This research proposal is based on the overall hypothesis that non-collagenous extracellular matrix (ECM) proteins play vital roles in osteogenesis and odontogenesis. Specifically, we are focusing upon the biological functions of dentin matrix protein 1 (DMP1) and dentin sialophosphoprotein (DSPP). The significance of these two proteins in the formation of mineralized tissues is supported by a number of gene studies showing that mice lacking the genes coding for DMP1 and DSPP display defects in bone and/or dentin formation/mineralization. Although these studies have shown the associations between these proteins and the formation of healthy mineralized tissues, the exact mechanisms, by which DMP1 and DSPP participate in the formation of bone and dentin, remain ill-defined. DMP1 is proteolytically processed to form the N-terminal (37 kDa) and C-terminal (57 kDa) fragments while DSPP is processed into DSP (N- terminal) and DPP (C-terminal);these fragments are present in significant quantity in the ECM of bone and dentin. Recent findings in our group and others have led us to believe that the processed fragments of DMP1 and DSPP may be involved in cell signaling and differentiation, in addition to their direct roles in matrix mineralization. We hypothesize that the processed fragments of DMP1 and DSPP function in extracellular matrix mineralization, cell signaling, and cell differentiation. To test these hypotheses, we propose the following specific aims:
Specific Aim 1 is to examine the effects of DMP1, DSPP, and their fragments on biomineralization. In this specific aim, we will study the effects of these proteins on the mineralization capability of osteogenic and dentinogenic cells.
Specific Aim 2 is to study the effects of DMP1, DSPP and their fragments on cell signaling and differentiation in dentinogenesis and osteogenesis. Collectively, data from these studies will help us better understand the controlling mechanisms involved in the formation of bone and dentin. Award of the F30 fellowship is necessary for me to fulfill the specific aims and to get training on my way towards becoming an independent dentist scientist.
Fundamental information about the controlling mechanisms of mineralization is essential to enhanced understanding concerning pathogeneses of defects in bone and dentin occurring in systemic diseases such as osteomalacia and dentinogenesis imperfecta. A better understanding of the pathogeneses underlying these bone and dental defects is essential for establishing scientifically based treatment modalities for such diseases. The studies proposed for this fellowship are aimed to uncover evidence which will provide a better understanding of the mechanisms controlling mineralization during osteogenesis and dentinogenesis.