We are interested in membrane transport proteins and their roles in human health and disease. Most of our focus is on understanding the mechanisms of drug sensitivity and resistance, especially those mediated by members of the ATP-binding cassette (ABC) superfamily of transmembrane proteins.
Multidrug Resistance Protein (MRP1) [gene symbol ABCC1] is a 190 kDa plasma membrane protein that can confer multidrug resistance on previously sensitive tumour cells. It does this primarily by reducing the drug concentration in cells by actively pumping drugs out. Low levels of MRP1 are also found in normal cells where it influences how drugs used to treat cancer and other human diseases are distributed to various organs in the body. Thus MRP1 can protect normal tissues by acting as a barrier and impeding entry of foreign chemicals, including environmental toxins. Many organic anions (including glutathione (GSH) and glucuronide conjugated xenobiotics) are also transported by MRP1. And finally, MRP1 also mediates the cellular efflux of important physiological molecules such as the pro-inflammatory signalling molecule, cysteinyl leukotriene LTC4, and the ubiquitous antioxidant GSH.
Ongoing MRP1-related projects include: (i) investigations of how GSH affects the structure and activity of MRP1; (ii) mapping of the drug binding sites on MRP1; (iii) investigation of novel compounds and naturally occurring compounds that are substrates or modulators of MRP1 activity; (iv) identifying protein-protein interactions that affect the activity and/or cellular localization of MRP1; and (v) investigations of ABCC1/MRP1 polymorphisms that affect drug efficacy or toxicity.
We are also interested in the structural and functional differences between MRP1 and its homologs MRP2, MRP3 and MRP4. MRP4 is of particular interest because it effluxes antiviral drugs as well as the signalling molecules cAMP and prostaglandin E2. In epithelial and endothelial (ie polarized) cells, MRP4 has the unusual ability to localize to different membranes (apical versus basolateral) depending on the type of cell it is expressed.
Ongoing MRP4/ABCC4-related projects include: (i) investigation of protein-protein interactions that determine basolateral vs apical localization of MRP4 in polarized cells. (ii) identifying the structural determinants of MRP4 substrate specificity and membrane localization; and (iii) exploring the consequences of genetic variations of ABCC4.
The discoveries made by our group have been of both academic and commercial interest.