Phosphate Modulation of Dental Tissues

牙齿组织的磷酸盐调节

• 批准号: 7124442
• 负责人: Martha J Somerman
• 金额: $ 3.94万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-15 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7124442
• 关键词: cementum; clinical research; dentin; gene mutation; genes; phosphates; proteins; regeneration; tissues

DESCRIPTION (provided by applicant): For normal biological mineral deposition to proceed, a tight balance is required between the levels of extracellular inorganic phosphate (Pi and pyrophosphate (PPi)) The periodontium, the collection of upportive structures of the tooth root, is especially sensitive to Pi/PPi balance, as evidenced by dramatic cementum phenotypes resulting from mutations that alter local levels of Pi and PPi. A markedly increased cementum was demonstrated on the root surfaces of fully developed teeth in mice presenting mutations in either the multiple-pass transmembrane ankylosis protein (ANK) or plasma cell membrane glycoprotein-1 (PC-1); both mutations result in reduced extracellular PPi though via different mechanisms. Conversely, mice and humans with defective tissue nonspecific alkaline phosphatase (TNAP) present locally increased levels of PPi, leading to defective formation of acellular cementum, and subsequently, premature tooth loss. In contrast to these cementum phenotypes, the underlying mineralized tissue, dentin, seems to develop normally in conditions of altered Pi/PPi. Based on these observations, we hypothesize that periodontal ligament (PDL) cells adjacent to the tooth root cementum are more sensitive to changes in Pi levels than pulp cells adjacent to the dentin. In order to resolve the differential regulation of these two mineralized tissues, the following aims are set: (1) To determine basal differences in gene/protein expression in pulp vs. PDL cells in healthy and hypophosphatasia-diagnosed (HPP) subjects, focusing on genes/proteins associated with differentiation/mineralization and Pi/PPi metabolism; (2) To determine the effect that Pi treatment exerts on pulp vs. PDL cells, in vitro; and (3) To demonstrate that knocking down TNAP function in pulp and PDL cells harvested from healthy subjects results in a more dramatic change in PDL vs. pulp cell behavior, in vitro. Establishing the mechanisms by which Pi/PPi influence the periodontium is a critical step towards understanding the development of these tissues, with the ultimate goal of applying further insight to the design of therapies to regenerate periodontal tissues.

描述（由申请人提供）：对于正常的生物学矿物沉积以进行，需要在细胞外无机磷酸盐水平（PI和Pyrophophate（PPI））之间保持紧密的平衡。牙周（牙齿的收集）牙齿的收集，牙齿根的收集，尤其是PPI的敏感性，因为PI/PPI尤为敏感，这是由Pi -ppi的层次平衡的。在多通跨膜强直性强化蛋白（ANK）或浆细胞膜糖蛋白-1（PC-1）的小鼠中，在完全发育的牙齿的根表面上表现出明显增加的牙骨。两种突变都通过不同的机制导致细胞外PPI降低。相反，小鼠和人类患有缺陷的组织非特异性碱性磷酸酶（TNAP）呈现局部升高的PPI水平，从而导致无细胞胶质的形成缺陷，随后导致过早的牙齿脱落。与这些牙骨质表型相反，潜在的矿化组织牙本质似乎在PI/PPI改变的条件下正常发展。基于这些观察结果，我们假设牙周韧带（PDL）细胞与牙齿根胶质相邻的细胞对PI水平的变化比与牙本质相邻的纸浆细胞更敏感。为了解决这两个矿化组织的差异调节，设定了以下目的：（1）确定在果肉和下磷酸诊断（HPP）受试者中，果肉/蛋白质表达的基础差异（HPP）受试者，重点是与分化/矿物质和PI/PI/PPI/PPI METBOLISM相关的基因/蛋白质； （2）确定PI处理对PULP与PDL细胞的作用； （3）证明从健康受试者收获的纸浆和PDL细胞中敲低TNAP功能会导致PDL与纸浆细胞行为发生更大的变化，并在体外。建立PI/PPI影响牙周的机制是理解这些组织发展的关键步骤，其最终目标是将进一步的见解应用于疗法设计以再生牙周组织。