Investigating the molecular mechanism of P-gp/NHERF-1 network at feto maternal interface and role of paracrine signaling of EVs containing drug transporter proteins

摘要

ABSTRACT Pharmacotherapy during pregnancy is inevitable and current interventional strategies are not successful in reducing the risks of pregnancy related disorders. A better understanding of the drug transport mechanisms involved at feto-maternal interface (FMi) is required to improve the pregnancy and neonatal outcomes. The expression levels of the drug transporter proteins decrease as the gestation period progresses. Our data suggested that sodium hydrogen exchange regulatory factor-1 (NHERF-1) interacts with efflux transporter protein, permeability glycoprotein (P-gp), and this interaction is predominantly more in the fetal membrane rather than the placenta. Consistent with this data, efflux drug mechanism is also higher in the chorion cells of fetal membrane than placenta trophoblast cells. On the other hand, extracellular vesicles derived from fetal membrane are involved in the paracrine signaling that induce inflammatory changes in maternal decidua and myometrium. Along with that, EVs carry drug transporter proteins as their cargo proteins and are involved in modifying maternal cells for transporter protein functional activities. This proposal builds on these observations; the central hypothesis is the NHERF-1 in the fetal membrane could be targeted to regulate the drug transportation during pregnancy. We will determine the mechanistic network of P-gp/NHERF-1 across fetal maternal interface using innovative FM-PLA - organ on chip (OOC) devices (Aim-1). In Aim 1, we will use the OOC that mimic an in-utero environment to test the kinetics of P-gp substrate, Tacrolimus across the FMi in normal healthy and disease conditions along with in presence and absence of NHERF-1. The expression of the P-gp and NHERF-1 will be determined across the FMi. EVs derived from the fetal membrane carry drug transporter proteins but their role in the regulation of drug transportation remains unknown. In Aim-2 we will explore the uptake mechanism of the EVs by maternal cells and determine their role in regulating drug transportation using P-gp knock down mice. Given the critical role of NHERF-1 and EVs from the fetal membrane regulates the drug transportation is of significant scientific and clinical importance. The successful completion of the study will provide novel insights into how the fetal membrane TPs and EVs derived at FMi have a role in drug pharmacokinetics during pregnancy beyond the boundaries of the placenta and will help to design drug delivery strategies to treat adverse pregnancy outcomes.