IRF6 PATHWAYS AND GENE TARGETS IN PALATE DEVELOPMENT

味觉发育中的 IRF6 通路和基因靶标

• 批准号: 6845929
• 负责人: BRIAN C SCHUTTE
• 金额: $ 19.91万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6845929
• 关键词: biological models; biological signal transduction; cell population study; cell type; cleft lip; cleft palate; cognition disorders; congenital oral /facial /cranial defect; developmental genetics; disease /disorder etiology; functional /structural genomics; gene expression; gene expression profiling; gene mutation; genetic models; genetically modified animals; histogenesis; human subject; immunocytochemistry; microarray technology; palate; patient oriented research; syndrome; transcription factor; transforming growth factors

The goal of Project 0003 is to discover the genes that contribute to isolated cleft lip and palate, a common disorder with complex etiology. This project will study IRF6, a gene that encodes the transcription factor Interferon Regulatory Factor 6. Mutations in IRF6 cause Van der Woude syndrome (VWS). VWS is an outstanding clinical model for isolated cleft lip and palate because the phenotypes of VWS and isolated cleft lip and palate are similar. It is also an outstanding genetic model, since alleles of IRF6 are highly associated with isolated cleft lip and palate in nine geographically distinct populations. These results prove that IRF6 is a key component of a critical pathway in palate development. In this proposal we use mouse models to identify the IRF6 pathway and other genes therein. There are two main hypotheses, 1) IRF6 is a mediator of Tgfb signaling and 2) IRF6 gene targets are essential for palate development. There are three Specific Aims. Specific Aim 1 will determine which cell-type expresses Irf6 in the palate. This basic information will immediately suggest Irf6 pathways and gene targets. Specific Aim 2 will determine which pathways require Irf6 for palate development. The Tgfb3 signaling pathway is essential for palate development and Tgfb3 is expressed at about the same time and place as Irf6. Knockout mice will be used to test the hypotheses that Tgfb3 is essential for expression of Irf6 in the palate shelves. Specific Aim 3 will use microarray analysis to identify the target genes for Irf6 during palate development. In addition, if Irf6 is a mediator for Tgfb3, then gene expression in the palate will be similar in Tgfb3-/- and Irf6-/- mice. Addressing these aims will advance our understanding of Irf6, a gene that is essential in craniofacial development. Further, the IRF6 pathways and targets, discovered in this proposal, will be assessed for their involvement in cleft lip and palate in Project 0001 and in palate development in Project 0004 and Cores 9003 and 9004. This aggregate knowledge will enhance our ability to determine the causes of, and develop preventive interventions for, orofacial clefts.

项目0003的目标是发现导致孤立性唇腭裂的基因，唇腭裂是一种病因复杂的常见疾病。该项目将研究IRF 6，一种编码转录因子干扰素调节因子6的基因。IRF 6突变导致货车德沃德综合征（VWS）。VWS与单纯性唇腭裂的表型相似，是孤立性唇腭裂的一种优秀的临床模型。它也是一个杰出的遗传模型，因为IRF 6的等位基因与9个地理上不同的人群中的孤立性唇腭裂高度相关。这些结果证明IRF 6是腭发育中关键途径的关键组分。在这个建议中，我们使用小鼠模型来识别 IRF 6通路和其中的其他基因。有两个主要假设，1）IRF 6是Tgfb信号传导的介导者，2）IRF 6基因靶标对于腭发育是必需的。有三个具体目标。 具体目标1将确定哪种细胞类型在腭中表达Irf 6。这些基本信息将立即提示Irf 6途径和基因靶点。具体目标2将确定哪些途径需要Irf 6用于腭发育。Tgfb 3信号通路对于腭发育是必需的，并且Tgfb 3与Irf 6在大约相同的时间和位置表达。将使用敲除小鼠来检验Tgfb 3对于Irf 6在腭架中的表达是必需的这一假设。Specific Aim 3将使用微阵列分析来鉴定在腭发育期间Irf 6的靶基因。此外，如果Irf 6是Tgfb 3的介体，那么在Tgfb 3-/-和Irf 6-/-小鼠中腭中的基因表达将是相似的。实现这些目标将促进我们对Irf 6的理解，Irf 6是颅面发育中必不可少的基因。此外，IRF 6途径和目标，发现在这个建议，将评估他们参与唇腭裂， 项目0001和项目0004以及核心9003和9004中的腭开发。这些知识的积累将提高我们确定口面裂的原因和制定预防措施的能力。