Nonclassical β-catenin signaling in odontogenesis

牙发生中的非经典β-连环蛋白信号传导

• 批准号: 10714280
• 负责人: Wei Hsu
• 金额: $ 54.2万
• 依托单位: ADA FORSYTH INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-06 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10714280
• 关键词: AXIN2 gene; Ameloblasts; Amelogenesis; Autologous; Cell Communication; Cells; Characteristics; Comparative Study; Crowns; Data; Defect; Dental; Dental Enamel; Dental Implants; Dental Pulp; Development; Developmental absence of tooth; Disease; Drosophila genus; Epithelium; Evaluation; Gene Expression; Generations; Genes; Genetic; Genetic Models; Genetic Transcription; Genetic study; Germ; Health; Human; Human Development; Human Genetics; Hypodontia; Interruption; Knowledge; Link; Maintenance; Mediating; Medicine; Mesenchymal; Mesenchyme; Modeling; Morphogenesis; Mouse Strains; Mus; Mutant Strains Mice; Mutation; Odontoblasts; Odontogenesis; Organ Culture Techniques; Pathogenesis; Pathway interactions; Phenotype; Play; Prosthodontic specialty; Proteins; Regulation; Role; Signal Transduction; Signaling Molecule; Supernumerary Tooth; Syndrome; Testing; Tissues; Tooth Germ; Tooth regeneration; Tooth structure; Transforming Growth Factor beta; Transplantation; WNT Signaling Pathway; WNT10A gene; beta catenin; comparative; differential expression; genetic approach; genome editing; insight; knowledge base; loss of function; mouse genetics; mouse model; mutant; next generation; novel; permanent tooth; regenerative; regenerative approach; repaired; restorative dentistry; single-cell RNA sequencing; stem cells; tissue regeneration; transcriptomics

Abstract The primary objective of this application is to elucidate the regulatory mechanisms underlying odontogenesis mediated by nonclassical β-catenin signaling. Tooth agenesis is the most common congenital dental abnormality, characterized by the absence of one or more permanent teeth including Anodontia, Oligodontia, and Hypodontia. Human genetic studies of nonsyndromic tooth agenesis have revealed approximately 16 causative genes of which 6 of them are involved in the Wnt pathway indicating its significance in disease pathogenesis. Missing teeth are currently treated by dental implants, tooth transplants, or prosthodontic repairs. However, they are not permanent treatments and also are associated with considerable complications. For next-generation therapies, new regenerative approaches to interrupt tooth formation/maintenance or develop an autologous tooth replacement are highly attractive concepts. Therefore, it is critical to advance our knowledge of odontogenesis and elucidate the mechanisms underlying reciprocal interactions of dental epithelium and mesenchyme. Canonical Wnt signaling mediated by β-catenin has been well established to play an essential role in early odontogenesis. Mouse genetic studies have demonstrated the importance of Wnt signaling in various aspects of dental medicine, e.g. tooth development, dental pulp, enamel, odontogenesis, and amelogenesis. Expression of a degradation-deficient form of β-catenin causes continuous tooth generation and development of supernumerary teeth, further suggesting that tooth renewal can be unlocked by increasing the intrinsic level of odontogenic potential. β-catenin acts as a master regulator of this intrinsic potential to promote tooth formation. However, β-catenin is a multifaced protein that possesses other functions in addition to acting as a master regulator for transducing canonical Wnt signaling. Preliminary studies of our new genetic models argue against current knowledge and implicate the requirement of nonclassical β-catenin in odontogenesis. First, we will characterize new β-catenin mutant mice to rigorously assess the dual function of β-catenin in the development of odontogenic ability, and differentiation of odontoblasts and ameloblasts. Second, we will identify the master regulators acting downstream of β-catenin by a single-cell transcriptomic approach to decipher the genetic regulatory network associated with the nonclassical signaling cascade. The objective of this study has great significance in human health and regenerative dental medicine. Elucidating the mechanism underlying the regulation of odontogenesis promises important insights into next-generation therapy for dental restoration.

抽象的 该应用的主要目的是阐明牙肠发生的调节机制 由非经典β-catenin信号传导介导。牙齿产生是最常见的先天性牙齿 异常，其特征是缺乏一个或多个恒牙，包括阳极，寡头， 和下调。非同步牙齿产生的人类遗传研究显示约16 其中6个参与WNT途径的病因基因表明其在疾病中的重要性 发病。目前缺少牙齿的牙齿，牙齿移植或假肢治疗 维修。但是，它们不是永久治疗，也与考虑并发症有关。 对于下一代疗法，新的再生方法中断牙齿形成/维护或 开发自体牙齿替代是非常有吸引力的概念。因此，促进我们的 了解牙本质发生并阐明牙齿相互作用的机制 上皮和间质。由β-catenin介导的规范Wnt信号已被很好地确定 在早期发生的早期发生中起着至关重要的作用。小鼠遗传研究表明了Wnt的重要性 牙科医学各个方面的信号传导，例如牙齿发育，牙髓，牙釉质，牙骨发生， 和未偿还作用。 β-catenin降解形式的表达会导致连续牙齿产生 并发育超牙齿，进一步表明可以通过增加牙齿更新 牙源性潜力的内在水平。 β-catenin充当了这种内在潜力的主要调节剂 促进牙齿形成。但是，β-catenin是一种多缩蛋白，还具有其他功能 充当用于传输规范Wnt信号传导的主调节器。我们新通用的初步研究 模型反对当前的知识，并暗示非经典β-catenin在 牙骨发生。首先，我们将表征新的β-catenin突变小鼠以严格评估 β-catenin在牙源性能力的发展以及牙胶细胞和成成木细胞的分化中。 其次，我们将通过单细胞转录组来识别β-catenin下游作用的主调节器 破译与非经典信号级联相关的遗传调节网络的方法。 这项研究的目的在人类健康和再生牙科医学方面具有重要意义。阐明 调节牙本质发生的基础机制有望对下一代的重要见解 治疗牙科修复。