Program seeks Council approval for an initiative titled “Elucidation and validation of the role of transmembrane transporter proteins in nutrient and drug disposition.”
It is estimated that 10% of the human genome encodes small molecule and micromineral transmembrane transport proteins (e.g., solute carrier (SLC) and ATP-binding cassette (ABC) families). Despite the key role that these transporters play in the uptake and disposition of ingested nutrients and minerals, dietary metabolites, exogenous chemicals, and pharmaceutical drugs across cell and organelle membranes, most of these genes are poorly characterized regarding solute specificity, organ- and life stage-specific distribution and expression, and functional consequence of allelic and splice variants. Research in this area is a critical need to enabling precision medicine and precision nutrition.
The goal of the initiative is to address significant knowledge gaps around transporter biology as it relates to disposition of drugs and nutrients. The initiative is timely due to new enabling technologies for transporter characterization, including but not limited to advances in high throughput functional screening capabilities, mass spectrometry techniques for drug and nutrient fluxomics across membranes, single-cell omics technologies, and use of high resolution cryo-electron microscopy to resolve transporter structures. Human tissues and engineered biomimetic organoid/chip systems provide new opportunities for resolving function and membrane localization of transporters in native biological contexts. Tissues of interest relevant to drug and nutrient disposition in the body include the placenta, lactating mammary gland, liver, gastrointestinal tract, and kidney, among others. Also in scope are mechanistic studies addressing key developmental windows to elucidate the relationship between life stage-dependent expression and function of transporters and associated differences in xenobiotic and nutrient absorption and bioavailability (e.g., in infants versus adolescents).
The proposed initiative aligns with NICHD Vision areas of [Theme 1] Understanding the molecular, cellular, and structural basis of development, [Theme 3] Setting the foundation for healthy pregnancies and lifelong wellness, and [Theme 5] Advancing safe and effective therapeutics and devices for pregnancy and lactating women, children, and people with disabilities.
The proposed initiative aligns with OPPTB research priorities to “understand differences and heterogeneity in pediatric disease treatment” and “pharmacology and pathophysiology of pregnancy”, PPB’s goals to “increase infant survival and ensure the long-term health of mothers and their children” and with PGNB’s goals to “support translational and systems-based research in the application of behavioral, medical, and nutritional science to develop interventions aimed at promoting health and mitigating disease during critical periods in human development.”
The proposed initiative is being developed as a trans-NIH effort in partnership with the NIH Office of Nutrition Research.
Program Contact
Alison Harrill
Obstetric and Pediatric Pharmacology and Therapeutics Branch (OPPTB)
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