SKI-Regulated Networks in Facial and Skull Defects

SKI 监管的面部和颅骨缺陷网络

• 批准号: 6856548
• 负责人: CLEMENCIA COLMENARES
• 金额: $ 32.69万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6856548
• 关键词: biological signal transduction; bone morphogenetic proteins; cell line; clinical research; congenital oral /facial /cranial defect; craniosynostosis; developmental genetics; gene expression; gene mutation; genetic polymorphism; genetic regulation; genetic transcription; genetically modified animals; human genetic material tag; human tissue; immunocytochemistry; immunoprecipitation; in situ hybridization; laboratory mouse; microarray technology; polymerase chain reaction; tissue /cell culture; transforming growth factors

DESCRIPTION (provided by applicant): Craniofacial defects are among the most common human malformations. We have developed a mouse model of facial clefting and defective cranial bone suture closure by generating a knockout of the Ski gene. The craniofacial abnormalities in Ski-null mice correctly predicted the involvement of human Ski in 1p36 deletion syndrome, a human disorder that includes open fontanelles and a low incidence of facial clefting among its diverse features. The incidence of clefting in Ski -null mice is strain-specific, and in mixed backgrounds is determined by a small number of modifier genes. We will use the strain dependent model of facial clefting to identify polymorphisms in modifier loci by their association with clefting in the C57BL/6J strain, but not in 129 mice that do not exhibit facial clefting. Modifiers of this type are likely to be involved in clefting in 1p36 patients, and may be involved in common forms of clefting which are influenced by multiple genes. Mechanistic studies will focus on Ski as a co-regulator of transcription related to the BMP pathway because the BMP-regulated genes, Msx-1, Msx-2 and Cbfa1 play critical roles in craniofacial development, and have been implicated in many facial and cranial disorders similar to those resulting from the loss of Ski. We will also search for genes in the affected craniofacial regions that are deregulated in the absence of Ski using microarray technology. Genes identified in this way are likely to play a role in these defects in mice and will make excellent candidates for genes likely to be involved in human craniofacial abnormalities. We propose to identify polymorphisms in the non-deleted allele of human Ski because loss of function mutations of that allele may underlie susceptibility to facial clefting and other defects in 1p36 patients. Finally, we will generate Ski transgenic mice to determine whether they reproduce the craniosynostosis phenotype resulting from a duplication of the Ski locus in humans. These studies will contribute to our understanding of the gene regulatory networks that control craniofacial development, and of how disruption of these networks result in craniofacial defects.

描述（由申请人提供）：颅面缺陷是人类最常见的畸形之一。我们通过产生滑雪基因的敲除，开发了一种面部裂口和有缺陷的颅骨缝合闭合的小鼠模型。滑雪无关小鼠的颅面异常正确地预测了人类滑雪中的1p36缺失综合征，一种人类疾病，包括开放的fontanelles和较低的面部裂解率在其多样的特征中。滑雪液小鼠中裂fling的发生率是特异性的，在混合背景下，由少数修饰符基因确定。我们将使用面部裂口的应变依赖性模型来鉴定修饰基因座中的多态性，通过它们与C57BL/6J菌株中的裂解相关联，但在129只没有表现出面部裂口的小鼠中却没有。这种类型的修饰符可能参与1P36例患者的clu养家，并且可能参与了受多个基因影响的常见c裂形式。机械研究将集中于滑雪剂作为与BMP途径相关的转录的共同调节因子，因为BMP调节的基因MSX-1，MSX-2和CBFA1在颅面发育中起着关键作用，并且与许多面部和颅骨疾病有关，类似于与SKI丧失相似的面部和颅骨疾病。我们还将在没有微阵列技术滑雪的情况下搜索受影响的颅面区域中的基因。以这种方式鉴定出的基因可能在小鼠的这些缺陷中起作用，并将为可能涉及人类颅面异常的基因提供出色的候选。我们建议在人类滑雪的未删除等位基因中识别多态性，因为该等位基因的功能突变可能是对面部裂口的敏感性和1P36患者的其他缺陷的敏感性。最后，我们将生成滑雪转基因小鼠，以确定它们是否重现了人类滑雪座基因座的重复作用导致的颅骨突变表型。这些研究将有助于我们理解控制颅面发育的基因调节网络，以及这些网络的破坏如何导致颅面缺陷。