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.

项目摘要 牙列的发育是一个高度复杂的过程，涉及一系列相互作用的上皮细胞， 间充质相互作用由五个保守的信号通路调节，即Bmp，Fgf，Wnt，Eda 还有嘘这样一个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 最常见的遗传性人类疾病，影响高达10%的人口，并施加显着 加重了患者及其家属的负担。PAX 9是一种配对结构域转录因子， 特异性表达于牙间充质，导致人类牙齿发育不全。小鼠中Pax 9的缺失导致 牙齿停滞在芽阶段，从而强调其关键的诱导作用，在牙齿间充质。更好 了解Pax 9在牙齿诱导期牙间充质中的分子作用 形态发生为发展有形的治疗方法提供了希望， 发育不全我们对Pax 9-/-牙齿器官的微阵列分析表明，Wnt信号基因在牙齿中的表达最为显著。 与Bmps、Fgfs、Shh和Eda相关的基因发生沿着改变。我们人类基因分析的结果， 来自其他研究组的数据证实，WNT 10A的突变是大多数人类肿瘤病例的原因。 牙齿发育不全值得注意的是，我们的初步实验表明，Wnt激动剂，当给予 怀孕的Pax 9 +/-母亲能够挽救腭裂和牙齿停止的突变表型。尽管 这些进展对Pax 9与Wnt的精确分子关系知之甚少 信号通路的牙齿间充质和如何这样的基础科学知识可以转化为新的 人类牙齿发育不全的治疗进展。总的来说，我们的数据为以下方面提供了框架： 这些研究将系统地检验Pax 9是牙齿发育中信号事件的关键调节剂这一假设， 间充质细胞在早期牙齿形态发生过程中通过其Wnt途径中的基因调控。的 因此，在Pax 9和Wnt 10a突变体牙齿间充质中恢复Wnt信号传导可能使牙齿正常化。 形态发生Aim 1研究将采用多管齐下的方法， 牙胚发育早期牙间充质中Pax 9与Wnt信号通路调控基因的关系 形态发生，因为这种关系不如BMP和FGF途径研究得那么好。目标2将 测试导致人类牙齿发育不全的Pax 9和Wnt 10A突变如何影响 这些基因导致牙齿发育停滞。目的3将确定Pax 9的上游关系 通过评估新的基于Wnt的治疗剂在体内给药时是否可以纠正Pax 9-/-牙齿， 通过Wnt功能的恢复来改善发育不全表型。这些基础科学和翻译的数据 这些研究将促进我们对牙齿间充质中信号分子的理解， 开发和测试非侵入性疗法以恢复人类牙齿发育的框架 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， 都无法治愈