Signaling Mechanisms in Early Tooth Development

早期牙齿发育的信号机制

• 批准号: 7840963
• 负责人: Rena N. D'Souza
• 金额: $ 1.47万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-02 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7840963
• 关键词: Affect; Bicuspid; Biochemical; Biomedical Engineering; Candidate Disease Gene; Complex; Data; Dental; Dentition; Development; Emotional; Epithelial; Failure; Family; Family member; Feedback; Gene Expression; Gene Expression Regulation; Gene Mutation; Gene Proteins; Genes; Goals; Homeodomain Proteins; Human; Human Genetics; Inborn Genetic Diseases; Knowledge; Laboratories; Lead; MSX1 gene; Maintenance; Mediating; Mediator of activation protein; Mesenchymal; Mesenchyme; Molecular; Molecular Genetics; Morphogenesis; Mus; Mutation; Outcome; Pathway interactions; Patients; Phenotype; Population; Positioning Attribute; Process; Proteins; Regulation; Research; Role; Screening procedure; Series; Signal Pathway; Signal Transduction; Site; Staging; Testing; Therapeutic Intervention; Tissues; Tooth Germ; Tooth structure; Transactivation; Work; base; genetic analysis; innovation; promoter; protein function; public health relevance; transcription factor

DESCRIPTION (provided by applicant): The development of dentition involves a complex series of epithelial-mesenchymal signaling interactions. It is not surprising that such a process is prone to disturbances which then manifest as congenital tooth agenesis in up to 10% of the population and impose significant functional, emotional and financial burdens on patients. Mutations in the paired domain transcription factor, PAX9, contribute to human tooth agenesis. Genetic and molecular studies in mice also indicate a key role for Pax9 in tooth development. Similar to other Pax family members that act in a highly tissue-specific manner, Pax9 is likely to mediate its tooth-specific functions through its interactions with other proteins. Multiple studies point to an important partnership between Pax9 and the Msx1 homeprotein in regulating gene expression in dental mesenchyme. Our long-term goal is to understand how transcription factors like Pax9 mediate key signaling actions in tooth development and how aberrations in Pax9 functions lead to tooth agenesis. The objective of this proposal, which is the next step to accomplish this goal, is to study how Pax9 achieves its selective functions in dental mesenchyme. Based on our preliminary data, we hypothesize that Pax9 maintains the inductive potential of dental mesenchyme through its transactivation functions and protein interactions within a positive feedback loop involving Msx1, Bmp4, and other partner genes. We will achieve our goals by testing the central hypothesis in three specific aims. Aim 1 will define the molecular basis for the relationship between Pax9, Msx1 and Bmp4. Studies in Aim2 will assess if other candidate genes that are coordinately expressed with Pax9 are involved in the Pax9- Msx1 signaling pathway with Bmp4. Aim3 will use a human genetics approach to identify additional genes that are responsible for human tooth agenesis and may partner with Pax9 during tooth development. The proposed work is innovative as it capitalizes on a new means to uncover the molecular functions of Pax9 by use of biochemical and human genetics approaches uniquely available in our laboratory. The work will positively impact the field of tooth development by deepening our understanding of the network of interactions that coordinate signaling. Such knowledge may lead to innovative treatments for patients with tooth agenesis including the possibility of bioengineering new teeth. PUBLIC HEALTH RELEVANCE: Congenitally missing teeth are a consequence of gene mutations which interrupt the process of normal tooth development. Only a few of these genes have been identified. We propose to discover additional genes and show how several of these genes interact in normal tooth development and what disturbs their interaction in patients with missing teeth.

描述（由申请人提供）：牙列的发育涉及一系列复杂的上皮间质信号相互作用。毫不奇怪，这一过程很容易出现干扰，然后在高达 10% 的人群中表现为先天性牙齿发育不全，给患者带来显着的功能、情感和经济负担。配对结构域转录因子 PAX9 的突变导致人类牙齿发育不全。对小鼠的遗传和分子研究也表明 Pax9 在牙齿发育中发挥着关键作用。与以高度组织特异性方式发挥作用的其他 Pax 家族成员类似，Pax9 很可能通过与其他蛋白质的相互作用来介导其牙齿特异性功能。多项研究表明 Pax9 和 Msx1 家乡蛋白在调节牙齿间充质基因表达方面存在重要的伙伴关系。我们的长期目标是了解 Pax9 等转录因子如何介导牙齿发育中的关键信号传导作用，以及 Pax9 功能的畸变如何导致牙齿发育不全。该提案的目的是研究 Pax9 如何在牙齿间充质中实现其选择性功能，也是实现这一目标的下一步。根据我们的初步数据，我们假设 Pax9 通过其反式激活功能和涉及 Msx1、Bmp4 和其他伙伴基因的正反馈环内的蛋白质相互作用来维持牙齿间质的诱导潜力。我们将通过测试三个具体目标的中心假设来实现我们的目标。目标 1 将定义 Pax9、Msx1 和 Bmp4 之间关系的分子基础。 Aim2 中的研究将评估与 Pax9 协调表达的其他候选基因是否与 Bmp4 一起参与 Pax9-Msx1 信号通路。 Aim3 将使用人类遗传学方法来识别导致人类牙齿发育不全的其他基因，并可能在牙齿发育过程中与 Pax9 合作。拟议的工作具有创新性，因为它利用了我们实验室独有的生化和人类遗传学方法来揭示 Pax9 分子功能的新方法。这项工作将加深我们对协调信号传导的相互作用网络的理解，对牙齿发育领域产生积极影响。这些知识可能会为牙齿发育不全患者带来创新的治疗方法，包括生物工程新牙齿的可能性。 公共卫生相关性：先天性牙齿缺失是基因突变的结果，基因突变会中断正常牙齿发育的过程。这些基因中只有少数已被识别。我们建议发现其他基因，并展示其中一些基因在正常牙齿发育中如何相互作用，以及是什么干扰了牙齿缺失患者的相互作用。