Grant: CIHR New Investigator

The digestive system is complex and by consequent is the site of multiple diseases. Inflammatory bowel disease (IBD) affect 1 in 150 Canadians, while colorectal cancer is among the most common and lethal malignancy. Although these two diseases are different, they both are linked to a cellular mechanism called autophagy. Autophagy is the process by which cells degrade and recycle their own constituents. Autophagy is induced by different stresses. In intestinal cells, autophagy helps in the removal of pathogenic bacteria. On the other hand, cancer cells grow very rapidly in environments lacking proper nutrients supply. Hence, cancer cells will rely on autophagy to stay alive. Cells of the body are composed of multiple types of membranes. These membranes are highly controlled and the mechanisms regulating them are collectively called 'membrane trafficking'. Autophagy is vastly controlled by membrane trafficking events. Thus, understanding how membrane trafficking regulates autophagy is important to find new therapeutic avenues for both IBD and colorectal cancer. My work has uncovered regulators of membrane trafficking necessary for autophagy. I found that their role is temporally controlled and that activation and recruitment of specific effectors is important for autophagy progression. In this proposal, I will characterize how one regulator of membrane traffic is activated and inhibited by certain proteins, and how it controls autophagy. I will also study how these regulators and effectors assemble into protein complexes (molecular machines) to control membrane trafficking. Importantly, I will test the newly identified components and aspects of their temporal regulation for their roles in autophagy in normal intestinal epithelium and for their requirements in colorectal cancer cell growth and in IBD models. This work will represent a key step in understanding how we can specifically control autophagy to prevent IBD or to target and eliminate colorectal cancer cells.