AHR-TIPARP axis in autoimmune disease

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that is known for mediating the toxic responses of environmental pollutants, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin; TCDD). However, AHR is increasingly recognized as an essential gatekeeper integrating signals from the diet and endogenous metabolism to modulate intestinal homeostasis and can convey both pro- and anti-inflammatory effects in different diseases. It has been shown in models of inflammatory bowel disease and multiple sclerosis that AHR inhibition or loss of its expression worsens disease progression. How the mechanism by which AHR regulates these processes is not fully defined. Recently, we found that the loss of TCDD-inducible poly-ADP-ribose polymerase (TIPARP), an AHR target gene, a mono-ADP-ribosyltransferase and a repressor of transcription, increasing AHR signaling and thus may influence its inflammatory action. We propose that elucidating the mechanisms of AHR activity will provide a foundation for the precise therapeutic targeting of the AHR signaling pathway in a range of autoimmune and inflammatory diseases. In this study we will use genetically modified TIPARP knockout mice, TIPARP H532A mice that express a catalytically defective TIPARP and genetically modified AHR mice to study the role of TIPARP on the ability of AHR to protect against chronic inflammatory diseases. We anticipate using n=8 per treatment group and that the mice will experience mild to moderate distress during the induction of inflammation. Supportive care will be used to minimize distress and discomfort. We will carefully monitor our breeding to maximize the use of experimental animals. In addition, we will generate primary and immortalized cell lines from the mouse models and to reduce future animal use as well as strictly adhere to our established protocols to minimize stress pain and discomfort. Our studies will characterize how AHR through dietary or therapeutic intervention can be used to treat chronic inflammatory diseases, including inflammatory bowel disease.