One of the most important goals of dentistry and the NIDCR/NIH is to generate a whole ?Bio- Tooth?. Dentin is a critical structural component of tooth. Although it has made great progress of dentin development benefit for numerous hereditary syndromes and chromosomal anomalies, many gaps have been remained. Understanding signaling pathways of dental mesenchymal lineages and dentin formation would provide an avenue for repair and regeneration of dentin. Dentin sialophosphoprotein (Dspp) is highly expressed in odontoblasts and dentin and processed in to dentin sialoprotein (Dsp) and dentin phosphoprotein (Dpp). Dsp and Dpp mutations are associated with dentinogenesis imperfecta (DGI), which is the most common dentin genetic disorder. Our long-ranged goal is to elucidate the biological mechanisms controlling dentin formation, which will fill a key gap of knowledge leading to dentin regenerating. The objective here is to define the signaling pathways essential for dentinogenesis. Our central hypothesis is that the novel control mechanisms, in which the several signals among Bmp2-pAkt-pErk-Dlx3-Sp7-Gcn5-Dspp as well as Dsp-integrin ?6 and Dsp-occludin play synergic roles in controlling dentin formation. The hypothesis is based on our strong preliminary data produced using both global knockout (KO) and conditional KO (cKO) mouse models as well as in vitro cellular and molecule approaches.
Three Specific Aims are proposed to test this hypothesis: 1). to determine Bmp2 signaling in Dspp expression and dentin formation. Bmp2 signal plays functional roles: Dspp expression via up- regulation of Bmp2-pAkt-Erk-Dlx3-Sp7-Gcn5G signaling pathways. 2). to rescue dentin formation in Bmp2 KO mice by overexpression of Dspp gene. Due to dramatically decrease of Dspp expression and dentin defect in Bmp2 KO mice, the hypothesis is that Dspp overexpression in Bmp2 KO mice is able to rescue dentin formation. 3). to determine Dsp signaling in dental mesenchymal cell differentiation and dentin formation. Dsp is processed by MMP9 into active fragments, which as ligands bind to cell membrane receptors, integrin ?6 and occludin. The Dsp-?6 complex positively stimulates Dspp expression and odontoblast homeostasis through up-regulation of Smad1/5/8 signaling. Dsp-occludin signal enhances phosphorylation of focal adhesion kinase (FAK), promoting dental mesenchymal cell differentiation. The proposed research is innovative because 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 and dentin regeneration.
Dentinogenesis imperfecta (DGI) is the most common disease affecting the dentition with an estimated incidence between 1:6,000 and 1:8,000 in population. Dentin sialophosphoprotein (Dspp) is the most abundant non-collagenous protein in dentin and this gene mutation causes DGI-II, DGI-III and dentin dysplasia type II (DD-II), the most common dentin hereditary disorder. Teeth with Dspp mutations display tooth attrition, widened predentin, thin dentin and enlarged dental pulp chambers with obliterated pulp chambers, affecting quality of people life. Also, dental caries is the most common dental disease and untreated carious cavities have a significant impact on the general health of people and on the social and economic well being of communities.This reseach proposal will test a novel way to facilitate dental mesenchymal cell differentiation and dnetin formation. Specically, we plan to use genetically engineered mouse models combined with dental mesenchymal cell lines to study siganling pathways during dentinogenesis. The accmplishment of this project will have a broad impact on dentists to use the new technique for repair and regeneration of dentin in the future.
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|Chen, Zhuo; Zhang, Qi; Wang, Han et al. (2017) Klf5 Mediates Odontoblastic Differentiation through Regulating Dentin-Specific Extracellular Matrix Gene Expression during Mouse Tooth Development. Sci Rep 7:46746|
|Li, Wentong; Chen, Lei; Chen, Zhuo et al. (2017) Dentin sialoprotein facilitates dental mesenchymal cell differentiation and dentin formation. Sci Rep 7:300|
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|Wan, Chunyan; Yuan, Guohua; Luo, Daoshu et al. (2016) The Dentin Sialoprotein (DSP) Domain Regulates Dental Mesenchymal Cell Differentiation through a Novel Surface Receptor. Sci Rep 6:29666|
|Chen, Zhuo; Li, Wentong; Wang, Han et al. (2016) Klf10 regulates odontoblast differentiation and mineralization via promoting expression of dentin matrix protein 1 and dentin sialophosphoprotein genes. Cell Tissue Res 363:385-98|
|He, Y D; Sui, B D; Li, M et al. (2016) Site-specific function and regulation of Osterix in tooth root formation. Int Endod J 49:1124-1131|
|Wu, Lian; Wang, Feng; Donly, Kevin J et al. (2015) Establishment of Immortalized Mouse Bmp2 Knock-Out Dental Papilla Mesenchymal Cells Necessary for Study of Odontoblastic Differentiation and Odontogenesis. J Cell Physiol 230:2588-95|
|Guo, Feng; Feng, Junsheng; Wang, Feng et al. (2015) Bmp2 deletion causes an amelogenesis imperfecta phenotype via regulating enamel gene expression. J Cell Physiol 230:1871-82|
|Ni, Qingwen; Chen, Shuo (2014) Assessing the Effect of Matrix Metalloproteinase-9 on the Growth of Mice Teeth by NMR. J Biol Pharm Chem Res 1:192-204|
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