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

基本信息

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
项目类别：
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

项目摘要

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（由适用提供）：牙科车和牙髓炎会导致儿童和青少年牙齿牙齿牙根的发育停滞。宽开的根尖易受创伤和感染的影响，经常导致年轻时牙齿脱落（通常<18岁）。儿童和青春期患者的牙齿脱落是毁灭性的，因为钛牙齿牙齿是由于金属在肺泡骨中的沉积而构成的，从而经历了活跃的垂直生长。当前，对于儿童和青少年患者，尚无有效的临床治疗，该治疗具有开放式牙齿。促进牙本质形成和持续根源发育的再生细胞或提示提供了满足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牙本质细胞。我们的初步数据表明，当颅面间充质茎/祖细胞分化为odontopoblasts时，一组948个基因和转录因子被上调或下调。我们交付了两个合理选择的因素在体内的临床前模型中经过牙髓处理的根管中，以电子显微镜证明的牙齿牙本质的形式发现了坚固的牙本质再生。再生牙本质的机械性能与天然牙本质相吻合，该牙本质是新形成的新形成的再生牙本质的底物。令人惊讶的是，没有细胞在牙髓处理的根管中移植。这是所有重生牙本质的源自这两个分子提示募集的宿主内源性细胞。在此应用中，我们将成熟牙齿中内源性牙本质再生的新知识转化为未成熟的牙齿，在临床前大型动物模型中，具有宽阔的根尖，该模型等同于在儿童和青少年患者中发展永久牙齿。从成熟牙齿到不成熟牙齿的这种翻译远非一个简单的时间顺序转换，但是将解决两个科学未知和临床相关的问题：1）单个分子提示不仅可以诱导足够的内源性顶乳头茎/祖细胞募集，还可以将它们转化为牙本质生成牙蛋白的Odontotoblasts吗？ 2）分子提示的时空递送可以促进牙本质的生长以完成根源发展吗？根据对PAR-13-137（生物工程研究补助金，BRG）的响应，该提案的总体目标是在未成熟的牙齿中开发出牙本质再生的新型策略，该牙齿在临时性大型动物模型中具有广泛的敞开根尖。我们的总体假设是，通过诱导内源性茎/祖细胞的募集和分化的新型分子提示的信号梯度，具有宽阔的根尖的未成熟牙齿的牙本质再生。