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

描述（由申请人提供）：牙釉质是防止蛀牙的第一道防线，牙釉质的正确形成是牙齿强壮健康的先决条件。驱动釉质形成（成釉）的分子和细胞通路异常导致成釉不完全性，这是许多非综合征性和综合征性釉质缺陷的广义名称。更好地了解淀粉性发育的机制对于设计新的和改进的预防、诊断和治疗龋齿和遗传性疾病（如淀粉性发育不全）的策略是重要的。由于牙釉质在矿化组织中的上皮起源是独一无二的，参与上皮发育和完整性的基因，如Perp，是极好的候选成釉发生调节因子。PERP（与PMP-22相关的p53效应物）是一种膜蛋白，在桥粒的稳定组装中起着至关重要的作用，桥粒是细胞间粘附的大分子，对上皮完整性和稳态至关重要。我最近发现Perp的失活会导致牙釉质缺陷，部分原因是由于成釉细胞从下层中间层（SI）脱离。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-null小鼠的牙齿中发现了大量的差异调控基因。这些基因中有几个先前被描述为成浆发育的调节因子，但大多数从未被证明在这一过程中发挥作用。除了我的初步研究外，对Perp在淀粉体发育中的功能和调控知之甚少。在这个应用中，我建议测试Perp的功能和调节在淀粉体发育中起核心作用的假设。这将通过分析抗体处理的小鼠和各种小鼠遗传模型，以及使用细胞培养的实验来完成。这些研究的成功完成对于人类口腔健康与牙齿发育有关的问题具有重要意义。

DESCRIPTION (provided by applicant): 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 were 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.