Project 176617

The barrier function performed by the epithelial cells that line the gut is important for the maintenance of an individual's health. This barrier is regulated to prevent the entry of the vast array of bacteria that live in the human colon from entering the tissue; a breach of the barrier by the bacteria would evoke local inflammation, and if they move into the bloodstream the result can be sepsis and multi-organ failure. Interferon gamma (IFNg) is an important immune cell-derived factor that helps activate the immune response to combat bacterial and viral infections. However, IFNg has also been shown to disrupt epithelial barrier function, and in this context it could induce harmful responses and contribute to the initiation of inflammatory disease, such as inflammatory bowel disease (IBD). This research proposal aims to determine whether IFNg evokes increases in epithelial permeability by activating a specific signal in the epithelial cell, namely phosphoinositide 3-kinase (PI3K). By understanding the molecular signaling basis of the impact of IFNg on epithelial barrier function (i.e. PI3K and associated factors) I aim to identify specific means to prevent the epithelial barrier disruption elicited by IFNg. Therefore, this research will provide novel insights into the mechanism(s) of IFNg control of epithelial barrier function. Ultimately the data obtained can be translated into new treatments for gut diseases characterized by increased epithelial permeability in which IFNg has been identified as a participant. In a broader context, this information may be of value in treating other idiopathic gut disease, where barrier function is once again perturbed.