Growth factors-induced dentinogenesis

项目摘要：制定纸浆战略的必要性越来越大 通过再生疗法克服因龋齿、修复术或 精神创伤。目前，我们对分子的理解有很大的差距。 以及调节修复性牙本质形成的细胞机制。我们的长期目标 是为了获得关于人类牙髓细胞生态位的基础知识并应用于 减轻因龋齿造成的牙齿损伤负担的知识，修复 程序，或者创伤。这个应用程序的目标是阐明 牙髓巢中ewitinB1和IGF-1的相互作用诱导牙本质形成 在活体内。最重要的假设是IGF-1调节牙髓细胞 小生境，并诱导牙本质的形成通过ewitinB1。在强劲的初步数据的指引下， 将通过追求以下两个具体目标来检验这一假设：目标1： 确定ewitinB1控制成牙本质细胞数量的机制 祖细胞及其在牙髓中的增殖和分化。目标2：确定 胰岛素样生长因子-1调节血管紧张素转换酶b1表达的细胞和分子机制 使用小鼠模型的体内和使用人DPSCs和人口腔粘膜的体外模型 干细胞。一种已产生的成牙本质细胞特异的eparinB1基因敲除小鼠系 (使用由DMP1或骨钙素启动子驱动的cre)，以及IGF-1的小鼠系 受体(DMP1-IGF-1RKO)和肝脏IGF-1转基因株(HIT)将用于 实现这两个目标。重要的是，我们的模型的初步特征表明 IGF-1和ewitinB1在体内均参与牙本质的形成。拟议的研究是 概念上的创新，因为我们首次展示了 在体牙本质形成过程中的ewitinB1和IGF-1。此外，我们还提供了一种直接方法来 使用独特的老鼠模型以及主要的人类模型来确定这些交互 牙髓细胞培养。这项拟议的研究意义重大，因为预计它将 推进再生性牙髓治疗程序领域，并将影响整体努力 以保留损伤后自然的第三牙本质形成过程。

Project summary: There is an increasing need to develop strategies for pulp regeneration therapy to overcome tooth injury due to caries, restorative procedures, or trauma. Currently, there is a significant gap in our understanding of the molecular and cellular mechanisms regulating reparative dentinogenesis. Our long-term goal is to gain fundamental knowledge on the human dental pulp cellular niche and to apply that knowledge to lessen the burdens of tooth injury due to caries, restorative procedures, or trauma. The objective for this application is to elucidate how the interactions between ephrinB1 and IGF-1 in the dental pulp niche induce dentinogenesis in vivo. The overarching hypothesis is that IGF-1 regulates cells of the tooth pulp niche, and induces dentinogenesis via ephrinB1. Guided by strong preliminary data, this hypothesis will be tested by pursuing the following two specific aims: Aim 1: Determine the mechanism by which ephrinB1 controls the number of odontoblast progenitors, their proliferation, and differentiation in the tooth pulp. And Aim 2: Determine the cellular and molecular mechanisms by which IGF-1 regulates ephrinB1 expression in vivo using mouse models and ex vivo using human DPSCs and human oral mucosa stem cells. An already-generated odontoblast-specific ephrinB1 knockout mouse lines (using cre driven by the DMP1 or osteocalcin promoters), and mouse lines of IGF-1 receptor (DMP1-IGF-1RKO) and the hepatic IGF-1 transgenic (HIT) line will be used to achieve the two aims. Importantly, initial characterization of our models indicates that both IGF-1 and ephrinB1 involved in dentinogenesis in vivo. The proposed research is conceptually innovative because we show, for the first time, the interactions between ephrinB1 and IGF-1 during dentinogenesis in vivo. Further, we offer a direct approach to determine these interactions using unique mouse models, as well as primary human dental pulp cell cultures. The proposed research is significant because it is expected to advance the field of regenerative endodontic procedures and will impact the overall effort to retain the natural tertiary dentin formation process following injury.