The Role of the C-terminus of Amelogenen in Enamel Structure

Amelogenen C 末端在牙釉质结构中的作用

• 批准号: 7883501
• 负责人: Megan Kardon Pugach
• 金额: $ 5.47万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7883501
• 关键词: Ablation; Affinity; Ameloblasts; Amelogenesis Imperfecta; Binding; Biomechanics; C-terminal; Clinical Treatment; Defect; Dental Enamel; Deposition; Development; Dimensions; Disease; Enamel Formation; Excision; Gene Mutation; Genes; Growth; Hereditary Disease; Histologic; Human; Hydroxyapatites; Immunohistochemistry; In Situ; Knockout Mice; Knowledge; Lead; Length; Measures; Mechanics; Minerals; Morphology; Mus; Mutation; Nanosphere; Patients; Pattern; Peptide Hydrolases; Phenotype; Process; Property; Proteins; Psychological reinforcement; Regulation; Research; Role; Staging; Structure; Surface; Testing; Thick; Tissues; Tooth structure; Transgenic Mice; Transgenic Organisms; Wild Type Mouse; amelogenin; density; enamel matrix proteins; improved; mineralization; mouse model; nanomechanical; protein aggregate; public health relevance; retinal rods; tooth surface

DESCRIPTION (provided by applicant): Proper enamel formation requires coordinated secretion of both structural matrix proteins and proteases along with mineralization to form the hardest and most mineralized tissue in the body. Amelogenins constitute 90% of the organic matrix secreted by ameloblasts and are required for enamel mineralization. Mutations in amelogenin cause Amelogenesis Imperfecta (Al), which is a genetic disorder that causes enamel defects. Different regions of the amelogenin protein are responsible for varying aspects of the enamel mineralization process. Amelogenins are processed by proteolytic enzymes also secreted by ameloblasts, such as MMP20, during enamel formation. The C-terminus of amelogenin is thought to be required for proper formation and assembly of nanospheres, spherical protein aggregates that guide mineral crystal growth, and interaction with hydroxyapatite mineral. To examine the role of the C-terminus of amelogenin in enamel structural integrity using transgenic and amelogenin null mice, this proposal will: 1) determine the effect of the lack of the amelogenin C-terminus on enamel microstructure and nanomechanical properties; 2) determine the importance of MMP20 processing of amelogenin at the C-terminus on enamel microstructure, nanomechanical properties, and organic matrix removal; and 3) examine rod organization and ameloblast Tomes' process morphology in mice with an amelogenin C-terminal mutation. PUBLIC HEALTH RELEVANCE: This research will contribute to the current knowledge of the role of enamel matrix proteins in enamel development and mineralization. Analysis of transgenic mouse models with mutations in amelogenin and other enamel matrix genes can lead to increased understanding of different Al phenotypes and their corresponding genetic mutations in patients. As a result, clinical treatments and approaches for humans with Al and other enamel disorders can be improved.

描述（由申请人提供）：正确的牙釉质形成需要结构基质蛋白和蛋白酶的协调分泌以及矿化，以形成体内最坚硬和矿化程度最高的组织。釉原蛋白占成釉细胞分泌的有机基质的 90%，是牙釉质矿化所必需的。釉原蛋白突变会导致釉质生成不全 (Al)，这是一种导致釉质缺陷的遗传性疾病。釉原蛋白的不同区域负责牙釉质矿化过程的不同方面。釉原蛋白在牙釉质形成过程中由成釉细胞分泌的蛋白水解酶（例如 MMP20）加工。牙釉蛋白的 C 末端被认为是纳米球、引导矿物质晶体生长的球形蛋白质聚集体以及与羟基磷灰石矿物质相互作用的正确形成和组装所必需的。为了利用转基因小鼠和无牙釉蛋白小鼠研究牙釉蛋白 C 端在牙釉质结构完整性中的作用，本提案将： 1) 确定牙釉蛋白 C 端缺失对牙釉质微观结构和纳米力学特性的影响； 2) 确定C端牙釉蛋白MMP20加工对牙釉质微观结构、纳米力学性能和有机基质去除的重要性； 3) 检查具有牙釉蛋白 C 末端突变的小鼠的视杆组织和成釉细胞 Tomes 的过程形态。 公共健康相关性：这项研究将有助于加深对牙釉质基质蛋白在牙釉质发育和矿化中作用的了解。对具有釉原蛋白和其他牙釉质基质基因突变的转基因小鼠模型进行分析可以加深对患者不同Al表型及其相应基因突变的了解。因此，可以改善患有铝和其他牙釉质疾病的人类的临床治疗和方法。