DMP1 Mutations: Defects in Odontogenesis

DMP1 突变：牙发育缺陷

基本信息

批准号：
7872825
负责人：
JIAN Q. FENG
金额：
$ 33.72万
依托单位：
TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-30 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7872825
关键词：
Amino Acids Animal Model Applications Grants Bypass C-terminal Cell Nucleus Cells Clinical Complex Data Defect Dental Dental Pulp Dentin Dentin Formation Dentinogenesis Dentition Development Disease Drug Formulations Event Exhibits Familial hypophosphatemic bone disease Functional disorder Gene Mutation Generations Genes Genetic Transcription Goals Human In Vitro Individual Intervention Knockout Mice Lead Light MAP Kinase Gene MAP Kinase Signaling Pathways Mediating Minor Molecular Molecular Analysis Molecular Genetics Morphogenesis Mus Mutation Odontoblasts Odontogenesis One-Step dentin bonding system Oral health Osteogenesis Pathogenesis Pathway interactions Patients Pattern Peptide Fragments Phenotype Physiological Physiology Play Prevention Process Production Proteins Pulp Chambers Regulation Research Research Proposals Role Signal Pathway Signal Transduction Staging Testing Therapeutic Therapeutic Intervention Tooth Abnormalities Tooth structure Transcriptional Regulation Transgenic Mice Width Work biomineralization cell growth dentin matrix protein 1 falls gain of function improved in vivo insight mineralization mouse model novel programs promoter public health relevance research study tool transcription factor wisdom tooth

项目摘要

DESCRIPTION (provided by applicant): Tooth development requires the precise spatial and temporal coordination of programs for cell growth, differentiation, and mineralization. In a search for genes required for normal tooth morphogenesis we have studied Dentin matrix protein1 (DMP1), a non- collagenous matrix protein highly expressed in pulp/odontoblast cells, using in vivo loss- and gain-of-function approaches. Dmp1-null mice display profound tooth abnormalities with enlarged pulp chambers, increased width of the predentin zone, hypomineralization, and delayed 3rd molar formation. Realizing that autosomal recessive hypophosphatemic rickets (ARHR) patients manifest phenotypic changes very similar to those observed in Dmp1-KO mice, we recently discovered two DMP1 mutations in these patients. We have concluded that these mutations are causes of the phenotypes resembling those of Dmp1-KO mice, although minor differences exist. In a search for mechanisms by which DMP1 controls odontogenesis, we unexpectedly observed a sharp reduction of osterix in the null pulp/odontoblasts. Osterix is a transcriptional factor that is essential for osteogenesis but its role in odontogenesis is unknown. Targeted re-expression of DMP1 in Dmp1-KO pulp/odontoblast cells restores osterix expression and rescues the defects in tooth formation. Notably, we found similar dentin abnormalities in Dmp1-KO, and osterix (conventional or conditional) KO mice. Therefore, we propose that DMP1 mutations are the cause of dentin defects in ARHR patients, and that DMP1 regulates osterix expression at an early stage of tooth development, which plays a critical role for odontogenesis. To test this hypothesis we will study the molecular genetics and pathophysiology of DMP1 mutations through creation of a mouse model with DMP1 mutations. We will also determine the mechanisms by which DMP1 modulates odontogenesis through Osterix via direct action at the nucleus and/or MAPK pathways. The successful completion of these studies will lead to 1) generation of an animal model mimicking these human mutations; 2) understanding the mechanism by which DMP1 controls odontogenesis through osterix via a direct mechanism within the nucleus level and/or MAPK signaling; and 3) identification of bioactive fragment(s) of DMP1 which can ultimately be used in translational applications that will benefit the public by providing therapeutic approaches corresponding to genetic alterations, leading to improved dental/oral health. PUBLIC HEALTH RELEVANCE: Patients with autosomal recessive hypophosphatemic rickets (ARHR) patients manifest phenotypic changes very similar to dentin defects we observed in Dmp1-KO mice. Our discovery of DMP1 mutations in these patients led to the formulation of the current research proposal. Our successful completion of these studies will provide mechanistic details about dentin formation, and will ultimately shed light on the prevention of structural defects in dentin. In addition, the mouse models which to be generated from these studies can be used to correlate individual gene mutations with the appropriate clinical intervention.

描述（由申请人提供）：牙齿发育需要对细胞生长，分化和矿化的程序进行精确的空间和时间协调。在搜索正常牙齿形态发生所需的基因时，我们研究了一种在果肉/odontoblast细胞中高度表达的非胶原基质蛋白（DMP1），使用体内损失和功能获得的方法。 DMP1-NULL小鼠表现出严重的牙齿异常，牙髓增大，predentin区域的宽度增加，低矿化和延迟的第三摩尔形成。意识到常染色体隐性低磷酸盐病（ARHR）患者表现出与在DMP1-KO小鼠中观察到的表型变化非常相似，因此我们最近在这些患者中发现了两个DMP1突变。我们得出的结论是，这些突变是类似于DMP1-KO小鼠的表型的原因，尽管存在较小的差异。在搜索DMP1控制牙胎发生的机制时，我们意外地观察到了无效纸浆/odontoblasts中osterix的急剧减少。 Osterix是对成骨的转录因子，但其在牙肠发生中的作用尚不清楚。 DMP1在DMP1-KO纸浆/Odontoblast细胞中的靶向重新表达可恢复Osterix的表达并挽救牙齿形成中的缺陷。值得注意的是，我们在DMP1-KO中发现了类似的牙本质异常，而Osterix（常规或条件）KO小鼠。因此，我们提出DMP1突变是ARHR患者牙本质缺陷的原因，并且DMP1在牙齿发育的早期阶段调节Osterix的表达，这对于牙生物来说起着至关重要的作用。为了检验该假设，我们将通过创建具有DMP1突变的小鼠模型来研究DMP1突变的分子遗传学和病理生理学。我们还将确定DMP1通过在细胞核和/或MAPK途径上直接作用通过Osterix调节牙本质发生的机制。这些研究的成功完成将导致1）生成模仿这些人类突变的动物模型； 2）理解DMP1通过核水平和/或MAPK信号传导内的直接机制通过Osterix控制牙骨的机制； 3）DMP1的生物活性片段的识别，最终可以用于转化应用中，通过提供与遗传改变相对应的治疗方法，从而使公众受益，从而改善了牙齿/口腔健康。公共卫生相关性：常染色体隐性肾上腺磷酸盐rick（ARHR）患者表现出表型变化与我们在DMP1-KO小鼠中观察到的牙本质缺陷非常相似。这些患者中DMP1突变的发现导致了当前的研究建议的制定。我们成功完成这些研究将提供有关牙本质形成的机械细节，并最终阐明预防牙本质中的结构缺陷。此外，这些研究要产生的小鼠模型可用于将单个基因突变与适当的临床干预相关联。