Grant: Operating Grant

According to the Canadian Hemochromatosis Society (www.cdnhemochromatosis.ca), hereditary hemochromatosis (HH) is the most common genetic disorder affecting Canadians. Up to 1 Canadian in 9 is a carrier of the gene responsible for this disease and 1 in 300 Canadians of European descent is affected. HH causes an increase in the absorption of dietary iron leading to iron overload, which may degenerate towards organ damage and failure. Although patients can be treated by phlebotomy (bloodletting) the intervention is inconvenient, invasive, painful and may not be tolerated by some. Recent results of mutations in the TMPRSS6 gene in patients with another blood disorder, iron-refractory iron deficiency anemia, have shown that TMPRSS6, a proteolytic enzyme, is directly involved in regulating iron levels in the blood. This information plus the fact that TMPRSS6 is uniquely expressed in the liver fully justify an approach to control the activity of the enzyme in iron overload disorders. Our group has had a long-standing interest in the role of proteolytic enzymes in health and disease. This application is focused on understanding how we can control TMPRSS6 enzymatic activity and whether this control brings beneficial effects in iron overload diseases such as HH and others such as beta-thalassemia, a disorder with very limited treatment options characterized by iron overload. We will investigate how TMPRSS6 functions and we will elucidate its three-dimensional structure. This information will help us in using bioinformatics and medicinal chemistry to screen for and design compounds that will inhibit TMPRSS6 enzymatic activity. Finally, we will validate the use of these compounds in established animal models of HH and beta-thalassemia. Using these strategies we believe our multidisciplinary group can validate TMPRSS6 as a therapeutic target in iron overload disorders.