DSPP signaling in dentinogenesis

牙本质发生中的 DSPP 信号传导

基本信息

批准号：
8268940
负责人：
Shuo Chen
金额：
$ 29.11万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
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/8268940
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

项目摘要

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（由申请人提供）：这些研究的长期目标是阐明牙本质生成中牙本质唾液磷蛋白（DSPP）的机制，从而为诱导牙齿的修复和再生提供了新的途径。牙本质中最丰富和最重要的蛋白质是胶原蛋白I型和DSPP。 DSPP的突变与最常见的牙本质遗传疾病（DGI）有关。 DSPP蛋白通过蛋白酶加工成几个功能片段。 DSP，DPP等。这些域在牙抑制性过程中起着独特的生物学功能。初步数据显示1）。 BMP2诱导DSPP表达。 BMP2 NULL小鼠中的牙齿与DSPP突变的DGI相似，DSPP和DLX3和OSX转录因子的表达也降低了BMP2敲除小鼠。 2）。 MMP-9特别催化DSP进入NH2末端和COOH末端片段。 DSP的NH2-和COOH末端片段显示出牙齿分布的明显差异。在MMP-9无效小鼠中发现了牙齿缺陷和DSPP加工的干扰。 3）。 NH2-末端和COOH末端结构域与其受体（在细胞膜上结合了整联蛋白26和CD105）。基于这些发现，我们提出了以下假设：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，速率和程度很重要。为了检验该假设，我们提出了以下特定目的：1。确定牙本质发生过程中DSPP转录中的BMP2信号通路。 2。通过MMP-9确定DSP和DSP裂解位点的处理模式。 3。在发育过程中通过整合素26和CD105确定DSP信号通路。这是一个创新的假设，即DSP/DSPP的转录，翻译后处理和信号转导的每个步骤对于形成健康的牙本质都是必要的。这种知识将促进我们对威胁牙本质结构完整性的遗传性疾病的发病机理的理解，并为治疗牙齿疾病提供潜在的线索。公共卫生相关性：牙本质唾液磷蛋白（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生不完美，这是最常见的牙本质遗传疾病。在这里，我们提出了用于DSPP转录调控，蛋白水解处理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修复和再生牙齿提供新的途径。