Growth factors-induced dentinogenesis

生长因子诱导的牙本质发生

• 批准号: 9979634
• 负责人: Emi Shimizu
• 金额: $ 39.74万
• 依托单位: RBHS-SCHOOL OF DENTAL MEDICINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9979634
• 关键词: Address; Affect; Ameloblasts; Cell Culture Techniques; Cell membrane; Cells; Clinic; Complex; DSPP gene; Data; Dental Enamel; Dental Pulp; Dental Pulp Capping; Dental caries; Dental crowns; Dentin; Dentin Formation; Dentinogenesis; Dentition; Development; Endodontics; Environment; Eph Family Receptors; Ephrins; Extracellular Domain; Family; GHR gene; Gene Deletion; Gene Expression; Goals; Growth Factor; Growth Hormone Receptor; Hepatic; Human; Incisor; Injury; Insulin-Like Growth Factor I; Insulin-Like-Growth Factor I Receptor; Knockout Mice; Knowledge; Lasers; Lead; Ligands; Liver; Mediator of activation protein; Membrane; Mission; Modeling; Molecular; Morphogenesis; Morphology; Mus; Natural regeneration; Odontoblasts; Odontogenesis; Oral mucous membrane structure; Osteocalcin; Outcome; Physiological; Plant Roots; Play; Procedures; Process; Public Health; Receptor Protein-Tyrosine Kinases; Recovery; Reporting; Research; Role; Serum; Signal Transduction; Somatotropin; Specimen; Testing; Therapeutic; Time; Tissues; Tooth Cell; Tooth Germ; Tooth Injuries; Tooth structure; Transgenic Mice; Transgenic Organisms; Trauma; Tyrosine Kinase Domain; United States National Institutes of Health; base; bone cell; calcium hydroxide; density; in vivo; injured; innovation; member; migration; mineralization; mouse model; osteoprogenitor cell; progenitor; promoter; regenerative; regenerative therapy; repaired; response; scaffold; src-Family Kinases; stem cells

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.

项目摘要：越来越需要制定纸浆策略 再生疗法以克服龋齿，修复程序或 创伤。当前，我们对分子的理解存在很大的差距 和调节修复性牙本质发生的细胞机制。我们的长期目标 是为了获得有关人牙纸浆细胞生态位的基本知识，并应用 这些知识可以减轻因龋齿而造成的牙齿损伤负担 程序或创伤。此应用的目的是阐明 牙浆生丁基中的ephrinb1和igf-1之间的相互作用诱导齿状发生 体内。总体假设是IGF-1调节牙齿的细胞 利基市场，并通过ephrinb1诱导牙齿发生。在强大的初步数据的指导下， 该假设将通过追求以下两个具体目的来检验：目标1： 确定ephrinb1控制odontoblast的数量的机制 祖细胞，它们的增殖和牙齿果肉的分化。和目标2：确定 IGF-1在细胞和分子机制中调节ephrinb1在 使用鼠标模型的体内使用人DPSC和人类口服粘膜进行体内 干细胞。已经生成的Odontoblast特异性Ephrinb1敲除鼠标线 （使用由DMP1或骨钙蛋白启动子驱动的CRE）和IGF-1的小鼠系 受体（DMP1-IGF-1RKO）和肝IGF-1转基因（HIT）系将用于 实现两个目标。重要的是，我们的模型的初始表征表明 IGF-1和ephrinb1均参与体内牙抑素发生。拟议的研究是 从概念上创新，因为我们首次展示了 ephrinb1和igf-1在体内牙线发生过程中。此外，我们提供了一种直接的方法 使用独特的鼠标模型以及主要人类来确定这些相互作用 牙髓细胞培养物。拟议的研究很重要，因为它有望 推进再生牙髓程序的领域，并将影响整体努力 在受伤后保留自然的第三次牙本质形成过程。