Cellular and Molecular Determinants of Tooth Eruption

牙齿萌出的细胞和分子决定因素

• 批准号: 6909098
• 负责人: HITESH KAPADIA
• 金额: $ 10.44万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-15 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6909098
• 关键词: biological signal transduction; cell differentiation; dentinogenesis; developmental genetics; gene expression; immunocytochemistry; in situ hybridization; laboratory mouse; osteoclasts; polymerase chain reaction; protein biosynthesis; transcription factor

DESCRIPTION: (provided by applicant) This new Mentored Clinical Scientist Award (K08) application requests support for a five-year period of formal research training towards a Ph.D. degree. The candidate is a recent dental graduate with a firm commitment to developing his academic career as a clinician scientist. On completing his Ph.D., the candidate will pursue certificate training in Orthodontics. The career development plan proposes a phased and integrated series of didactic instruction and supervised research training. The overall objectives are to develop the applicant's expertise to conduct independent and creative research in an area of oral biomedical sciences that is relevant to the specialty of Orthodontics. The doctoral research will focus on tooth eruption, a multifactorial process of key signaling interactions between osteoblasts, osteoclasts, and the dental follicle. Despite recent advances in identifying some of the molecules involved in tooth eruption there is little known about the precise nature of the eruptive process. The recent discovery that mutations in Cbfa1, a transcription factor, cause a genetic disorder in humans called cleidocranial dysplasia (CCD) has opened up a new dimension of research in skeletal biology. In addition to skeletal defects, CCD patients have multiple supernumerary teeth and permanent teeth that fail to erupt. Studies in our laboratory have shown high levels of Cbfa1 mRNA expression in dental follicle cells through all phases of tooth eruption. Interestingly, mice that are heterozygous for the null allele, Cbfa(+/-) mice, reveal a skeletal phenotype that closely resembles human CCD. When compared to Cbfa(+/+) littermates, molars in Cbfa1 (+1-) mice are fully formed but fail to erupt. The proposed studies will use Cbfa1 (+/-) mice as an excellent model to study the failure of eruption in human CCD. The central hypothesis to be tested proposes that Cbfa1 plays a key role in dental follicle-mediated signaling of osteoclasts during tooth eruption. Aim 1 will evaluate the temporo-spatial patterns of Cbfa1 mRNA and protein expression in dental follicle cells during all phases of first mandibular molar eruption using molecular and immunochemical methods. Aim 2 studies will characterize the tooth eruption defect in Cbfa(+/-) mice using histomorphometric and molecular methods. The effect of the partial absence of Cbfa1 on potential downstream target molecules in dental follicle, in particular those involved in osteoclast signaling, will be studied. Aim 3 proposes to evaluate potential defects in osteoclast differentiation and function in Cbfa1(+/-) mice. The effects of the partial absence of Cbfa1 on osteoclast numbers and gene expression will be studied. These data will provide new insights into the role of Cbfa1 in signaling events that are specifically mediated by the dental follicle during tooth eruption and will increase our understanding of the pathogenesis of human CCD and other conditions of eruption failure. The proposed research is consistent with the candidate's present level of research experience. Knowledge gained on the basic mechanisms of tooth eruption will prepare the applicant for future involvement in clinical research that will be directed towards the development of therapeutics to aid in the prevention and treatment of anomalies of tooth eruption in humans.

描述：（由申请人提供）这个新的指导临床科学家奖 (K08)申请要求支持为期五年的正式研究 攻读博士学位℃下候选人是一个最近的牙科毕业生， 坚定地致力于发展他作为临床科学家的学术生涯。 完成博士学位后，候选人将接受证书培训， 牙齿矫正职业发展计划提出了一个分阶段和综合的 一系列的教学指导和监督研究培训。整体 目标是发展申请人的专业知识， 口腔生物医学科学领域的创造性研究，与 正畸学的专业。博士研究将集中在牙齿 爆发，一个多因素的关键信号相互作用的过程， 成骨细胞破骨细胞和牙囊。尽管最近的进展， 识别一些与牙齿萌出有关的分子的工作还很少 对喷发过程的精确性质有所了解。最近发现 转录因子Cbfa 1的突变会导致一种遗传疾病， 人类称为锁骨颅骨发育不良（CCD）开辟了一个新的层面， 骨骼生物学的研究除了骨骼缺陷，CCD患者 有多颗多生牙和恒牙未能萌出。 我们实验室的研究表明，在人乳腺癌中， 牙囊细胞贯穿牙齿萌出的各个阶段。有趣的是，老鼠 对于无效等位基因为杂合的Cbfa（+/-）小鼠，揭示了骨骼 表型与人类CCD非常相似。与Cbfa相比（+/+） 在同窝出生的小鼠中，Cbfa 1（+1-）小鼠的磨牙完全形成，但未能萌出。的 拟议的研究将使用Cbfa 1（+/-）小鼠作为研究 人类CCD喷发失败。待检验的中心假设提出， Cbfa 1在牙囊介导的 破骨细胞在牙齿萌出过程中。目标1将评估时空 牙囊细胞中Cbfa 1 mRNA和蛋白表达的变化 下颌第一磨牙萌出的所有阶段， 免疫化学方法。目标2研究将描述牙齿萌出的特征 使用组织形态计量学和分子方法在Cbfa（+/-）小鼠中检测缺陷。的 部分缺乏Cbfa 1对潜在下游靶分子的影响 在牙囊中，特别是参与破骨细胞信号传导的那些， 被研究。目的3建议评估破骨细胞的潜在缺陷 在Cbfa 1（+/-）小鼠中的分化和功能。部分的影响 将研究Cbfa 1缺失对破骨细胞数量和基因表达的影响。 这些数据将为Cbfa 1在信号事件中的作用提供新的见解 在牙齿萌出期间由牙囊特异性介导， 将增加我们对人类CCD和其他疾病发病机制的了解， 喷发失败的条件。拟议的研究与 候选人目前的研究经验水平。从基础知识中获得的知识 牙齿萌出的机制将为申请人将来参与 在临床研究中， 帮助预防和治疗牙齿异常的治疗剂 人类的爆发