Expression and Regulation of LEF-1 During Odontogenesis

牙发育过程中LEF-1的表达和调控

• 批准号: 6869843
• 负责人: PETROS PAPAGERAKIS
• 金额: --
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-01 至 2005-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6869843
• 关键词: cell line; clinical research; congenital oral /facial /cranial defect; dental development; dental pulp; developmental genetics; gene deletion mutation; gene expression; genetic promoter element; genetic regulation; genetically modified animals; immunocytochemistry; in situ hybridization; laboratory mouse; messenger RNA; periodontium; phenotype; transcription factor; transfection

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.

描述（由申请人提供）：该K08指导的临床科学家发展奖将为牙科学术职业赛道提供必要的培训，以在高度支持性的多学科健康科学中心环境中，以快速过渡到Papagerakis博士向独立的临床医生。五年的培训计划包括三个相互关联的组成部分：（1）通过精心计划的研究建议，对最先进的分子颅面遗传学和基因调节进行了高级培训； （2）正畸住院医师计划中的临床培训； （3）颅面遗传疾病患者的诊断和牙科治疗培训。与人类疾病的研究有关，将与临床培训一起进行临床培训，从而获得正畸证书。候选人将参加与多学科团队成员一起工作的颅面遗传学诊所。在奖励的最后一年，将提交NIDCR R01申请。候选者的主要研究重点是确定Runx2转录因子突变引起与CCD相关的牙齿和骨骼表型的分子机制。这项研究可用的独特资源是牙髓和牙周韧带细胞系，这些细胞系来自CCD患者和正常年龄匹配的个体。初步研究表明，正常牙齿发育的关键转录因子LEF-1在正常牙科细胞中表达，但在CCD牙髓细胞中不表达，这表明该因子的缺乏表达可能在CCD表型的发展中起作用。要测试的假设为1）LEF-1在晚期发生和牙周组织形成期间表达； 2）LEF-1改变表达导致CCD牙本质肺泡表型； 3）RUNX2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与牙科/牙周细胞种群中Runx2共表达的程度； 2）在体外分析LEF-1基因的Runx2调控的特异性和复杂性； 3）将体外发现与Runx2转基因小鼠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在颅面遗传学领域实现合并的研究和临床培训，以便为Papagerakis博士做好准备，以成功地成为一名富有成效的独立研究者的职业生涯。