Evaluation molekularer Mechanismen während der osteogenen Differenzierung in Vorläuferzellen des dentalen Follikels (DFV)

牙囊祖细胞（DFV）成骨分化过程中分子机制的评估

• 批准号: 60331293
• 负责人: Professor Dr. Christian Morsczeck
• 金额: --
• 依托单位: Klinik und Poliklinik für Mund-, Kiefer- und Gesichtschirurgie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2008
• 资助国家: 德国
• 起止时间: 2007-12-31 至 2013-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/60331293?language=en
• 关键词: Evaluation; molekularer; Mechanismen; hrend; der

Dental follicle progenitor/stem cells (DFCs) could be used for cellular therapies in the future, but little is known about their osteogenic differentiation mechanisms. In the previous work of the funded project it could be shown that the osteogenic differentiation of DFCs can be induced with BMP2 or dexamethasone. EDX analyses have shown that DFCs produce biominerals, which are comparable to those of differentated mesenchymal bone marrow stem cells. Since differentiated DFCs did not express dentinogenic markers, they are also very interesting for research on the mechanisms of cementoblasts or alveolar osteoblasts differentiation. Previous results of this project suggested a BMP-independent pathway for the differentiation of DFCs. In genome-wide expression studies, the transcription factor (TF) ZBTB16 was identified as a starting point for the evaluation of putative BMP-independent mechanisms of differentiation. However, initial studies with ZBTB16 revealed that ZBTB16 induces BMP2 while the TF DLX3 induces ZBTB16. DLX3 was already identified as a putative factor for the osteogenic differentiation of DFCs before the start of this project. Investigations of this project showed that the TF DLX3 supports the osteogenic differentiation of DFCs by a BMP2-feedback control. Based on these results, the project will now focus on factors/pathways that are associated with the BMP2/DLX3 feedback loop. Here, there is evidence that DLX3 regulates the TF EGR1, the NOTCH and WNT signaling pathways, which are also associated with differentiating DFCs. Moreover, extracellular matrix (ECM) proteins also influence the differentiation of DFCs. The renewal proposal will now examine the functional relationship of identified molecular processes during osteogenic differentiation in DFCs. In the first part of the project sub-processes are analyzed, which are associated with the DLX3 supported differentiation. Here, the TF EGR1 or biological processes or molecular functions such as the WNT signaling pathway will be examined for their relation to the TF DLX3 supported osteogenic differentiation of DFCs. In the second part of the project the influence of ECM protein binding integrins and their associated signaling pathways will be investigated. This influence should be evaluated on the level of molecular mechanisms in differentiating DFCs; especially on that of the BMP2/DLX3-pathway. The obtained detailed knowledge about the differentiation will provide new insights into the development of the periodontium and may also improve options for the therapeutic use of DFCs, e.g. procedures of bone-augmentation.

牙囊前体/干细胞(DFC)可用于未来的细胞治疗，但其成骨分化机制尚不清楚。在该项目之前的工作中，可以证明BMP2或地塞米松可以诱导DFCs的成骨分化。EDX分析表明，DFC产生的生物矿物质与分化的骨髓间充质干细胞相当。由于分化的DFC不表达牙本质形成标志物，因此它们对成牙骨质细胞或牙槽骨成骨细胞分化机制的研究也非常有意义。本项目以前的研究结果表明，DFCs的分化存在BMP非依赖性途径。在全基因组表达研究中，转录因子(Tf)ZBTB16被确定为评估假定的BMP非依赖性分化机制的起点。然而，对ZBTB16的初步研究表明，ZBTB16诱导BMP2，而TFDLX3诱导ZBTB16。在本项目开始之前，DLX3已经被确定为DFC成骨分化的推定因子。本项目的研究表明，TFDLX3通过BMP2反馈调控支持DFCs的成骨分化。基于这些结果，该项目现在将专注于与BMP2/DLX3反馈环相关的因素/途径。这里，有证据表明DLX3调节Tf Egr1，Noch和WNT信号通路，这也与DFC的分化有关。此外，细胞外基质(ECM)蛋白也影响DFC的分化。更新方案现在将检查DFC成骨分化过程中已确定的分子过程的功能关系。在项目的第一部分中，分析了与DLX3支持的差异化相关的子流程。在这里，我们将研究Tf Egr1或生物学过程或分子功能，如WNT信号通路，以了解它们与Tf DLX3支持的DFC成骨分化的关系。在项目的第二部分，将研究细胞外基质蛋白结合整合素及其相关信号通路的影响。这种影响应该在分化DFC的分子机制水平上进行评估，尤其是对BMP2/DLX3通路的影响。获得的关于牙周组织分化的详细知识将为牙周组织的发育提供新的见解，并可能改进DFC的治疗应用，例如骨增强手术。