Interests: Developmental exposure to environmental chemicals. Epigenetic memory and nuclear receptor-signaling to modulate drug metabolism and transport during and beyond childhood. Gut microbiome, drug metabolism and obesity. Developmental reprogramming of gut microbiome by probiotics and antibiotics and modulating pediatric pharmacology and childhood obesity.
Projects
Developmental regulation of drug-processing genes. Despite recent rapid progress in understanding the expression patterns and regulatory mechanisms of drug-processing genes, namely drug-metabolizing enzymes and transporters in adults, little is known about these in the pediatric period. The long-term goal is to understand mechanisms of ontogenic regulation of drug-processing genes so that efficacious and safe drug treatments can be achieved in children. This study is novel because it uses a genome-wide approach to elucidate how alterations of hormones and transcription factors modulate epigenetic signatures and hepatic ontogenic expression of drug-processing genes. Results will provide basic knowledge on the ontogenic expression patterns of drug-processing genes and nuclear receptors in liver, kidney and intestine and help to understand how perinatal alterations in hormones and nuclear receptors, via modulating epigenetic signatures, affect stage-specific and long-term expression of drug-processing genes.
Developmental regulation of drug metabolism by targeting the gut microbiome. Very little is known about the developmental regulation of drug-metabolizing enzymes and transporters (together called "drug-processing genes" [DPGs]) in the liver, placing newborns and children at a much higher risk of adverse drug reactions. Using RNA-Seq, we have shown that drug metabolism is the top most differentially regulated pathway in the entire liver transcriptome of germ-free mice, suggesting that there is a novel interaction between gut microbiome and hepatic DPGs. The goal of this research is to utilize multidisciplinary approaches, including germ-free and genetically engineered mice, BA metabolomics, Next-Generation Sequencing and human fecal samples, to unveil the role of gut microbiota in modulating signaling from the two most critical xenobiotic-sensing nuclear receptors in the liver, namely the pregnane X receptor and constitutive androstane receptor, and the subsequent ontogenic re-programming of DPGs in the liver. The research will lead to a paradigm shift in pediatric pharmacology by establishing a new concept in considering adverse drug reactions in children.
Epigenetic regulation of drug metabolism by developmental exposure to PBDEs. Developmental exposure to the flame-retardant polybrominated diphenyl ethers (PBDEs) has attracted growing concerns because these highly persistent environmental toxicants are accumulated much more in infants through breast milk and produce multiple detrimental effects. Little is known about the potential involvement of PBDEs in modulating the pharmacokinetics of drugs in newborns and children. The objective of this research is to utilize multidisciplinary approaches to strategically investigate the epigenetic mechanisms of PBDEs in modulating the transcriptional activities of the major xenobiotic-sensing nuclear receptors pregnane X receptor (PXR) and constitutive and rostane receptor (CAR) and drug-processing capacities during and beyond the neonatal period on a genome-wide scale.
