CLONING AND CHARACTERIZATION OF THE VAN DER WOUDE GENE

VAN DER WOUDE 基因的克隆和表征

• 批准号: 6617324
• 负责人: BRIAN C SCHUTTE
• 金额: $ 14.26万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-10 至 2002-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6617324
• 关键词: cleft lip; cleft palate; clinical research; family genetics; gene complementation; gene mutation; genetic mapping; genetic screening; genetically modified animals; human subject; laboratory mouse; molecular cloning

Cleft lip and palate (CL/P) is a major congenital structural anomaly that is notable for significant lifelong morbidity and complex etiology.. The extensive psychological, surgical, speech and dental involvement emphasize the importance of understanding the underlying causes. For the investigator, cleft lip and palate, like other complex diseases, provides a challenge in determining the multiple genetic, environmental and stochastic factors that lead to its phenotype. In this proposal, we will pursue the complex causes of cleft lip and palate through our investigations of a genetically simple form of clefting, Van der Woude syndrome (VDWS). VDWS is the most frequent syndromic form of cleft lip and palate and the form we fell is best suited to contribute to an increased understanding of the more common non-syndromic form of cleft lip and palate and the form we feel is best suited to contribute to an increased understanding of the more common non-syndromic form. Specific goals in this project will include: 1) identification of the VDWS gene. A genetic screen for disease-causing micro-deletions will be used to further restrict the region that contains the VDWS gene. Powerful gene-finding techniques, including the sequence analysis of the entire critical region, will be used to identify transcriptional units. Mutation screens will then be used to find disease causing changes in the DNA. Extensive mutation screens will be performed to search for functional domains. 2) characterization of the VDWS gene and its mouse homolog, including complete cDNA and genomic sequence analysis, the study of temporal and tissue-specific expression to identify developmental pathways that require the VDWS gene functional and screens for gene homologs which may function in the same pathway. 3) identification of sequences that regulate VDWS gene expression and the development of transgenic mouse models, including a mouse knockout that will be used in 4) long-term studies that will include complementation experiments to identify other genes in the pathway and investigate the effects of environmental factors on the VDWS gene and other genes in the same pathway. The impact of this project is that studies of CL/P are valuable, both for the importance of the defect itself as a contributor to morbidity and for providing a model for a complex human birth defect. The identification of the VDWS and VDWS-like genes will immediately provide for better risk counseling, and their characterization under environmental stresses hold the promise for contribution to preventative strategies and improved therapeutics. In addition, the identification of the VDWS gene is relevant to studies of CL/P because of its similarities to the more frequent non-syndromic forms of CL/P and because it will provide a foothold into the earliest steps of craniofacial development.

唇裂（Cl/p）是一种主要的先天性结构异常，在重大的终身发病率和复杂的病因中引人注目。广泛的心理学，外科手术，言语和牙齿参与强调了理解潜在原因的重要性。对于研究者而言，与其他复杂疾病一样，唇裂和口感在确定导致其表型的多种遗传，环境和随机因素方面也带来了挑战。在此提案中，我们将通过研究一种遗传简单形式的clefting，Van der Woude综合征（VDWS）来追求唇裂和口感的复杂原因。 VDWS是唇裂和pa裂最常见的综合征形式，我们掉落的形式最适合对更常见的非同伴形式的left唇和pape来提高理解，而我们认为我们认为最常见的形式是对更常见的非伴侣形式的更多理解。该项目中的具体目标将包括：1）识别VDWS基因。用于疾病的微缺失的遗传筛选将用于进一步限制包含VDWS基因的区域。强大的基因调查技术，包括整个关键区域的序列分析，将用于识别转录单元。然后，突变筛查将用于查找导致DNA变化的疾病。将执行广泛的突变屏幕以搜索功能域。 2）对VDWS基因及其小鼠同源物的表征，包括完整的cDNA和基因组序列分析，对时间和组织特异性表达的研究，以识别需要VDWS基因功能的发育途径，并筛选可能在同一途径中起作用的基因同源物。 3）鉴定调节VDWS基因表达的序列和转基因小鼠模型的发展，包括将在4）长期研究中使用的小鼠敲除，其中包括互补实验，以鉴定途径中的其他基因并研究环境因素对VDWS基因和其他途径中其他基因的影响。该项目的影响是，CL/P的研究是有价值的，这既是缺陷本身作为发病率的贡献的重要性，并为复杂的人类出生缺陷提供了模型。 VDW和类似VDWS的基因的识别将立即提供更好的风险咨询，并且它们在环境压力下的表征构成了对预防策略和改善治疗剂的贡献的希望。此外，VDWS基因的识别与Cl/P的研究有关，因为它与Cl/p的更频繁的非综合性形式的相似性，并且因为它将立足于颅面发育的最早步骤。