Molecular Mechanisms of PITX2 During Craniofacial Development

PITX2在颅面发育过程中的分子机制

基本信息

批准号：
7923229
负责人：
BRAD A AMENDT
金额：
$ 36.26万
依托单位：
TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-03-01 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7923229
关键词：
Ameloblasts Applications Grants Boxing Cell Line Cells Chromatin Chromatin Remodeling Factor Code Complex DNA Microarray Chip Data Defect Dental Development Embryo Embryonic Development Epithelium Gene Expression Gene Targeting Genes Histone H4 Histones Incisor Knock-out Knowledge Methodology MicroRNAs Molecular Morphogenesis Mouse Cell Line Mus Mutant Strains Mice Mutation Natural regeneration Odontoblasts Odontogenesis Pattern Process Program Development Recruitment Activity Role Signal Transduction Specific qualifier value Staging Techniques Testing Therapeutic Time Tissue-Specific Gene Expression Tissues Tooth Germ Tooth Tissue Tooth structure Transgenic Mice Two-Hybrid System Techniques Yeasts base cDNA Library combinatorial craniofacial homeodomain human DICER1 protein islet novel promoter protein protein interaction public health relevance research study selective expression tool transcription factor

项目摘要

DESCRIPTION (provided by applicant): In recent years a number of new genes have been identified that are involved in tooth morphogenesis. Though much progress has been made in identifying new genes and the signaling mechanisms that regulate morphogenetic stages of tooth development have been documented, the transcriptional mechanisms that regulate proliferation and differentiation of the odontoblasts and ameloblasts are poorly understood. Better understanding of the mechanistic aspect of this process is necessary, not only to understand normal tooth morphogenesis, but also to regenerate teeth, and eventually be able to develop and deliver better therapeutic strategies. PITX2 provides a unique tool for studying the molecular control of tooth formation since it is selectively expressed at the earliest stage of tooth development. We have only begun to understand the molecular mechanisms of PITX2, its role in tooth development and the downstream hierarchy of transcription factors involved in craniofacial/tooth development. The focus of this continuing grant application is to understand the molecular mechanisms by which PITX2 interacts with other factors to regulate tooth development. Our previous results demonstrate that PITX2 acts in concert with other factors to regulate gene expression. We propose to test our hypothesis that PITX2 differentially regulates gene expression through specific protein-protein interactions with T-box factors Tbx1 and Tbx18 and the LIM homeodomain factors Islet-1 and Lhx6. HMG-17, a chromatin associated factor recruits PITX2 to active chromatin and is activated through Wnt/-catenin signaling. We will test our hypothesis that the transcriptional activity of PITX2 is tightly regulated during development by its interaction with HMG-17, -catenin, acetylated histones and chromatin remodeling factors. MicroRNAs (miR's) are critical to controlling gene expression however little is known about their role in craniofacial/tooth development. Preliminary data demonstrates that miR's directly control the patterning of incisors and molars, specifying a combinatorial code of miR's expression for normal craniofacial/tooth development. We will test our hypothesis that specific miR's expressed during tooth development control the activities of specific transcription factors and the patterning of teeth. Understanding how these components interact to promote normal craniofacial development will further our understanding of genetic defects. PUBLIC HEALTH RELEVANCE: The identification of new genes involved in craniofacial/tooth development will increase our knowledge about the basic development programs required for normal embryogenesis. Understanding how these components interact to promote normal craniofacial development will further our understanding of genetic defects. We can then promote methodologies to inhibit severe craniofacial anomalies once a molecular basis has been assigned to a specific defect or component.

描述（由申请人提供）：近年来，已鉴定出许多与牙齿形态发生有关的新基因。尽管在识别新基因和调节牙齿发育形态发生阶段的信号机制方面已经取得了很大进展，但调节成牙本质细胞和成釉细胞增殖和分化的转录机制却知之甚少。更好地了解这一过程的机制是必要的，不仅是为了了解正常的牙齿形态发生，也是为了再生牙齿，并最终能够开发和提供更好的治疗策略。 PITX2 为研究牙齿形成的分子控制提供了一种独特的工具，因为它在牙齿发育的最早阶段选择性表达。我们才刚刚开始了解 PITX2 的分子机制、其在牙齿发育中的作用以及参与颅面/牙齿发育的转录因子的下游层次结构。这项持续拨款申请的重点是了解 PITX2 与其他因素相互作用以调节牙齿发育的分子机制。我们之前的结果表明 PITX2 与其他因子协同作用来调节基因表达。我们建议检验我们的假设，即 PITX2 通过与 T-box 因子 Tbx1 和 Tbx18 以及 LIM 同源域因子 Islet-1 和 Lhx6 的特定蛋白质-蛋白质相互作用来差异调节基因表达。 HMG-17 是一种染色质相关因子，将 PITX2 招募到活性染色质，并通过 Wnt/-连环蛋白信号传导激活。我们将检验我们的假设，即 PITX2 的转录活性在发育过程中通过其与 HMG-17、β-连环蛋白、乙酰化组蛋白和染色质重塑因子的相互作用受到严格调节。 MicroRNA (miR) 对于控制基因表达至关重要，但人们对其在颅面/牙齿发育中的作用知之甚少。初步数据表明，miR 直接控制门牙和磨牙的模式，指定了正常颅面/牙齿发育的 miR 表达的组合代码。我们将检验我们的假设，即牙齿发育过程中表达的特定 miR 控制特定转录因子的活性和牙齿的模式。了解这些成分如何相互作用以促进正常颅面发育将进一步加深我们对遗传缺陷的理解。公共健康相关性：识别与颅面/牙齿发育相关的新基因将增加我们对正常胚胎发生所需的基本发育程序的了解。了解这些成分如何相互作用以促进正常颅面发育将进一步加深我们对遗传缺陷的理解。一旦分子基础被分配给特定的缺陷或成分，我们就可以推广抑制严重颅面异常的方法。