Growth factors-induced dentinogenesis

项目概要： 有越来越多的需要发展的策略，牙髓再生治疗，以克服 由于龋齿、修复程序或创伤造成的牙齿损伤。目前，有一个重要的 我们对调节修复的分子和细胞机制的理解存在差距， 牙本质形成我们的长期目标是获得人类牙髓的基础知识 细胞生态位，并应用这些知识，以减轻牙齿损伤的负担，由于龋齿， 恢复性治疗或创伤本申请的目的是阐明 ephrinB1和IGF-1在牙髓龛中的相互作用在体内诱导牙本质形成。 总体假设是IGF-1调节牙髓龛的细胞，并诱导 通过ephrinB1的牙本质形成。在强有力的初步数据的指导下， 目标1：确定 ephrinB1控制成牙本质细胞祖细胞的数量、增殖和分化， 牙髓目的2：确定IGF-1在细胞和分子水平上的作用机制。 使用小鼠模型在体内和使用人DPSC离体调节ephrinB1表达 和人口腔粘膜干细胞。一种已经产生的成牙本质细胞特异性ephrinB1 敲除小鼠系（使用由DMP1或骨钙蛋白启动子驱动的cre），和小鼠 IGF-1受体（DMP1-IGF-1RKO）和肝IGF-1转基因（HIT）系将被 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ephrinB1均参与牙本质形成。拟议的研究是 概念上的创新，因为我们第一次展示了ephrinB1之间的相互作用， 和IGF-1在体内牙本质形成过程中的作用。此外，我们提供了一种直接的方法来确定这些 使用独特的小鼠模型，以及原代人牙髓细胞培养物的相互作用。 这项研究意义重大，因为它有望推动再生能源领域的发展。 并将影响保留天然三级牙本质的整体努力 受伤后的形成过程。

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.