Ameloblastin Function in Periodontal Development

描述（由申请人提供）：哺乳动物牙周组织是一种独特的支撑结构，通过提供牢固的附着和对压力的弹性反应，将牙齿固定在颌骨中。连接牙根表面和牙槽骨的非矿化牙周韧带（PDL）促进了牙周组织的弹性。我们实验室最近的研究表明，在牙周重塑过程中，成釉蛋白（AMBN）上调了300倍（Holliday等人2005年，Luan等人2007年）。此外，我们将AMBN定位在Hertwig's上皮根鞘（HERS）中，并发现AMBN在溶液和凝胶中对PDL矿化和晶体形成有抑制作用。我们的K14启动子驱动、AMBN过表达的转基因小鼠模型与野生型对照相比，具有强健的牙周表型，其根骨质表面结构、颈牙槽骨高度、牙周韧带宽度和牙釉质结构都发生了变化。临床研究表明，牙釉质基质衍生物（EMD）对预防强直有积极作用（Iqbal和Bamaas 2001年，Filippi等人2001年），成釉细胞素和淀粉原蛋白基因敲除模型显示PDL高钙化的证据（Fukomoto等人2004年，Hatakeyama等人2006年），这些研究结果都强调了我们的发现。总之，这些初步研究为研究计划提供了基础，其中我们将解决AMBN是否是参与牙周发育和矿物质稳态的独特HERS产品的问题。拟议的研究旨在探索和开发新的临床辅助手段，以造福数百万患有牙周病的美国人。

DESCRIPTION (provided by applicant): The mammalian periodontium is a unique support structure that anchors teeth in the jaw bone by providing firm attachment and resilient responsiveness to pressures. Much of the resilient properties of the periodontium are facilitated by a non-mineralized periodontal ligament (PDL) that connects the root surface with the alveolar bone. Recent studies from our laboratory have suggested that ameloblastin (AMBN) was 300-fold upregulated during periodontal remodeling (Holliday et al. 2005, Luan et al. 2007). In addition, we have localized AMBN in Hertwig's Epithelial Root Sheath (HERS) and revealed an inhibitory effect of AMBN on PDL mineralization and crystal formation in solution and gels. Our K14 promoter-driven, AMBN overexpressing transgenic mouse model featured a robust periodontal phenotype with changes in root cementum surface structure, cervical alveolar bone height, periodontal ligament width, and altered enamel structure compared to wild-type controls. Our findings were underscored by clinical studies that have shown a positive effect of enamel matrix derivatives (EMD) on the prevention of ankylosis (Iqbal and Bamaas 2001, Filippi et al. 2001) and by ameloblastin and amelogenin gene knockout models displaying evidence of PDL hypercalcification (Fukomoto et al. 2004, Hatakeyama et al. 2006). Together, these preliminary studies provide the basis for a research plan in which we will address the question whether AMBN is a unique HERS product involved in periodontal development and mineral homeostasis. Proposed studies are designed to explore and develop novel clinical aids to the benefit of Millions of Americans suffering from periodontal disease. PUBLIC HEALTH RELEVANCE: One of the most unique features of tooth gums is the elastic but firm attachment of tooth roots to the jaw bone. Here we will conduct a series of studies to investigate the effect of a unique gene product (called ameloblastin) in the formation of tooth attachment. These studies might eventually lead to novel cures for gum diseases.