Developmental Dynamics of Enamel Formation

描述(申请人提供)：牙冠的形态由编码釉质基质蛋白的成釉细胞特定基因的严格时空表达控制。一旦成釉细胞沿着牙本质-釉质连接处(DEJ)进入分化阶段，并开始分泌釉质基质蛋白，它们也开始离开DEJ并向外釉质表面(OES)移动，同时形成釉质棱柱。一旦成釉细胞到达OES，同位生长在局部终止，这种过渡扩散到位于尖端更远的细胞，直到到达宫颈边缘(CM)的细胞。当釉质因同位生长而增厚时，它也会变宽(随着更多的成釉细胞分化并将DEJ延伸到牙冠的斜坡上)。随着最后一环的成釉细胞进入分泌期，这种延伸最终减慢并最终停止，也是在CM处。釉质的形成受到分子节律信号的影响，分子信号以短时间(24小时)出现，并产生交叉条纹，或垂直于每个棱镜的线。另一种更明显的干扰发生在较长的周期内(每6-10天发生一次，视个体而定)，并诱导形成雷祖斯纹状体(SR)，这是长期生长的标志。人们对牙釉质形成的调控机制知之甚少，但对短期和长期生长线的仔细分析应该可以量化决定发育过程中牙冠形状的关键参数。我们假设，这些发育事件可以在一个概念性框架内得到最好的理解，该框架设想釉质冠形状由五个参数的生物调节决定：1)同位生长速率，2)同位生长持续时间，3)延长率，4)成釉细胞延展持续时间，5)同位终止扩展速率。我们还假设，由于釉质形成的记录可以通过横纹和SR线来识别，因此获得控制成釉细胞层形状的五个参数的准确数值是可行的，并可能改善我们对釉质形成的理解。我们的具体目标是：(1)测量代表对位、延伸和终止过程的釉质生长线之间的距离，并确定记录每日釉质形成的标志物；以及(2)开发一个数学模型，通过基于对实际决定牙冠形状的生长和发育参数的测量，精确模拟牙釉质生长，生成牙冠的3D计算机化重建。这些信息将填补我们对釉质发育知识的关键空白，提高对病理性釉质形成的理解，也可能为牙齿组织工程提供数学基础。 与公共健康相关：牙齿逐渐形成，牙釉质中有特有的短期和长期生长标记。我们假设可以使用显微技术的组合准确地测量这些标记。我们还认为，获得的值可以用数学表示并用于生成牙釉质形成的3D模型，目的是增加我们对牙釉质发育和影响牙釉质的疾病的了解。

DESCRIPTION (provided by applicant): The morphology of a dental crown is controlled by a strictly regulated spatio-temporal expression of ameloblast specific genes encoding for enamel matrix proteins. Once ameloblasts enter the differentiation stage along the dentino-enamel junction (DEJ) and begin to secrete enamel matrix proteins, they also start moving away from the DEJ and toward the outer enamel surface (OES) whilst forming enamel prisms. Once ameloblasts reach the OES, appositional growth terminates locally and this transition spreads to the cells located farther down the cusp until it reaches the cells at the cervical margin (CM). As the enamel thickens due to appositional growth, it also broadens (as more ameloblasts differentiate and extend the DEJ down the slopes of the crown). This extension eventually slows down and finally stops as the last ring of ameloblasts enter secretory stage, also at the CM. Enamel formation is subjected to rhythmical molecular signals that occur on short (24 hour) periods and give rise to cross-striations, or lines perpendicular to each prism. Another, more marked disturbance, occurs over longer periods (once every 6-10 days depending upon the individual), and induces the formation of striae of Retzius (SR), which are long-period growth markers. Little is known about the mechanisms regulating enamel formation, but careful analysis of short- and long-period growth lines should permit quantification of the critical parameters that determine crown shape during development. We hypothesize that these developmental events are best understood within a conceptual framework that envisions enamel crown shape to be determined by the biological regulation of five parameters: 1) appositional growth rate, 2) duration of appositional growth, 3) extension rate, 4) the duration of ameloblast extension, and 5) spreading rate of appositional termination. We also hypothesize that because a record of enamel formation can be identified by cross- striations and SR lines, obtaining accurate numerical values for the five parameters governing the shape of the ameloblast layer is feasible and might improve our understanding of how enamel forms. Our specific aims are: (1) To measure the distances between enamel growth lines representative of the apposition, extension, and termination processes and to identify landmarks documenting daily enamel formation; and (2) To develop a mathematical model that generates a 3D computerized reconstruction of the crown by accurately simulating dental enamel growth based upon measurements of the growth and developmental parameters that actually determine crown form. This information will fill critical gaps in our knowledge of enamel development, improve understanding pathological enamel formation and may also provide a mathematical foundation for dental tissue engineering. PUBLIC HEALTH RELEVANCE: Teeth form incrementally with characteristic short- and long-period growth markings in enamel. We hypothesize that these markings can be accurately measured using a combination of microscopic techniques. We also believe that the values obtained can be represented mathematically and used to generate a 3D model of enamel formation with the aim of increasing our understanding of development and of diseases affecting enamel.