Grant: Operating Grant

P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) were first discovered in drug resistant cancer cells. More recently, P-gp and BCRP have been discovered in normal cells of the blood-brain-barrier. Here, P-gp and BCRP act to prevent passage of xenobiotics from the blood into the brain. These multidrug resistance pumps are unique in that they can exclude a wide range of compounds, including anticancer drugs, HIV protease inhibitors, cardiac glycosides, antibiotics, herbicides and pesticides. In addition to excluding drugs, P-gp and BCRP can also exclude a number of steroids, suggestive of an important role in normal physiology. We have shown that high levels of P-gp and BCRP are located in microvessels of the fetal brain, which constitute the primary blood-brain-barrier. Here, they actively prevent xenobiotics and some hormones from entering the brain. The fetal brain is extremely susceptible to the teratogenic effects of several substances found in the environment and therefore the maternal circulation (i.e. pesticides and herbicides) as well as drugs administered to the mother in pregnancy (including anticancer drugs and steroids). While the blood-brain-barrier is developed early in fetal life and P-gp and BCRP have been localized to endothelial cells of the brain vasculature, little is known about their regulation at the fetal blood-brain-barrier. This is clearly important as alterations in P-gp and BCRP mediated efflux will have significant effects on transfer of xenobiotics into the fetal brain. A large number of these substances adversely affect the developing brain. This project is designed to determine the function and regulation of the multidrug resistance genes and their products, P-gp and BCRP in the fetal blood-brain-barrier. Understanding the role and regulation of P-gp and BCRP during normal development and disease will enable us to begin to develop therapeutic strategies focused towards optimizing brain health in the fetus and infant.