The Role of DPP in Dental Pulp Stem Cells and its Potential in Tissue Regeneration

项目摘要 深龋和牙髓暴露通常通过盖髓或部分牙髓治疗 切断以保持牙髓的活力。控制龋齿是一个主要的公众 健康计划。牙髓干细胞（DPSC）的发现开辟了新的 牙髓-牙本质复合体再生或修复的途径。成人干的使用 用于组织再生和修复的细胞在再生医学中是重要的。另一 用于组织工程的重要组分是生物活性信号分子。为 在过去的二十年里，我们一直在研究有机酸的酸性磷蛋白， 骨和牙本质的基质。除了它们在细胞外基质中的功能外， 这些蛋白质现在与刺激信号事件有关。一种这样的蛋白质 在牙本质基质中鉴定的是牙本质磷蛋白（DPP）。直到最近， DPP被认为是结构性的;然而，最近的研究表明， 可能在细胞信号传导中具有其他功能。我们的初步数据表明，DPP 激活Wnt信号通路促进牙本质细胞分化 牙髓干细胞。Wnt 5a是DPP在DPSC中激活的特异性Wnt。的 我们打算研究的Wnt 5a信号传导的下游效应物是β-连环蛋白， TAZ和RhoC。我们假设这些DPP介导的效应子激活 负责DPSC的分化及其迁移特性。为了验证这一 假设我们建议使用分子方法：（a）研究分子 DPP介导Wnt信号激活以稳定β-连环蛋白的机制 （B）为了检测DPSC和TAZ之间的相互作用， DPP刺激对RhoC GT3信号传导的影响及其对 DPSC中肌动蛋白细胞骨架的重组导致细胞形状的变化， （c）评价DPP作为牙本质异位模型的治疗剂， 纸浆再生总的来说，这些研究的结果将揭示一个前所未有的 由DPP调节的信号传导框架，可用于未来开发治疗方法 修复丢失、受损或患病的牙本质-牙髓复合体， 生存

PROJECT SUMMARY Deep caries and pulp exposures are normally treated by pulp capping or partial pulp amputation to preserve the vitality of the pulp. Control of dental caries is a major public health program. Discovery of the dental pulp stem cells (DPSCs) have opened up new avenues for regeneration or repair of the pulp-dentin complex. The use of adult stem cells for tissue regeneration and repair is important in regenerative medicine. Another important component for tissue engineering is a bioactive signaling molecule. For the last two decades we have been studying the acidic phosphoproteins of the organic matrix of bone and dentin. Besides their function in the extracellular matrix, many of these proteins are now implicated in stimulating signaling events. One such protein identified in the dentin matrix is dentin phosphophoryn (DPP). Until recently, the function of DPP was thought to be structural; however, recent studies have suggested that DPP may have other functions in cell signaling. Our preliminary data indicate that DPP activates the Wnt signaling pathway to promote odontoblast differentiation of the dental pulp stem cells. Wnt5a was the specific Wnt activated by DPP in DPSCs. The downstream effectors of Wnt5a signaling that we propose to investigate are β-catenin, TAZ and RhoC. We hypothesize that these DPP-mediated activation of these effectors are responsible for differentiation of DPSC's and their migratory properties. To test this hypothesis we propose to use molecular approaches : (a) To investigate the molecular mechanisms by which DPP mediates the activation of Wnt signaling to stabilize β-catenin and TAZ resulting in the differentiation of DPSCs into odontoblasts; (b) To examine the influence of DPP stimulation on RhoC GTPase signaling and its effect on the reorganization of the actin cytoskeleton in DPSCs leading to changes in cell shape and migration; (c ) To evaluate DPP as a therapeutic agent in an ectopic model for dentin- pulp regeneration. Overall, results from these studies would reveal an unprecedented signaling framework modulated by DPP that could be utilized in the future to develop therapies to restore lost damaged or diseased dentin-pulp complex with a vital pulp leading to tooth survival.