New Molecules and Cures for Tooth Agenesis

牙齿发育不全的新分子和治疗方法

• 批准号: 9759906
• 负责人: Rena N. D'Souza
• 金额: $ 36.22万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9759906
• 关键词: Adverse effects; Affect; Agonist; Applications Grants; Basic Science; Binding; Biological Assay; Cleft Palate; Complex; Data; Defect; Dental; Dentition; Development; Disease; Elements; Emotional; Epithelial; Epithelium; Equilibrium; Esthetics; Event; Family; Female; Financial Hardship; Future; Gene Expression; Gene Expression Profiling; Gene Expression Regulation; Genes; Genetic; Genetic Models; Genetic study; Goals; Hereditary Disease; Human; Human Genetics; In Vitro; Inherited; Injections; Knowledge; Mediating; Mesenchymal; Mesenchyme; Microarray Analysis; Molecular; Morphogenesis; Mothers; Mus; Mutant Strains Mice; Mutation; Nature; Odontogenesis; Organ; Pathway interactions; Patients; Pattern; Phase; Phenotype; Play; Population; Process; Promoter Regions; Proteins; Replacement Therapy; Reporter Genes; Reporting; Research; Role; Series; Signal Pathway; Signal Transduction; Signaling Molecule; Signaling Protein; Tail; Testing; Therapeutic; Time; Tooth structure; Translating; Translations; Variant; Veins; WNT Signaling Pathway; WNT10A gene; base; clinically relevant; design; experimental study; functional restoration; genetic analysis; improved; in vivo; inhibitor/antagonist; insight; mutant; novel; novel therapeutic intervention; novel therapeutics; pregnant; promoter; pup; restoration; small molecule; synergism; targeted treatment; transcription factor; transcriptome sequencing; translational approach; translational study

PROJECT SUMMARY The development of dentition is a highly complex process that involves a series of reciprocal epithelial- mesenchyme interactions that are regulated by five conserved signaling pathways, namely Bmp, Fgf, Wnt, Eda and Shh. That such a precise process is often perturbed is not surprising. Indeed, tooth agenesis is one of the most commonly inherited human disorders that affects up to 10% of the population and imposes significant burdens on patients and their families. Mutations in PAX9, a paired-domain transcription factor that is specifically expressed in dental mesenchyme, cause human tooth agenesis. The deletion of Pax9 in mice leads to tooth arrest at the bud stage, thus underscoring its key inductive role within dental mesenchyme. Better understanding the molecular actions of Pax9 in dental mesenchyme during the induction phase of tooth morphogenesis offers hope for the development of tangible therapies that can benefit patients with tooth agenesis. Our microarray analyses of Pax9-/- tooth organs show that Wnt signaling genes are most markedly altered along with the Bmps, Fgfs, Shh and Eda-related genes. The results of our human genetic analyses and data from other groups confirm that mutations in WNT10A are responsible for the majority of cases of human tooth agenesis. Significantly, our preliminary experiments suggest that Wnt agonists, when administered to pregnant Pax9+/- mothers, are able to rescue the mutant phenotype of cleft palate and tooth arrest. Despite these advances there is little understood about the precise molecular relationship of Pax9 with the Wnt signaling pathway in dental mesenchyme and how such basic science knowledge can be translated into new advances for the treatment of human tooth agenesis. Taken together, our data provide the framework for studies that will systematically test the hypothesis that Pax9 is a key modulator of signaling events in dental mesenchyme during early tooth morphogenesis through its regulation of genes in the Wnt pathway. The restoration of Wnt signaling in Pax9 and Wnt10a mutant dental mesenchyme is hence likely to normalize tooth morphogenesis. Aim 1 studies will use multipronged approaches to provide new data on the molecular relationship of Pax9 with genes that regulate Wnt signaling activities in dental mesenchyme during early morphogenesis since this relationship is not as well studied as that with the Bmp and Fgf pathways. Aim 2 will test how human tooth agenesis-causing mutations in Pax9 and Wnt10A affect the functional relationship of these genes to result in an arrest in tooth development. Aim 3 will confirm the upstream relationship of Pax9 by assessing whether novel Wnt-based therapeutics when administered in-vivo, can correct the Pax9-/- tooth agenesis phenotype through a restoration of Wnt function. Data from these basic science and translational studies will advance our understanding about the signaling molecules in dental mesenchyme and will provide the framework for developing and testing non-invasive therapies to restore tooth development in humans affected by non-syndromic tooth agenesis, an important problem of high clinical relevance and for which there are no cures.

项目概要 牙列的发育是一个高度复杂的过程，涉及一系列相互的上皮细胞 间充质相互作用受五个保守信号通路调节，即 Bmp、Fgf、Wnt、Eda 和嘘。如此精确的过程经常受到干扰并不奇怪。事实上，牙齿发育不全是其中之一 最常见的遗传性人类疾病，影响高达 10% 的人口，并造成严重影响 给患者及其家属带来负担。 PAX9 的突变，PAX9 是一种配对结构域转录因子 特异表达于牙齿间充质，导致人类牙齿发育不全。小鼠体内 Pax9 的缺失导致 使牙齿在芽期停止，从而强调其在牙齿间充质中的关键诱导作用。更好的 了解牙齿诱导阶段 Pax9 在牙齿间充质中的分子作用 形态发生为开发有形疗法带来希望，使牙齿患者受益 发育不全。我们对 Pax9-/- 牙齿器官的微阵列分析表明，Wnt 信号基因最显着 与 Bmps、Fgfs、Shh 和 Eda 相关基因一起改变。我们的人类基因分析结果和 其他小组的数据证实，WNT10A 突变是导致大多数人类病例的原因。 牙齿发育不全。值得注意的是，我们的初步实验表明，当给予 Wnt 激动剂时 怀孕的 Pax9+/- 母亲，能够挽救腭裂和牙齿停滞的突变表型。尽管 这些进展对于 Pax9 与 Wnt 的精确分子关系知之甚少 牙齿间充质中的信号通路以及如何将这些基础科学知识转化为新的知识 治疗人类牙齿发育不全的进展。总而言之，我们的数据提供了框架 研究将系统地检验 Pax9 是牙科信号事件关键调节剂的假设 间充质在早期牙齿形态发生过程中通过调节 Wnt 通路中的基因来发挥作用。这 Pax9 和 Wnt10a 突变体牙齿间充质中 Wnt 信号的恢复因此可能使牙齿正常化 形态发生。目标 1 研究将使用多管齐下的方法来提供分子生物学的新数据 Pax9与早期牙间充质Wnt信号活性调节基因的关系 形态发生，因为这种关系不像 Bmp 和 Fgf 途径那样得到充分研究。目标2将 测试引起人类牙齿发育不全的 Pax9 和 Wnt10A 突变如何影响功能关系 这些基因导致牙齿发育停滞。目标3将确认Pax9的上游关系 通过评估基于 Wnt 的新型疗法在体内施用时是否可以矫正 Pax9-/- 牙齿 通过恢复 Wnt 功能来实现发育不全表型。来自这些基础科学和转化的数据 研究将增进我们对牙齿间充质信号分子的理解，并将提供 开发和测试恢复人类牙齿发育的非侵入性疗法的框架 受非综合征性牙齿发育不全的影响，这是一个具有高度临床相关性的重要问题，为此有 没有治愈方法。