Key Modulators of Cementogenesis

牙骨质形成的关键调节剂

• 批准号: 8122261
• 负责人: TRACY E POPOWICS
• 金额: $ 33.71万
• 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 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8122261
• 关键词: Address; Affect; Alkaline Phosphatase; Ankylosis; Behavior Control; Binding Sites; Calvaria; Cells; Cementoblast; Cementogenesis; Cementum Formation; Collaborations; Cytoplasm; Data; Defect; Dental Cementum; Dental Pulp; Dental caries; Dentin; Dentin Formation; Dentinogenesis; Development; Diphosphates; Disease; Electrons; Endopeptidases; Enzymes; Exhibits; Feedback; Fibrin; Fibroblast Growth Factor; 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; 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; public health relevance; repaired; response; scaffold; 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。

项目成果

Hypophosphatasia-associated deficiencies in mineralization and gene expression in cultured dental pulp cells obtained from human teeth.

• DOI: 10.1016/j.joen.2012.02.008
• 发表时间: 2012-07
• 期刊: Journal of endodontics
• 影响因子: 4.2
• 作者: Rodrigues TL;Foster BL;Silverio KG;Martins L;Casati MZ;Sallum EA;Somerman MJ;Nociti FH Jr
• 通讯作者: Nociti FH Jr

Immobilization of alkaline phosphatase on microporous nanofibrous fibrin scaffolds for bone tissue engineering.

• DOI: 10.1016/j.biomaterials.2009.05.022
• 发表时间: 2009-09
• 期刊: BIOMATERIALS
• 影响因子: 14
• 作者: Osathanon, Thanaphum;Giachelli, Cecilia M.;Somerman, Martha J.
• 通讯作者: Somerman, Martha J.

Correction of hypophosphatasia-associated mineralization deficiencies in vitro by phosphate/pyrophosphate modulation in periodontal ligament cells.

• DOI: 10.1902/jop.2011.110310
• 发表时间: 2012-05
• 期刊: Journal of periodontology
• 影响因子: 4.3
• 作者: Rodrigues TL;Foster BL;Silverio KG;Martins L;Casati MZ;Sallum EA;Somerman MJ;Nociti FH Jr
• 通讯作者: Nociti FH Jr

Aberrant cementum phenotype associated with the hypophosphatemic hyp mouse.

• DOI: 10.1902/jop.2009.090129
• 发表时间: 2009-08
• 期刊: Journal of periodontology
• 影响因子: 4.3
• 作者: Fong H;Chu EY;Tompkins KA;Foster BL;Sitara D;Lanske B;Somerman MJ
• 通讯作者: Somerman MJ

Laser capture microdissection enables cellular and molecular studies of tooth root development.

• DOI: 10.1038/ijos.2012.15
• 发表时间: 2012-03
• 期刊: International journal of oral science
• 影响因子: 14.9
• 作者: Sun JX;Horst OV;Bumgarner R;Lakely B;Somerman MJ;Zhang H
• 通讯作者: Zhang H