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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

Award Number: R01HD113193
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $277,200 )
2024	2024	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Child Health and Human Development Extramural Research	000	2	6/4/2024	NON-COMPETING CONTINUATION	$277,200
														Subtotal = $277,200

Issue Date FY: 2023 ( Subtotal = $356,400 )
2023	2023	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Child Health and Human Development Extramural Research	000	1	8/1/2023	NEW	$356,400
														Subtotal = $356,400

Grand Total All Awards = $633,600

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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

Award Number: R01HD113193

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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