Cellular and Molecular Determinants of Tooth Eruption

牙齿萌出的细胞和分子决定因素

• 批准号: 6903840
• 负责人: HITESH KAPADIA
• 金额: $ 0.09万
• 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 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6903840
• 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：(由申请者提供)这个新的临床科学家导师奖(K08)申请申请为期五年的正式研究 准备攻读博士学位的培训。应聘者是一名刚毕业的牙科学生， 坚定地致力于发展他作为临床科学家的学术生涯。 在完成博士学位后，候选人将接受以下方面的证书培训 正畸学。职业发展计划提出了分阶段和综合性的 一系列教学指导和有监督的研究培训。总体目标是发展申请人的专业知识，以进行独立和 口腔生物医学领域的创造性研究，与 正畸的特长。博士研究的重点将放在牙齿上 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。尽管最近在 确定一些与牙萌出有关的分子的情况很少 已知喷发过程的确切性质。最新的发现 转录因子Cbfa1的突变会导致 人类被称为锁骨颅骨发育不良症(CCD)，开辟了一种新的 骨骼生物学研究。除了骨骼缺陷，CCD患者 有多颗多生牙齿和恒牙，但不会萌出。 我们实验室的研究表明，Cbfa1基因在血管内皮细胞中高水平表达 牙囊细胞贯穿于牙齿萌发的各个阶段。有趣的是，老鼠 零等位基因CBFA(+/-)小鼠的杂合子揭示了一种骨骼 与人类ccd非常相似的表型。与CBFA(+/+)相比 Cbfa1(+1-)小鼠的窝沟、磨牙已完全形成，但未能萌出。这个 拟议的研究将使用Cbfa1(+/-)小鼠作为研究 人眼内窥镜检查中的喷发失败。要检验的中心假说提出 Cbfa1在牙囊介导的信号转导中起关键作用 牙萌出过程中的破骨细胞。目的1研究慢性牙周炎患者牙囊细胞Cbfa1mRNA和蛋白表达的时空模式。 应用分子生物学技术研究下颌第一磨牙萌出的各个阶段 免疫化学方法。目的2利用组织形态计量学和分子生物学方法对CBFA(+/-)小鼠的牙萌出缺陷进行研究。这个 Cbfa1基因部分缺失对潜在下游靶分子的影响 在牙囊中，尤其是那些参与破骨细胞信号传递的细胞中，将 被研究。目的3评估Cbfa1(+/-)小鼠破骨细胞分化和功能的潜在缺陷。部分金融危机的影响 缺乏Cbfa1对破骨细胞数量和基因表达的影响将被研究。 这些数据将为Cbfa1在信号事件中的作用提供新的见解 在牙萌出过程中由牙囊特异性地调节， 将增加我们对人类CD和其他疾病发病机制的理解 喷发失败的条件。这项拟议的研究与 应聘者目前的研究经验水平。在基础上学到的知识 牙齿萌出的机制将使申请者为将来的参与做好准备 在临床研究中，将致力于发展 帮助预防和治疗牙齿畸形的治疗学 在人类身上喷发。