DMP1 and DSPP in Osteogenesis and Dentinogenesis

描述(申请人提供)：这项研究建议基于一个总体假设，即非胶原性细胞外基质(ECM)蛋白在成骨和牙齿形成中发挥重要作用。特别是牙本质基质蛋白1(DMP1)和牙本质涎磷蛋白(DSPP)的生物学功能。这两种蛋白在矿化组织形成中的意义得到了许多基因研究的支持，这些研究表明，缺乏DMP1和DSPP基因的小鼠在骨和/或牙本质形成/矿化方面存在缺陷。尽管这些研究表明这些蛋白质与健康矿化组织的形成之间存在关联，但DMP1和DSPP参与骨和牙本质形成的确切机制仍不清楚。DMP1被蛋白质降解形成N端(37 KDa)和C端(57 KDa)片段，而DSPP被加工成DSP(N端)和DPP(C端)，这些片段大量存在于骨和牙本质的ECM中。我们和其他人的最新发现使我们相信，DMP1和DSPP的加工片段除了在基质矿化中发挥直接作用外，还可能参与细胞信号和分化。我们推测DMP1和DSPP的加工片段在细胞外基质矿化、细胞信号转导和细胞分化中起作用。为了验证这些假设，我们提出了以下具体目标：具体目标1是研究DMP1、DSPP及其片段对生物矿化的影响。在这个特定的目标下，我们将研究这些蛋白质对成骨细胞和牙本质细胞矿化能力的影响。目的2研究DMP1、DSPP及其片段在牙本质形成和成骨过程中对细胞信号和分化的影响。总的来说，这些研究的数据将帮助我们更好地理解骨和牙本质形成的控制机制。获得F30奖学金对我实现具体目标和在成为一名独立牙科科学家的道路上接受培训是必要的。 公共卫生相关性：有关矿化控制机制的基本信息对于加深对骨和牙本质缺陷的发病机制的理解至关重要，这些缺陷发生在系统性疾病中，如骨软化症和牙本质形成不全。更好地了解这些骨和牙齿缺陷的发病机制对于建立科学的此类疾病的治疗模式是至关重要的。这项研究的目的是为了发现证据，为更好地理解成骨和牙本质形成过程中的矿化控制机制提供证据。

DESCRIPTION (provided by applicant): This research proposal is based on the overall hypothesis that non-collagenous extracellular matrix (ECM) proteins play vital roles in osteogenesis and odontogenesis. Specifically, we are focusing upon the biological functions of dentin matrix protein 1 (DMP1) and dentin sialophosphoprotein (DSPP). The significance of these two proteins in the formation of mineralized tissues is supported by a number of gene studies showing that mice lacking the genes coding for DMP1 and DSPP display defects in bone and/or dentin formation/mineralization. Although these studies have shown the associations between these proteins and the formation of healthy mineralized tissues, the exact mechanisms, by which DMP1 and DSPP participate in the formation of bone and dentin, remain ill-defined. DMP1 is proteolytically processed to form the N-terminal (37 kDa) and C-terminal (57 kDa) fragments while DSPP is processed into DSP (N- terminal) and DPP (C-terminal); these fragments are present in significant quantity in the ECM of bone and dentin. Recent findings in our group and others have led us to believe that the processed fragments of DMP1 and DSPP may be involved in cell signaling and differentiation, in addition to their direct roles in matrix mineralization. We hypothesize that the processed fragments of DMP1 and DSPP function in extracellular matrix mineralization, cell signaling, and cell differentiation. To test these hypotheses, we propose the following specific aims: Specific Aim 1 is to examine the effects of DMP1, DSPP, and their fragments on biomineralization. In this specific aim, we will study the effects of these proteins on the mineralization capability of osteogenic and dentinogenic cells. Specific Aim 2 is to study the effects of DMP1, DSPP and their fragments on cell signaling and differentiation in dentinogenesis and osteogenesis. Collectively, data from these studies will help us better understand the controlling mechanisms involved in the formation of bone and dentin. Award of the F30 fellowship is necessary for me to fulfill the specific aims and to get training on my way towards becoming an independent dentist scientist. PUBLIC HEALTH RELEVANCE: Fundamental information about the controlling mechanisms of mineralization is essential to enhanced understanding concerning pathogeneses of defects in bone and dentin occurring in systemic diseases such as osteomalacia and dentinogenesis imperfecta. A better understanding of the pathogeneses underlying these bone and dental defects is essential for establishing scientifically based treatment modalities for such diseases. The studies proposed for this fellowship are aimed to uncover evidence which will provide a better understanding of the mechanisms controlling mineralization during osteogenesis and dentinogenesis.