CEMENTOGENESIS: ROLE OF HERTWIG'S EPITHELIAL ROOT SHEATH

本研究的长期目标是从形态学、组织学和生物学角度了解根的发育过程， 细胞和分子水平，包括根牙本质，牙骨质和牙周的机制 韧带形成，导致健康牙周组织中的牙根附着。为了实现这一目标，我们 集中我们的努力在理解的作用Hertwig的上皮根鞘（HERS）在这一过程中。 为了达到这个目的，在整个生命周期的赠款，我们已经建立了几个不同的永生细胞系， 与冠和根形成相关的组织，并使用这些细胞系，我们提供了证据， HERS直接参与脱细胞牙骨质的形成。我们还证明了分子 HERS对牙周膜细胞表达的表型有调节作用。在这些 在过去几年的支持下，我们继续努力了解根形成的过程， 由转录因子核因子I-C（NFI-C）的功能丧失引起的小鼠模型。独特的 这些动物的表型是存在过度生长的上颌切牙，缺乏可见的下颌切牙 牙根很短或缺失。这种表型表明Nfi-c基因产物对于肿瘤的发生是必需的。 根的形成过程。我们还确定，有一个异常形状的短根的形成 表现为牙本质发育不良，在发育后期被吸收， 延迟牙齿萌出。Nfi-c在根发育中的重要性被最近的一项研究报告所证实。 一个常染色体隐性遗传根性牙本质发育不良家族的NFI-C基因突变。在这 竞争更新应用，我们提出，Nfi-c调节根发育的初始阶段， 调控基因与HERS的形成，增殖和迁移，从而控制根 形态发生、成牙本质细胞分化、牙本质生成和牙骨质形成。此外，失败 HERS功能将导致一系列的牙根缺损，导致牙根吸收。以下具体目标 我们将检验这一假设：1）确定Nfi-c调节HERS形成、增殖、 2）确定HERS控制根生长的机制 成牙本质细胞分化; 3）确定HERS控制牙骨质形成的机制; 4） 确定根发育中的Nfi-c相互作用和下游基因。本研究中生成的数据将 提供了与根形成过程和参与根形成的调节因子相关的急需的信息。 这个过程这些数据对于了解导致根发育不全的遗传缺陷具有重要的健康意义 导致牙齿过早脱落。此外，了解根和牙周组织的发展是至关重要的 建立牙周组织再生的基因和组织工程疗法。

It is the long-term objective of this study to understand the process of root development at the morphological, cellular and molecular levels including the mechanisms underlying root dentin, cementum and periodontal ligament formation which leads to root attachment in the healthy periodontium. To accomplish this goal, we have focused our efforts in understanding the role of Hertwig¿s epithelial root sheath (HERS) in this process. Towards this end, throughout the life of this grant, we have established several different immortal cell lines of the tissues associated with crown and root formation and using these cells lines we have provided evidence that HERS participate directly in the formation of acellular cementum. We have also shown that molecules secreted by HERS have a regulatory effect on the phenotype expressed by periodontal ligament cells. In these last years of support we continued our efforts to understand the process of root formation using a ¿rootless¿ mice model resulting from the loss of function of the transcription factor Nuclear Factor I-C (NFI-C). The unique phenotype of these animals is the presence of overgrown maxillary incisors, lack of visible mandibular incisors and very short or absent molar roots. This phenotype indicates that the Nfi-c gene product is essential for the process of root formation. We also determined that there is formation of an abnormal shaped short root presenting with dentin dysplasia, which gets resorbed at later stages of development and there is marked delay in tooth eruption. The significance of Nfi-c in root development is validated by the recent report of a mutation in the NFI-C gene in a family affected by autosomal recessive radicular dentin dysplasia. In this competing renewal application we propose that Nfi-c regulates the initial stages of root development by regulating genes associated with HERS formation, proliferation and migration which in turn control root morphogenesis, odontoblast differentiation, dentin production and cementum formation. Furthermore, failure of HERS function will result in a cascade of root defects leading to root resorption. The following Specific Aims will test this hypothesis: 1) determine the mechanisms by which Nfi-c regulates HERS formation, proliferation and apical migration during root development; 2) determine the mechanism by which HERS control odontoblast differentiation; 3) determine the mechanism by which HERS controls cementum formation and 4) determine Nfi-c interactions and down-stream genes in root development. The data generated in this study will provide much needed information related to the process of root formation and the regulatory factors involved in this process. This data is of great health relevance to understand genetic defects resulting in root agenesis which result in premature tooth loss. Additionally, understanding root and periodontium development is critical to establish genetical and tissue engineering therapies for periodontium regeneration.