Expression and Regulation of LEF-1 During Odontogenesis

描述（由申请人提供）：该K 08指导临床科学家发展奖将在高度支持的多学科健康科学中心环境中为Papagerakis博士快速过渡到独立的临床科学家提供必要的牙科学术职业培训。五年的培训计划包括三个相互关联的组成部分：（1）通过精心策划的研究计划，在最先进的分子颅面遗传学和基因调控方面进行高级培训;（2）正畸住院医师计划的临床培训;（3）颅面遗传病患者的诊断和牙科治疗培训。与人类疾病锁骨颅骨发育不良（CCD）相关的研究将与临床培训同时进行，以获得正畸学证书。候选人将参加颅面遗传学诊所与多学科团队成员的工作。在获奖的最后一年，将提交NIDCR R 01申请。候选人的主要研究重点是确定RUNX 2转录因子突变导致与CCD相关的牙齿和骨骼表型的分子机制。这项研究的独特资源是来自CCD患者和正常年龄匹配个体的牙髓和牙周膜细胞系。初步研究表明，正常牙齿发育的关键转录因子LEF-1在正常牙细胞中表达，但在CCD牙髓细胞中不表达，这表明该因子表达的缺乏可能在CCD表型的发育中起作用。待检验的假设是1）LEF-1在晚期牙形成和牙周组织形成期间表达; 2）LEF-1改变的表达导致CCD牙槽骨表型; 3）RUNX 2控制LEF-1牙齿和牙周组织表达。研究这些假设的具体目的是：1）确定LEF-1与RUNX 2在牙齿/牙周细胞群中共表达的程度; 2）体外分析RUNX 2调控LEF-1基因的特异性和复杂性; 3）将体外发现与RUNX 2转基因小鼠敲除模型中的体内牙齿表型和Lef-1表达相关联。该项目的长期目标是实现颅面遗传学领域的研究和临床培训相结合，以便为Papagerakis博士作为一名富有成效的独立研究者的成功职业生涯做好准备。

DESCRIPTION (provided by applicant): This K08 Mentored Clinical Scientist Development Award will provide necessary training for a dental academic career track within a highly supportive multidisciplinary Health Science Center environment for the rapid transition of Dr. Papagerakis to an independent clinician scientist. The five year training plan consists of three inter-related components: (1) advanced training in state-of-the-art molecular craniofacial genetics and gene regulation through a well-planned research proposal; (2) clinical training in an Orthodontics residency program; and (3) training in the diagnosis and dental treatment of patients with craniofacial genetic diseases. Research related to the human disease cleidocranial dysplasia (CCD) will be pursued concomitant with clinical training leading to a certificate in Orthodontics. The candidate will participate in the Craniofacial Genetics Clinic working with multidisciplinary team members. In the last year of the award an NIDCR R01 application will be submitted. The major research focus of the candidate is to determine the molecular mechanisms by which mutation(s) in the RUNX2 transcription factor cause the tooth and bone phenotypes associated with CCD. Unique resources available for this study are dental pulp and periodontal ligament cell lines derived from CCD patients and normal age matched individuals. Preliminary studies have demonstrated that critical transcription factors for normal tooth development, LEF-1, is expressed in normal dental cells, but not in CCD dental pulp cells, suggesting that the lack of expression of this factor may play a role in development of the CCD phenotype. The hypotheses to be tested are 1) LEF-1 is expressed during late odontogenesis and periodontal tissue formation; 2) LEF-1 altered expression results in the CCD dento-alveolar phenotype; 3) RUNX2 controls LEF-1 dental and periodontal tissue expression. The specific aims to investigate these hypotheses are 1) to identify the extent to which LEF-1 is co-expressed with RUNX2 in dental/periodontal cell populations; 2) to analyze in vitro the specificity and complexity of RUNX2 regulation of LEF-1 gene; 3) to correlate in vitro findings with the in vivo dental phenotype and Lef-1 expression in RUNX2 transgenic mice knock out model. The long-term goal of this project is to achieve combined research and clinical training in the area of craniofacial genetics, in order to prepare Dr. Papagerakis for a successful career as a productive independent investigator.