Lai PengFollow

Date of Completion

7-3-2014

Embargo Period

7-3-2014

Keywords

Drug metabolism, Liver development, FXR, Regulation of gene expression

Major Advisor

Xiao-bo Zhong

Associate Advisor

José Manautou

Associate Advisor

Xiuling Lu

Field of Study

Pharmaceutical Science

Degree

Doctor of Philosophy

Open Access

Open Access

Abstract

Liver is a critical organ for drug metabolism and is the primary site for the expression of Phase-I drug metabolizing enzymes, which mainly catalyze the oxidation, reduction, and hydrolysis of xenobiotics. However, in the fetus, the major function of liver is hematopoiesis. From infants to adults, dramatic changes occur in liver functions and the Phase-I gene expression, which can markedly affect the metabolism of drugs in newborns and children. Characterization of the expression profiles and regulatory mechanisms of liver development and Phase-I genes is needed for more rational drug therapy of pediatric patients. An animal model is indispensable for studying the mechanisms of postnatal development of Phase-I genes. In this dissertation, we systemically characterized the model of mouse liver during postnatal development and examined the ontogenic expression of all major Phase-I drug metabolizing genes by RNA-sequencing. Gene ontology analysis demonstrated that cell proliferation and immune activation pathways were active in liver at neonatal ages and different metabolic processes were matured at different stages during development, with the age of day 25 as the approximate time of maturation for the liver transcriptome. Significant functional transitions in liver accompanied the ontogeny of Phase-I genes. Four ontogenic expression patterns were identified among the 71 significantly expressed cytochrome P450s, which categorized genes into neonatal-,adolescent-, adolescent/adult-, and adult-enriched groups. Diverse expression patterns were also elucidated in another 11 families of Phase-I genes, which provided a valuable foundation for further mechanistic studies. Long non-coding RNAs (lncRNAs) and farnesoid X receptor (FXR) mediated regulation of gene expression were explored and addressed. The developmental expression patterns of lncRNAs were initially characterized, which strongly suggested the involvement of lncRNAs in the control of liver ontogeny. Comparisons of liver transcriptome between wild-type and age-matched FXR-null mice revealed a critical role of FXR in promoting proper liver maturation and in control of Phase-I gene expressions during development. In conclusion, the present dissertation has built up a valuable platform for the study of liver developmental gene expression and regulation. Our results also provide novel insights into identifying and further understanding the molecular targets for safe and efficacious drug treatments in children.

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