Cloning and characterization of the Van Der Woude gene

Van Der Woude 基因的克隆和表征

• 批准号: 7467631
• 负责人: BRIAN C SCHUTTE
• 金额: $ 2.07万
• 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/7467631
• 关键词: Cities; Clinical; Cloning; Complex; Critical Pathways; Dental; Development; Diagnostic tests; Disease; Doctor of Philosophy; England; Enhancers; Environmental Risk Factor; Etiology; Face; Family; Funding; Future; Genes; Genetic; Genetic Models; Genetic Transcription; Genetic Variation; Goals; Growth Factor; Heterozygote; Human; Human Resources; Instruction; Interferon Type I; Interferons; Iowa; Knowledge; Lip structure; Modeling; Morbidity - disease rate; Mus; Mutant Strains Mice; Mutate; Mutation; Names; Numbers; Operative Surgical Procedures; Palate; Pathway interactions; Preventive Intervention; Principal Investigator; Printing; Process; Research Personnel; Research Project Grants; Risk; Role; Signal Transduction; Speech; Testing; Transforming Growth Factors; Transgenic Mice; Universities; Van der Woude syndrome; Yang; base; cleft lip and palate; gene discovery; gene interaction; in vivo; member; mouse model; novel; orofacial; programs; psychologic; transcription factor

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 0,3 (TgfliS), since TgflJ3 is necessary for palate development and for Irf6 expression in the palate. Mice that are double heterozygotes for Irf6 and TgflJS will be analyzed for palate development. Also, to examine the potential role for Irf6 in transducing the TgfliS signal during palate development. 3) To identify the enhancer that regulates Irf6 expression in the palate using transgenic mice. Does TgffJS regulate Irf6 through the SMADs or by other transcription factors or both? Completion of these aims will advanceour 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.

唇裂和pa是一种常见的先天性异常，具有明显的终生发病率。广泛的 心理，外科，言语和牙科参与强调了理解的重要性 根本原因。我们的长期目标是发现有助于的基因和环境因素 这个疾病。但是，唇裂和pa的病因很复杂，并且给定大量基因 吉恩发现预计将参与孤立的唇裂和pa裂，构成了重大挑战。这 这里使用的方法将是研究一种遗传简单的口面裂基模型，即范德沃德综合征。 Van der Woude综合征是孤立的嘴唇和口感的出色临床模型，它唯一 区分特征是较低唇部的凹坑。干扰素调节因子6（IRF6）导致van der der的凹坑 Woude综合征。此外，IRF6的遗传变异赋予了孤立的嘴唇和pa的风险，证明 那个范德沃德综合症也是一种出色的遗传模型。因此，IRF6对于关键至关重要 pape发育中的途径及其发现代表了这一途径的立足点。主要目标 建议是通过首先确定IRF6的体内功能，然后识别来划定IRF6途径 调节IRF6表达的因素。有3个目标：1）生成范德尔的鼠标模型 Woude综合征通过突变IRF6，并对中的致病过程进行全面分析 这些小鼠的口感发展。调查I型干扰素在小鼠pa发育中的作用， IRF6是干扰素调节因素的成员。 2）评估潜在的遗传 由于TGFLJ3是必要的 用于口感的发育和IRF6在口感中的表达。小鼠是IRF6的双重杂合子和 TGFLJ将进行分析以进行pap酸开发。同样，要检查IRF6在传递中的潜在作用 TGFLIS信号在味蕾发育过程中。 3）识别调节口感中IRF6表达的增强子 使用转基因小鼠。 TGFFJ是通过SMADS还是其他转录因子或两者兼而有之的IRF6？ 这些目标的完成将促进对IRF6在pape depantmens中的作用的理解，并确定 新型的基因相互作用和可能导致孤立的唇裂和pa裂的基因，这是一种常见的人类疾病。 这些知识将为增强诊断测试和未来预防性干预提供基础。