Key Modulators of Cementogenesis

描述（由申请人提供）：磷酸盐（Pi）和焦磷酸盐（PPi）代谢的调节对于矿化组织（包括牙本质和牙骨质）的发育和维持至关重要。局部Pi/PPi调节剂（ANK，PC-1，TNAP）的破坏影响牙骨质形成，尽管牙本质形成似乎正常，这表明牙本质矿化的调节与牙骨质不同。当调节循环Pi的因子（FGF-23，PHEX）被破坏时，初步检查表明牙本质/牙髓受到影响，而牙骨质显示出最小的干扰。基于这些数据，提出了以下广泛的假设：虽然牙骨质和牙本质形成都依赖于Pi稳态，但控制形成和再生的基因/蛋白质可能是不同的。我们认为，牙骨质形成是由离子转运蛋白/局部代谢酶，包括ANK，PC-1和TNAP控制，而牙本质形成是由控制循环Pi水平的因素，包括FGF-23和PHEX调制。目的：目的1将确定ANK，PHEX和FGF-23在牙骨质形成与牙根牙本质形成中的作用。目的2证明Pi对成牙骨质细胞表型的调控是通过调控特定的转录因子来实现的。目的3将证明使用纤维蛋白支架递送系统增加愈合部位的局部Pi水平将促进矿化。 公共卫生相关性：这些研究将提供有关控制牙骨质和牙本质形成的基因/因素的关键信息。最终，所获得的知识将导致用于治疗矿化组织病症和疾病的改进疗法，包括牙科疾病（龋齿/牙周病）、低磷酸盐血症、异位钙化和骨质疏松症，以及用于再生患病组织的新策略。

DESCRIPTION (provided by applicant): Modulation of phosphate (Pi) and pyrophosphate (PPi) metabolism is critical for development and maintenance of mineralized tissues, including dentin and cementum. Disruption of local Pi/PPi regulators (ANK, PC-1, TNAP) impacts cementogenesis, though dentin formation appears normal, suggesting dentin mineralization is regulated differently than cementum. When factors regulating circulating Pi (FGF-23, PHEX) were disrupted, initial examination indicated that dentin/pulp were affected, while cementum showed minimal disturbance. Based on these data, the following broad hypothesis is set forth: While both cementum and dentin formation are dependent on Pi homeostasis, the genes/proteins controlling formation and regeneration are likely different. We propose that cementogenesis is controlled by ion transporters/local metabolic enzymes including ANK, PC-1, and TNAP, while dentinogenesis is modulated by factors that control levels of circulating Pi, including FGF-23 and PHEX. Aims: Aim 1 will determine the role of ANK, PHEX and FGF-23 during cementogenesis versus root dentinogenesis. Aim 2 will prove that Pi regulation of specific transcription factors controls the cementoblast phenotype. Aim 3 will prove that increasing local levels of Pi at healing sites using fibrin scaffold delivery systems will promote mineralization. Public Health Relevance: These studies will provide critical information about the genes/factors controlling cementum and dentin formation. Ultimately, the knowledge gained will result in improved therapies for treatment of mineralized tissue disorders and diseases, including dental diseases (caries/periodontal disease), hypophosphatemic conditions, ectopic calcification, and osteoporosis, and in new strategies for regeneration of diseased tissues.