Circular RNA regulators of common drug-eliminating genes

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Children signify a population with highly dynamic physiology and pharmacology at increased vulnerability to drug toxicities. Biotransformation genes, commonly referred to as drug metabolizing enzymes and transporters, have both pharmacological and toxicological significance. We have shown a robust postnatal surge in hepatic expression of all biotransformation genes tested. In striking contrast, these very genes did not show such surge in the duodenum, another major biotransformation organ. Interestingly, CYP3A4 mRNA (cytochrome P450) decreased with age but CYP3A4 protein increased in the duodenum. Circular RNAs (circRNAs) are emerging regulators and implicated to increase protein production by functioning as microRNA sponges. As described in the Preliminary Study, we have shown the presence of circRNAs for CES1 (carboxylesterase-1), CES2, CYP3A4, and PXR (pregnane x receptor, a master regulator of biotransformation genes). Their expression patterns varied between the liver and duodenum as well as age. The central hypothesis of the proposed project is that circRNAs regulate the expression of biotransformation and related genes in an age and organ-dependent manner. The Specific Aims are: (1) to characterize sequences and functionality of circRNAs for biotransformation genes, and (2) to specify molecular actions of the circRNAs for regulatory activities. To specify the functionality of circRNAs, the authenticity of detected circRNAs will be sequence-confirmed, their organ/age-specific expression will be determined; and their regulatory activities toward their parent and related genes will be specified. To ascertain the molecular action for the regulatory activity, a circRNA will be tested for altered transcription rate, decay of mRNA, translational efficiency and protein stability of a target gene. The circRNA-miRNA-mRNA network, known to support the sponging mechanism, will be constructed bioinformatically for different organs. The scientific premise is strong and original. The originality stems from the novelty of circRNAs as critical regulators of biotransformation genes and the dependence of their regulatory activity on age and an organ. circRNAs have been increasingly recognized to exert critical pathophysiological functions, however, their presence and functionality for biotransformation genes remain largely unknown. These studies will have filled knowledge gaps on how circRNAs participate in regulating biotransformation genes, critical determinants in drug efficacy and safety. Clearly, information collected will serve a strong foundation for a bigger project.