# 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

> **NIH NIH R01** · UNIVERSITY OF TEXAS MED BR GALVESTON · 2024 · $277,200

## Abstract

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.

## Key facts

- **NIH application ID:** 10897024
- **Project number:** 5R01HD113193-02
- **Recipient organization:** UNIVERSITY OF TEXAS MED BR GALVESTON
- **Principal Investigator:** Ananth kumar Kammala
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $277,200
- **Award type:** 5
- **Project period:** 2023-08-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10897024

## Citation

> US National Institutes of Health, RePORTER application 10897024, 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 (5R01HD113193-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10897024. Licensed CC0.

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