DSPP signaling in dentinogenesis

牙本质发生中的 DSPP 信号传导

• 批准号: 8056605
• 负责人: Shuo Chen
• 金额: $ 28.52万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-18 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8056605
• 关键词: Affect; BMP2 gene; Binding; Biochemical; Biological Process; Categories; Cells; Cellular Membrane; Cleaved cell; Collagen; Collagen Type I; DSPP gene; Data; Defect; Dentin; Dentin Formation; Dentinogenesis; Dentinogenesis Imperfecta; Development; Disease; ENG gene; Event; Extracellular Matrix Proteins; Family; Gelatinase B; Gene Cluster; Genetic; Genetic Transcription; Goals; Hereditary Disease; Human; Inborn Genetic Diseases; Integrins; Knockout Mice; Knowledge; Lead; Length; Ligand Binding; Membrane; Mesenchymal; Molecular; Mutation; N-terminal; Natural regeneration; Nature; Odontoblasts; Osteoblasts; Osteogenesis; Pathogenesis; Pathway interactions; Pattern; Peptide Hydrolases; Play; Post-Translational Protein Processing; Process; Proteins; Proteolytic Processing; Regulation; Research; Research Personnel; Role; Series; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Site; Structure; Testing; Tooth Diseases; Tooth structure; Transcriptional Regulation; Work; base; biomineralization; bone; design; innovation; insight; member; novel; public health relevance; receptor; repaired; research study; transcription factor

DESCRIPTION (provided by applicant): The long-ranged goal of these studies is to elucidate the mechanism (s) of dentin sialophosphoportein (DSPP) in dentinogenesis and thereby provide new avenues for inducing the repair and regeneration of teeth. The most abundant and important proteins in dentin are collagen type I and DSPP. Mutations of DSPP are associated with dentinogenesis imperfectas (DGI), the most common dentin genetic disorders. DSPP protein is processed by proteases into several functional fragments; DSP, DPP and others. These domains play unique biological functions during dentinogenesis. Preliminary data showed that 1). BMP2 induced DSPP expression. Teeth in BMP2 null mice are similar to DGI with DSPP mutations and expression of DSPP and Dlx3 and Osx transcriptional factors were also decreased in BMP2 knock-out mice; 2). MMP-9 specially catalyzes DSP into the NH2-terminal and COOH-terminal fragments. The NH2- and COOH-terminal fragments of DSP show a clear difference in tooth distributions. Defect in teeth and interference of DSPP processing were seen in MMP-9 null mice. 3). The NH2-terminal and COOH-terminal domains bind to their receptors, integrin 26 and CD105, on cellular membrane. Based on these findings, we propose the following hypothesis that the transcriptional regulation, posttranslational modification and signal transduction of DSPP are important for controlling the initiation, rate and extent of dentin biomineralization. To test this hypothesis, we propose the following Specific Aims: 1. to determine BMP2 signaling pathways in DSPP transcription during dentinogenesis. 2. To determine processing patterns of DSP and cleaved sites of DSP by MMP-9. 3. To determine DSP signaling pathways via integrin 26 and CD105 during tooth development. This is an innovative hypothesis that each step of transcription, posttranslational processing and signaling transduction of DSP/DSPP is necessary for the formation of healthy dentin. Such knowledge will advance our understanding of the pathogenesis of inherited disorders that threaten the structural integrity of dentin and provide a potential clue for treating dental diseases. PUBLIC HEALTH RELEVANCE: Dentin sialophosphoprotein (DSPP) protein is important for dentin formation as DSPP mutations cause dentinogenesis imperfectas, the most common dentin genetic diseases. Here, we propose a novel pathway for DSPP transcriptional regulation, proteolytic processing and signaling transduction pathway for dentinogenesis. Thereafter, better understanding of the mechanisms of DSPP biological functions will provide new avenues for repair and regeneration of teeth.

描述（申请人提供）：这些研究的长期目标是阐明牙本质唾液酸磷酸蛋白（DSPP）在牙本质发生中的机制，从而为诱导牙齿修复和再生提供新途径。牙本质中最丰富、最重要的蛋白质是 I 型胶原蛋白和 DSPP。 DSPP 突变与牙本质发育不全 (DGI) 相关，这是最常见的牙本质遗传性疾病。 DSPP蛋白被蛋白酶加工成多个功能片段； DSP、DPP 等。这些结构域在牙本质发生过程中发挥独特的生物学功能。初步数据表明1）． BMP2 诱导 DSPP 表达。 BMP2缺失小鼠的牙齿与具有DSPP突变的DGI相似，并且BMP2敲除小鼠中DSPP、Dlx3和Osx转录因子的表达也降低； 2）。 MMP-9 专门将 DSP 催化成 NH2 末端和 COOH 末端片段。 DSP 的 NH2 和 COOH 末端片段在齿分布上显示出明显的差异。在 MMP-9 缺失小鼠中观察到牙齿缺陷和 DSPP 加工干扰。 3）。 NH2 末端和 COOH 末端结构域与其细胞膜上的受体整合素 26 和 CD105 结合。基于这些发现，我们提出以下假设：DSPP的转录调控、翻译后修饰和信号转导对于控制牙本质生物矿化的起始、速率和程度非常重要。为了检验这一假设，我们提出以下具体目标： 1. 确定牙本质发生过程中 DSPP 转录中的 BMP2 信号通路。 2.确定DSP的加工模式和MMP-9对DSP的切割位点。 3. 确定牙齿发育过程中通过整合素26和CD105的DSP信号通路。这是一个创新的假设，DSP/DSPP的转录、翻译后加工和信号转导的每一步对于健康牙本质的形成都是必要的。这些知识将增进我们对威胁牙本质结构完整性的遗传性疾病发病机制的理解，并为治疗牙科疾病提供潜在线索。 公共健康相关性：牙本质唾液酸磷蛋白 (DSPP) 蛋白对于牙本质形成很重要，因为 DSPP 突变会导致牙本质发育不全，这是最常见的牙本质遗传病。在这里，我们提出了一种用于牙本质发生的 DSPP 转录调控、蛋白水解加工和信号转导途径的新途径。此后，更好地了解DSPP生物学功能的机制将为牙齿的修复和再生提供新的途径。