CLEIDOCRANIAL DYSPLASIA DENTAL PHENOTYPE AND GENOTYPE CORRELATIONS

锁颅骨发育不良牙齿表型和基因型相关性

• 批准号: 8300802
• 负责人: David K Crossman
• 金额: $ 10.99万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-13 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8300802
• 关键词: Address; Affect; Cell Culture Techniques; Cell Line; Cells; Characteristics; Cleidocranial Dysplasia; Clinical Treatment; Core Facility; Data; Defect; Dental; Dental Pulp; Dentists; Dentition; Development; Disease; Family; Family member; Fostering; Gene Deletion; Gene Expression; Gene Mutation; Genes; Genetic Variation; Genomics; Genotype; Goals; Hereditary Disease; Human; Human Resources; Informed Consent; Laboratories; Lead; Molecular; Molecular Profiling; Morphology; Mus; Mutation; Natural regeneration; Online Mendelian Inheritance In Man; Organ; Osteogenesis; Other Genetics; Patients; Pattern; Phenotype; Physicians; Qualifying; Replacement Therapy; Resources; Role; Signal Pathway; Staging; Structure; Supernumerary Tooth; Surveys; System; Tertiary Protein Structure; Testing; Time; Tissues; Tooth structure; Variant; base; bone; cell type; clavicle; human tissue; innovation; novel; skeletal; tool; transcription factor

DESCRIPTION (provided by applicant): RUNX2 is a critical master transcription factor for bone formation. RUNX2 mutations are associated with the human autosomal dominant (AD) disease cleidocranial dysplasia (CCD, OMIM #119600). CCD patients presents with skeletal defects such as clavicle agenesis and short stature as well as dental defects including supernumerary teeth. Mice with targeted Runx2 gene deletion (Runx2 ) mimics the skeletal defects of CCD showing complete lack of bone formation, but not the major CCD dental phenotype of supernumerary teeth as seen in humans. In fact, Runx2 mice show early arrested tooth formation (bud/cap stage). Therefore, since mice have only a single dentition, the mouse Runx2 phenotype varies significantly from that seen in human CCD patients. Thus, it is critical to study the function of RUNX2 in human dental tissues related to CCD. The long-range goal of this application is to understand the role of RUNX2 during human tooth formation and how specific RUNX2 mutations cause formation of a third dentition for application in tooth regeneration. The short-term aim of this application is to study the genotype-phenotype correlation of genetic variation in CCD patients related to their dental findings through utilization of unique human CCD dental cell lines. The hypothesis of this application is that specific RUNX2 mutations occurring within the functional domain of this protein lead to characteristic alterations in human dentition associated with unique patterns in tooth number and tooth morphology/structure. Specific Aim1 is to correlate the dental phenotype of identified CCD families with their genotype and Specific Aim 2 is to establish stable dental pulp cell lines from developing tooth organs of CCD patients with or without defined RUNX2 mutations. This study could correlate precise RUNX2 mutations with dental phenotypes and establish the unique resource of human CCD dental cell lines with characterized RUNX2 mutations. These studies could ultimately foster new strategies for tooth replacement therapies in addition to increasing our understanding of tooth formation and genetic diseases altering tooth patterning.

描述（由申请人提供）：RUNX 2是骨形成的关键主转录因子。RUNX 2突变与人类常染色体显性（AD）疾病锁骨颅骨发育不良（CCD，OMIM #119600）相关。CCD患者存在骨骼缺陷，如锁骨发育不全和身材矮小，以及牙齿缺陷，包括多生牙。具有靶向Runx 2基因缺失（Runx 2）的小鼠模拟了显示完全缺乏骨形成的CCD的骨骼缺陷，但不是如在人类中所见的多生牙的主要CCD牙齿表型。事实上，Runx 2小鼠显示出早期停滞的牙齿形成（芽/帽阶段）。因此，由于小鼠只有一个牙列，小鼠Runx 2表型与人类CCD患者中观察到的表型显著不同。因此，研究RUNX 2在人牙本质组织中与CCD相关的功能具有重要意义。本申请的长期目标是了解RUNX 2在人类牙齿形成过程中的作用，以及特定的RUNX 2突变如何导致第三牙列的形成，以应用于牙齿再生。本申请的短期目的是通过利用独特的人CCD牙细胞系研究CCD患者与其牙齿发现相关的遗传变异的基因型-表型相关性。本申请的假设是，在该蛋白质的功能结构域内发生的特定RUNX 2突变导致与牙齿数量和牙齿形态/结构的独特模式相关的人类牙列的特征性改变。具体目标1是将鉴定的CCD家族的牙齿表型与其基因型相关联，具体目标2是从具有或不具有确定的RUNX 2突变的CCD患者的发育中的牙齿器官建立稳定的牙髓细胞系。这项研究可以将精确的RUNX 2突变与牙齿表型相关联，并建立具有特征性RUNX 2突变的人CCD牙齿细胞系的独特资源。这些研究最终可以促进牙齿替代疗法的新策略，除了增加我们对牙齿形成和改变牙齿模式的遗传疾病的理解。