Bone Morphogenetic Protein Controls Links Between Dentinogenesis and Angiogenesis

骨形态发生蛋白控制牙本质发生和血管生成之间的联系

• 批准号: 8527448
• 负责人: Audrey Rakian
• 金额: $ 4.56万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-15 至 2017-05-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8527448
• 关键词: Address; Animal Model; BMP2 gene; Biology; Biomedical Engineering; Blood Vessels; Blood capillaries; Bone Morphogenetic Proteins; Cells; Complex; DSPP gene; Defect; Dental; Dental Pulp; Dentin; Dentinogenesis; Dentinogenesis Imperfecta; Development; Genes; Goals; Growth Factor; Health; Human; Immunofluorescence Immunologic; Immunohistochemistry; Inherited; Investigation; Knock-out; Knockout Mice; Knowledge; Lead; Link; Modality; Modeling; Molecular Biology; Mus; Mutation; Natural regeneration; Odontoblasts; Oral cavity; Oral health; Pericytes; Personal Satisfaction; Persons; Phenotype; Plant Roots; Play; Population; Process; Pulp Chambers; Quality of life; Regulation; Research; Role; Scientist; Signaling Molecule; Smooth Muscle Actin Staining Method; Source; Stem cells; Structure; Syndrome; Tooth Crowns; Tooth root structure; Tooth structure; Training; Work; angiogenesis; bone morphogenetic protein 2; capillary; craniofacial; dental structure; human NFIC protein; improved; in vivo; innovation; mRNA Expression; mouse model; novel; novel therapeutic intervention; public health relevance; research study; skills; stem cell population; taurodontism

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.

描述（由申请人提供）：口腔和周围颅面结构的健康对一个人的整体健康和幸福至关重要。牙齿发育受多种信号分子和生长因子的调控，其中骨形态发生蛋白2 （bone morphogenetic protein 2, Bmp2）起着至关重要的作用。因此，Bmp2的作用不仅对正常牙齿发育和异常的理解至关重要，而且在新的牙齿结构的生物工程中也有应用。拟议的研究将确定Bmp2在血管生成和牙本质形成的密切关联中的作用，血管相关的SMA+细胞/周细胞是连接这些过程的共同因素。牙本质涎磷蛋白（DSPP）基因在成牙细胞终末分化过程中表达，并受Bmp2调控，因此Bmp2可能在牙本质发育不全（DGI）和牛牙症等发育异常中发挥作用，表现出牙本质和发育缺陷。我们利用两种新的Bmp2条件敲除模型（Bmp2- ckosp7cre和Bmp2- cko¿SMA-CreERt2）评估了Bmp2在牙齿发育中的作用，这些模型在小鼠成牙细胞和牙髓细胞亚群中去除了Bmp2基因。这些小鼠表现出严重的牙本质缺陷，血管和相关的周细胞以及干细胞减少。磨牙根短，牙髓腔增大，与牛牙畸形相似，成牙细胞中核因子I- C (Nfic) mRNA表达减少。这种Nfic的减少是重要的，因为Nfic基因的突变会导致人类牙根发育的主要缺陷。总之，这些结果表明Bmp2在牙齿发育中与牙本质形成和血管生成相关的关键作用。这些研究的综合结果将提供关于Bmp2在正常发育中的作用以及当该基因改变时确定的缺陷的基础知识。这些知识也可以应用于生物工程和牙髓再生策略，用于再生新的牙齿结构。我们的工作假设是成牙细胞来源于血管相关的周细胞群，Bmp2是招募新血管/周细胞和诱导周细胞分化成成牙细胞所必需的。这将通过以下具体目标来解决：1a)在体内证明周细胞向成牙细胞的分化。1b)确定Bmp2对体内周细胞的影响。2)确定Bmp2对参与牙齿血管生成的不同信号分子的影响。这些研究将提供分子生物学、小鼠模型、组织形态计量学、免疫组织化学、免疫荧光和共聚焦分析方面的培训。由于Bmp2在牙髓和牙根发育中对血管生成的调节尚未被探索，因此提出的研究具有创新性。提出的研究是重要的，因为它将扩大我们的理解复杂的生物学参与牙齿的形成。这些发现将对治疗牙齿发育异常的新治疗方法和再生新牙齿结构的生物工程策略的后续发展产生显著影响。通过这些学习，我将获得最先进的知识和技能，我的目标是成为一名成熟的牙科科学家。