Patterning the Vertebrate Dentition Through Replacement and Repair

描述（由申请人提供）：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性疾病。更高的百分比发展牙齿缺陷（例如，牙齿脱落、龋齿）。人类在其生命的早期仅更换一次完整的牙列，并且更换畸形或缺失牙齿的常见策略使用合成材料。现在，人们对通过牙齿干细胞再生的自然机制进行牙齿修复产生了浓厚的兴趣。因此，研究针对的是牙齿发育的复杂过程;如果我们了解自然如何制造和替换牙齿和牙齿组织，我们可能会更好地理解如何设计生物牙齿修复。虽然许多牙齿发育的细节已经使用实验室小鼠学习，我们还没有完全了解牙齿发生。这是因为小鼠只有一个单一的（非替代），高度衍生的牙列，包括一个门牙和三个臼齿在每个下颌象限。老鼠的门牙通过唇侧干细胞龛持续生长，但臼齿则不然。其他模型尚未完全开发，以补充小鼠的研究;鸟类完全没有牙齿，斑马鱼咽部的齿列减少（没有口腔颌齿）。我们的研究重点是如何在一个进化模型系统中表现出非凡的牙齿多样性的齿系图案的基本问题。我们研究慈鲷鱼马拉维湖（东非），并已使用以前的NIH支持（R 03，R21），将这种自然组合的物种转化为一个强大的发展模式。我们的目标是使用遗传和基因组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。该提案有三个具体目标，将：（i）识别天然牙齿替换模式的分子，（ii）在自然人群中将牙齿形状基因座精细映射到基因分辨率，以及（ii）通过阶段和浓度特定的化学处理来操纵（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，通过动态牙科干细胞龛将牙齿替换和更新与牙齿形状相结合。这些目标是重要的，因为他们描述了新的生物学发现，通过一个强有力的整合策略，在一个新的动物模型的牙。 公共卫生相关性：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），确定牙齿形状的新遗传调节因子（目标2），并通过实验操纵这些途径来调节牙齿形状和替换（目标3）。慈鲷牙齿替换和形状的遗传和发育基础的知识，将提供一般的洞察脊椎动物牙发生和牙齿干细胞生物学，并将在小鼠和斑马鱼的研究提供重要的比较数据。结果可能会确定新的治疗目标，人类牙齿疾病，和新的途径，生物修复，保证进一步测试在哺乳动物和鱼类模型。

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.