Project Summary/Abstract Monogenic diseases that have a close association with the development of type 1 diabetes have been informative for unraveling critical pathways that keep this disease in check. Examples of success using this approach include the study of AIRE and FOXP3 which have been informative for identifying pathways in the thymus and T regulatory cells that keep type 1 diabetes in check. Here, we will leverage the recent knowledge that gain of function mutations (GOF) in STAT3 are tightly associated with the development of type 1 diabetes by developing a robust animal model of the syndrome. Our specific aims are: Aim 1: Model the effects of STAT3 GOF in a novel mouse model of autoimmune diabetes (NOD.STAT3K392R/+) Aim 2: Identify and characterize key immune cell populations that are defective in the NOD.STAT3K392R/+ model and in patients with similar STAT3 GOF mutations Aim 3: Identify how central tolerance is potentially altered in STAT3 GOF models These studies will be performed in close collaboration with PPG projects 1 (Cooper) and 3 (Marson) and will help improve our understanding of how the immune tolerance is controlled by STAT3 and how alterations in this molecule can provoke type 1 daibetes.