Grant: Operating Grant

. In inflammation the tissue proteins are dissolved by enzymes termed "proteases" causing loose teeth in gum disease and swollen, sore joints in arthritis. To do this most tissues and white blood cells that fight infection make important enzyme proteases called MMPs. These destroy tissue by dissolving collagens found in joints and gums, which normally are rope-like structures that add strength to these tissues. We have found that MMPs do much more than just dissolve tissue. By cutting a cells signal molecules, MMPs also orchestrate healing and the way white blood cells protect the body from infection. Signal molecules are like traffic signals. Cells go differently when the signals are in the "on" or "off" position. So proteases are like light switches as they turn signals on and off. However, if important ones are left on, then disease can result. We first developed new techniques (proteomics) to identify 1000s of proteins in inflamed tissues and so obtain an overall picture of the disease. Our methods specifically detect the dissolved protein stubs left after proteases work and by knowing these we can decipher which signal molecules that proteases are leaving on or off. Surprisingly, we found that certain proteins that are normally inside the cell can on occasion occur outside the cell and some of these play important signaling roles in inflammation. We call these proteins "moonlighting proteins" as they have different activities depending on when and where they go to different places. Understanding these moonlighting proteins is important in order to fully understand the ways inflammation destroys tissues and gives disease. Luckily, the dissolved protein stubs leave important tell tale signs of the disease called biomarkers. We hope that these biomarkers will improve disease diagnosis. We trust our research will also discover new drug targets to fight inflammation in disease.