Transcriptional Regulation of Dentin Mineralization

描述(申请人提供)：牙本质是牙齿中含量最丰富的成分，是成牙本质细胞产生的矿化组织。导致牙本质矿化缺陷的遗传性疾病最常见的原因是牙本质基质蛋白编码基因或磷酸盐代谢基因的突变，这突显了基质组成和磷酸盐稳态在牙本质正常形成中的关键作用。然而，成牙本质细胞调节的磷酸盐稳态和细胞外基质矿化的转录调控还不是很清楚。我们的初步数据发现，一种新的转录因子Trps1是成牙本质细胞功能和牙本质矿化的重要调节因子，主要针对涉及磷酸盐稳态的基因。利用体内和体外方法，我们发现成牙本质前细胞中Trps1缺乏与启动矿化的磷酸酶下调有关，并导致成牙本质细胞矿化潜力的丧失。反过来，在成熟的成牙本质细胞中，Trps1上调导致抑制牙本质矿化，并下调与低磷血症性软骨病相关的磷酸盐稳态基因。基于这些数据，我们假设Trps1在牙本质形成中的作用是上下文相关的：Trps1支持在新分化的成牙本质细胞中启动牙本质矿化，但在成熟的成牙本质细胞中，Trps1作为矿化的抑制因子。我们建议进行机制研究，将Trps1整合到控制成牙本质细胞分化和功能的分子网络中，特别关注成牙本质细胞调节的磷酸盐稳态。该项目的结果将确定成牙本质细胞中Trps1上下文相关活性的分子决定因素，并为我们理解牙本质矿化障碍的机制提供新的见解。

DESCRIPTION (provided by applicant): Dentin, the most abundant component of teeth, is a mineralized tissue produced by odontoblasts. Genetic disorders resulting in defective dentin mineralization are most commonly caused by mutations in genes coding for dentin matrix proteins or in phosphate metabolism genes, underscoring the critical role of matrix composition and phosphate homeostasis in proper dentin formation. However, the transcriptional control of odontoblast-regulated phosphate homeostasis and extracellular matrix mineralization is not well understood. Our preliminary data identified a novel transcription factor Trps1 as an important regulator of odontoblast function and dentin mineralization that targets primarily genes involved in phosphate homeostasis. Using in vivo and in vitro approaches, we uncovered that Trps1 deficiency in pre-odontoblasts is associated with downregulation of phosphatases initiating mineralization, and results in loss of the odontoblast mineralization potential. In turn, Trps1 upregulation in mature odontoblasts results in repression of dentin mineralization associated with downregulation of phosphate homeostasis genes that are involved in hypophosphatemic rickets. Based on these data we hypothesize that the role Trps1 plays in dentinogenesis is context-dependent: Trps1 supports initiation of dentin mineralization in newly differentiated odontoblasts, but in mature odontoblasts Trps1 acts as a repressor of mineralization. We propose mechanistic studies that will integrate Trps1 into molecular networks that control odontoblast differentiation and function, with specific focus on odontoblast-regulated phosphate homeostasis. Results of this project will define the molecular determinants of Trps1 context-dependent activity in odontoblasts and provide new insights into our understanding of the mechanisms underlying dentin mineralization disorders.