Grant: Doctoral Award - Frederick Banting and Charles Best Canada Graduate Scholarships

The ATP-binding cassette (ABC) proteins are found in all living cells. These proteins influence the elimination of many drugs used to treat not only cancer, but also viral and bacterial infections, and cardiovascular and other human disorders. The "C" subfamily of ABC proteins contains 12 members, nine of which are known to transport drugs. This project focuses on one of these known as ABCC4 or MRP4. In some cell types, the MRP4 protein faces into the lumen (gut, bile duct, kidney) ("apical" membrane) and in others, it faces towards blood vessels (basolateral membrane). Thus, in kidney cells MRP4 can pump drugs into urine, whereas in the brain, MRP4 limits the ability of certain cancer drugs to penetrate the central nervous system. Thus in mice, MRP4 can confer drug resistance in brain tumors. The overall goal of my research is to determine how MRP4 can localize to different membranes in different cell types. We have previously shown that MRP4 binds to a "scaffolding" protein called "NHERF1", which increases the amount of MRP4 on the surface of kidney cells. However, NHERF1 is only one of several "scaffold" proteins, each of which has a special role in "tethering" proteins into a specific compartment of the cell. I want to investigate whether other scaffolding proteins (such as NHERF2, NHERF3, NHERF4, Shank2) affect how much MRP4 is found on the cell membrane. I also plan to determine the pathways used by MRP4 to reach the cell surface. In summary, trafficking of MRP4 to the membrane appears to be regulated by various protein complexes and these will be investigated in my research. Understanding these cellular processes is important for elucidating the roles of MRP4 in drug disposition and toxicity as well as optimizing the safety and efficacy of drugs currently in clinical practice as well as those under development.