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: 8114589
• 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 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8114589
• 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. PUBLIC HEALTH RELEVANCE: The project is to study the role of RUNX2 in tooth formation by survey the relationship between dental phenotype and genotype of genetic defects in cleidocranial dysplasia (CCD) and to establish stable pulp cells from CCD patients with characterized RUNX2 or other genetic defects.

描述（由申请人提供）：RUNX2是骨形成的关键主转录因子。RUNX2突变与人类常染色体显性（AD）疾病锁骨颅发育不良（CCD, omim# 119600）有关。CCD患者表现为锁骨发育不全、身材矮小等骨骼缺陷，以及多牙等牙齿缺陷。靶向Runx2基因缺失的小鼠（Runx2）模仿CCD的骨骼缺陷，显示完全缺乏骨形成，但不像人类那样出现主要的CCD牙齿多牙表型。事实上，Runx2小鼠显示出早期的牙齿形成阻滞（芽/帽阶段）。因此，由于小鼠只有一个牙列，小鼠的Runx2表型与人类CCD患者的显着不同。因此，研究RUNX2在与CCD相关的人牙组织中的功能至关重要。这项应用的长期目标是了解RUNX2在人类牙齿形成过程中的作用，以及特定的RUNX2突变如何导致第三个牙列的形成，从而应用于牙齿再生。本申请的短期目的是通过利用独特的人类CCD牙齿细胞系，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。该应用的假设是，在该蛋白的功能域中发生的特定RUNX2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。特异性目的1是将已鉴定的CCD家族的牙齿表型与其基因型联系起来，特异性目的2是从具有或不具有明确RUNX2突变的CCD患者发育中的牙齿器官中建立稳定的牙髓细胞系。本研究可以将RUNX2突变与牙齿表型精确关联起来，并建立具有RUNX2突变特征的人CCD牙齿细胞系的独特资源。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之外，这些研究最终可以促进牙齿替代疗法的新策略。