Grant: Project Grant

Multidrug transporters in the fetal blood-brain barrier (BBB) protect the developing brain from factors entering the fetus from the maternal circulation. They limit the transfer of a spectrum of factors (steroids, cytokines), drugs (anticancer/HIV drugs, antibiotics, statins) and toxins (pesticides) into the brain. However, very little is known as to how they are regulated in the developing brain and how they are modified in common pregnancy complications. This is important because the developing brain is a major target for drugs and hormones as well as neurotoxic factors. It is estimated that approximately 75% of pregnant people are prescribed drugs, many of which can be transported by the multidrug transporters. Further, many of the most administered drugs to babies born preterm are normally prevented from entering the brain by these transporters in babies born at normal term. Due to reduced levels of these transporters in the preterm infant brain, there is increased risk of neurotoxicity. We have also recently shown that astrocytes (which are key cells supporting the BBB) are important for indirectly regulating multidrug transporters. In the present proposal, we will; 1) Determine the mechanisms by which astrocytes support multidrug transporter function at the fetal BBB; 2) Establish how bacterial and viral infection and commonly administered therapeutic drugs (glucocorticoids) influence multidrug transporters; 3) Determine the molecular mechanisms by which multidrug transporters are regulated in the fetus and identify potential new drug targets. This program will lead to a significant advance in understanding of the mechanisms by which drug transporters protect the developing brain in healthy and high-risk pregnancies. This new knowledge will be translated to assist in the development of novel strategies to enhance brain protection in the fetus and in infants born preterm, who are extremely vulnerable.