Dentin is produced by specialized matrix producing cells called odontoblasts. Although it is known that the extracellular matrix (ECM) plays an important role in epithelial-mesenchymal interactions during tooth development, little is known about the molecular mechanisms controlling odontoblast terminal differentiation and dentin formation. A long range goal of the proposed research is to study the regulatory autocrine and paracrine factors that influence odontoblast formation during tooth development. Multiple lines of evidence suggest that the transforming growth factor-beta (TGF-beta) gene family controls embryonic processes and terminal differentiation events by modulating ECM. The fundamental hypothesis to be addressed by these studies is that members of the TGF-beta family are intrinsic regulators of tooth development whose coordinated action plays a major role in ECM formation by odontoblasts. The developing tooth provides a powerful, yet unexplored opportunity to study the role of TGF-beta in regulating these events. To test this hypothesis, we will perform correlative and functional studies using in vivo and in vitro developing tooth systems and a combination of immunohistochemical, organ culture, biochemical and molecular techniques.
The Specific Aims are: 1. To study the temporal and spatial patterns of expression of TGF-beta during rat molar development in vivo. 2. To determine whether TGF-beta is synthesized and secreted by rat molar organs in culture. 3. To study the effects of TGF-beta on ECM formation by rat odontoblasts in vitro. 4. To determine whether a NF-1 binding site involved in TGF-beta activation of the alpha2(1) collagen promoter, mediates activation of this gene in odontoblasts. Collectively, these studies will provide new data on the biology of the TGFs-beta and will increase our understanding of the mechanisms controlling odontoblast differentiation and function. This information can be applied to studies on reparative dentinogenesis where odontoblasts respond to caries, dental materials and operative procedures by producing a distinct ECM, and to the mechanisms of odontogenic tumorigenesis.
