Role of ameloblastin for ameloblasts and enamel formation

描述（由申请人提供）：NIDCR的指导临床科学家研究职业发展奖（K08）将为申请人提供成功的学术生涯和作为牙医科学家的科学独立性的培训。牙釉质的形成导致人体最硬的生物矿物。牙釉质形成障碍导致发育不全或矿化不足的牙釉质层或遗传或环境起源。为了培养成釉质病理生理学专家，提出了一个由教学课程和实验技术组成的培养计划。本实验旨在通过反馈机制研究釉基质蛋白在成釉细胞分化和成釉过程中的作用。我以前的工作对釉基质蛋白成釉蛋白（Ambn）已确定的主要裂解位点，产生片段与相反的定位和相反的命运。Ambn对于适当的釉质形成是必不可少的，因为釉质在Ambn缺失的小鼠中不存在，但是当作为Ambn转基因提供时，以剂量依赖性方式重新获得。这些发现导致了成釉细胞接受来自釉基质的反馈信号来调节其功能和釉质矿化的假设。在目的1中，Ambn在成釉细胞分化中的作用在体内被定义。在目标2中，通过突变主要切割位点来确定Ambn切割的相关性。在目的3中，探索通过去除釉质蛋白的潜在反馈机制。长期目标是了解釉基质和成釉细胞之间的信号通路，作为牙科新的诊断和治疗策略的方法。这些针对釉质矿化的细胞机制的研究对日常牙科实践产生了影响。

DESCRIPTION (provided by applicant): The Mentored Clinical Scientist Research Career Development Award (K08) from NIDCR will provide the applicant with training for a successful, academic career and scientific independence as a dentist-scientist. Enamel formation results in the hardest biomineral of the human body. Disturbances of enamel formation result in a hypoplastic or hypomineralized enamel layer or inherited or environmental origin. To develop into an expert in enamel pathophysiology, a training plan consisting of didactic courses and experimental techniques is proposed. The experimental plan aims to study the role of enamel matrix proteins for ameloblast cell differentiation and enamel formation though feedback mechanism. My previous work on the enamel matrix protein ameloblastin (Ambn) has identified the major cleavage site that generates fragments with opposing localizations and opposing fates. Ambn is essential to proper enamel formation, as enamel is absent in mice null for Ambn, but is regained in a dose-dependent manner when supplied as an Ambn transgene. These findings lead to the hypothesis that ameloblasts receive feedback signal from the enamel matrix to regulate their function and enamel mineralization. In Aim 1 the role of Ambn in ameloblasts differentiation is defined in vivo. In Aim 2 the relevance of Ambn cleavage is determined by mutating the major cleavage site. In Aim 3 potential feedback mechanisms via removal of enamel proteins are explored. The long-term goal is to understand the signaling pathways between enamel matrix and ameloblasts as an approach to new diagnostic and therapeutic strategies in dentistry. These studies directed at cellular mechanisms for enamel mineralization have impact on the daily dental practice.