Project 456415

A large percentage of the general population is affected by periodontal diseases. Associated with this inflammation is loss of tooth-supporting bone and, if severe, loss of teeth and ultimately function. In addition, periodontal diseases have been associated with heart disease, diabetes, and preterm low-birthweight babies. Development of novel disease intervention strategies is needed to help patients manage these chronic, common, and costly diseases. Previously we identified an enzyme (monoamine oxidase) that was increased with disease and, if inhibited with a commercial drug, reduced disease. However, use of these drugs is limited in part due to the side-effects associated with their permeability into the brain. To address this issue, we developed novel MAO inhibitors that no longer cross into the brain but have anti-inflammatory properties. We have recently determined that our drug reduced two key aspects of periodontal disease. These include the expression of inflammatory mediators that drive disease and also the formation of bone-resorbing cells. Bone loss due to these bone-resorbing cells is a key negative outcome of disease and explains why tooth loss occurs. Understanding the mechanisms by which the drugs work is absolutely critical if they are to be developed for commercial use. Using a wide variety of cell culture, protein and gene analysis techniques, we will examine the mechanisms by which these novel drugs regulate the expression of inflammatory mediators (Objective 1) and the formation and function of bone-resorbing cells (Objective 2). Using an animal model, we will then examine these signalling pathways in the context of periodontal disease and test the therapeutic efficacy of our drugs at reducing disease (Objective 3).