Patterning the vertebrate dentition through replacement and repair

描述（由申请人提供）：拟议研究的主要目标是了解牙齿更新的分子机制和再生牙列中复杂牙齿形状的模式。牙齿更新的现象在脊椎动物中广泛保守（即，人类在生命早期更换每颗牙齿一次），但在实验室小鼠中不存在。我们的研究得益于实验系统的明确整合（慈鲷鱼，小鼠，人类）和一种独特的方法，将新的分子和遗传生物学从鱼类转化为哺乳动物。在研究计划的具体目标1和2中描述的实验使用分子和化学生物学来识别和操纵负责(i)牙齿替换和（ii）牙齿替换形状的细胞群和发育信号中心。我们强调了牙齿和味蕾之间的新关系，并利用鱼类、小鼠和人类系统的优势来测试协调器官形状/更新的模型。在Specific Aim 3下的实验从慈鲷鱼的新分化筛选开始，发现控制脊椎动物替代牙齿形状的新基因。由于我们鉴定的基因之前没有在牙列中进行过研究，因此我们在小鼠中使用基因靶向，在人类中使用分子生物学来探索其功能。总的来说，我们的合作方法旨在解决在标准实验室模型中难以研究的问题，因为它们要么不能替换牙齿（小鼠），要么完全没有口腔牙齿（斑马鱼，小鸡）。我们要填补的空白

DESCRIPTION (provided by applicant): The broad goal of the proposed research is to understand molecular mechanisms of dental renewal and the patterning of complex tooth shapes in regenerating dentitions. The phenomenon of tooth renewal is broadly conserved across vertebrates (i.e., humans replace each tooth once early in life) but is absent in the laboratory mouse. Our research benefits from explicit integration of experimental systems (cichlid fishes, mouse, human) and a unique approach translating new molecular and genetic biology from fishes to mammals and back. Experiments described in Specific Aims 1 and 2 of the research plan use molecular and chemical biology to identify and manipulate cell populations and developmental signaling centers responsible for (i) tooth replacement and (ii) replacement tooth shape. We highlight a novel relationship between teeth and taste buds and exploit the strengths of fish, mouse and human systems to test a model of coordinated organ shape/renewal. Experiments under Specific Aim 3 follow from a new differentiation screen in cichlid fishes to discover novel genes controlling vertebrate replacement tooth shape. Because the genes we identify have not been studied in dentitions before, we use gene targeting in the mouse and molecular biology in humans to explore function. Overall, our collaborative approach is designed to solve problems difficult to study in standard lab models because they either do not replace teeth (mouse) or lack oral teeth altogether (zebrafish, chick). The gaps we aim to fill are significant. One in five humans presents with a genetic disorder affecting the dentition and nearly 100% develop problems (e.g, cavities) with age. 30% of people worldwide over the age of 65 lack teeth entirely. Our proposed research will provide answers to the basic question of how regenerating teeth are partitioned into coordinated zones of renewal and differentiation, as new dental organs develop from their predecessors and cusps form on tooth tips. Insights should promote innovative strategies for bio-inspired regenerative dentistry.