Patterning the Vertebrate Dentition Through Replacement and Repair

通过更换和修复来塑造脊椎动物的牙列

• 批准号: 8231481
• 负责人: Jeffery Todd Streelman
• 金额: $ 21.3万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-15 至 2013-03-20
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8231481
• 关键词: Activins; Adult; Affect; Africa; Age; Animal Model; Animals; Bicuspid; Biological; Biological Models; Biology; Birds; Chemicals; Chromosome Mapping; Chromosomes, Human, Pair 5; Cichlids; Complement; Complex; Couples; Coupling; Cuspid; Data; Defect; Dental; Dental caries; Dentition; Development; Embryo; Engineering; Erinaceidae; Exhibits; Fishes; Gene Expression; Genes; Genetic; Genetic Drift; Genetic Polymorphism; Genome; Genomics; Goals; Growth; Haplotypes; Hereditary Disease; Human; In Situ Hybridization; Incisor; Jaw; Knowledge; Laboratory mice; Learning; Ligands; Malawi; Maps; Mediating; Modeling; Molecular; Mus; National Human Genome Research Institute; Nature; Odontogenesis; Oral; Pathway interactions; Pattern; Pharyngeal structure; Phenotype; Population; Positioning Attribute; Process; Research; Resolution; SU5402; Shapes; Signal Pathway; Staging; Structure; Testing; Tissues; Tooth Diseases; Tooth Germ; Tooth Loss; Tooth structure; United States National Institutes of Health; Zebrafish; base; comparative; cyclopamine; dental genetics; developmental genetics; genetic pedigree; insight; interest; new therapeutic target; notch protein; novel; public health relevance; repaired; stem cell biology; stem cell division; stem cell niche

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.

描述（由申请人提供）：四分之一人的牙齿数量，牙齿间距和/或牙齿形状表现出牙科遗传疾病。随着年龄的增长，较高的百分比会出现牙齿缺陷（例如牙齿脱落，龋齿）。人类一生中只能更换一次全牙，而替换牙齿或缺失牙齿的常见策略则采用合成材料。现在，通过牙科干细胞更新的自然机制，人们对牙齿修复有浓厚的兴趣。因此，研究针对牙齿发育的复杂过程。如果我们了解自然如何制造和替代牙齿和牙科组织，我们可能会更好地欣赏如何设计生物牙齿修复。尽管使用实验室小鼠学习了许多牙齿发育的细节，但我们尚未完全理解牙胎。这是因为小鼠只有一个（非替代），高度衍生的牙齿，由一个切牙和三个牙齿象限组成。小鼠门牙通过唇干细胞生态位不断生长，但磨牙却没有。其他模型尚未完全开发以补充小鼠中的研究。鸟类完全缺乏牙齿，斑马鱼在咽部的牙列降低（无口腔下颌牙齿）。我们的研究重点是在表现出非凡牙齿多样性的进化模型系统中如何对牙齿进行图案的基本问题。我们研究来自马拉维湖（东非）的丽鱼科鱼，并使用了先前的NIH支持（R03，R21）将物种的天然组合转变为强大的发展模型。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依据。该提案具有三个特定的目的：（i）确定对天然牙齿替代的分子，（ii）牙齿形状的牙齿形状基因座量到自然种群中的基因分辨率，以及（ii）通过（I）和（II）通过阶段和浓度特定的化学处理来操纵在（I）和（II）中发现的分子途径。我们将整合这些研究的目的是测试通过动态牙科干细胞生态位测试将牙齿替代并更新为牙齿形状的模型。这些目标很重要，因为它们描述了通过新的牙形成动物模型中强烈整合策略发现的新生物学。 公共卫生相关性：实现此处概述的特定目的将：确定将牙齿替换为牙齿形状的分子途径（AIM 1），确定牙齿形状的新遗传调节剂（AIM 2），并在实验中操纵这些途径以调节牙齿形状和替换（AIM 3）。了解丽鱼科替代牙齿和形状的遗传和发育基础的知识将为脊椎动物牙肠发生和牙科干细胞生物学提供一般见解，并将为小鼠和斑马鱼研究提供重要的比较数据。结果可能会确定人类牙齿疾病的新型治疗靶标，以及生物修复的新途径，需要在哺乳动物和鱼类模型中进行进一步测试。