Bone Morphogenetic Protein Controls Links Between Dentinogenesis and Angiogenesis

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DESCRIPTION (provided by applicant): The health of the mouth and the surrounding craniofacial structures is essential to a person's overall health and well-being. Tooth development is regulated by many signaling molecules and growth factors, including the critical role played by bone morphogenetic protein 2 (Bmp2). Therefore, the role played by Bmp2 in not only critical to the understanding of normal tooth development and abnormalities, but also has applications in the bioengineering of new dental structures. The proposed studies will define the role of Bmp2 in the intimate association of angiogenesis and dentinogenesis, with vascular-associated ¿SMA+ cells/pericytes being the common factor linking these processes. Dentin sialophosphoprotein (DSPP) gene is expressed during terminal differentiation of odontoblasts and is regulated by Bmp2, and so a role for Bmp2 is likely in developmental abnormalities such as dentinogenesis Imperfecta (DGI) and taurodontism that show dentin and developmental defects. We have evaluated the role of Bmp2 in tooth development with the use of two novel Bmp2 conditional knockout models (Bmp2-cKOSp7Cre and Bmp2-cKO¿SMA-CreERt2) that removed the Bmp2 gene in mouse odontoblasts and a subset of dental pulp cells. These mice displayed severe dentin defects with a reduction of blood vessels and associated pericytes, as well as stem cells. The molars have short roots with an enlarged pulp chamber similar to the phenotype seen in taurodontism, and show reductions in nuclear factor I- C (Nfic) mRNA expression in odontoblasts. This Nfic reduction is important since mutations in Nfic gene results in major defects in human tooth root development. Together, these results suggest a critical role for Bmp2 in tooth development related to both dentinogenesis and angiogenesis. The combined results of these investigations will provide foundational knowledge regarding the role of Bmp2 in normal development and the defects identified when this gene is altered. This knowledge may also be applied to bioengineering and pulp regeneration strategies used to regenerate new dental structures. Our working hypothesis is that odontoblasts are derived from a population of vascular-associated pericytes, and Bmp2 is required for both the recruitment of new vessels/pericytes and the induction of pericyte differentiation into odontoblasts.. This will be addressed by the following specific aims: 1a) demonstrate the differentiation of pericytes into odontoblasts in vivo. 1b) define the effect of Bmp2 on pericytes in vivo. 2) establish the effect o Bmp2 on different signaling molecules involved in angiogenesis of the tooth. These studies will provide training in molecular biology, mouse models, histomorphometry, immunohistochemistry, immunofluorescence and confocal analysis. The proposed studies are innovative because the regulation of angiogenesis in the pulp and tooth-root development by Bmp2 has not been explored. The proposed research is significant in that it will expand our understanding of the complex biology involved in tooth formation. These findings will have a notable impact on the subsequent development of novel therapeutic approaches for the treatment of tooth developmental anomalies and on bioengineering strategies to regenerate new dental structures. Through these studies, I will acquire state-of-the-art knowledge and skills toward my goal in becoming an established dental scientist.