Grant: Project Grant

Autophagy is an essential "junk removal" system used by all cells in our bodies to package large objects such as cellular organelles and protein aggregates and deliver these packages to the "cellular incinerator" the lysosome for breakdown. Malfunction of autophagy affects the normal balance between production and breakdown and has been shown to lead to a wide range of human diseases from neurodegeneration, cancer, to infectious diseases. To determine how autophagy is disrupted in the disease state, our laboratory is trying to obtain a comprehensive understanding of how autophagy operates at the molecular level by studying the dedicated protein machinery that coordinates this multi-step process. This project grant application focuses on three components of this machinery (EPG5, HOPS complex, Rab3GAP1/2 complex). Mutations to EPG5, HOPS, and Rab3GAP1/2 lead to the congenital disorders Vici syndrome, HOPS-associated dystonia, and Warburg micro syndrome, respectively. We will investigate the molecular mechanisms of how these proteins and protein complexes check the identities of the junk packages and facilitate their delivery to the lysosome for breakdown. Our proposed research will fill key knowledge gaps in our knowledge on how cells control and execute autophagy degradation essential to health. In the long term, our research will pave the way for the development of autophagy-targeted therapeutics for treating different human diseases, and improve the quality of life of the large number of Canadians suffering from these disorders.