DESCRIPTION (provided by applicant): The long-ranged goal of these studies is to elucidate the mechanism (s) of dentin sialophosphoportein (DSPP) in dentinogenesis and thereby provide new avenues for inducing the repair and regeneration of teeth. The most abundant and important proteins in dentin are collagen type I and DSPP. Mutations of DSPP are associated with dentinogenesis imperfectas (DGI), the most common dentin genetic disorders. DSPP protein is processed by proteases into several functional fragments; DSP, DPP and others. These domains play unique biological functions during dentinogenesis. Preliminary data showed that 1). BMP2 induced DSPP expression. Teeth in BMP2 null mice are similar to DGI with DSPP mutations and expression of DSPP and Dlx3 and Osx transcriptional factors were also decreased in BMP2 knock-out mice; 2). MMP-9 specially catalyzes DSP into the NH2-terminal and COOH-terminal fragments. The NH2- and COOH-terminal fragments of DSP show a clear difference in tooth distributions. Defect in teeth and interference of DSPP processing were seen in MMP-9 null mice. 3). The NH2-terminal and COOH-terminal domains bind to their receptors, integrin 26 and CD105, on cellular membrane. Based on these findings, we propose the following hypothesis that the transcriptional regulation, posttranslational modification and signal transduction of DSPP are important for controlling the initiation, rate and extent of dentin biomineralization. To test this hypothesis, we propose the following Specific Aims: 1. to determine BMP2 signaling pathways in DSPP transcription during dentinogenesis. 2. To determine processing patterns of DSP and cleaved sites of DSP by MMP-9. 3. To determine DSP signaling pathways via integrin 26 and CD105 during tooth development. This is an innovative hypothesis that each step of transcription, posttranslational processing and signaling transduction of DSP/DSPP is necessary for the formation of healthy dentin. Such knowledge will advance our understanding of the pathogenesis of inherited disorders that threaten the structural integrity of dentin and provide a potential clue for treating dental diseases. PUBLIC HEALTH RELEVANCE: Dentin sialophosphoprotein (DSPP) protein is important for dentin formation as DSPP mutations cause dentinogenesis imperfectas, the most common dentin genetic diseases. Here, we propose a novel pathway for DSPP transcriptional regulation, proteolytic processing and signaling transduction pathway for dentinogenesis. Thereafter, better understanding of the mechanisms of DSPP biological functions will provide new avenues for repair and regeneration of teeth.

Dentin sialophosphoprotein (DSPP) protein is important for dentin formation as DSPP mutations cause dentinogenesis imperfectas, the most common dentin genetic diseases. Here, we propose a novel pathway for DSPP transcriptional regulation, proteolytic processing and signaling transduction pathway for dentinogenesis. Thereafter, better understanding of the mechanisms of DSPP biological functions will provide new avenues for repair and regeneration of teeth.