The Ctip2/Bcl11b transcriptional network in tooth development

牙齿发育中的 Ctip2/Bcl11b 转录网络

基本信息

批准号：
8101554
负责人：
MARK E LEID
金额：
$ 29.15万
依托单位：
OREGON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-05-01 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8101554
关键词：
Adult Ameloblasts Amelogenesis Amelogenesis Imperfecta Asthma Basic Science Biochemical Cardiovascular system Cell Lineage Cells Childhood Chromatin Chronic Complementary DNA Complex Congenital Abnormality Country Defect Dental Dental Enamel Dental caries Development Disease Elderly Embryo Enamel Formation Equipment Erinaceidae Event Exhibits FGF3 gene Follistatin Gene Expression Gene Expression Regulation Gene Targeting Genes Genetic Goals Growth Hay fever Health Human Immune In Situ Hybridization Incidence Incisor Lead Life Molecular Molecular Genetics Monoclonal Antibodies Morphogenesis Mus Natural regeneration Oral cavity Organ Outcome Pattern Phenotype Positioning Attribute Preparation Production Proteins Reagent Recruitment Activity Regulation Research Role Skin Specific qualifier value System Techniques Testing Tissues Tooth Loss Tooth structure Work amelogenin base enamelin experience gene therapy genome-wide in vivo malformation oral biology postnatal promoter protein complex protein function repaired restoration stem cell therapy transcription factor

项目摘要

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.

描述（由申请人提供）：形成牙齿的形态事件对遗传和环境扰动敏感，导致先天畸形的高发生率。此外，蛀牙是迄今为止最常见的慢性儿童疾病，其发病率比哮喘高 5 倍，比花粉热高 7 倍。蛀牙也是成人牙齿脱落的一个主要原因；在这个国家，大约三分之一的 65 岁以上成年人根本没有天然牙齿。因此，非常需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阐明了早期牙齿图案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具有相同的分子网络，因此牙齿发育基础科学的这些进步似乎将导致用于牙齿修复的干细胞疗法。该提案的目的是阐明 Ctip2 在门牙发育过程中作用的分子机制。这一目标将在我们的中心假设的背景下实现：Ctip2 调节负责门牙发育过程中成釉细胞成熟的关键转录网络。该项目的目标是鉴定口腔发育中 Ctip2 复合物的组成蛋白（目标 1），并阐明门牙发育过程中 Ctip2 调节靶基因表达的机制基础（目标 2）。完成这项研究后，我们预计我们将定义 Ctip2 控制的遗传和调控网络，该网络直接影响发育中门牙的细胞规格。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釉质形成过程中基因调控的理解，后者可能会导致开发出更有效的离体成釉细胞生长和最终牙釉质修复的治疗范例，目前这是不可能的。公共健康相关性：牙齿发育对遗传和环境干扰很敏感，这导致牙齿畸形的高发生率。非常需要了解调节牙齿发育和修复的分子机制。人类和小鼠分子遗传学的最新进展阐明了牙齿模式和形态发生的关键事件，并导致了细胞谱系再生和牙齿修复的潜在基因疗法。我们提出的研究的目的是确定 Ctip2/Bcl11b 在门牙发育中的作用。