Key Modulators of Cementogenesis

牙骨质形成的关键调节剂

• 批准号: 7468920
• 负责人: Martha J Somerman
• 金额: $ 35.1万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-15 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7468920
• 关键词: Address; Affect; Alkaline Phosphatase; Ankylosis; Behavior Control; Binding Sites; Calvaria; Cells; Cementoblast; Cementogenesis; Cementum Formation; Collaborations; Condition; Cytoplasm; Data; Defect; Dental Cementum; Dental Pulp; Dental caries; Dentin; Dentin Formation; Dentinogenesis; Development; Diphosphates; Disease; Disruption; Electrons; Endopeptidases; Enzymes; Exhibits; Feedback; Fibrin; Gene Expression; Gene Proteins; Genes; Healed; Homeostasis; Hormones; Human; Hydroxyapatites; Hypophosphatemia; Image; Immunohistochemistry; In Situ Hybridization; In Vitro; Integral Membrane Protein; Ions; Isoenzymes; Knockout Mice; Knowledge; Laboratories; Link; Location; Maintenance; Metabolic; Metabolism; Minerals; Modeling; Molecular Profiling; Monitor; Mus; Mutation; Natural regeneration; Odontoblasts; Osteomalacia; Osteoporosis; Partner in relationship; Periodontal Diseases; Phenotype; Plant Roots; Process; Progress Reports; Proteins; Public Health; Regulation; Reporting; Rodent; Role; Signaling Molecule; Site; Small Interfering RNA; System; Tissues; Tooth Diseases; Tooth structure; X Chromosome; X ray spectroscopy; base; calcification; cell behavior; extracellular; healing; improved; inorganic phosphate; insight; mineralization; nanocrystal; nanoindentation; novel; promoter; repaired; response; scaffold; size; tissue regeneration; transcription factor

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.

描述（由申请人提供）：磷酸盐（PI）和焦磷酸盐（PPI）代谢的调节对于包括牙本质和水泥在内的矿化组织的发展和维持至关重要。局部PI/PPI调节剂（ANK，PC-1，TNAP）的破坏会影响胶结发生，尽管牙本质形成似乎正常，这表明牙本质矿化的调节方式与胶结性不同。当调节循环PI（FGF-23，PHEX）的因素被破坏时，初始检查表明牙本质/果肉受到影响，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的形成都取决于PI稳态，但控制形成和再生的基因/蛋白质可能有所不同。我们提出，胶结发生由包括ANK，PC-1和TNAP在内的离子转运蛋白/局部代谢酶控制，而齿状发生受到控制循环PI水平的因素，包括FGF-23和PHEX。目的：AIM 1将确定ANK，PHEX和FGF-23在胶结发生与根齿状发生过程中的作用。 AIM 2将证明特定转录因子的PI调节控制胶质细胞表型。 AIM 3将证明，使用纤维蛋白支架递送系统在愈合部位提高局部PI的局部水平将促进矿化。 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，获得的知识将改善治疗矿物质组织疾病和疾病的治疗方法，包括牙齿疾病（龋齿/牙周疾病），下磷酸疾病，异位钙化和骨质疏松症以及新的疾病组织再生策略。