CEMENTOGENESIS: ROLE OF HERTWIG'S EPITHELIAL ROOT SHEATH

本研究的长期目标是从形态上了解根的发育过程， 细胞和分子水平，包括根部牙本质、牙骨质和牙周的机制 在健康的牙周组织中形成韧带，导致牙根附着。为了实现这一目标，我们 S上皮根鞘(HERS)在这一过程中的作用。 为此，在这笔赠款的整个生命周期中，我们建立了几个不同的永生细胞系 与冠根形成相关的组织，并利用这些细胞系，我们提供了证据 她的细胞直接参与脱细胞牙骨质的形成。我们还展示了分子 HERS分泌的激素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，我们继续努力了解无根植物的根形成过程 转录因子核因子I-C(NFI-C)功能丧失所致的小鼠模型。独一无二的 这些动物的表型是上颌门牙过度生长，缺乏可见的下颌门牙。 以及非常短或缺失的臼齿根。这一表型表明NFI-c基因产物对于 根的形成过程。我们还确定有一个形状异常的短根的形成 表现为牙本质发育不良，在发育的后期被吸收，有明显的 牙齿萌出延迟。NFI-c在根发育中的意义被最近的一份报告所证实 常染色体隐性遗传性根尖牙本质发育不良家系中NFI-C基因突变的研究在这 竞争续期申请我们建议NFI-c通过以下方式调节根发育的初始阶段 调节与其形成、增殖和迁移相关的基因，进而控制根 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，失败的原因 她的功能会导致一系列的牙根缺陷，导致牙根吸收。以下是具体目标 我将验证这一假设：1)确定NFI-c调节His的形成、增殖的机制 和根发育过程中的顶端迁移；2)确定她的控制机制 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NFI-c在根发育中的相互作用和下游基因。这项研究中产生的数据将 提供与根形成过程和涉及的调节因素有关的急需的信息 这一过程。这些数据对于理解导致根发育不全的遗传缺陷具有很大的健康意义。 这会导致牙齿过早脱落。此外，了解牙根和牙周组织的发育是至关重要的。 建立用于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.