PARENT GRANT ABSTRACT Given their physiochemical properties, medications and dietary supplements often require active transport using solute carriers (SLC) and ATP-binding cassette (ABC) transporters to cross trophoblast barriers. These same transporters are also involved in the delivery of nutrients to the fetus and one unintentional consequence of drug therapy during pregnancy can be disruption of these shared systems. Therefore, understanding the interplay between SLC and ABC transporters in the placental disposition of drugs and nutrients is one key step to optimizing therapeutic interventions that improve perinatal healthcare. Our research team has championed the advancement of novel approaches to study SLC and ABC transporters in the placenta. To expand these efforts, we have created the Integrated Transporter Elucidation Center (InTEC) which leverages translational research expertise across 4 academic institutions. Our central hypothesis is that novel regulation and functions of placental transporters can be elucidated using integrated experimental, epidemiological, and modeling approaches. Together, data and models generated can predict the placental disposition of therapeutics and nutrients and their subsequent effects on fetal development. To accomplish this goal, we will 1) identify critical factors that regulate placental transporters using state-of-the-art quantitative targeted absolute proteomics and genetics in a US-based birth cohort; 2) develop a novel computational modeling framework that predicts maternal-fetal chemical disposition according to placental transporter functions and regulation; and 3) evaluate SLC and ABC transport in novel placenta-on-a-chip microphysiological systems. We will test nutrients, supplements, drugs, and toxicants as substrates and inhibitors of placental transporters. InTEC will enable rapid acceleration of placenta transporter research and establish best practices for transporter biology. Resources and datasets will be disseminated via our CIIPro webportal created in 2017. Unique training opportunities will be provided to early career scientists (undergraduate students, MS/MPH/PhD students, and postdoc fellows) and clinicians (obstetrics residents and fellows) at the intersections of pharmacology, computational biology, public health, maternal-fetal medicine, and biomedical engineering. Through innovative research and training, InTEC will lead to novel breakthroughs in the field of placental transport and ensure a well-trained workforce to improve maternal and perinatal health.

PROJECT NARRATIVE This is a request to support Michael Campbell through a “Supplement to Promote Diversity in Health-Related Research” (PA-23-189), under Lauren Aleksunes’ (PI) award UC2HD113039. Michael Campbell is a predoctoral fellow in the Joint Graduate Program in Toxicology at Rutgers University. The studies outlined in this proposal will extend the parent grant to elucidate the specific OATP placental isoforms responsible for uptake of the harmful algal bloom toxin, microcystin, as well as evaluate 3D placental spheroids as a translational model for placental xenobiotic uptake.