The Ctip2/Bcl11b transcriptional network in tooth development

描述（由申请人提供）：形成牙齿的形态学事件对遗传和环境扰动敏感，导致先天性畸形的高发。此外，蛀牙是迄今为止最常见的儿童慢性疾病，其发病率比哮喘高5倍，比花粉热高7倍。蛀牙也是成年人牙齿脱落的一个主要原因；这个国家65岁以上的成年人中大约有三分之一根本没有天然牙齿。因此，有必要详细了解调节牙齿形成和修复的分子机制。人类和小鼠分子遗传学的最新进展揭示了早期牙齿形成和形态发生的关键事件。由于这些早期发育事件与再生组织共享相同的分子网络，因此牙齿发育基础科学的这些进展似乎可能会导致用于牙齿修复的干细胞疗法。本研究的目的是阐明Ctip2在切牙发育过程中的分子机制。这一目标将在我们的中心假设的背景下完成：Ctip2调节门牙发育过程中负责成釉细胞成熟的关键转录网络。本项目的目标是鉴定发育中的口腔中Ctip2复合物的组成蛋白（目的1），并阐明门牙发育过程中Ctip2调控靶基因表达的机制基础（目的2）。在这项研究完成后，我们期望我们将定义ctip2控制的遗传和调控网络，它直接影响发育中的门牙细胞规格。我们的研究将对人类健康产生重大的积极影响，因为这些结果将加深对门牙发育和成釉发生过程中的基因调控的理解，后者可能导致开发出更有效的体外成釉细胞生长和最终牙釉质修复的治疗范式，这是目前不可能的。

DESCRIPTION (provided by applicant): The morphological events forming the tooth are sensitive to genetic and environmental perturbations resulting in a high incidence of congenital malformations. Furthermore, tooth decay is by far the most common chronic childhood disease, with a 5-fold greater incidence than asthma, and a 7-fold greater incidence than hay fever. Tooth decay is also a major cause of tooth loss in adults; approximately one-third of adults over the age of 65 in this country have no natural teeth at all. Thus, there is a great need to understand the molecular mechanisms regulating tooth formation and repair in detail. Recent advances in human and mouse molecular genetics have illuminated key events of early tooth patterning and morphogenesis. Because these early developmental events share the same molecular networks with regenerating tissues, it seems likely that these advances in the basic science of tooth development will lead to stem cell therapies for tooth repair. The objective of this proposal is to elucidate the molecular mechanisms underlying the action of Ctip2 during incisor development. This objective will be accomplished in the context of our central hypothesis: Ctip2 regulates a key transcriptional network(s) responsible for ameloblast maturation during incisor development. The goals for this project are to identify component proteins of Ctip2 complexes in the developing oral cavity (Aim 1), and to elucidate the mechanistic basis for regulation of target gene expression by Ctip2 during incisor development (Aim 2). After completion of this research, we expect that we will have defined Ctip2-controlled genetic and regulatory networks, which directly impact cell specification in the developing incisor. Our studies will have significant, positive effects on human health because these outcomes will provide an enhanced understanding of gene regulation during incisor development and amelogenesis, the latter of which may lead to development of more efficacious treatment paradigms for ex vivo ameloblast growth and ultimately enamel restoration, which is not currently possible. PUBLIC HEALTH RELEVANCE: Tooth development is sensitive to genetic and environmental perturbations, which lead to a high incidence of dental malformations. There is a great need to understand the molecular mechanisms regulating tooth development and repair. Recent advances in human and mouse molecular genetics have illuminated key events of tooth patterning and morphogenesis, and have lead to potential gene therapies for cell lineage regeneration and tooth repair. The objective of our proposed studies is to define the role of Ctip2/Bcl11b in incisor development.