MOLECULAR REGULATION OF PERIODONTIUM FORMATION

周期形成的分子调控

• 批准号: 7933915
• 负责人: Margarita Zeichner-David
• 金额: $ 39.42万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-17 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7933915
• 关键词: Affect; Ameloblasts; Animal Model; Cell Line; Cells; Cementum Formation; Data; Defect; Dental; Dental Cementum; Dental Enamel; Dental crowns; Dentin; Dentin Dysplasia; Development; Developmental Biology; Epithelial; Extracellular Matrix; Future; Gene Mutation; Genes; Genetic; Health; Hereditary Disease; Human; Inner Enamel Epithelium; Knockout Mice; Knowledge; Laboratories; Lead; Link; Mesenchymal; Microarray Analysis; Molecular; Morphogenesis; Mus; Mutation; Natural regeneration; Odontoblasts; Organ; Outer Enamel Epithelium; Patients; Periodontal Ligament; Periodontium; Phenotype; Plant Roots; Process; Production; Proteins; Regulation; Reporting; Role; Severities; Staging; Stellate Reticulum; Stratum Intermedium; Stream; Structure; Testing; Time; Tissue Engineering; Tissues; Tooth Loss; Tooth structure; Transgenic Animals; Work; base; human NFIC protein; loss of function; premature; protein function; public health relevance; small hairpin RNA; transcription factor

DESCRIPTION (provided by applicant): It is the long-term objective of this study to understand the genetic control of root development and periodontium formation. Advances in molecular and developmental biology have linked the function of numerous genes to specific stages of organ development. In the case of tooth development, more than 300 hundred genes have been reported as having some role in this process. As expected, mutations in these genes can result in dental defects which vary in severity depending on how the mutation affects the function of that protein or what process that particular gene regulates. Much of the knowledge relating a gene to its function is derived from the use of transgenic animals which has allowed the creation of animal models for genetic diseases. In the case of tooth formation, many of the genes involved in the early stages of tooth development and crown formation have been established. A few years ago we reported that the loss of function of the transcription factor Nuclear Factor I-C (NFI-C) in mice results in a unique phenotype characterized by molars with very short or no roots at all. No other phenotype was found and no defects in the crowns were detected indicating that the NFI-C gene product is essential for the process of root formation. NFI- C is the first and up to date only gene that has been found to regulate root development and therefore periodontium formation. Root formation, like crown formation, is dependent on epithelial-mesenchymal interactions resulting in differentiation of the corresponding tissues and production of the mineralized extracellular matrices. Since the main difference between the crown and root is its epithelial component which in the crown is composed by the outer and inner enamel epithelia separated by the stellate reticulum and the stratum intermedium. The root contains only inner and outer enamel epithelia forming the structure known as Hertwig's Epithelial Root Sheath (HERS). Based on this difference and data presented in the preliminary data section, we propose to test the central hypothesis that Nfi-c controls periodontium development by regulating the function of HERS which in turn control root morphogenesis, odontoblast differentiation, dentin and cementum production and periodontal ligament formation. We propose to test this hypothesis by realizing the following Specific Aims: establish the role of NFI-C on HERS differentiation and maturation; determine NFI-C down-stream genes associated with HERS differentiation and maturation; determine NFI-C interactions in cells associated with root development; determine the mechanism by which HERS control odontoblast differentiation and determine the mechanism by which HERS control periodontal ligament and cementum formation. These studies will use the NFI-C knockout mice as well as our established immortal cell lines for the tissues associated with root formation, shRNA and microarray technology. The data generated in this study will provide much needed information related to the process of normal and abnormal root and periodontium formation and the regulatory factors involved in this process. This data is of great health relevance to understand genetic mutations resulting in root defects, root agenesis and/or premature tooth loss which is critical to establish future genetical and tissue engineering therapies for periodontium regeneration. PUBLIC HEALTH RELEVANCE: It is the long-term objective of this study to understand the process of root development and periodontium formation at the morphological, cellular and molecular levels. This includes the mechanisms underlying root dentin, cementum and periodontal ligament formation which lead to root attachment in the healthy periodontium. This application will focus on the role of the transcription factor NFI-C which appears to be essential for periodontium formation. The data generated in this study is of great health relevance to understand genetic defects resulting in root agenesis and periodontium defects which result in premature tooth loss. Additionally, understanding root and periodontium development is critical to establish genetical and tissue engineering therapies for periodontium regeneration.

描述（由申请人提供）：了解本研究的长期目的是了解根部发育和牙周形成的遗传控制。分子和发育生物学的进步将许多基因的功能与器官发育的特定阶段联系起来。就牙齿发育而言，据报道有30000多个基因在此过程中起作用。正如预期的那样，这些基因中的突变会导致牙齿缺陷，这些缺陷在严重程度上取决于突变如何影响该蛋白质的功能或特定基因调节的过程。与其功能有关的许多知识来自于使用转基因动物，这些动物允许创建动物模型作为遗传疾病。在形成牙齿的情况下，已经建立了许多参与牙齿发育和牙冠形成早期的基因。几年前，我们报告说，小鼠转录因子核因子I-C（NFI-C）功能的丧失导致独特的表型，其特征是磨牙根本没有根。没有发现其他表型，也没有检测到牙冠中的缺陷，表明NFI-C基因产物对于根形成过程至关重要。 NFI-C是发现根源发育并因此是牙周形成的最新基因。根形成，例如冠状形成，取决于上皮 - 间质相互作用，从而导致相应组织的分化和矿化细胞外基质的产生。由于牙冠和根之间的主要差异是其上皮成分，在冠中，其由外部和内搪瓷上皮组成，由星状网状和层中间层组成。根部仅包含内部和外搪瓷上皮，形成了称为赫特维格上皮根鞘（她）的结构。基于此差异和初步数据部分中提供的数据，我们建议通过调节其功能来测试NFI-C控制牙周发育的中心假设，该功能反过来又控制了根部形态发生，牙本质细胞分化，牙本质和牙骨质产生和牙周韧带形成。我们建议通过意识到以下特定目的来检验这一假设：确定NFI-C对自己的分化和成熟的作用；确定与他的分化和成熟相关的NFI-C下游基因；确定与根发育相关的细胞中的NFI-C相互作用；确定HERS控制Odontoblast分化的机制，并确定HERS控制牙周韧带和牙骨质形成的机制。这些研究将使用NFI-C基因敲除小鼠以及我们已建立的与根形成，SHRNA和微阵列技术相关的组织的不朽细胞系。本研究中产生的数据将提供与正常和异常根和牙周形成过程以及此过程中涉及的调节因素有关的急需信息。该数据具有很大的健康相关性，可以理解导致根部缺陷，根部发育和/或过早牙齿脱落的基因突变，这对于建立未来的基因和组织工程疗法至关重要。 公共卫生相关性：这项研究的长期目标是了解形态，细胞和分子水平的根源发育和牙周形成的过程。这包括根牙本质，牙骨质和牙周韧带形成的机制，这些机制导致健康牙周的根附着。该应用将集中在转录因子NFI-C的作用上，这似乎对于牙周形成至关重要。这项研究中产生的数据具有很大的健康相关性，可以理解导致根部性和牙周缺陷的遗传缺陷，从而导致过早的牙齿脱落。另外，了解根和牙周发育对于建立牙周再生的基因和组织工程疗法至关重要。