Control of reptilian dental patterning and tooth replacement in 4D

4D 中爬行动物牙齿图案和牙齿替换的控制

• 批准号: 9394998
• 负责人: Theresa Marie Grieco
• 金额: $ 0.97万
• 依托单位: UNIVERSITY OF BRITISH COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-16 至 2018-01-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9394998
• 关键词: Address; Adult; Agonist; Anatomy; Animals; Anterior; Apoptosis; Back; Biological; Biological Models; Bite; Black Panther; Cell Proliferation; Cells; Child; Cichlids; Circadian Rhythms; Clinical; Data; Dental; Dental Care; Dental arch structure; Dentition; Development; Diffusion; Disease; Embryo; Epithelial; Epithelium; Evaluation; Family; Frequencies; Gene Expression; Gene Expression Profile; Generations; Genes; Goals; Growth; Hereditary Disease; Human; In Vitro; Injectable; Injury; Investigation; Jaw; Knowledge; Label; Lead; Learning; Length; Life; Location; Longitudinal Studies; Mammals; Maps; Measurement; Mesenchyme; Methods; Microscopic; Modeling; Modernization; Molecular; Molecular Analysis; Morphology; Mus; Mutation; Natural regeneration; Observational Study; Odontogenesis; Operative Surgical Procedures; Oral cavity; Pathway interactions; Pattern; Periodicity; Phenotype; Postdoctoral Fellow; Process; Proliferating; Reagent; Regulation; Reptiles; Research; Role; Signal Pathway; Signal Transduction; Site; Skin; Speed; Stem cells; Structure; Testing; Time; Tissues; Tooth structure; Trauma; WNT Signaling Pathway; Waxes; Work; X-Ray Computed Tomography; Zebrafish; adult stem cell; base; bone; deciduous tooth; egg; experimental study; hatching; impression; in vivo; infancy; inhibitor/antagonist; insight; interest; notch protein; outcome prediction; public health relevance; reconstruction; regenerative; response; small molecule; transmission process

DESCRIPTION (provided by applicant): The long term goal of the proposed research is to discover the molecular basis for life-long tooth succession in reptiles and to apply this knowledge to the regeneration of human teeth. The post-doctoral fellow will be using a unique model, the leopard gecko, for this project. There are two main benefits to using reptiles as opposed to the more typical model, the mouse. First, reptiles are amniotes and thus share a common ancestry with mammals. What we learn in reptiles is relevant for humans. Second, tooth replacement in reptiles is on-going, independent of wear or injury and is rapid (30-90 days) thus it is feasible to study the process in a lab setting. In contrast, mammals have at most two sets of teeth and usually the second generation continues to form well into the post-natal period. The first question to be addressed is what is the precise timing and pattern of tooth replacement in healthy adult reptiles? To answer these questions, the leopard gecko is used as the model. These animals are easy to handle and it is possible to adapt many dental procedures used for humans to their smaller mouths. Miniature, serial wax bites and �CT scans will be taken over a 6 month period and measurements of when teeth are lost and replaced will be taken. The tooth replacement phenotypes will then be correlated with the expression of genes in the dental tissues. We are interested in finding genes that are periodically expressed along the length of the jaw since some of these may coordinate tooth spacing and timing of induction of replacement teeth. The second question to be addressed is what are the long term sequelae of disrupting the activity of the dental lamina on the patterns of tooth replacement? To answer this question, micro surgeries will be carried out in adult geckos including cutting of the dental lamina. The outcomes are predicted to be a change in the spacing or rate of tooth replacement that can be traced back to molecular changes in the dental epithelium. The third and final question to be asked is what are the molecular controls of tooth patterning and induction during embryonic initiation and adult replacement? The roles of two candidate molecules will be studied. These two pathways, called Wingless related (Wnt) and Notch were selected in part because mutations in Wnt increase or decrease tooth number in humans, and because Notch- Delta signalling is known to regulate cell fate decisions between adult stem cell renewal and differentiation along with its role in regulating developmental clock mechanisms. To mirror the human condition, to look for evidence of homeostatic switches regulating tooth renewal, activators or inhibitors of Wnt and Notch will be injected into eggs and the effects on tooth epithelial growth and patterning will be studied. The synergistic research partnership between the applicant/postdoctoral fellow and supervisor will one day lead to more natural ways to replace teeth lost to disease or injury.

描述（由申请人提供）：拟议研究的长期目标是发现爬行动物终身牙齿继承的分子基础，并将这些知识应用于人类牙齿的再生。博士后研究员将使用一个独特的模型，豹壁虎，为这个项目。使用爬行动物与更典型的模型小鼠相比有两个主要好处。第一，爬行动物是爬行动物，因此与哺乳动物有着共同的祖先。我们在爬行动物身上学到的东西与人类有关。第二，爬行动物的牙齿替换是持续的，与磨损或损伤无关，并且是快速的（30-90天），因此在实验室环境中研究这个过程是可行的。相比之下，哺乳动物最多有两套牙齿，通常第二代在出生后继续形成。第一个要解决的问题是什么是健康的成年爬行动物牙齿更换的精确时间和模式？为了回答这些问题，豹壁虎被用作模型。这些动物很容易处理，并且可以使许多用于人类的牙科手术适应它们较小的嘴。微型，连续蜡咬和CT扫描将采取超过6个月的时间和测量时，牙齿丢失和更换将采取。然后将牙齿替换表型与牙齿组织中的基因表达相关联。我们感兴趣的是寻找基因，周期性表达沿着长度的颌骨，因为其中一些可能协调牙齿间距和时间的诱导更换牙齿。第二个要解决的问题是什么是长期的后遗症破坏活动的牙板上的牙齿更换的模式？为了回答这个问题，将在成年壁虎身上进行显微手术，包括切割牙板。预测结果是牙齿替换的间距或速率的变化，其可以追溯到牙齿上皮的分子变化。第三个也是最后一个要问的问题是，在胚胎发育和成人替换过程中，牙齿形成和诱导的分子控制是什么？将研究两个候选分子的作用。选择这两种称为无翼相关（Wnt）和Notch的途径部分是因为Wnt中的突变增加或减少人类的牙齿数量，并且因为Notch-Delta信号传导已知调节成体干细胞更新和分化之间的细胞命运决定，沿着其在调节发育时钟机制中的作用。为了反映人类的状况，寻找调节牙齿更新的稳态开关的证据，将Wnt和Notch的激活剂或抑制剂注射到鸡蛋中，并研究对牙齿上皮生长和图案的影响。申请人/博士后研究员和导师之间的协同研究伙伴关系有一天将带来更自然的方法来替换因疾病或受伤而失去的牙齿。