Biphasic Roles of OSX-WNT-B-Catenin Signaling Pathway in Tooth Root Formation

OSX-WNT-B-Catenin 信号通路在牙根形成中的双相作用

• 批准号: 9268435
• 负责人: JIAN Q. FENG
• 金额: $ 36.46万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2020-05-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9268435
• 关键词: Achievement; Address; Affect; Animal Model; Area; Biological; Cell Differentiation process; Cells; Clinical; DSPP gene; Data; Dental; Dental Enamel; Dental Students; Dental crowns; Dentin; Dentin Formation; Dentistry; Deposition; Development; Felis catus; Future; Generations; Genes; Genetic Engineering; Genetically Engineered Mouse; Goals; Hereditary Disease; In Vitro; Incisor; Inherited; Inhibition of Cell Proliferation; Investigation; Knock-out; Knockout Mice; Knowledge; Minerals; Modeling; Molecular; Molecular Biology; Mus; National Institute of Dental and Craniofacial Research; Natural regeneration; Odontoblasts; Pathway interactions; Patients; Periodontal Diseases; Periodontitis; Phenotype; Plant Roots; Play; Regulation; Research; Research Proposals; Role; Signal Pathway; Signal Transduction; Stem Cell Research; Stem cells; Structure; Syndrome; System; Testing; Thinness; Time; Tissues; Tooth Components; Tooth Crowns; Tooth Fractures; Tooth Germ; Tooth root structure; Tooth structure; Trauma; beta catenin; dosage; gain of function; in vivo; innovation; insight; mineralization; mouse model; mutant; nestin protein; novel; nuclear factor 1; postnatal; public health relevance; self-renewal; transcription factor; transcriptome sequencing; translational study

DESCRIPTION (provided by applicant): One of the most important goals of dentistry and the NIDCR is to generate a whole "Bio-Tooth", which would be composed of crown and root. In the last three decades, considerable achievements have been made in studies of tooth germ and crown formation, although the root studies lag behind due to the lack of appropriate animal models available, plus the inherent difficulties associated with handling mineralized dentin. Nevertheless, it is important to recognize that the root is a critical structural component of the tooth because: i) There are numerous hereditary syndromes and chromosomal anomalies that affect the root structure; and ii) There is an urgent need to generate a root for treatment of dental trauma, tooth agenesis, and periodontal diseases. Our long-term goal is to understand the biological mechanisms controlling root formation, which will fill a key gap of knowledge leading to the goal of regenerating a whole "Bio-Tooth". The objective here, which is our next step in the pursuit of that goal, is to define the emerging signaling pathway(s) essential for root but not for crown dentin formation. Our central hypothesis is that the novel control mechanism in root dentin formation is different from that in the tooth crown formation, in which the interaction among NFIC, OSX, ß-catenin, and DSPP play key roles. This hypothesis is formulated on the basis of our strong preliminary data produced using both global knockout (KO) and conditional KO (cKO) mouse models, as well as in vitro molecular approaches. Two Specific Aims are proposed to test this hypothesis: 1). To demonstrate the critical role of OSX, the key downstream transcriptional factor of NFIC, in control of postnatal root - but not crown - dentin formation by means of the negative regulation of Wnt-ß-catenin and positive regulation of DSPP; and 2).To determine whether blocking the elevated ß-catenin level rescues the Osx cKO tooth phenotype in vivo and to define whether re- expressions of DSPP either in the Osx cKO or the CA-ß-catenin mice restore dentin tubule formation and mineralization. The proposed research is innovative because i) these genetically engineered animal models developed astonishing tooth root phenotypes with no apparent changes in the crown; and ii) the approaches proposed will delineate the novel roles of each molecule in this emerging signaling pathway in a tissue- and temporal-dependent manner. The studies proposed are significant because the valuable information gained can be applied to fill the critical knowledge gap in this understudied area and contribute to investigations on the generation of a future biological tooth replacement.

描述（由申请人提供）：牙科和NIDCR最重要的目标之一是产生一个完整的“生物牙齿”，它将由冠和根组成。在过去的三十年中，牙胚和牙冠形成的研究取得了相当大的成就，尽管由于缺乏适当的动物模型，再加上处理矿化牙本质的固有困难，对牙根的研究滞后。然而，重要的是要认识到牙根是牙齿的关键结构组成部分，因为：1)有许多遗传综合征和染色体异常影响牙根结构；ii)迫切需要生成牙根以治疗牙外伤、牙齿发育不全和牙周病。我们的长期目标是了解控制牙根形成的生物学机制，这将填补一个关键的知识空白，从而实现再生整个“生物牙齿”的目标。这里的目标是我们追求这一目标的下一步，是定义对根必不可少但对冠状牙本质形成无关的新兴信号通路。我们的中心假设是牙根牙本质形成的新控制机制与牙冠形成的新控制机制不同，其中NFIC、OSX、ß-catenin和DSPP之间的相互作用发挥了关键作用。这一假设是基于我们使用全局敲除（KO）和条件敲除（cKO）小鼠模型以及体外分子方法产生的强有力的初步数据而制定的。本文提出了两个具体目标来检验这一假设：1)。通过Wnt-ß-catenin的负调控和DSPP的正调控，证明NFIC的关键下游转录因子OSX在控制出生后牙根而非牙冠形成中的关键作用；和2)。确定阻断升高的ß-catenin水平是否能在体内挽救Osx cKO牙齿表型，并确定在Osx cKO或CA-ß-catenin小鼠中重新表达DSPP是否能恢复牙本质小管的形成和矿化。拟议的研究是创新的，因为i)这些基因工程动物模型产生了惊人的牙根表型，而冠没有明显变化；ii)提出的方法将以组织和时间依赖的方式描述每个分子在这一新兴信号通路中的新作用。所提出的研究具有重要意义，因为所获得的有价值的信息可以用于填补这一研究不足领域的关键知识空白，并有助于研究未来生物牙齿替代的产生。