NIDCR Dentist Scientist K99;Function and Regulation of Perp in Amelogenesis

摘要 釉质是防止龋齿的第一道也是主要的一道防线，它的正确形成是预防龋齿的先决条件 坚固健康的牙齿。驱动牙釉质形成的分子和细胞途径的异常 (成釉作用)导致成釉不全，这是对一些非综合征和 牙釉质缺陷症。更好地理解釉质发生的机制对于设计新的 并改进了预防、诊断和治疗龋齿和遗传性疾病的策略 如釉质发生不完全。因为牙釉质是上皮部矿化组织中独一无二的 起源，参与上皮发育和完整性的基因，如perp是很好的候选调节器 成釉作用。 PERP(与PMP-22相关的P53效应蛋白)是一种膜蛋白，在细胞的稳定过程中起着至关重要的作用。 桥粒的组装，桥粒是细胞-细胞黏附大分子，对上皮完整性和 动态平衡。我最近发现，perp的失活会导致牙釉质缺陷，部分原因是 成釉细胞从中间层(SI)下层脱落。成釉细胞-SI界面为 PERP和桥粒之间的共同定位区域，高倍率图像显示 桥粒缺陷症。此外，perp基因缺失小鼠牙齿中的大量差异调控基因 已被确认。这些基因中有几个以前被描述为釉质发生的调节者，但大多数 从未被证明在这一过程中起到了作用。除了我最初的研究，我对它的功能知之甚少 以及PERP在成釉过程中的调控。 在这个应用程序中，我建议检验以下假设：perp的功能和调节在 成釉作用。这将通过对抗体处理的小鼠和各种小鼠遗传模型的分析来完成， 以及使用细胞培养的实验。成功完成这些研究对以下问题非常重要 人类的口腔健康关系到牙齿的正常发育。

ABSTRACT Enamel is the first and main line of defense against dental decay, and its proper formation is a prerequisite for strong, healthy teeth. Abnormalities in the molecular and cellular pathways that drive enamel formation (amelogenesis) result in amelogenesis imperfecta, a broad designation for a number of non-syndromic and syndromic enamel defects. A better mechanistic understanding of amelogenesis is important to devise new and improved strategies in the prevention, diagnosis, and treatment of dental caries and inherited disorders such as amelogenesis imperfecta. Because enamel is unique amongst mineralized tissues in its epithelial origin, genes involved in epithelial development and integrity such as Perp are excellent candidate regulators of amelogenesis. PERP (P53-effector related to PMP-22) is a membrane protein that plays an essential role in the stable assembly of desmosomes, which are cell-cell adhesion macromolecules central to epithelial integrity and homeostasis. I have recently found that inactivation of Perp leads to enamel defects, in part, due to the detachment of ameloblasts from the underlying stratum intermedium (SI) layer. The ameloblast-SI interface is an area of co-localization between PERP and desmosomes, and high magnification images revealed desmosomal defects. In addition, a large number of differentially regulated genes in the teeth of Perp-null mice was identified. Several of these genes are previously characterized regulators of amelogenesis but the majority has never been shown to play a role in this process. Beyond my initial studies, little is known about the function and regulation of Perp in amelogenesis. In this application, I propose to test the hypothesis that the function and regulation of Perp play a central role in amelogenesis. This will be done by the analyses of antibody-treated mice and various mouse genetic models, as well as experiments using cell culture. Successful completion of these studies is important for issues of human oral health related to proper tooth development.