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

基本信息

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
项目类别：
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

项目摘要

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）：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) 疾病锁骨颅骨发育不良 (CCD, OMIM #119600) 相关。 CCD 患者存在锁骨发育不全、身材矮小等骨骼缺陷以及多生牙等牙齿缺陷。具有靶向 Runx2 基因缺失的小鼠 (Runx2 ) 模仿了 CCD 的骨骼缺陷，显示完全缺乏骨形成，但不是人类中看到的多生牙的主要 CCD 牙齿表型。事实上，Runx2 小鼠表现出早期停止的牙齿形成（芽/帽阶段）。因此，由于小鼠只有一个牙列，因此小鼠 Runx2 表型与人类 CCD 患者的表型存在显着差异。因此，研究RUNX2在人类牙组织中与CCD相关的功能至关重要。该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 突变如何导致第三牙列的形成，以应用于牙齿再生。该应用的短期目标是通过利用独特的人类 CCD 牙科细胞系，研究 CCD 患者与其牙科表现相关的遗传变异的基因型-表型相关性。本申请的假设是，该蛋白质功能域内发生的特定 RUNX2 突变会导致人类牙列的特征性改变，与牙齿数量和牙齿形态/结构的独特模式相关。具体目标 1 是将已识别的 CCD 家族的牙齿表型与其基因型相关联，具体目标 2 是从有或没有确定的 RUNX2 突变的 CCD 患者的正在发育的牙齿器官中建立稳定的牙髓细胞系。这项研究可以将精确的 RUNX2 突变与牙齿表型关联起来，并建立具有 RUNX2 突变特征的人类 CCD 牙科细胞系的独特资源。这些研究除了增加我们对牙齿形成和改变牙齿图案的遗传疾病的理解之外，最终还可以促进牙齿替代疗法的新策略。