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

摘要 牙釉质是防止蛀牙的第一道也是最主要的防线，它的正确形成是防止蛀牙的先决条件。 坚固、健康的牙齿。在驱动釉质形成的分子和细胞途径中的抑制作用 （釉质发生）导致釉质发生失稳，这是对许多非综合征和 综合征性牙釉质缺损更好地理解釉质发生的机制对于设计新的 以及预防、诊断和治疗龋齿和遗传性疾病的改进策略 如釉质发生的非特异性。由于釉质是其上皮中的矿化组织中唯一的 起源，参与上皮发育和完整性的基因，如Perp是极好的候选调节因子 釉质形成的过程 PERP（P53-effector related to PMP-22）是一种膜蛋白，其在稳定的细胞周期中起重要作用。 桥粒的组装，桥粒是上皮完整性的细胞-细胞粘附大分子， 体内平衡我最近发现Perp的失活导致牙釉质缺陷，部分原因是 成釉细胞从下面的中间层（SI）层分离。成釉细胞-SI界面是 PERP和桥粒之间的共定位区域，高倍图像显示 桥粒缺陷此外，在Perp基因敲除小鼠的牙齿中， 被确认了这些基因中有几个以前被表征为釉质形成的调节因子，但大多数 从未被证明在这个过程中发挥作用。除了我最初的研究， 以及Perp在釉质形成中的调节作用。 在这个应用中，我建议测试的假设，功能和调节的Perp发挥核心作用， 釉质形成这将通过分析抗体处理的小鼠和各种小鼠遗传模型来完成， 以及使用细胞培养的实验。成功完成这些研究对于解决 人类口腔健康与牙齿发育有关。

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.