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: 8300822
• 负责人: Andrew H. Jheon
• 金额: $ 12.74万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-13 至 2013-08-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8300822
• 关键词: Adult; Affect; Ameloblasts; Amelogenesis; Amelogenesis Imperfecta; Animals; Antibodies; Area; Cell Culture Techniques; Cell-Cell Adhesion; 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

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.

描述（由申请人提供）：牙釉质是防止蛀牙的第一道也是主要防线，其正确形成是牙齿坚固、健康的先决条件。驱动牙釉质形成（牙釉质生成）的分子和细胞途径异常会导致牙釉质生成不全，这是许多非综合征性和综合征性牙釉质缺陷的广义名称。更好地理解釉质生成的机制对于设计预防、诊断和治疗龋齿和遗传性疾病（例如釉质生成不全）的新的和改进的策略非常重要。由于牙釉质在其上皮起源的矿化组织中是独一无二的，因此参与上皮发育和完整性的基因（例如 Perp）是釉质生成的极好的候选调节剂。 PERP（与 PMP-22 相关的 P53 效应子）是一种膜蛋白，在桥粒的稳定组装中发挥重要作用，桥粒是细胞间粘附大分子，对上皮完整性和稳态至关重要。我最近发现 Perp 失活会导致牙釉质缺陷，部分原因是成釉细胞与下面的中间层 (SI) 层分离。成釉细胞-SI 界面是 PERP 和桥粒之间的共定位区域，高放大倍数图像显示桥粒缺陷。此外，在 Perp-null 小鼠的牙齿中发现了大量差异调节基因。其中一些基因以前被认为是釉质形成的调节因子，但大多数从未被证明在这一过程中发挥作用。除了我最初的研究之外，人们对 Perp 在釉质形成中的功能和调节知之甚少。 在本申请中，我建议检验 Perp 的功能和调节在釉质形成中发挥核心作用的假设。这将通过对抗体治疗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。成功完成这些研究对于与牙齿正常发育相关的人类口腔健康问题非常重要。

项目成果

Characterization of X-linked hypohidrotic ectodermal dysplasia (XL-HED) hair and sweat gland phenotypes using phototrichogram analysis and live confocal imaging.

• DOI: 10.1002/ajmg.a.35959
• 发表时间: 2013-07
• 期刊: AMERICAN JOURNAL OF MEDICAL GENETICS PART A
• 影响因子: 2
• 作者: Jones, Kyle B.;Goodwin, Alice F.;Landan, Maya;Seidel, Kerstin;Dong-Kha Tran;Hogue, Jacob;Chavez, Miquella;Fete, Mary;Yu, Wenli;Hussein, Tarek;Johnson, Ramsey;Huttner, Kenneth;Jheon, Andrew H.;Klein, Ophir D.
• 通讯作者: Klein, Ophir D.