Project Summary Recent genetic studies have identified numerous genetic variations that are associated with higher risk of autoimmune diseases. For example, several genetic variations at the SIRPG gene are associated with higher risk of type 1 diabetes. SIRPG is expressed almost exclusively in T lymphocytes. However, its physiological function is still unknown due to the lack of a mouse homologue. Nor do we understand how its genetic variations contribute to the pathogenesis of type 1 diabetes. These important questions will be addressed in this project with cutting edge genetic engineering technology to ablate SIRPG or reproduce its genetic variations in human T cells. Data generated from this project will advance our understanding of not only the function of SIRPG but also the pathogenesis of type 1 diabetes, and eventually lead to novel therapeutic approaches of autoimmune diseases.