Project Summary Mounting evidence from our laboratory and others suggests that a lysosomal degradation pathway, called autophagy, plays a central role in orchestrating inflammation and cancer biology. Recently, our laboratory generated UVRAG (UV irradiation resistance associated gene) mutant mice that show normal levels of basal autophagy but are deficient in stimulus-induced autophagy. With this mouse model, we demonstrate that autophagy dysregulation could exacerbate inflammation and promote spontaneous cancers. However, major gaps still exist in our understanding of intricate relationship between autophagy, inflammation and cancer, including 1) what are the mechanisms by which inadequate autophagy perpetuates inflammasome response and drives inflammation-associated pathologies? and 2) how does basal autophagy suppression affect tissue homeostasis and promote cancer susceptibility? This project will fill these gaps by focusing on two Specific Aims, including 1) investigating molecular mechanism of autophagy dysfunction on inflammatory signaling and inflammation-associated pathologies; and 2) identifying molecular mechanism of autophagy inhibition in Wnt/b- catenin signaling activation and spontaneous tumorigenesis. These aims will be addressed using multidisciplinary innovative approaches that integrate state-of-the-art genetic, biochemistry, single cell analysis, and physiological assays in cells, 3D organoid culture, and mice with targeted mutations in genes related to UVRAG function and autophagy deregulation. Together, we anticipate that these studies will elucidate the mechanisms underlying the intricate dialog between imbalance of autophagy, uncontrolled inflammation, and spontaneous tumorigenesis, thereby providing important new insights into the functional repertoire of autophagy and facilitating the development of much-needed new strategies for the treatment of inflammatory pathologies and cancer, particularly those associated with autophagy defects.