Role of ameloblastin for ameloblasts and enamel formation

描述(由申请者提供)：NIDCR颁发的临床科学家指导研究职业发展奖(K08)将为申请者提供作为牙医科学家的成功的学术生涯和科学独立性的培训。牙釉质的形成会导致人体内最坚硬的生物矿物。釉质形成障碍会导致釉质发育不良或矿化程度较低的釉质层，或遗传或环境原因。为了发展成为牙釉质病理生理学的专家，提出了一种由教学课程和实验技术组成的培训计划。本实验旨在通过反馈机制研究釉质基质蛋白在成釉细胞分化和釉质形成中的作用。我之前在釉质基质蛋白成釉蛋白(AmBN)上的工作已经确定了产生具有相反定位和相反命运的片段的主要切割位点。AMBN对于牙釉质的正常形成是必不可少的，因为在小鼠体内不存在AMBN阴性的釉质，但当提供AMBN转基因时，它会以剂量依赖的方式重新获得。这些发现导致了一种假设，即成釉细胞从釉质基质中接收反馈信号来调节其功能和釉质矿化。目的1在体内研究AMBN在成釉细胞分化中的作用。在目标2中，AMBN裂解的相关性是通过突变主要裂解位点来确定的。在AIM中，通过去除釉质蛋白来探索3种潜在的反馈机制。长期目标是了解釉质基质和成釉细胞之间的信号通路，以此作为牙科新的诊断和治疗策略的途径。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.