Patterning the Vertebrate Dentition Through Replacement and Repair

描述(申请人提供)：四分之一的人类在牙齿数量、牙齿间距和/或牙齿形状方面表现出牙齿遗传疾病。随着年龄的增长，出现牙齿缺陷(例如，牙齿脱落、龋齿)的比例更高。人类在生命的早期只更换一次完整的牙列，而更换畸形或缺失牙齿的常见策略是使用合成材料。现在人们对通过牙齿干细胞更新的自然机制进行牙齿修复非常感兴趣。因此，研究的目标是牙齿发育的复杂过程；如果我们了解大自然是如何创造和取代牙齿和牙齿组织的，我们可能会更好地理解如何设计生物牙齿修复。虽然已经通过实验室小鼠了解了牙齿发育的许多细节，但我们还没有完全了解牙齿发育。这是因为小鼠只有一个(不可替代的)高度衍生的牙列，由每个颌象限的一颗门牙和三颗磨牙组成。小鼠的门牙通过唇部干细胞巢持续生长，但磨牙不能。其他模型还没有被完全开发来补充在老鼠身上的研究；鸟类完全没有牙齿，斑马鱼在咽部的牙齿减少(没有口腔颌牙)。我们的研究集中在一个基本问题上，即在一个显示出非凡的牙齿多样性的进化模型系统中，牙列是如何形成模式的。我们研究了来自马拉维湖(东非)的慈嘴鱼，并利用先前的NIH支持(R03，R21)将这种自然物种组合转变为强大的发展模式。我们的目标是使用遗传学和基因组学方法来了解牙齿发育的复杂性，因为这些数据可以为生物牙齿修复提供信息。这项提议有三个具体目标，这将：(I)识别形成自然牙齿替换模式的分子，(Ii)精细地将牙齿形状基因座映射到自然种群中的基因分辨率，以及(Ii)通过特定阶段和特定浓度的化学处理来操纵(I)和(Ii)中发现的分子途径。我们将整合这些研究，旨在测试一种模型，该模型通过动态的牙齿干细胞利基将牙齿替换和更新与牙齿形状结合起来。这些目标意义重大，因为它们描述了通过在一种新的牙齿发育动物模型中采用高度整合的策略发现的新生物学。 与公共卫生相关：实现这里概述的具体目标将：确定将牙齿替换与牙齿形状相结合的分子途径(目标1)，确定新的牙齿形状遗传调节因子(目标2)，并通过实验操作这些途径来调节牙齿形状和替换(目标3)。对齿轮齿替换和形状的遗传和发育基础的了解将有助于对脊椎动物牙齿发生和牙齿干细胞生物学的总体洞察，并将为老鼠和斑马鱼的研究提供重要的比较数据。结果可能确定人类牙病的新治疗靶点，以及生物修复的新途径，这些值得在哺乳动物和鱼类模型中进行进一步测试。

DESCRIPTION (provided by applicant): A quarter of all humans exhibit dental genetic disorders in tooth number, tooth spacing, and/or tooth shape. A higher percentage develops dental defects (e.g., tooth loss, dental caries) with age. Humans replace a full dentition only once early in their lifetimes, and common strategies to replace malformed or missing teeth employ synthetic materials. There is now keen interest in tooth repair via natural mechanisms of dental stem cell renewal. Research has therefore targeted the complex process of tooth development; if we understand how nature makes and replaces teeth and dental tissues, we may better appreciate how to engineer biological tooth repair. While many specifics of tooth development have been learned using the laboratory mouse, we do not yet fully understand odontogenesis. This is because mice possess only a single (non-replacing), highly derived dentition comprised of one incisor and three molars on each jaw quadrant. The mouse incisor grows continually via a labial stem cell niche, but molars do not. Other models have not been fully developed to complement research in the mouse; birds lack teeth altogether and zebrafish have a reduced dentition in the pharynx (no oral jaw teeth). Our research focuses on the basic question of how dentitions are patterned in an evolutionary model system exhibiting extraordinary dental diversity. We study cichlid fishes from Lake Malawi (East Africa) and have used prior NIH support (R03, R21) to transform this natural assemblage of species into a powerful developmental model. Our goal is to use genetic and genomic approaches to understand the complexities of tooth development, because these data can inform biological tooth repair. This proposal has three specific aims, which will: (i) identify the molecules that pattern natural tooth replacement, (ii) fine-map a tooth shape locus to gene resolution in natural populations, and (ii) manipulate the molecular pathways found in (i) and (ii) via stage- and concentration-specific chemical treatments. We will integrate these research aims to test a model that couples tooth replacement and renewal to tooth shape via a dynamic dental stem cell niche. These aims are significant because they describe new biology discovered via a strongly integrative strategy in a new animal model of odontogenesis. PUBLIC HEALTH RELEVANCE: Accomplishing the specific aims outlined here will: identify the molecular pathways that couple tooth replacement to tooth shape (Aim 1), identify a new genetic regulator of tooth shape (Aim 2), and experimentally manipulate these pathways to modulate tooth shape and replacement (Aim 3). Knowledge of the genetic and developmental basis of cichlid tooth replacement and shape will lend general insight into vertebrate odontogenesis and dental stem cell biology, and will contribute important comparative data for studies in mouse and zebrafish. Results may identify novel therapeutic targets for human dental disorders, and new pathways for biological repair, that warrant further testing in mammalian and fish models.