As stem cell-based therapies move towards clinical application, it is clear that more relevant animal models are required to demonstrate the safety and efficacy of stem cells for specific human diseases. Rats are the preferred animal model for many human diseases. The main goal of this project is to develop rat models for assessing the safety and efficacy of human stem cell grafts. We proposed to use the classical embryonic stem cell-based gene-targeting technology to generate rat models mimicking human heart failure, diabetes and neurodegenerative diseases. During the current budget year, we have made the following progress: 1) Completed the construction of all the targeting vectors necessary for generation of the proposed rat models; 2) Generated or in the progress of generating embryonic stem cells used for the generation of the proposed rat models; 3) Generated several chimeric rats from these gene-targeted rat embryonic stem cells; 4) Generated a motor neuron reporter human embryonic stem cell line. This cell line will be used for the generation and purification of motor neurons.