Elucidating basis for detrimental vs.beneficial functions of the aryl hydrocarbon receptor in intestinal stem cell differentiation

The aryl hydrocarbon receptor (AHR) is a ligand dependent transcription factor originally discovered for mediating the toxicity of xenobiotics such as dioxins, PCBs and PAHs.

In recent years, the discovery of natural ligands has pinpointed important physiological functions of AHR, particularly in barrier organs such as the skin, lung and gut.

Yet, the juxtaposition of detrimental effects of AHR in response to xenobiotics and its beneficial functions still poses a dilemma in the field, hampering its progress.A key to understanding the role of AHR in physiological vs. toxicity processes is to decipher the mechanisms of AHR regulation in health and disease.

We discovered that negative feedback regulation via the AHR-induced Cyp1 enzymes is critical for AHR function.

Here we will test the hypothesis that activation by xenobiotics may lead to abnormal AHR signalling due to these ligands being poorly metabolised by Cyp1, which in turn interferes with physiological functions elicited by the rapidly metabolised natural ligands.To test this, we will use well-defined molecular AHR functions in the gut required for regulated differentiation of intestinal stem cells.

We will combine kinetic studies using CYP1 enzymes with effect studies using colon organoids, tissues and serum derived from mutant mouse lines modified in AHR or CYP1 expression.

Linking biological effect data with ligand kinetic parameters, should finally allow the distinction of detrimental and beneficial AHR functions.