Gene Regulation of Rat Dentin Sialoprotein

大鼠牙本质唾液酸蛋白的基因调控

• 批准号: 6897588
• 负责人: HELENA H Ritchie
• 金额: $ 24.29万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-09-30 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6897588
• 关键词: calcium; chemical binding; dentin; dentinogenesis; developmental genetics; gene induction /repression; genetic promoter element; hydroxyapatites; in situ hybridization; laboratory rat; odontoblasts; polymerase chain reaction; protein structure function; tissue /cell culture; transcription factor

DESCRIPTION (provided by applicant): During tooth development, odontoblasts modulate dentin formation by producing a predentin matrix into which additional NCPs are subsequently secreted to initiate the mineralization process so necessary for healthy tooth formation. Abnormalities in dentin mineralization due to genetic diseases such as dentinogenesis imperfecta II (DGI-II; affecting 1 in 7,000 newborns) leave these children few choices other than placement of crowns on the teeth or a complete denture. A nonsense mutation, located in the coding sequence for dentin sialoprotein (DSP) is likely responsible for blocking both DSP and phosphophoryn (PP) expression in these individuals because these two NCPs are located on a single DSP-PP transcript. Importantly, some DGI patients also experience tinnitus as well as balancing problems making it necessary to consider problems in DSP-PP transcript and protein expression as an important public health concern. This application proposes a series of studies to better define DSP-PP transcript expression and DSP/PP protein function in dentin mineralization. The specific aims of this proposal are 1) to test the hypothesis that odontoblast-specific factors acting on the DSP-PP gene promoter, regulate DSP-PP expression, 2) to test the hypothesis that multiple DSP-PP transcripts generate functionally distinct PP isoforms with distinct calcium binding capacity and hydroxyapatite forming ability which are required for orderly dentin mineralization, 3) to correlate DSP-PP transcript and DSP-only transcript expression patterns with dentin mineralization, and 4) to validate Aims 2 and 3 by examining mineral formation as a function of DSP and PP isoform expression in cell culture. These ongoing studies, which combine gene regulation and protein function approaches, will reveal underlying mechanisms of dentin mineralization and will later be applicable to reparative dentistry.

描述（由申请人提供）：在牙齿发育期间，Odontoblasts通过产生predentin矩阵来调节牙本质形成，随后将其他NCP分泌到该基质中以启动矿化过程，因此健康牙齿形成所必需。由于遗传性疾病（例如牙本质发生不完美II（DGI-II；影响7,000名新生儿）造成的牙本质矿化异常，除了将牙冠放在牙齿上或完整的牙齿上以外，这些孩子几乎没有其他选择。位于牙本质唾液蛋白（DSP）的编码序列中的一个废话突变很可能导致这些个体中的DSP和Phophophophoryn（PP）表达同时阻止，因为这两个NCP位于单个DSP-PPP转录本上。重要的是，一些DGI患者还经历了耳鸣以及平衡问题，因此有必要将DSP-PP PPP转录本和蛋白质表达中的问题视为重要的公共健康问题。该应用提出了一系列研究，以更好地定义牙本质矿化中的DSP-PP转录物表达和DSP/PP蛋白功能。该提案的具体目的是1）检验以下假说：作用于DSP-PP基因启动子的Odontoblast特异性因素调节DSP-PP表达，2），以测试多个假设，即多个DSP-PP-PPP转录在功能上产生功能上不同的PP同工型具有独特的钙化能力和三个校正能力，该校正能力是校正的，该校正能力是DINT的pP，dient dient dient dient dent dent dient diN diN diN diN diN dININ，dININ DININ，分别为dININ，分别为DININ，分别为DININ，分别为DININ，分别为dININ，dININ DINN带有牙本质矿化的转录本和仅DSP的转录本表达模式，以及4）通过检查矿物形成在细胞培养中的DSP和PP同工型表达的函数，以验证目标2和3。这些正在进行的研究结合了基因调节和蛋白质功能方法，将揭示牙本质矿化的潜在机制，后来将适用于修复牙科。