Grant: Project Grant

The tissue environment of inflammatory diseases like arthritis & cancer is known to produce increased amounts of digestive enzymes. Our published work to date has uncovered a cell signaling mechanism (proteinase-activated receptors, or PARs) that is driven by these tissue digestive enzymes like the blood clotting factor, thrombin, central to the body's rapid inflammatory response to injury. Our rationale is that this 'ignition' point driven by digestive enzymes underlies & is in common with a surprisingly broad number of disease states, including atopic dermatitis, ulcerative colitis, arthritis, asthma, multiple sclerosis-neurodegenerative disease and cancer. Thus, understanding this mechanism whereby digestive enzymes drive the 'injury response' may be a common single key that may unlock the treatment of multiple diseases by targeting a single process. Our aims are therefore 1. to identify tissue digestive enzymes that are elevated in tissue inflammation and cancer settings that can kindle this 'inflammation fire'. and 2. Identify the 'receptor switches' including the PARs that fuel the fire. To this end, we will identify digestive enzyme triggers found in tumor-derived cell cultures & in tissue fluids from patients with dermatitis, arthritis, colitis and bladder cancer. Further we will use specialized cell culture systems to assess how the PAR switches work to fuel the cancer-producing 'fire'. Finally, we will use intact mouse inflammation model assays (arthritis, colitis, pain sensation) to develop ways of blocking the inflammatory enzyme signaling actions; & we will analyse patient-derived tissues to see if their PARs are activated. By identifying the enzymes produced by tumor cells & inflamed human tissues and by determining the ways that enzyme-induced inflammation in our animal models can be blocked, our data will identify new potential therapeutic targets for treating multiple inflammatory diseases (e.g. atopic dermatitis, arthritis, colitis) & cancer.