Two major mineralized tissues of a tooth, hard and brittle enamel and a softer and more elastic dentin are joined together via a unique interface called dentino-enamel junction (DEJ). Despite huge differences in their structure, composition and mechanical properties these two tissues normally perform together for tens of years without a major failure, which is especially amazing, considering the fact that they do not remodel. Improtantly, in the patients with diseases caused by mutations in major tooth proteins, the interface between these two tissues is compromised, which is often manifested by delamination of dentin and enamel layers. These data suggest that these matrix proteins are essential elements contributing to the mechanical resilience of the DEJ. Specifically we believe that these proteins regulate mineral formation and structural organization at the interface as well as contribute to the toughening to DEJ in mature teeth. To test this hypothesis we propose to conduct a comprehensive study using in vivo and in vitro approaches. We propose in Aim1: To study formation, structure and composition of the DEJ in genetic mice models lacking major tooth proteins in order to reveal how they control formation and organization of this interface; in Aim 2: To study the mechanisms of control of mineral formation by complexes of dentin and enamel proteins in an in vitro model system; and in Aim 3: To conduct studies of the roles of the major proteins of dentin and enamel, in toughening of the DEJ by studies of the crack propagation in the KO animals lacking major tooth proteins. We anticipate that such understanding will greatly benefit the clinical dentistry by providing the scientific basis for novl treatment procedures and improving quality and longevity of crown restorations. We also expect that our results of will aid in the development of novel smart nanomaterials with high interfacial stability for medical and dental applications.