Grant: Operating Grant: Fall 2008 Priority Announcement (IMHA)

Enamel is the hardest mineralized tissue in the human body. It covers the crowns of teeth and protects the teeth from decay and functional wear during chewing and grinding the teeth together. It is the only calcified tissue in the body that is produced by epithelial-derived cells called ameloblasts. During enamel formation, ameloblasts produce and process extracellular matrix that then becomes calcified to form fully mineralized enamel. A number of proteins that are crucially important for enamel formation have been discovered. Human mutations in some of these proteins cause inherited conditions in which enamel is poorly developed or calcified (called Amelogenesis Imperfecta; AI). This can lead to extensive wear and decay in both the primary and permanent dentition. Often, patients with AI lose their teeth at a young age or need to go through extensive restorative work to protect teeth from decay and attrition. We have recently discovered that mice lacking ameloblast surface protein alpha-v-beta-6 integrin show weakly calcified rough enamel that poorly resists wear during chewing. This integrin regulates cell adhesion to proteins that have an arginine-glycine-aspartic acid (RGD) amino acid motif but its function in ameloblasts is not known. In this grant proposal, we will characterize in detail the enamel defect caused by alpha-v-beta-6 integrin deficiency and investigate the molecular mechanism by which alpha-v-beta-6 integrin regulates calcification of enamel. Understanding the molecular mechanism of enamel calcification would help us not only to better diagnose genetic and acquired conditions that affect enamel formation and prevent destruction of crowns of teeth but also facilitate future endeavours aimed at tooth regeneration.