Transcriptional Regulation of Dentin Mineralization

项目摘要/摘要 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。遗传 导致牙本质矿化缺陷的疾病最常见的原因是基因编码突变。 对于牙本质基质蛋白或磷酸盐代谢基因，强调基质的关键作用 牙本质形成中的成分和磷酸盐动态平衡。然而，对转录的控制 成牙本质细胞调节的磷酸盐稳态和细胞外基质矿化还不是很清楚。 我们的初步数据确定了一个新的转录因子Trps1是成牙本质细胞的重要调节因子 主要针对涉及磷酸盐稳态的基因的功能和牙本质矿化。使用中 体内和体外方法，我们发现前成牙本质细胞中Trps1缺乏与以下因素有关 磷酸酶下调启动矿化并导致成牙本质细胞矿化丧失 潜力。反过来，成熟成牙本质细胞中Trps1的上调导致牙本质矿化的抑制 与低磷血症相关的磷酸盐稳态基因下调相关 软骨病。根据这些数据，我们假设Trps1在牙本质形成中扮演的角色是上下文相关的： Trps1支持在新分化的成牙本质细胞中启动牙本质矿化，但在成熟细胞中 成牙本质细胞Trps1是矿化的抑制因子。我们提出了机械论的研究，将整合 Trps1进入控制成牙本质细胞分化和功能的分子网络，特别关注 成牙本质细胞调节的磷酸盐稳态。该项目的结果将定义分子决定因素 Trps1在成牙本质细胞中依赖于上下文的活动，并为我们对 牙本质矿化障碍的机制。

PROJECT SUMMARY/ABSTRACT 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.