DSPP signaling in dentinogenesis

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蛋白(DSPP)在牙本质形成中的机制(S)，从而为诱导牙齿修复和再生提供新的途径。牙本质中最丰富和最重要的蛋白质是I型胶原和DSPP。DSPP基因突变与牙本质发育不全(DGI)有关，DGI是最常见的牙本质遗传病。DSPP蛋白被蛋白酶加工成几个功能片段：DSP、DPP等。这些结构域在牙本质形成过程中发挥着独特的生物学功能。初步数据显示，1)。BMP2诱导DSPP表达。BMP2基因敲除小鼠的牙齿与DGI相似，存在DSPP突变，DSPP和DLX3及OSX转录因子的表达也降低。基质金属蛋白酶-9专门催化DSP形成NH2-末端和COOH-末端片段。DSP的NH2-和COOH-末端片段显示出明显不同的牙齿分布。在MMP9基因缺失的小鼠中发现牙齿缺陷和DSPP处理的干扰。3)。NH2末端和COOH末端结构域与细胞膜上的整合素26和CD105受体结合。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、速度和程度是重要的。为了验证这一假说，我们提出了以下具体目标：1.确定牙本质形成过程中DSPP转录过程中的BMP2信号通路。2.用基质金属蛋白酶-9确定DSP的加工方式和切割位点。3.研究整合素26和CD105在牙齿发育过程中的信号转导途径。这是一个创新的假说，认为DSP/DSPP的转录、翻译后处理和信号转导的每一步都是形成健康牙本质所必需的。这些认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制的理解，并为牙科疾病的治疗提供潜在的线索。 公共卫生相关性：牙本质涎磷蛋白(DSPP)蛋白对牙本质的形成很重要，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，我们提出了一个新的途径，DSPP的转录调控，蛋白分解加工和信号转导途径的牙本质发生。因此，更好地了解DSPP的生物学功能机制将为牙齿的修复和再生提供新的途径。

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.