Growth factors-induced dentinogenesis

项目概述：越来越需要制定纸浆战略 再生治疗，以克服由于龋齿，修复程序，或 外伤目前，在我们对分子生物学的理解上， 和调节修复性牙本质形成的细胞机制。我们的长期目标 是获得人类牙髓细胞生态位的基础知识， 知识，以减轻负担的牙齿损伤，由于龋齿，恢复 手术或创伤本申请的目的是阐明 ephrinB 1和IGF-1在牙髓龛中相互作用诱导牙本质形成 in vivo.总体假设是IGF-1调节牙髓细胞 niche，并通过ephrinB 1诱导牙本质形成。在强有力的初步数据的指导下， 将通过以下两个具体目标来检验这一假设：目标1： 确定ephrinB 1控制成牙本质细胞数量的机制 牙髓中的祖细胞、它们的增殖和分化。目标2：确定 IGF-1调节肝纤维化中ephrinB 1表达的细胞和分子机制 体内使用小鼠模型和离体使用人DPSC和人口腔粘膜 干细胞已建立的成牙本质细胞特异性ephrinB 1基因敲除小鼠系 （使用由DMP 1或骨钙蛋白启动子驱动的cre），和IGF-1的小鼠系 受体（DMP 1-IGF-1 RKO）和肝IGF-1转基因（HIT）系将用于 实现这两个目标。重要的是，我们模型的初步特征表明， IGF-1和ephrinB 1均参与牙本质形成。拟议的研究是 在概念上是创新的，因为我们第一次展示了 ephrinB 1和IGF-1在牙本质形成过程中的作用。此外，我们还提供一种直接的方法， 使用独特的小鼠模型以及主要的人类模型来确定这些相互作用。 牙髓细胞培养这项研究意义重大，因为它有望 推进再生牙髓手术领域，并将影响整体工作 以保持损伤后的天然三级牙本质形成过程。

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.