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: 8639518
• 负责人: Jeffery Todd Streelman
• 金额: $ 31.83万
• 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 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8639518
• 关键词: Affect; Africa; Age; Agonist; Apoptosis; Back; Bicuspid; Biological Assay; Biology; Biomedical Engineering; Bromodeoxyuridine; Cell Proliferation; Cells; Cervical; Chemicals; Chickens; Cichlids; Cilia; Competence; Complex; Coupling; DNA Sequence; Data; Defect; Dental; Dental Implants; Dentistry; Dentition; Development; Elderly; Engineering; Epithelial; Epithelium; Exhibits; Family; Fibroblast Growth Factor; Fishes; Follistatin; Gene Expression; Gene Expression Profile; Gene Targeting; Generations; Genes; Genetic; Goals; Grant; Hereditary Disease; Human; In Situ Hybridization; In Situ Nick-End Labeling; Individual; Knockout Mice; Knowledge; Label; Laboratory mice; Life; Mammals; Modeling; Molecular; Molecular Biology; Molecular Genetics; Molecular Profiling; Morphogenesis; Mus; Mutation; Natural regeneration; Oral; Organ; Pathway interactions; Pattern; Phenocopy; Physiologic pulse; Population; Problem Solving; Process; Recruitment Activity; Reporting; Research; Resources; Shapes; Signal Transduction; Stem cells; Structure; System; Taste Buds; Testing; Tooth Germ; Tooth structure; Translating; Variant; Vertebrates; World Health Organization; Zebrafish; base; data integration; deciduous tooth; design; immunocytochemistry; improved; innovation; insight; interest; mouse model; mutant; myogenesis; notch protein; novel; permanent tooth; postnatal; public health relevance; regenerative; repaired; research study; small molecule; stem; tongue papilla

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.

描述（由申请人提供）：拟议研究的广泛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。我们的研究受益于实验系统（慈鲷鱼，小鼠，人类）的明确整合和一种独特的方法，将新的分子和遗传生物学从鱼类转化为哺乳动物。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）替换牙齿形状的细胞群和发育信号中心。我们强调牙齿和味蕾之间的一种新的关系，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。具体目标3下的实验遵循慈鲷鱼的新分化筛选，以发现控制脊椎动物替换牙齿形状的新基因。因为我们识别的基因以前没有在牙列中进行过研究，所以我们在小鼠中使用基因靶向技术，在人类中使用分子生物学技术来探索功能。总的来说，我们的合作方法旨在解决标准实验室模型难以研究的问题，因为它们要么不替换牙齿（小鼠），要么完全缺乏口腔牙齿（斑马鱼，小鸡）。我们致力于填补的空白 意义重大五分之一的人患有影响牙列的遗传性疾病，并且几乎100%的人随着年龄的增长而出现问题（例如蛀牙）。全世界65岁以上的人中有30%完全没有牙齿。我们提出的研究将为再生牙齿如何被划分为更新和分化的协调区域的基本问题提供答案，因为新的牙齿器官从它们的前辈和牙尖上形成。洞察力应该促进生物启发再生牙科的创新策略。