Role of Mineralization-Regulating Transcription Factors in Susceptibility to Dental Caries

摘要 根据NIH的数据，龋齿是美国儿童和成人最常见的慢性疾病。 虽然它是高度可预防的，但它仍然是一个重大的公共卫生问题和误解的条件。 牙齿矿化的发育缺陷已被报道会增加龋齿的风险。虽然作用 细胞外基质蛋白和调节剂的矿物离子稳态在牙齿矿化已很好 研究表明，在理解这一独特过程的转录调控及其对 龋病易感性全基因组关联研究（GWAS）和罕见遗传病研究提供了 牙齿矿化组织形成的转录调控可能是一个促成因素 对龋齿发生和发展的易感性。拟议研究的目标是 了解以下患者龋齿易感性增加的分子病理学 编码TRPS 1转录因子的TRPS 1基因中的杂合突变。使用基因 改良小鼠和体外方法，我们将确定Trps 1缺陷型 牙齿组织影响龋齿的易感性。此外，我们将描述 Trps 1和Osx，两个调节牙齿发育和矿化的转录因子，以确定 Trps 1调控牙齿矿化的分子机制。本研究的具体目的是（1） 目的：探讨牙体组织矿化与牙本质损害易感性之间的关系， （2）确定Osx在Trps 1依赖的矿化启动中的作用， (3)探讨成牙本质细胞中Trps 1-Osx分子间的相互作用。实验设计采用Trps 1 +/- 和Trps 1条件性敲除小鼠，细胞模型中分子相互作用和矿化的分析， 和先进的矿化组织评估方法。这项研究将提供更好的 了解遗传因素和调控牙齿过程的分子途径的影响 矿化，以及它们如何影响龋齿的易感性。此外，它还可以为 为遗传决定的龋齿增加的个体制定有效的龋齿预防策略 由于牙齿矿化受损而易患龋齿。拟议的研究和培训计划将 为申请人提供生物矿化和翻译分子生物学的全面培训 调节这一过程，强调牙齿矿化缺陷是龋齿的危险因素。一队 矿化组织和龋齿研究方面的专家将提供所需的培训， 申请人的职业发展走向独立，专注于在龋病学的转化研究。的 申请人的职业发展计划包括课程/工作坊， 牙矿化组织结合龋齿易感性分析，根据指南进行 的导师团队。

ABSTRACT According to the NIH, Dental Caries is the most common chronic disease in children and adults in the US. Although it is highly preventable, it remains a significant public health problem and a misunderstood condition. Developmental defects of tooth mineralization, have been reported to increase risk of caries. While the role of extracellular matrix proteins and regulators of mineral ions homeostasis in tooth mineralization has been well studied, there is a gap in understanding the transcriptional regulation of this unique process and its impact on caries susceptibility. Genome-Wide Association Studies (GWAS) and studies of rare genetic diseases provide evidence that transcriptional regulation of formation of tooth mineralized tissues may be a contributing factor to the susceptibility to dental caries initiation and progression. The goal of the proposed research is to understand the molecular pathology underlying increased susceptibility to dental caries in patients with heterozygous mutations in the TRPS1 gene coding for the TRPS1 transcription factor. Using genetically modified mice and in vitro approaches, we will determine whether decreased mineralization of Trps1-deficient dental tissues affects the susceptibility to dental caries. Furthermore, we will delineate the interactions between Trps1 and Osx, two transcription factors regulating tooth development and mineralization, to determine molecular mechanisms, by which Trps1 regulates tooth mineralization. The specific aims of this study are (1) To establish the relationship between mineralization of dental tissues and increased susceptibility to dental caries in Trps1-deficiency, (2) To determine the role of Osx in Trps1-dependent initiation of mineralization, and (3) To delineate Trps1-Osx molecular interactions in odontoblasts. The experimental design employs Trps1+/- and Trps1 conditional knockout mice, analyses of molecular interactions and mineralization in cellular models, and advanced methodology of mineralized tissue assessment. The proposed research will provide better understanding of the impact of genetic factors and molecular pathways regulating the process of tooth mineralization, and how they affect susceptibility to dental caries. In addition, it may set foundation for the development of effective caries prevention strategies for individuals with genetically determined increased susceptibility to caries due to impaired tooth mineralization. The proposed research and training plan will provide the applicant with the comprehensive training in molecular biology of biomineralization and translational regulation of this process with an emphasis on dental mineralization defects as a caries risk factor. A team of experts in mineralized tissues and in dental caries research will provide the required training to facilitate the applicant’s career progress towards independence, focusing on translational research in cariology. The applicant’s career development plan includes courses/workshops, comprehensive experimental training in dental mineralized tissues combined with dental caries susceptibility analysis, performed under the guidelines of the mentoring team.