Aicardi-Goutières Syndrome (AGS) is a severe inflammatory disease occurring in infants and for which no treatment options are available. The disease has a major psycho-social impact on both patients and their parents. Mutations in one out of nine genes cause AGS. These include loss-of-function mutations in ADAR, the gene encoding for the RNA editing enzyme ADAR1. In order to develop novel therapies for AGS, three major gaps in our understanding about ADAR1 function need to be addressed. Firstly, we need to pinpoint the exact immune pathways that drive pathology. Secondly, we have to study how mutations in functionally different protein domains of ADAR1 cause disease, and thirdly, we have to understand how these mutations disrupt normal ADAR1 function. To address these questions, we propose to create new genetic mouse models of AGS. The unique strength of our approach lies within the fact that we will generate mice that carry the exact genetic mutations that occur in AGS patients. This will allow us for the first time to study the exact genotypic-phenotypic relationship of these mutations. At the same time we will use these innovative mouse models to genetically dissect the immune pathways that drive disease and evaluate the use of pharmacological inhibitors of these pathways to treat AGS. Through this project, our goal is to provide better treatment for AGS and possibly other type-I IFN-driven pathologies such as lupus.