Mass action kinetic modeling of membrane transport networks:
Our primary project is the study of Multidrug resistance transporters. We have long-standing collaboration with GlaxoSmithKline to develop a quantitative kinetic model of transcellular transport mediated by the multidrug resistance protein P-gp. This transporter is found in many human tissues, where it is responsible for inhibiting uptake of foreign molecules, e.g. the colon, the kidney, the liver, gonads a nd the b picks up amphiphilic compounds from the inner apical membrane, which faces the “outside” world, and uses the energy of ATP hydrolysis to eject the compound back to the “outside” world. However, many cancer cells have acquired or amplified the gene for this transporter since it will also inhibit their uptake of chemotherapeutic agents. It is thought that this acquired resistance is responsible for much of the failure of cancer chemotherapy. P-gp has 12 transmembrane domains and a very large range of substrates, which has complicated the elucidation of its binding and active sites. Our approach is to create a rigorous analysis of its transport kinetics, which will allow a clear focus on the how compound structure and transporter mutations affect elementary rate constants of transport for this protein. This can guide more precise structure-function relationships for P-gp and hopefully effective inhibitors.