Thomas Chang PhD

Nuclear receptors are evolutionarily-related DNA-binding transcription factors that regulate the expression of a broad array of genes involved in various biological processes. There are 48 known members in the superfamily of nuclear receptors in the human genome. Of particular interest to Dr. Chang’s laboratory are nuclear receptors that govern the actions of genes (e.g. transporters such as P-glycoprotein and drug-metabolizing enzymes such as cytochromes P450), and regulate the transport, bioactivation and detoxification of xenobiotics (e.g., drugs, environmental chemicals) and endogenous substances (e.g., steroid hormones, vitamins, bile acids). These nuclear receptors include constitutive androstane receptor (CAR) and pregnane X receptor (PXR). The overall goal of Dr. Chang’s research program is to enhance our understanding of the molecular and cellular determinants that regulate the transport, bioactivation and detoxification of drugs, and how they affect inter-individual differences in drug action. Dr. Chang’s research program is supported by the Canadian Institutes of Health Research and the Michael Smith Foundation for Health Research.

Chemical Biology and Pharmacology of Nuclear Receptors

Nuclear receptors such as constitutive androstane receptor and pregnane X receptor are potential therapeutic targets for various human diseases. Thus, it is important to identify chemical modulators of these receptors. Studies are underway that focus on natural products and synthetic drugs. This will pave the way for future drug development efforts to find selective, potent and effective modulators. Other studies include elucidating the cellular and molecular mechanisms by which drugs and other chemicals activate constitutive androstane receptor and pregnane X receptor, and identifying the various factors that regulate the expression and function of these nuclear receptors.

Functional Analysis of Splice Variants of Nuclear Receptors

Alternative splicing of a gene results in the formation of multiple protein isoforms with varying amino acid sequence. The splice variants may have different regulation, function and tissue distribution when compared with the wild-type isoform. There are many splice variants of the human constitutive androstane receptor, several of which are expressed predominantly in the liver. Various studies are ongoing to investigate the functionality of naturally occurring splice variants of the human constitutive androstane receptor (e.g., hCAR-SV23, hCAR-SV24).