators upon request.