IRF6 PATHWAYS AND GENE TARGETS IN PALATE DEVELOPMENT

项目0003的目标是发现导致孤立唇腭裂的基因，这是一种具有复杂病因的常见疾病。这个项目将研究IRF6，这是一个编码转录因子干扰素调节因子6的基因。IRF6的突变会导致范德伍德综合征(VWS)。VWS是治疗孤立性唇腭裂的优秀临床模型，因为VWS与孤立性唇腭裂的表型相似。这也是一个杰出的遗传模型，因为IRF6等位基因与九个地理上不同的人群中的孤立唇腭裂高度相关。这些结果证明，IRF6是腭部发育关键途径的关键组成部分。在本提案中，我们使用鼠标模型来识别 IRF6途径和其中的其他基因。有两个主要的假设：1)IRF6是TGFb信号的中介体；2)IRF6基因靶点对腭部发育是必不可少的。有三个具体目标。 特定的目标1将决定哪种细胞类型在腭部表达IRF6。这些基本信息将立即提示IRF6途径和基因靶点。具体目标2将确定哪些通路需要IRF6来发育上颚。TGFB3信号通路对腭部发育至关重要，TGFB3与IRF6在同一时间、同一地点表达。基因敲除的小鼠将被用来检验TGFB3对IRF6在味架上的表达是必不可少的假设。特殊目标3将使用微阵列分析来确定腭部发育过程中IRF6的目标基因。此外，如果Irf6是TGFB3的中介物，那么在TGFB3-/-和Irf6-/-小鼠中，腭部的基因表达将是相似的。解决这些目标将促进我们对irf6的理解，irf6是头面部发育中必不可少的基因。此外，在这项提案中发现的IRF6通路和靶点将被评估它们在唇腭裂中的参与。 0001项目和0004项目中的腭部开发，以及9003和9004岩心。这些综合知识将增强我们确定口腔裂隙的原因和制定预防干预措施的能力。

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.