Grant: Operating Grant

Many chronic, debilitating diseases of the digestive tract (eg inflammatory bowel disease, celiac disease and enteric infections) are characterized by increased intestinal permeability or leakiness. Increased permeability allows bacteria and antigens in the lumen of the intestine to invade the intestinal wall to trigger disease. Permeability is controlled by the epithelium, a single layer of cells that makes up the inner lining of the intestine. One of the most important components of the epithelial barrier is the tight junction, a cluster of specialized proteins that join epithelial cells together and which limits the passage of material between them. We are looking at ways to improve the barrier function of the epithelial tight junctions as a way of preventing intestinal diseases. We are particularly interested in the new concept that proteases can regulate tight junctions. Proteases are enzymes that break down proteins and which have diverse functions throughout the body. We have observed that certain proteases in the gut can enhance the epithelial barrier by strengthening tight junctions. The mechanism for this is unclear, but our preliminary studies show that the effect is through a family of cellular receptors called the epidermal growth factor receptor (EGFR) family. We propose to use epithelial cells grown in cell culture to discover how proteases activate EGFR to bolster the structure of the tight junction and thereby enhance the epithelial barrier. In addition, we know that the intestine produces protease inhibitors (called serpins) that block the function of many proteases. We will use a mouse model of inflammatory bowel disease to determine if an imbalance between proteases and serpins contributes to increased intestinal permeability in disease. It is our hope that these studies will uncover new ways to help patients living with chronic intestinal diseases that are characterized by epithelial barrier dysfunction.