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: 8644652
• 负责人: Audrey Rakian
• 金额: $ 4.25万
• 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/8644652
• 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（通过应用程序提供）：口腔和周围颅面结构的健康对于一个人的整体健康和福祉至关重要。牙齿发育受许多信号分子和生长因子的调节，包括骨形态发生蛋白2（BMP2）所起的关键作用。因此，BMP2在不仅对正常牙齿发育和异常的理解至关重要的情况下所起的作用，而且在新牙科结构的生物工程中都有应用。拟议的研究将定义BMP2在血管生成和牙本质生成的亲密关联中的作用，而血管相关�SMA+细胞/周细胞是将这些过程联系起来的常见因素。牙本质唾液磷蛋白（DSPP）基因在牙糖细胞的末端分化过程中表达并受BMP2的调节，因此BMP2的作用可能在发育异常中，例如牙本质异常（例如牙本质生成型Inperfecta（DGI）（DGI））和表现出牙本质和发育缺陷的tauro症。我们通过使用两种新型的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，该模型删除了小鼠Odontolblasts中的BMP2基因和牙根浆细胞的子集。这些小鼠表现出严重的牙齿缺陷，血管和相关周期以及干细胞的减少。磨牙的根源很短，其纸浆腔室的肿大类似于牛头珠的表型，并且在odontoblasts中显示出核因子I-C（NFIC）mRNA表达的降低。由于NFIC基因的突变导致人类牙根发育的主要缺陷，因此这种NFIC还原很重要。总之，这些结果表明，BMP2在与牙本质生成和血管生成有关的牙齿发育中起着至关重要的作用。这些研究的综合结果将提供有关BMP2在正常发育中的作用以及该基因改变时发现的缺陷的基础知识。这些知识也可以应用于用于再生新牙科结构的生物工程和纸浆再生策略。我们的工作假设是，牙植物细胞源自与血管相关的周细胞的种群，而BMP2既需要募集新容器/周细胞，又需要将周细胞分化为odontotoblasts。 1b）定义BMP2对体内周细胞的影响。 2）建立OBP2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的训练。拟议的研究具有创新性，因为尚未探讨BMP2对果肉和牙根发育中血管生成的调节。拟议的研究很重要，因为它将扩大我们对牙齿形成涉及的复杂生物学的理解。这些发现将对随后的新型治疗方法的发展产生显着影响，用于治疗牙齿发育异常和生物工程策略，以再生新的牙科结构。通过这些研究，我将获得最先进的知识和技能，以成为一名既定的牙科科学家的目标。