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（申请人提供）：龋齿和牙髓炎会导致儿童和青少年恒牙牙根发育停滞。根尖张开的情况容易受到外伤和感染，经常导致年轻时（通常<18岁）牙齿脱落。儿童和青少年患者的牙齿缺失是毁灭性的，因为钛牙种植体是禁忌的，因为金属浸入正在经历积极垂直生长的牙槽骨中。目前，临床上尚无针对儿童和青少年根尖开放的恒牙感染感染的治疗方法。促进牙本质形成和牙根持续发育的再生细胞或信号是解决这一未满足的临床需求的唯一希望。发育中的颅面间充质干/祖细胞分化成形成牙本质的成牙本质细胞。我们的初步数据表明，当颅面间充质干细胞/祖细胞分化为成牙本质细胞时，一组 948 个基因和转录因子被上调或下调。我们提供了两个合理选择的因素 在体内临床前模型中经过牙髓治疗的根管中，发现牙本质以管状牙本质的形式再生，具有牙本质小管和成牙本质细胞过程，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。引人注目的是，没有细胞被移植到经过牙髓治疗的根管中。因此，所有再生的牙本质都源自由这两种分子线索招募的宿主内源细胞。在这项应用中，我们将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张开的未成熟牙齿，相当于儿童和青少年患者恒牙的发育。这种从成熟牙齿到未成熟牙齿的转变远不是一个简单的时间顺序转换，而是解决两个科学上未知和临床相关的问题：1）单分子线索不仅可以诱导足够的内源性根尖乳头干/祖细胞的募集，而且可以将它们转化为产生牙本质的成牙本质细胞吗？ 2）分子线索的时空传递能否促进牙本质定向生长以完成牙根发育？因此，响应 PAR-13-137（生物工程研究补助金，BRG），该提案的总体目标是在临床前大型动物模型中开发具有宽开根尖的未成熟牙齿牙本质再生的新策略。我们的总体假设是，牙根尖张开的未成熟牙齿的牙本质再生是通过诱导内源干/祖细胞的募集和分化的新型分子线索的信号梯度实现的。