Micro-RNA regulation of hepatic drug metabolism : age-related changes in micro-RNA expression and genetic variants in micro-RNA target sites

dc.contributor.advisorSkaar, Todd C.
dc.contributor.authorBurgess, Kimberly Sherrelle
dc.contributor.otherArrizabalaga, Gustavo
dc.contributor.otherCummins, Theodore
dc.contributor.otherDesta, Zeruesenay
dc.contributor.otherNass, Richard
dc.contributor.otherZhang, Jian-Tian
dc.date.accessioned2018-01-10T16:52:47Z
dc.date.available2018-12-28T10:30:13Z
dc.date.issued2017-08-31
dc.degree.date2017en_US
dc.degree.disciplineDepartment of Pharmacology & Toxicology
dc.degree.grantorIndiana Universityen_US
dc.degree.levelPh.D.en_US
dc.descriptionIndiana University-Purdue University Indianapolis (IUPUI)en_US
dc.description.abstractDevelopmental changes in the liver significantly impact drug disposition. Due to the emergence of microRNAs as important regulators of drug disposition, we hypothesize that age-dependent change in microRNA expression and genetic variants in microRNA target sites contribute to variability in drug disposition. In human liver tissues, expression of 533 microRNAs and over 14,000 genes were measured. In all, 114 microRNAs were upregulated and 72 downregulated from fetal to pediatric, and 2 and 3, respectively, from pediatric to adult. Among these microRNAs, 99 microRNA-mRNA interactions were predicted or have previously been validated to target drug disposition genes and over 1,000 significant negative correlations were observed between miRNA-mRNA pairs. We validated these interactions using various cell culture models. Genetic variants in the promoter and coding regions of drug disposition genes have also been shown to alter enzyme expression and/or activity. However, these variants do not account for all variability in enzyme activity. Emerging evidence has shown that variants in the 3’UTR may explain variable drug response by altering microRNA regulation. Five 3’UTR variants were associated with significantly altered CYP2B6 activity in healthy human volunteers. The rs70950385 (AG>CA) variant was associated with decreased CYP2B6 activity among normal metabolizers. In vitro luciferase assays confirmed that the CA allele altered miR 1275 targeting of CYP2B6 mRNA. Due to the large number of 3’UTR variants predicted to alter microRNA regulation, a high-throughput method, PASSPORT-seq, was developed to test over 100 3’UTR variants simultaneously in different cell lines. Thirty-eight variants resulted in FDR-significant altered expression between wild-type and variant sequences. Our data suggest a mechanism for the marked changes in hepatic gene expression between the fetal and pediatric developmental periods, support a role for these age dependent microRNAs in regulating drug disposition, and provide strong evidence that 3’UTR variants are also an important source of variability in drug disposition.en_US
dc.embargo1 yearen_US
dc.identifier.doi10.7912/C2X35R
dc.identifier.urihttps://hdl.handle.net/1805/14971
dc.identifier.urihttp://dx.doi.org/10.7912/C2/329
dc.language.isoen_USen_US
dc.subjectDevelopmentalen_US
dc.subjectDrug metabolismen_US
dc.subjectHepaticen_US
dc.subjectmicroRNAen_US
dc.subjectPharmacogeneticsen_US
dc.subjectSNPsen_US
dc.titleMicro-RNA regulation of hepatic drug metabolism : age-related changes in micro-RNA expression and genetic variants in micro-RNA target sitesen_US
dc.typeDissertation
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