Enamel Mineral Formation during Murine Odontogenesis

小鼠成牙过程中牙釉质矿物质的形成

基本信息

批准号：
7904365
负责人：
Carolyn Gibson
金额：
$ 21.79万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-01 至 2012-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7904365
关键词：
129 Mouse A/J Mouse Acids Affect Amelogenesis Imperfecta Amino Acids Animal Model Anxiety Appearance Backcrossings Biomechanics C-terminal Characteristics Classification Clinical Clinical Treatment Congenic Mice Congenic Strain DNA Defect Dental Dental Enamel Development Dimensions Environment Extracellular Matrix Proteins Gene Mutation Gene-Modified Genes Genetic Genomics Growth Heterogeneity Human Human Development Individual Inherited Intervention Knockout Mice Knowledge Lead Light Link MMP-20 Minerals Modeling Mouse Strains Mus Mutate Mutation Odontogenesis Oral Oral health Pain Patients Phenotype Play Polymorphic Microsatellite Marker Process Proteins Proteolytic Processing Rodent Role Scanning Transmission Electron Microscopy Procedures Severity of illness Speed Structure Testing Therapeutic Thick Tooth structure Transgenes Transgenic Mice Transgenic Model Transgenic Organisms Western Blotting Work amelogenin base congenic design enamelin improved in vivo insight interdisciplinary approach kindred leucine-rich amelogenin peptide microleakage mouse model null mutation prevent restoration restorative treatment social therapy design treatment planning

项目摘要

DESCRIPTION (provided by applicant): The amelogenin proteins have a fundamental role in development of normal dental enamel. Evidence for this comes from patients with mutations in the amelogenin (AMELX) gene, who have the enamel defect amelogenesis imperfecta (AI), and from Amelx null mice, which have a condition similar to the X-linked form of AI. Null and transgenic murine models that correspond to various types of AI identified in human patients have begun to reveal roles of both the normal and mutated enamel proteins. Mice null for matrix metalloproteinase-20 (MMP-20) also have an enamel defect similar to a human AI, due to deficiency in proteolytic processing of amelogenins and other enamel proteins during development. These animal models provide information concerning basic processes in human development because of similarities between rodent and human enamel proteins, mineral and dental development in general. In this competitive renewal application, we propose the following aims: (i) To analyze the rescued enamel phenotype in transgenic mice with an Amelx null genomic mutation to determine roles of the 180 and 59 amino acid amelogenin proteins, using light, scanning and transmission electron microscopy; (ii) To evaluate enamel thickness, structure and crystal dimensions and orientation in the Amelx null, MMP20 null, and Amelx null mice with normal and mutated amelogenin transgenes for fundamental information about the role of the amelogenin C-terminus in vivo; (iii) To determine the role of genetic background in the observed enamel phenotypic heterogeneity in null mice; and (iv) To use murine models with different classifications of enamel defects in an interdisciplinary approach to develop enamel bonding treatments for AI in patients with different enamel gene mutations. At the conclusion of this work, a better understanding of the function of individual amelogenins during enamel development, and insight into the role that other proteins play in disease severity, will lead to new treatments designed for individuals with different AI mutations. This combination of basic and clinical approaches will generate fundamental knowledge as well as translational application that will benefit the public by providing therapeutic approaches that correspond to genetic alterations, leading to improved dental/oral health. Project Narrative: Patients with defective enamel frequently have prolonged clinical treatment, pain and social anxiety because of the appearance of their teeth. An understanding of how inherited gene mutations cause enamel defects will lead to insight into how enamel develops and shed more light on how to prevent structural defects from developing. Mouse models mimic the human defects and can be used to correlate individual gene mutations with appropriate clinical intervention. Project Narrative Patients with defective enamel frequently have prolonged clinical treatment, pain and social anxiety because of the appearance of their teeth. An understanding of how inherited gene mutations cause enamel defects will lead to insight into how enamel develops and shed more light on how to prevent structural defects from developing. Mouse models mimic the human defects and can be used to correlate individual gene mutations with appropriate clinical intervention.

描述（由申请人提供）：釉原蛋白在正常牙釉质的发育中具有基本作用。这方面的证据来自于牙釉质蛋白 (AMELX) 基因突变的患者（患有牙釉质缺陷釉质生成不全症 (AI)），以及来自 Amelx 缺失小鼠（其患有与 X 连锁 AI 类似的病症）。与人类患者中鉴定出的各种类型的人工智能相对应的无效和转基因小鼠模型已经开始揭示正常和突变牙釉质蛋白的作用。基质金属蛋白酶 20 (MMP-20) 缺失的小鼠也有与人类 AI 类似的牙釉质缺陷，这是由于发育过程中牙釉质蛋白和其他牙釉质蛋白的蛋白水解加工缺陷所致。由于啮齿动物和人类牙釉质蛋白、矿物质和牙齿发育之间的相似性，这些动物模型提供了有关人类发育基本过程的信息。在此竞争性更新应用中，我们提出以下目标：（i）使用光、扫描和透射电子分析具有 Amelx 无效基因组突变的转基因小鼠中挽救的牙釉质表型，以确定 180 和 59 氨基酸釉原蛋白的作用显微镜检查； (ii) 评估具有正常和突变的牙釉蛋白转基因的 Amelx null、MMP20 null 和 Amelx null 小鼠的牙釉质厚度、结构和晶体尺寸和方向，以获得关于牙釉蛋白 C 末端在体内的作用的基本信息； (iii) 确定遗传背景在无效小鼠中观察到的牙釉质表型异质性中的作用； (iv) 以跨学科方法使用具有不同牙釉质缺陷分类的小鼠模型，为具有不同牙釉质基因突变的患者的 AI 患者开发牙釉质粘合疗法。在这项工作结束时，更好地了解牙釉质发育过程中个体釉原蛋白的功能，并深入了解其他蛋白质在疾病严重程度中所起的作用，将导致为具有不同 AI 突变的个体设计新的治疗方法。这种基础方法和临床方法的结合将产生基础知识和转化应用，通过提供与基因改变相对应的治疗方法，从而改善牙齿/口腔健康，使公众受益。项目叙述：牙釉质有缺陷的患者经常因为牙齿的外观而遭受长期的临床治疗、疼痛和社交焦虑。了解遗传基因突变如何导致牙釉质缺陷将有助于深入了解牙釉质如何发育，并为如何预防结构缺陷的发展提供更多线索。小鼠模型模仿人类缺陷，可用于将个体基因突变与适当的临床干预相关联。项目叙述牙釉质有缺陷的患者经常需要长期的临床治疗、疼痛以及由于牙齿外观而产生的社交焦虑。的理解遗传基因突变如何导致牙釉质缺陷将导致深入了解如何牙釉质的发展并为如何防止结构缺陷提供了更多线索发展。小鼠模型模仿人类缺陷，可用于将个体基因突变与适当的临床干预相关联。