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：
8528389
负责人：
BRAD A AMENDT
金额：
$ 35.52万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-10-01 至 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8528389
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 research study selective expression tool transcription factor

项目摘要

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 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.

近年来，已经确定了许多与牙齿有关的新基因形态发生。尽管在识别新基因和调节牙齿发育形态发生阶段的信号传导机制已记录了调节增殖和的转录机制牙胶细胞和成成细胞的分化知之甚少。更好的了解此过程的机械方面是必要的，不仅需要了解正常的牙齿形态发生，但也要再生牙齿，最终能够制定和提供更好的治疗策略。 PITX2提供了独特的研究牙齿形成的分子控制的工具，因为它被选择性地表达在牙齿发育的最早阶段。我们才开始了解 PITX2的分子机制，其在牙齿发育中的作用和下游颅面/牙齿发育涉及的转录因子的层次结构。重点这种持续的赠款应用是了解分子机制 PITX2与其他因素相互作用以调节牙齿发育。我们以前的结果证明PITX2与其他因素一起起作用以调节基因表达。我们建议测试PITX2差异调节基因表达的假设通过特定的蛋白质 - 蛋白质相互作用与T-box因子TBX1和TBX18和 Lim同源域因子ISLET-1和LHX6。 HMG-17，染色质因子将PITX2募集到活性染色质，并通过Wnt/-Catenin信号传导激活。我们将测试我们的假设，即PITX2的转录活性受到严格调节在开发过程中与HMG -17， - 蛋白酶，乙酰化组蛋白和染色质重塑因子。 microRNA（mir）对于控制基因至关重要然而，对它们在颅面/牙齿发育中的作用知之甚少。初步数据表明，MIR直接控制着门牙的模式和磨牙，指定正常颅面/牙齿的miR表达组合代码发展。我们将检验我们的假设，即特定MIR在牙齿中表达开发控制特定转录因子的活动和模式牙齿。了解这些成分如何相互作用以促进正常颅面发展将进一步理解遗传缺陷。

项目成果

期刊论文数量（23）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Dact2 represses PITX2 transcriptional activation and cell proliferation through Wnt/beta-catenin signaling during odontogenesis.

DOI：
10.1371/journal.pone.0054868
发表时间：
2013
期刊：
PloS one
影响因子：
3.7
作者：
Li X;Florez S;Wang J;Cao H;Amendt BA
通讯作者：
Amendt BA

MicroRNA-26b represses colon cancer cell proliferation by inhibiting lymphoid enhancer factor 1 expression.

DOI：
10.1158/1535-7163.mct-13-1000
发表时间：
2014-07
期刊：
Molecular cancer therapeutics
影响因子：
5.7
作者：
Zhang Z;Kim K;Li X;Moreno M;Sharp T;Goodheart MJ;Safe S;Dupuy AJ;Amendt BA
通讯作者：
Amendt BA

Tbx1 regulates progenitor cell proliferation in the dental epithelium by modulating Pitx2 activation of p21.

DOI：
10.1016/j.ydbio.2010.08.031
发表时间：
2010-11-15
期刊：
Developmental biology
影响因子：
2.7
作者：
Cao H;Florez S;Amen M;Huynh T;Skobe Z;Baldini A;Amendt BA
通讯作者：
Amendt BA

MicroRNAs play a critical role in tooth development.

DOI：
10.1177/0022034510369304
发表时间：
2010-08
期刊：
Journal of dental research
影响因子：
7.6
作者：
Cao H;Wang J;Li X;Florez S;Huang Z;Venugopalan SR;Elangovan S;Skobe Z;Margolis HC;Martin JF;Amendt BA
通讯作者：
Amendt BA

Fuz regulates craniofacial development through tissue specific responses to signaling factors.

DOI：
10.1371/journal.pone.0024608
发表时间：
2011
期刊：
PloS one
影响因子：
3.7
作者：
Zhang Z;Wlodarczyk BJ;Niederreither K;Venugopalan S;Florez S;Finnell RH;Amendt BA
通讯作者：
Amendt BA