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：
7582436
负责人：
Carolyn Gibson
金额：
$ 39.11万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
1995
资助国家：
美国
起止时间：
1995-06-01 至 2013-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7582436
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.

描述（由申请人提供）：氨基蛋白蛋白在正常牙齿牙釉质的发展中具有基本作用。这一点的证据来自具有搪瓷缺陷的ameleogenes imperfecta（AI）和Amelx null小鼠的患者（amelx）基因中的突变患者，其疾病类似于AI的X连锁形式。与人类患者中鉴定出的各种AI相对应的无效鼠模型已开始揭示正常和突变的搪瓷蛋白的作用。基质金属蛋白酶-20（MMP-20）的小鼠无效也具有类似于人AI的搪瓷缺陷，这是由于在发育过程中蛋白水解加工缺乏蛋白水解加工。这些动物模型提供了有关人类发展基本过程的信息，因为啮齿动物和人类搪瓷蛋白，矿物质和牙齿发育之间的相似之处。在此竞争性更新应用中，我们提出以下目的：（i）使用AMELX NAULL基因组突变分析转基因小鼠中拯救的牙釉质表型，以确定180和59氨基酸氨基蛋白蛋白的作用，使用光，扫描和传输电子和传输电子的作用显微镜；（ii）评估AMELX NULL，MMP20 NULL和AMELX NULL小鼠的牙釉质厚度，结构和晶体尺寸以及具有正常和突变蛋白转基因的Amelx Null小鼠的方向，以提供有关amelogen蛋白C-末端在VIVO中的作用的基本信息；（iii）确定遗传背景在无效小鼠中观察到的搪瓷表型异质性中的作用；（iv）在跨学科方法中使用具有不同分类的搪瓷缺陷分类的鼠模型，以开发不同牙釉质基因突变患者的AI牙釉质键合处理。在这项工作结束时，对搪瓷发育过程中单个氨基蛋白的功能的功能有了更好的了解，以及对其他蛋白质在疾病严重程度中起作用的作用的洞察力，将导致针对患有不同AI突变的个体设计的新疗法。基本和临床方法的这种结合将产生基本知识以及翻译应用，这些知识将通过提供与遗传改变相对应的治疗方法来使公众受益，从而改善牙科/口腔健康。项目叙述：由于牙齿的出现，牙釉质缺陷的患者经常长时间临床治疗，疼痛和社交焦虑。对遗传基因突变如何导致牙釉质缺陷的理解将导致深入了解搪瓷如何发展，并更多地了解如何防止结构缺陷发展。小鼠模型模仿人类缺陷，可用于将单个基因突变与适当的临床干预相关联。