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

说明(申请人提供)：釉质是防止龋齿的第一道也是主要的防线，其正确的形成是坚固健康牙齿的先决条件。驱动釉质形成的分子和细胞途径的异常(成釉发生)会导致成釉不全，这是对许多非综合征性和综合征性釉质缺陷的广泛称呼。更好地理解釉质发生的机制对于制定新的和改进的预防、诊断和治疗龋病和遗传性疾病(如釉质形成不全)的策略是重要的。由于釉质在矿化组织中是独一无二的，其上皮起源，参与上皮发育和完整性的基因，如perp，是釉质形成的优秀候选调节器。PERP(与PMP-22相关的P53效应蛋白)是一种膜蛋白，在桥粒的稳定组装过程中起着至关重要的作用，桥粒是细胞与细胞之间的黏附大分子，对上皮的完整性和动态平衡至关重要。我最近发现，Perp的失活会导致釉质缺陷，部分原因是成釉细胞从底层中间层(SI)分离。成釉细胞-SI界面是PerP和桥粒共同定位的区域，高倍镜下可见桥粒缺陷。此外，在perp基因缺失小鼠的牙齿中发现了大量差异调控基因。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发挥作用。除了我最初的研究，人们对Perp在成釉过程中的作用和调控知之甚少。在这一应用中，我建议检验Perp的功能和调控在成釉过程中发挥核心作用的假设。这将通过对抗体处理的小鼠和各种小鼠遗传模型的分析，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与牙齿正常发育相关的人类口腔健康问题非常重要。 与公众健康相关：釉质是牙齿的外层，是防止龋齿的主要防线，其适当的形成是坚固、健康牙齿的先决条件。鉴于釉质是人体中为数不多的不能再生的组织之一，更好地了解釉质形成的机制对于潜在地设计出预防、诊断和治疗龋齿和其他牙齿相关疾病的新的和改进的策略是很重要的。

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. PUBLIC HEALTH RELEVANCE: Enamel is the outer layer of teeth that is the main line of defense against dental decay, and its proper formation is a prerequisite for strong, healthy teeth. In light of the fact that enamel is one of the few tissues in our bodies that is not capable of regeneration, a better mechanistic understanding of enamel formation is important to potentially devise new and improved strategies in the prevention, diagnosis, and treatment of dental caries and other tooth-related disorders.