Chemical impact on tissue repair and regeneration – interrogating beneficial vs. toxicological functions of aryl hydrocarbon receptor signalling on tissue homeostasis

The purpose of this project is to investigate the impact of xenobiotic chemicals on the ability to repair tissue damage, focusing on the aryl hydrocarbon receptor (AHR) as a biological switch between beneficial and detrimental effects on key events of tissue repair.

The AHR is a transcription factor originally discovered for mediating the toxicity of xenobiotics such as dioxins and PCBs.

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.Successful tissue repair depends on synchronized and tightly controlled action of the immune system and proliferation/differentiation of tissue-specific stem cells at the site of injury, processes in which physiological AHR signalling has proven to be critical.

For example, we recently demonstrated that dysregulation of the AHR pathway in the context of enteric infection delayed the repair of the epithelial barrier, leading to chronic infection and increased risk of tumorigenesis.Our goal is to determine if and how xenobiotic chemicals may interfere with tissue repair processes by subverting AHR from its physiological functions, and to determine the consequences of such interference.

This will be achieved using zebrafish models for tissue repair and regeneration, and by combining unbiased effect screening with targeted analysis of established markers of stem cell differentiation, tissue integrity and inflammatory signalling.