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福祉至关重要。牙齿发育受许多信号分子和生长因子调节，包括骨形态发生蛋白2（Bmp 2）发挥的关键作用。因此，Bmp 2所起的作用不仅对理解正常牙齿发育和异常至关重要，而且在新牙齿结构的生物工程中也有应用。拟议的研究将确定Bmp 2在血管生成和牙本质形成的密切联系中的作用，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）基因在成牙本质细胞的终末分化过程中表达，并受Bmp 2调节，因此Bmp 2可能在显示牙本质和发育缺陷的发育异常中起作用，例如牙本质形成不全（DGI）和牛磺牙症。我们使用两种新型Bmp 2条件性敲除模型（Bmp 2-cKOSp 7 Cre和Bmp 2-cKO ² SMA-CreERt 2）评估了Bmp 2在牙齿发育中的作用，这些模型去除了小鼠成牙本质细胞和一部分牙髓细胞中的Bmp 2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。磨牙有短根，髓室扩大，类似于牛磺牙病的表型，成牙本质细胞核因子I-C（Nfic）mRNA表达减少。这种Nfic减少是重要的，因为Nfic基因的突变导致人类牙根发育的主要缺陷。总之，这些结果表明Bmp 2在牙齿发育中与牙本质生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有关Bmp 2在正常发育中的作用以及该基因被改变时所识别的缺陷的基础知识。这些知识也可以应用于生物工程和用于再生新牙齿结构的牙髓再生策略。我们的工作假设是，成牙本质细胞来源于血管相关周细胞的群体，并且Bmp 2是招募新血管/周细胞和诱导周细胞分化成成牙本质细胞所必需的。这将通过以下具体目标来解决：1a）证明周细胞在体内分化成牙本质细胞。1b）确定Bmp 2在体内对周细胞的作用。2)建立Bmp 2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。所提出的研究是创新的，因为尚未探索Bmp 2对牙髓和牙根发育中血管生成的调节。这项拟议中的研究意义重大，因为它将扩大我们对牙齿形成所涉及的复杂生物学的理解。这些发现将对随后开发用于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产生显着影响。通过这些学习，我将获得最先进的知识和技能，朝着成为一名公认的牙科科学家的目标前进。