Comparative Genomics and Morphometrics of Tooth Evolution in Rodents

啮齿动物牙齿进化的比较基因组学和形态计量学

• 批准号: 8313563
• 负责人: Vagan Mushegyan
• 金额: $ 3.96万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-15 至 2015-04-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8313563
• 关键词: Benign; Bioinformatics; Cell Line; Code; Complex; Congenital Abnormality; DNA Sequence; Defect; Dental; Development; Diagnosis; Disease; Elements; Embryonic Development; Enhancers; Etiology; Evolution; Fibroblast Growth Factor; Functional RNA; Gene Expression Profile; Gene Family; Genes; Genetic; Genetic Code; Genome; Genomics; Goals; Haplotypes; Head and neck structure; In Vitro; Investigation; Lead; Light; Modeling; Morphology; Muridae; Mus; Nucleic Acid Regulatory Sequences; Odontogenesis; Pathway interactions; Pattern; Phenotype; Phylogenetic Analysis; Play; Quality of life; Regulation; Regulator Genes; Rodent; Role; Signal Pathway; Signaling Molecule; Site; Study models; Surface; Testing; Tooth Cell; Tooth structure; Variant; Work; cleft lip and palate; comparative genomics; fitness; member; mouse model; prevent

DESCRIPTION (provided by applicant): Over the past several years, the Fibroblast Growth Factor (FGF) and Sprouty signalling pathways have been shown to play a key role in development of dental morphology. Yet despite the extensive investigation of this pathway in tooth development, a critical question has gone unanswered: what are the genetic mechanisms involved in patterning the different elements of the occlusal surface (cusps and crests)? Using 24 rodent species, we have begun to describe 66 unique dental morphologic characters for each species. In addition, we have identified 26 coding and non-coding regions of Fgf3,4,8,9, and 10, conserved among all 24 species. I hypothesize that the interspecific variation of murid dental morphology is governed by the variation of the regulatory genetic code, which works through the orchestration of the variable spatio-temporal expression of the signaling molecules involved in embryonic development. I propose to use the mouse model as well as several in-vitro mouse tooth models to investigate the role of the spatio-temporal variation in expression of FGF and Sprouty signalling pathway members in variation of tooth morphology. The overarching goal of this project is to further investigate the role of genetic regulatory machinery variation as a mechanism of creation of new dental phenotypes. Since such mechanisms may not only yield character states which promote a species' fitness, but sometimes greatly hinder it, as the case with defective phenotypes, understanding the precise genetic mechanisms which drive evolution can further our understanding of the origins of developmental anomalies. PUBLIC HEALTH RELEVANCE: Many head and neck birth defects, such as cleft lip and palate, can significantly decrease the quality of life and are difficult to treat. The etiology of hese defects is complex and requires additional investigation. By understanding the mechanisms of head and neck development, we can devise strategies to better diagnose, prevent, and treat these disorders.

描述（由申请人提供）：在过去的几年中，成纤维细胞生长因子（FGF）和 Sprouty 信号通路已被证明在牙齿形态的发育中发挥着关键作用。然而，尽管对牙齿发育中的这条途径进行了广泛的研究，但一个关键问题仍未得到解答：咬合面不同元素（牙尖和牙嵴）的形成涉及哪些遗传机制？使用 24 种啮齿动物，我们已经开始描述每个物种的 66 个独特的牙齿形态特征。此外，我们还鉴定了 Fgf3、4、8、9 和 10 的 26 个编码和非编码区，这些区域在所有 24 个物种中都是保守的。我假设鼠科动物牙齿形态的种间变异是由调控遗传密码的变异所控制的，遗传密码通过协调参与胚胎发育的信号分子的可变时空表达来发挥作用。我建议使用小鼠模型以及几种体外小鼠牙齿模型来研究 FGF 和 Sprouty 信号通路成员表达的时空变化在牙齿形态变化中的作用。该项目的总体目标是进一步研究基因调控机制的作用 变异作为创造新牙齿表型的机制。由于这些机制不仅可能产生促进物种适应性的特征状态，而且有时会极大地阻碍物种的适应性，例如有缺陷的表型，了解驱动进化的精确遗传机制可以进一步了解发育异常的起源。 公共卫生相关性：许多头颈部出生缺陷，例如唇裂和腭裂，会显着降低生活质量并且难以治疗。这些缺陷的病因很复杂，需要进一步研究。通过了解头颈部发育的机制，我们可以制定策略来更好地诊断、预防和治疗这些疾病。