CLONING AND CHARACTERIZATION OF THE VAN DER WOUDE GENE

VAN DER WOUDE 基因的克隆和表征

• 批准号: 6651305
• 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: 2002-08-01 至 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6651305
• 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.

唇腭裂 (CL/P) 是一种主要的先天性结构异常，以其显着的终生发病率和复杂的病因而著称。广泛的心理、外科、言语和牙科参与强调了了解根本原因的重要性。对于研究者来说，唇裂和腭裂与其他复杂疾病一样，在确定导致其表型的多种遗传、环境和随机因素方面提出了挑战。在本提案中，我们将通过研究一种遗传上简单的唇腭裂——范德沃德综合征 (VDWS)，来探究唇裂和腭裂的复杂原因。 VDWS 是唇腭裂最常见的综合征形式，我们认为的形式最适合有助于增进对更常见的非综合征形式的唇腭裂的了解，而我们认为的形式最适合有助于增进对更常见的非综合征形式的理解。该项目的具体目标包括：1）VDWS 基因的鉴定。致病微缺失的基因筛查将用于进一步限制含有 VDWS 基因的区域。强大的基因发现技术，包括整个关键区域的序列分析，将用于识别转录单位。然后，突变筛选将用于发现引起 DNA 变化的疾病。将进行广泛的突变筛选以搜索功能域。 2) 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、时间和组织特异性表达的研究，以确定需要VDWS基因功能的发育途径，并筛选可能在同一途径中发挥作用的基因同源物。 3) 鉴定调节 VDWS 基因表达的序列和开发转基因小鼠模型，包括将用于 4) 长期研究的小鼠敲除，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 基因和同一途径中其他基因的影响。该项目的影响在于，对 CL/P 的研究很有价值，既因为缺陷本身作为发病因素的重要性，又为复杂的人类出生缺陷提供了模型。 VDWS 和 VDWS 样基因的鉴定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有望为预防策略和改进治疗做出贡献。此外，VDWS 基因的鉴定与 CL/P 的研究相关，因为它与更常见的非综合征形式 CL/P 相似，并且因为它将为颅面发育的最早步骤提供立足点。