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: 9208130
• 负责人: Jeffery Todd Streelman
• 金额: $ 31.64万
• 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 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9208130
• 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 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; Reporting; Research; Resources; Shapes; Signal Transduction; Stem cells; Structure; System; Taste Buds; Testing; Tooth Germ; Tooth regeneration; Tooth structure; Translating; Variant; Vertebrates; World Health Organization; Zebrafish; beta catenin; collaborative approach; data integration; deciduous tooth; design; experimental study; immunocytochemistry; improved; innovation; insight; interest; mouse model; mutant; myogenesis; notch protein; novel; permanent tooth; postnatal; public health relevance; regenerative; repaired; small molecule; stem; tongue papilla; transcriptome

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）：拟议的研究的广泛目标是了解牙齿更新的分子机制和在再生牙齿中的复杂牙齿形状的模式。牙齿更新的现象在脊椎动物之间广泛保守（即，人类在生命的早期就替换每颗牙齿），但在实验室小鼠中不存在。我们的研究受益于实验系统（Cichlid Fishes，House，Human）的明确整合以及一种独特的方法，将新的分子和遗传生物学从鱼类转化为哺乳动物和背部。研究计划的特定目的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细胞种群以及负责（i）牙齿替代牙齿和（ii）替换牙齿形状的细胞群体和发育信号传导中心。我们重点介绍了牙齿和味蕾之间的新型关系，并利用鱼类，小鼠和人类系统的优势来测试一种协调的器官形状/更新模型。在特定目标下进行的实验3遵循丽鱼科鱼类的新分化筛查，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以前尚未在牙列中进行过研究，因此我们在人类中使用小鼠和分子生物学中的基因靶向来探索功能。总体而言，我们的协作方法旨在解决在标准实验室模型中难以研究的问题，因为它们要么完全替代牙齿（小鼠）或完全缺乏口腔牙齿（斑马鱼，小鸡）。我们旨在填补的空白 很重要。五分之一的人出现了影响牙列的遗传疾病，并且随着年龄的增长，几乎100％出现了问题（例如腔）。 65岁以上全球30％的人完全缺乏牙齿。我们拟议的研究将为如何将再生牙齿分配到更新和分化的协调区域的基本问题上，这是因为新的牙科器官从其前身和牙齿尖端上形成的新牙科器官。见解应促进以生物启发的再生牙科的创新策略。