Impact of Pregnancy Disease on the Regulation of Placenta Drug Transport

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SUMMARY The primary objective of this proposal is to facilitate my development into an independent research scientist. This objective will be accomplished through a combination of active mentorship, didactic training, enrichment activities, and research. 100% of my time is committed to research. The mentorship phase is well described by my mentors and includes weekly contact and formal course work. The core of my research focuses on the pathopharmacology of the maternal-placental-fetal unit. Intrauterine infection is a major threat to mother and fetus. It is associated with more than 50% of women who deliver prematurely and is implicated in fetal / neonatal neurological and respiratory damage. Antibiotics are the primary treatment for infections during pregnancy, but because of poor placental transfer, fetal concentrations achieved are subtherapeutic. How the placenta regulates the transfer of antibiotics to the fetus is unclear, as is the impact of infection on drug transport. My preliminary data indicate there is up- regulation of the drug efflux transporters, multidrug resistence protein 1 (MDR1) and breast cancer resistence protein (BCRP), in the placenta of women with infection and associated chorioamnionitis. MDR1 and BCRP induction at the placental barrier could result in altered fetal drug exposure due to their broad substrate specificity and high level of expression in human placenta. The progressive research proposal addresses three core question: First, how does intra-amniotic infection affect placental MDR1/Mdr1a/b and BCRP/Bcrp1 (Mdr1a/b, Bcrp1, murine homologs of human MDR1 and BCRP)? Second, how do changes in MDR1/Mdr1a/b and BCRP/Bcrp1 activity affect the placental transfer and efficacy of antibiotics? Third, can drug delivery be manipulated by inhibiting the pathways that regulate transporter expression? In Specific Aim 1, I test the hypothesis that infection alters placental Mdr1a/b and Bcrp1 using a relevant mouse model of Ureaplasma infection and quantifying placental transporter levels. In Specific Aim 2, I test the hypothesis that modulation of Mdr1a/b and Bcrp1 alters the fetal distribution and therapeutic efficacy of antibiotics by measuring fetal drug levels and neonatal outcomes in wild-type, Mdr1a/b-/- (knockout) mice, Bcrp1-/- (knock-out) mice, and infected (Ureaplasma) mice. In Specific Aim 3, I propose to inhibit several prostaglandin (PG) E2 cascade elements, using pharmacological inhibitors and siRNA to test the hypothesis that prostaglandin (PG) E2 differentially regulates placental MDR1/Mdr1a/b and BCRP/Bcrp1 expression. The results will help predict how pathophysiological responses to infection in pregnancy affect the placental transfer and therapeutic efficacy of antibiotics. By the completion of these studies, I will have greatly expanded the scope of knowledge in efflux transporter mechanisms relevant to pregnancy and achieved independence as a research scientist.