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

NIDCR 牙医科学家 K99；Perp 在釉质形成中的功能和调节

• 批准号: 8723644
• 负责人: Andrew H. Jheon
• 金额: $ 24.54万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-20 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8723644
• 关键词: Adult; Affect; Ameloblasts; Amelogenesis; Amelogenesis Imperfecta; Animals; Antibodies; Area; Cell Culture Techniques; Cell-Cell Adhesion; Cre-LoxP; Data; Defect; Dental Enamel; Dental caries; Dentists; Desmosomes; Development; Diagnosis; Disease; Enamel Formation; Epithelial; Epithelium; Gene Targeting; Genes; Genetic; Genetic Models; Homeostasis; Human; Image; In Vitro; Inborn Genetic Diseases; Incisor; Knockout Mice; Ligands; Light; Membrane Proteins; Mentors; Molecular; Mus; NOTCH1 gene; National Institute of Dental and Craniofacial Research; Natural regeneration; Notch Signaling Pathway; Oral health; Organ; Pathway interactions; Perinatal; Phase; Phenotype; Play; Prevention; Process; Proteins; RNA Interference; Regulation; Role; Scientist; Signal Transduction; Stratum Intermedium; TP53 gene; Testing; Tissues; Tooth eruption; Tooth structure; amelogenin; improved; in vitro Assay; in vivo; jagged1 protein; macromolecule; mouse model; notch protein; postnatal; prenatal; research study

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.

抽象的 搪瓷是针对牙齿衰减的第一和主要防御线，其适当的形成是前提的先决条件 坚固，健康的牙齿。驱动搪瓷形成的分子和细胞途径的异常 （ameleogeny）导致无骨生成不完美，这是多种非综合症和 综合征搪瓷缺陷。更好地理解临时性对于设计新的理解很重要 并改善了龋齿和遗传疾病的预防，诊断和治疗方面的策略 例如无骨发生不完美。因为搪瓷在其上皮的矿化组织中是独一无二的 起源，涉及上皮发育和完整性（如PERP）的基因是极好的候选调节剂 的关注。 PERP（与PMP-22相关的p53效应器）是一种膜蛋白，在稳定中起着至关重要的作用 脱糖体的组装，它们是细胞粘附的大分子上皮完整性中心的大分子和 稳态。我最近发现，perp的失活导致牙釉质缺陷，部分原因是 从基础层中间层（SI）层的成成木分离。 ameloblast-si接口是 PERP和脱染色体之间的共定位区域，以及高放大图像揭示了 脱骨缺陷。另外，在无效小鼠的牙齿中大量差异调节的基因 被确定。这些基因中的几个以前是特征的，但大多数的调节剂 从未被证明在此过程中发挥作用。除了我最初的研究之外，对功能知之甚少 和perp的调节。 在此应用程序中，我建议检验以下假设：PERP的功能和调节在 醒目。这将通过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。这些研究的成功完成对于问题 人类口腔健康与适当的牙齿发育有关。