Enamel with overexpressed ameloblastin

牙釉质过度表达成釉细胞

基本信息

批准号：
9883785
负责人：
Yong-Hee Patricia Chun
金额：
$ 36.18万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9883785
关键词：
Accounting Address Affect Ameloblasts Amelogenesis Attention Behavioral Bioinformatics Biological Cells Child Clinical Clinical Management Data Defect Dental Dental Care Dental Enamel Dental caries Dentin Development Diagnosis Disease Enamel Formation Enamel Organ Endocytosis Endocytosis Pathway Epithelial Epithelium Esthetics Event Excision Exhibits Fluorides Fracture Functional disorder High Prevalence Homeostasis Image Immunohistochemistry Impairment In Situ Hybridization In Vitro Incisor Individual Ions Lesion Life MMP-20 Mass Spectrum Analysis Methods Minerals Molecular Morphology Mus Oral Partner in relationship Pathogenesis Pathway interactions Phase Play Population Predisposition Prevalence Prevention therapy Process Proteins Proteomics Risk Role Scientist Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization Texas Therapeutic Tissues Tooth structure Transgenic Mice United States ameloblastin analytical tool base bioinformatics tool conventional therapy deciduous tooth enamel matrix proteins in vivo malformation microCT mineralization mouse model novel strategies overexpression permanent tooth protein transport public health relevance quantitative imaging restoration targeted treatment tool transcriptome uptake

项目摘要

PROJECT SUMMARY/ABSTRACT Developmental defects of enamel include molar-incisor hypomineralization (MIH). This condition affects the quality and quantity of enamel and severely disrupts oral functions in children with loss of occlusion, tooth sensitivity and increased caries susceptibility. Children with MIH have greater needs for dental treatment throughout their life and often exhibit dental behavioral management problems. MIH is found in many different populations worldwide with a prevalence ranging from 2.4% to 40.2%. The enamel organ epithelium is affected by unknown factors resulting in MIH. The pathophysiology of MIH is not understood. Therapeutic options are limited to conventional therapy with fluoride applications, restorations often with poor retention and extractions. Enamel formation into the hardest mineral is promoted by enamel matrix proteins. One of the enamel proteins is ameloblastin (Ambn) accounting for 5% of the enamel proteins. In hypomineralized enamel, the mineral content does not reach the necessary concentration. Ambn was identified in hypomineralized enamel of extracted teeth, but it is not clear if it plays a role in the pathogenesis of MIH. We have developed a mouse model to study the effect of Ambn overexpression in MIH-like enamel in enamel organ epithelium. When Ambn is overexpressed, the enamel in these mice displays white, demarcated ‘patches’ that fracture easily from the dentin. The MIH mouse model will serve to dissect the cellular and molecular events in enamel hypomineralization to identify strategies for the diagnosis, prevention and therapy of hypomineralized enamel. We have developed transgenic mice with demarcated, MIH-like lesions in enamel. Our preliminary results show that the lesions enlarge as the ameloblastin (Ambn) concentration increases. Normally, enamel matrix is rapidly processed, degraded and internalized by ameloblasts, but when Ambn is overexpressed, the enamel matrix lingers on and the accumulation of mineral is hampered, manifesting as hypomineralized enamel. We have developed tools to accurately quantify mineral content and enamel volume with microCT methods. In a transcriptome analysis of enamel organ epithelium pathways for enamel matrix, enzymatic degradation, protein trafficking and ion handling were dysregulated. Our overall hypothesis is that overexpressed ameloblastin influences the mechanisms of enamel formation resulting in MIH lesions in enamel. In SA1 we will determine the onset of demarcated opacities within the phased formation of enamel in mice overexpressing Ambn. In SA2, we will determine the biological pathways of endocytosis of enamel proteins in vivo and in vitro as a consequence of ameloblastin overexpression. In SA3, we will determine if endocytosis of overexpressed Ambn can be promoted in Ambn mice by increasing the enzymatic activity in the enamel matrix. For the proposed studies a team of clinician scientists, experts in quantitative imaging, proteomics and bioinformatics has been assembled for unique interaction and novel approaches.

项目摘要/摘要牙釉质的发育缺陷包括摩尔降低矿化（MIH）。这种情况影响牙釉质的质量和数量，严重破坏了闭塞，牙齿丧失的儿童的口服功能敏感性和龋齿敏感性提高。 MIH儿童对牙科治疗有更大的需求通过他们的生活，经常暴露牙科行为管理问题。在许多人中发现了mih 全球不同的人口范围从2.4％到40.2％。搪瓷器官上皮受到MIH导致未知因素的影响。 MIH的病理生理学尚不清楚。治疗选择仅限于使用氟化物应用的常规治疗，经常与保留和提取不良。搪瓷矩阵促进了进入最硬矿物的搪瓷形成蛋白质。牙釉质蛋白之一是氨基蛋白（AMBN），占搪瓷蛋白的5％。在低矿物化搪瓷，矿物质含量未达到必要的浓度。 Ambn是在拔出牙齿的低矿物化搪瓷中鉴定出来，但尚不清楚它是否在 MIH的发病机理。我们已经开发了一个小鼠模型来研究AMBN过表达的影响 MIH样牙釉质中的搪瓷器官上皮。当AMBN过表达时，这些小鼠中的搪瓷显示白色，划定的“补丁”，这些“斑块”很容易从牙本质上骨折。 MIH鼠标模型将服务剖析搪瓷低矿化中的细胞和分子事件，以鉴定低矿物化搪瓷的诊断，预防和治疗。我们已经开发了转基因小鼠在搪瓷中有划分的mih样病变。我们的初步结果表明随着蛋白纤维细胞素（AMBN）浓度的增加，病变会扩大。通常，搪瓷矩阵迅速处理，降解和内在化的成成木细胞，但是当AMBN过表达时，搪瓷基质徘徊在上面，矿物的积累受到阻碍，表现为低矿物搪瓷。我们开发了使用Microct准确量化矿物质含量和搪瓷量的工具方法。在搪瓷基质的搪瓷器官上皮途径的转录组分析中降解，蛋白质运输和离子处理失调。我们的总体假设是过表达的氨成蛋白会影响搪瓷形成的机制，导致MIH病变搪瓷。在SA1中，我们将确定在搪瓷中分阶段形成中的划界的发作过表达AMBN的小鼠。在SA2中，我们将确定牙釉质内吞作用的生物学途径蛋白质在体内和体外是由于蛋白细胞蛋白过表达而导致的。在SA3中，我们将确定是否通过增加在AMBN小鼠中，可以通过增加酶促活性来促进过表达AMBN的内吞作用搪瓷矩阵。对于拟议的研究，临床科学家团队，定量成像专家蛋白质组学和生物信息学已被组装，用于独特的相互作用和新方法。