Cloning and characterization of the Van Der Woude gene

Van Der Woude 基因的克隆和表征

• 批准号: 7216257
• 负责人: BRIAN C SCHUTTE
• 金额: $ 33.22万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7216257
• 关键词: Clinical; Cloning; Complex; Critical Pathways; Dental; Development; Diagnostic tests; Disease; Enhancers; Environmental Risk Factor; Etiology; Family; Funding; Future; Genes; Genetic; Genetic Models; Genetic Transcription; Genetic Variation; Goals; Growth Factor; Heterozygote; Human; Interferon Type I; Interferons; Knowledge; Lip structure; Modeling; Morbidity - disease rate; Mus; Mutant Strains Mice; Mutate; Mutation; Numbers; Operative Surgical Procedures; Palate; Pathway interactions; Preventive Intervention; Process; Risk; Role; Signal Transduction; Speech; Testing; Transforming Growth Factors; Transgenic Mice; Van der Woude syndrome; base; cleft lip and palate; gene discovery; gene interaction; in vivo; member; mouse model; novel; orofacial; psychologic; transcription factor

DESCRIPTION (provided by applicant): Cleft lip and palate is a common congenital anomaly with significant lifelong morbidity. The extensive psychological, surgical, speech and dental involvement emphasize the importance of understanding the underlying causes. Our long-term objective is to discover the genes and environmental factors that contribute to this disorder. However, the etiology of cleft lip and palate is complex, and given the large number of genes predicted to be involved in isolated cleft lip and palate, gene discovery poses a significant challenge. The approach used here will be to study a genetically simple model of orofacial clefting, Van der Woude syndrome. Van der Woude syndrome is an outstanding clinical model for isolated cleft lip and palate, as its only distinguishing features are pits in the lower lip. Mutations in Interferon Regulatory Factor 6 (IRF6) cause Van der Woude syndrome. Moreover, genetic variation in IRF6 confers risk for isolated cleft lip and palate, demonstrating that Van der Woude syndrome is also an outstanding genetic model. Thus, IRF6 is essential for a critical pathway in palate development, and its discovery represents a foothold in this pathway. The main goal of this proposal is to delineate the IRF6 pathway by first determining the in vivo function of IRF6 and then identifying factors that regulate the expression of IRF6. There are 3 Aims: 1) To generate a mouse model for Van der Woude syndrome by mutating Irf6, and to perform a comprehensive analysis of the pathogenic processes in palate development in these mice. To investigate a role for Type I interferons in palate development in mice, as IRF6 is a member of the Interferon Regulatory family of transcription factors. 2) To evaluate a potential genetic interaction between mutations in Irf6 and Transformation growth factor beta3 (Tgfbeta3), since Tgfa3 is necessary for palate development and for Irf6 expression in the palate. Mice that are double heterozygotes for Irf6 and Tgfbeta3 will be analyzed for palate development. Also, to examine the potential role for Irf6 in transducing the Tgfbeta3 signal during palate development. 3) To identify the enhancer that regulates Irf6 expression in the palate using transgenic mice. Does Tgfbeta3 regulate Irf6 through the SMADs or by other transcription factors or both? Completion of these aims will advance our understanding for the role of IRF6 in palate development, and identify novel gene interactions and genes that may contribute to isolated cleft lip and palate, a common human disorder. This knowledge will provide the basis for enhanced diagnostic tests and future preventive interventions.

描述（由申请人提供）：唇裂和口感是一种常见的异常，具有明显的终生发病率。广泛的心理，手术，言语和牙科参与强调了理解潜在原因的重要性。我们的长期目标是发现导致这种疾病的基因和环境因素。但是，唇裂和pa裂的病因很复杂，鉴于预测大量基因与孤立的唇裂和pape相关，基因发现构成了重大挑战。这里使用的方法是研究一种遗传简单的口面裂基，Van der Woude综合征。 Van der Woude综合征是孤立的嘴唇和口感的出色临床模型，因为其唯一的区别特征是下唇中的凹坑。干扰素调节因子6（IRF6）的突变引起范德沃德综合征。此外，IRF6的遗传变异赋予了孤立的唇裂和pa的风险，表明Van der Woude综合征也是一种出色的遗传模型。因此，IRF6对于pa发育中的关键途径至关重要，其发现代表了该途径的立足点。该提案的主要目标是首先确定IRF6的体内功能，然后识别调节IRF6表达的因素来描述IRF6途径。有3个目的：1）通过突变IRF6生成范德沃德综合征的小鼠模型，并对这些小鼠的味觉发育中的致病过程进行全面分析。为了调查I型干扰素在小鼠味发育中的作用，因为IRF6是干扰素调节转录因子家族的成员。 2）评估IRF6突变与转化生长因子beta3（TGFBETA3）之间的潜在遗传相互作用，因为TGFA3对于pa酸发育和口感中的IRF6表达是必不可少的。将分析IRF6和TGFBETA3的双重杂合子的小鼠以进行pa酸发育。同样，要检查IRF6在pa发育过程中转导TGFBETA3信号中的潜在作用。 3）确定使用转基因小鼠调节味觉中IRF6表达的增强子。 TGFBETA3是否通过SMAD或其他转录因子或两者兼有IRF6？这些目标的完成将提高我们对IRF6在口感发育中的作用的理解，并确定可能有助于孤立的人类疾病的新型基因相互作用和基因。这些知识将为增强诊断测试和未来预防性干预提供基础。