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Transcriptional Regulation of Dentin Mineralization

牙本质矿化的转录调控

基本信息

批准号：
8630687
负责人：
Dobrawa Napierala
金额：
$ 36.75万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-10 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8630687
关键词：
Address Affect Alkaline Phosphatase Biological Assay Cell Line Cells Code Data Defect Dental Dentin Dentin Formation Dentinogenesis Development Diphosphates Disease Down-Regulation Equilibrium Extracellular Matrix Familial hypophosphatemic bone disease Feedback Gene Expression Gene Targeting Genes Hereditary Disease Homeostasis Human In Vitro Mediating Mesenchyme Metabolism Molecular Morphogenesis Mus Mutation Odontoblasts Odontogenesis Pathology Phenotype Phosphoric Monoester Hydrolases Physiology Play Process Proteins Publishing Receptor Signaling Regulation Reporter Repression Role Signal Transduction Staging Syndrome Testing Tissues Tooth Components Tooth structure Transcriptional Regulation Transgenic Mice Up-Regulation Vesicle Vitamin D Vitamin D3 Receptor Work base bone chromatin immunoprecipitation in vitro Model in vivo inorganic phosphate insight mineralization novel osteogenic osteosarcoma overexpression prevent protein complex public health relevance research study transcription factor

项目摘要

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.

项目总结/摘要牙本质是由成牙本质细胞产生的矿化组织，是牙齿中最丰富的成分。遗传导致牙本质矿化缺陷的疾病最常见的是由编码牙本质基质蛋白或磷酸盐代谢基因，强调基质的关键作用，组成和磷酸盐稳态在适当的牙本质形成。然而，转录控制成牙本质细胞调节的磷酸盐体内平衡和细胞外基质矿化还不清楚。我们的初步数据确定了一个新的转录因子Trps 1作为成牙本质细胞的重要调节因子功能和牙本质矿化，主要针对磷酸盐稳态相关基因。使用in 通过体内和体外研究，我们发现前成牙本质细胞中Trps 1的缺乏与下调磷酸酶启动矿化，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Trps 1的上调导致牙本质矿化的抑制与参与低磷血症的磷酸盐稳态基因的下调有关佝偻病基于这些数据，我们假设Trps 1在牙本质形成中的作用是环境依赖性的： Trps 1支持新分化成牙本质细胞的牙本质矿化启动，但在成熟成牙本质细胞中，成牙本质细胞Trps 1作为矿化的阻遏物。我们提出的机制研究，将整合 Trps 1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的分子决定因素 Trps 1在成牙本质细胞中的上下文依赖性活性，并为我们理解成牙本质细胞中的牙本质矿化障碍的机制。