Program seeks Council approval for renewal of an initiative titled “Elucidation and Validation of the Role of Transporters in the Placenta, Lactating Mammary Gland, Developing Gut, and Blood-Brain Barrier.” The scientific area is membrane transporter biology at perinatal epithelial and barrier interfaces, with emphasis on human-derived models, transporter-mediated exposure prediction, pregnancy, lactation, infant nutrition, pediatric pharmacology, and neurodevelopment.
Stimulation of this field remains needed because many solute carrier (SLC) and ATP-binding cassette (ABC) transporters remain poorly characterized in human perinatal tissues with respect to substrate specificity, tissue localization and polarity, developmental regulation, genetic variation, and functional consequences for fetal and infant exposure. These gaps are especially important during pregnancy, lactation, and early life, when transporter-mediated movement of nutrients, metabolites, medications, dietary supplements, microbiome-derived products, and environmental chemicals may influence development during sensitive windows. Advances in proteomics, metabolomics, structural biology, organoids, microphysiological systems, computational modeling, and machine learning now make it feasible to address these gaps in human-based systems.
The first cycle of this initiative established organ-focused foundations across the placenta, lactating mammary gland/milk, developing gut, and blood-brain barrier, and the field is now poised to advance toward a coordinated multi-barrier framework. Continued stimulation is needed to convert human-based models, methods, datasets, and mechanistic insights into harmonized measures, interoperable resources, and prototype approaches for evaluating how transport at maternal, fetal, and infant interfaces shapes downstream fetal and infant exposure.
The goal of the renewal initiative is to establish standards, datasets, model systems, and prototype linked multi-compartment modeling approaches for the perinatal multi-barrier transport network. The renewal initiative is intended to build frameworks for understanding how transport across connected maternal, placental, lactational, infant gastrointestinal, and neurovascular interfaces shapes perinatal exposure and provides a foundation for a more mature, transporter-resolved understanding of perinatal transport.
This proposed concept aligns with NICHD Strategic Plan areas focused on understanding the molecular, cellular, and structural basis of development; setting the foundation for healthy pregnancies and lifelong wellness; and advancing safe and effective therapeutics for pregnant and lactating individuals, children, and people with disabilities.
This proposed concept aligns with OPPTB priorities in pediatric therapeutics and pharmacology in pregnancy and lactation; PPB priorities in pregnancy, lactation, infant health, and long-term maternal-child health; and PGNB priorities in systems-based, translational, nutritional, environmental, and developmental research during critical periods of human development.
HIV/AIDS priorities are not applicable to this initiative, and the concept is not intended to address NIH HIV/AIDS research priorities or use AIDS-designated funds.
Prior Results and New Elements
In the first cycle, NICHD, ODS, and NIDA launched a coordinated network of four cooperative agreement centers focused on transporter function at perinatal epithelial and barrier interfaces. To date, the network has generated 20 publications, with early productivity concentrated in enabling resources, human-relevant model systems, transporter-informed exposure prediction, and barrier-specific datasets. The placenta-focused work has been especially productive, including maternal-fetal PBPK modeling for metformin and therapeutic antibodies, placental toxicology frameworks that incorporate microphysiological systems and toxicokinetic approaches, studies linking environmental exposures and placental transporter genotype to birth outcomes, and computational tools for transporter and toxicity prediction. These outputs begin to connect placental transporter biology to fetal exposure, perinatal susceptibility, and model-informed pharmacology.
The first cycle also established important foundations in the developing gut, blood-brain barrier, and lactating mammary gland/milk. Developing-gut outputs include human intestinal enteroid and enteroid monolayer systems for evaluating oral drug disposition, toxicity, efficacy, and inflammatory regulation of transporter expression and function. Blood-brain barrier outputs include a major human brain microvessel proteomic dataset across life stages, identification of age-associated changes in nutrient and drug-disposition transporters, and related work connecting these data to PBPK modeling for CNS drug distribution. Lactation-focused outputs have established human milk cells and milk-derived mammary organoids as practical, noninvasive platforms for studying mammary biology, nutrient transport, xenobiotic burden, and maternal-infant health. Across the network, the first cycle has also produced computational and predictive resources, including curated transporter-interaction datasets, machine-learning and QSAR approaches, non-animal toxicity models, and frameworks relevant to transporter de-orphanization and chemical exposure prediction.
These prior results are important because they move the field from broad recognition of transporter knowledge gaps toward reusable models, assays, datasets, and mechanistic anchors. They also show that the first version of the initiative successfully established organ-focused foundations across the placenta, developing gut, blood-brain barrier, and lactating mammary gland/milk. However, the published record remains strongest in platform development, barrier-specific methods, and early mechanistic or predictive outputs. The next scientific need is to determine how these components can be measured, compared, and connected across the maternal-fetal-infant continuum. The renewal initiative will address this need by emphasizing harmonization, interoperability, cross-model validation, and prototype multi-compartment implementation.
New elements in the renewal initiative will include codifying transport phenotypes across barriers; developing shared standards for transporter abundance, localization, polarity, kinetics, functional activity, and local biotransformation; integrating host and microbiome-derived transformation into transporter-focused exposure frameworks; evaluating transporter coding variants in physiologically relevant human systems; and incorporating developmental, nutritional, inflammatory, microbiome, genetic, and drug-exposure state variables. The renewal initiative will also expand the conceptual focus from isolated organ systems to linked barrier cascades spanning maternal gut, placenta, lactating mammary epithelium/milk, infant gut, and infant blood-brain barrier/brain proxy. By establishing perinatal multi-barrier transport network frameworks rather than assuming immediate delivery of a mature integrated network, the renewal initiative will create community infrastructure for future transporter-resolved studies of perinatal exposure, risk, intervention, and neurodevelopmentally relevant outcomes.
Program Contact
Aaron Pawlyk
Obstetric and Pediatric Pharmacology and Therapeutics Branch (OPPTB)
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