Continuous root formation in developing teeth by molecular cues

通过分子线索在牙齿发育过程中持续形成牙根

• 批准号: 9237255
• 负责人: JEREMY J MAO
• 金额: $ 72万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9237255
• 关键词: 18 year old; Acute; Address; Adolescent; Adopted; Adult; Age; Animal Model; Apical; BMP7 gene; Biomedical Engineering; Cell Differentiation process; Cells; Child; Chronology; Clinical; Clinical Treatment; Cues; Data; Dental Implants; Dental Pulp; Dental caries; Dentin; Dentin Formation; Development; Electron Microscopy; Endodontics; Family suidae; Genes; Genetic Transcription; Growth; Homeostasis; In Situ Hybridization; Infection; Knowledge; Mesenchymal; Messenger RNA; Metals; Minerals; Modeling; Molecular; Molecular Profiling; Natural regeneration; Neural Crest; Odontoblasts; Organ failure; Paper; Pathway interactions; Patients; Peer Review; Phenotype; Plant Roots; Pre-Clinical Model; Process; Proteins; Publishing; Pulp Canals; Pulpitis; Recruitment Activity; Reporting; Research Project Grants; Signal Transduction; Stem cells; Time; Titanium; Tooth Components; Tooth Loss; Tooth regeneration; Tooth root structure; Tooth structure; Translations; Transplantation; Trauma; Tubular formation; adolescent patient; alveolar bone; beta catenin; clinically relevant; craniofacial; genome-wide; in vivo Model; in vivo regeneration; innovation; mechanical properties; migration; novel; novel strategies; pediatric patients; permanent tooth; pre-clinical; public health relevance; regenerative; response; soft tissue; spatiotemporal; stem; tissue regeneration; tongue papilla; transcription factor

 DESCRIPTION (provided by applicant): Dental caries and pulpitis cause developmental arrest of tooth roots of permanent teeth in children and adolescents. Wide-open root apex is susceptible to trauma and infections, frequently resulting in tooth loss at a young age (typically <18 years old). Tooth loss in children and adolescent patients is devastating because titanium dental implants are contra-indicated due to metal submerge in the alveolar bone that undergoes active vertical growth. Currently, there is no effective clinical treatment for infected permanent teeth with open root apex in children and adolescent patients. Regenerative cells or cues that promote dentin formation and continuous root development offer the only hope to address this unmet clinical need. Craniofacial mesenchymal stem/progenitor cells in development differentiate into odontoblasts that form dentin. Our preliminary data show that a panel of 948 genes and transcriptional factors are up- or down-regulated when craniofacial mesenchymal stem/progenitor cells differentiate into odontoblasts. We delivered two rationally selected factors in endodontically treated root canals in a preclinical model in vivo and found robust dentin regeneration in the form of tubular dentin with dentinal tubules and odontoblast processes as demonstrated by electron microscopy. Mechanical properties of the regenerated dentin were at par with native dentin that served as a substrate for the newly formed, regenerated dentin. Strikingly, no cells were transplanted in endodontically treated root canals. Thus, all of the regenerated dentin was derived from host endogenous cells that were recruited by these two molecular cues. In this application, we transform our newly gained knowledge on endogenous dentin regeneration in mature teeth into immature teeth with wide-open root apex in a preclinical, large animal model that is equivalent to developing permanent teeth in children and adolescent patients. This translation from mature teeth to immature teeth is far from a simple chronological switch, but will address two scientifically unknown and clinically relevant questions: 1) Can single molecular cues not only induce the recruitment of sufficient endogenous apical papilla stem/progenitor cells, but also transform them into dentin-generating odontoblasts? 2) Can spatiotemporal delivery of molecular cues promote directional dentin growth to complete root development? Accordingly, the overall objectives of this proposal, in response to PAR-13-137 (Bioengineering Research Grants, BRG), are to develop novel strategies for dentin regeneration in immature teeth with wide open root apex in a preclinical, large animal model. Our overarching hypothesis is that dentin regeneration in immature teeth with wide-open root apex is enabled by signal gradients of novel molecular cues that induce the recruitment and differentiation of endogenous stem/progenitor cells.

 描述（由申请人提供）：龋齿和牙髓炎导致儿童和青少年恒牙牙根发育停滞。牙根尖的开放易受创伤和感染的影响，经常导致年轻时（通常<18岁）的牙齿脱落。儿童和青少年患者的牙齿缺失是毁灭性的，因为钛牙科种植体是禁忌的，因为牙槽骨中的金属碎屑会经历活跃的垂直生长。目前，对于儿童和青少年恒牙根尖开放感染的患者，尚无有效的临床治疗方法。促进牙本质形成和连续牙根发育的再生细胞或线索提供了解决这种未满足的临床需求的唯一希望。发育中的颅面间充质干/祖细胞分化为形成牙本质的成牙本质细胞。我们的初步数据显示，当颅面间充质干/祖细胞分化为成牙本质细胞时，一组948个基因和转录因子上调或下调。我们合理选择了两个因素 在体内临床前模型中的牙髓治疗根管中，发现了具有牙本质小管和成牙本质细胞突起的管状牙本质形式的稳健的牙本质再生，如电子显微镜所示。再生牙本质的机械性能与作为新形成的再生牙本质的基底的天然牙本质相当。令人惊讶的是，没有细胞被移植到牙髓治疗的根管中。因此，所有的再生牙本质都来源于被这两种分子信号招募的宿主内源性细胞。在这项应用中，我们将我们新获得的关于成熟牙齿内源性牙本质再生的知识转化为临床前大型动物模型中根尖完全开放的未成熟牙齿，相当于儿童和青少年患者的恒牙发育。这种从成熟牙齿到未成熟牙齿的转换远非简单的时间顺序转换，而是将解决两个科学上未知的和临床相关的问题：1）单一分子线索是否不仅可以诱导足够的内源性根尖乳头干/祖细胞的招募，而且还可以将它们转化为牙本质生成的成牙本质细胞？2)分子信号的时空传递能促进定向牙本质生长以完成牙根发育吗？因此，响应PAR-13-137（生物工程研究赠款，BRG），本提案的总体目标是在临床前大型动物模型中开发用于根尖开放的未成熟牙齿中牙本质再生的新策略。我们的总体假设是，在未成熟的牙齿与开放的根尖牙本质再生是由新的分子线索，诱导内源性干/祖细胞的招聘和分化的信号梯度。