In general, our laboratory is interested in how biological systems respond to exogenous chemicals.
Molecular mechanism(s) of toxicity, dioxin-mediated signal transduction, regulation of cellular homeostasis by the Ah receptor, Ah receptor-mediated control of gene expression; biochemistry of heat shock protein complexes
Ah receptor-mediated toxicity
We are interested in the long-term health effects of persistent exposure to industrial pollutants. Dioxin and other halogenated polycyclic aromatic hydrocarbons (HPAHs) are produced during the combustion of organic matter and as a result of bleaching paper. The Ah receptor plays a central role in the biological response to dioxin, which is both carcinogenic and toxic. The Ah receptor is a member of a family of helix-loop-helix/basic region transcriptional factors. Upon binding a HPAH, the Ah receptor translocates to the nucleus and heterodimerizes with Arnt, another helix-loop-helix/basic region protein. This heterodimer is subsequently able to bind to a specific enhancer core sequence in the nucleus, leading to alter transcription of a set of genes. This sequence of events is believed to result in the high level of toxicity observed with many HPAHs and perhaps the tumor-promoting properties of dioxins. We are examining a number of biochemical properties of the Ah receptor, including the level of receptor heterogeneity, composition of the inactive form of the receptor, proteolytic turnover of liganded receptor, and its ability to interact with other transcription factors. We are testing whether structurally diverse Ah receptor ligands can illicit differing gene expression patterns. Ligand-independent function of the Ah receptor in normal cellular processes is also being explored, using a variety of molecular techniques. The critical target genes regulated by the Ah receptor that lead to toxicity are being identified through DNA microarray analysis. Through this series of studies, we hope to gain an understanding of the multiple points of regulation of the Ah receptor and its role in dioxin-mediated toxicity and normal cell biology. Yet another issue that we are addressing is whether the human Ah receptor can mediate toxicity of dioxin in a transgenic mouse model.
Role of the Ah receptor in physiology
The Ah receptor plays an important role in normal cellular physiology; this is best exemplified by the phenotype in mice where the Ah receptor gene has been disrupted. Ah receptor null mice exhibit a number of defects, such as: low productive success, abnormal vasculature in the liver, small liver size and altered immune system. We are interested in how the activity of the Ah receptor is regulated under normal physiologic conditions; this is being explored by screening certain endogenous and dietary chemicals for their ability to activate the Ah receptor. A number of biochemical pathways important in human health are modulated by activation or repression of the Ah receptor.
We are perhaps the lead laboratory examining differences in the human versus rodent Ah receptor, critical in understanding whether mouse studies extrapolate to humans. In particular, we identified abundant tryptophan metabolites produced by the gut microbiome that are capable of preferentially activating the human Ah receptor. We have determined the critical tryptophan metabolites that are absorbed in the gut and are examining the bacteria that produce these metabolites and how the diet can modulate their production. These studies have profound implications in how Ah receptor activity is systemically induced and impact numerous pathways that influence overall health.
Because of the differences in human Ah receptor activity, we are developing a mouse model that expresses the human AHR and blocks expression of the mouse Ah receptor.
A second major area of investigation studies whether the Ah receptor is an important drug target to treat cancer. In particular, we are examining the ability of Ah receptor antagonists to alter metabolism and metastatic potential in head and neck cancer.