MiMA: Mother-infant Metabolite-transporter Atlas

ABSTRACT/SUMMARY The maternal-fetal/infant axis of transport represents one of, if not the highest duration and intimacy of long-distance communication across multi-tissue barriers between two individuals. Transporters enable such communication by controlling the uptake and distribution of metabolites across membranes, tissues, organs, and even between the mother and the infant. Remarkably, only a few hundred human transporters control the exchange of tens of thousands of nutrients and metabolites between different tissue compartments. A comprehensive map of transporters to tissue barriers, and to the substrates (nutrients, metabolites, dietary supplement constituents, xenobiotics, and drugs) whose passage they facilitate along the maternal-fetal/infant axis, are yet to emerge because we simply do not know the identity of most transported metabolites, or how to prioritize candidate hits. We propose to create a Mother-infant Metabolite-transporter Atlas (MiMA) devoted to the deorphanization of transporters, while prioritizing our studies by considering their expression, abundance, localization and importance at tissue barriers of mother and developing infant, including the fetal blood-brain barrier (BBB) and infant gut in the context of the lactating mother and child. MiMA will leverage existing advanced infrastructures and apply process innovations/expertise to produce an atlas that can be used as a basis for system integration of metabolomics, proteomics, and transporter biology. MiMA seeks to answer the following questions: (1) How does a network of only a few hundred transporters control and optimize levels of perhaps thousands of small molecules along the mother-infant mammary gland-gut-brain axis? (2) Which endogenous small molecules and xenobiotics/drugs does each of these transporters recognize and permeate? (3) Are there rules that ensure a homeostatic system (patterns of metabolite:transporter specificity, tissue distribution, function), and can these rules inform precision nutrition and precision medicine? This project is expected to generate a comprehensive atlas populated with precise knowledge of what metabolites bind to which transporters to be able to move across organ/tissue compartments. MiMA will also create a novel workflow to empirically validate specificity among interacting metabolite-transporter pairs, combining metabolomics and molecular structural biology. The project will validate specificity among interacting metabolite-transporter pairs and create advanced nanobody reagents to interrogate localization as perturb function of transporters. MiMA will produce omics-validated model systems to have better contextual understanding of transporters in normal and diseased human physiology. Taken together, MiMA is expected to deliver an integrated map or mother-infant metabolite-transporter atlas to formulate the “rules” that govern tissue/body homeostasis and serve as resource for many exciting research questions to be asked and solved.