Genetic Characterization of a Novel Model of Cleft Palate

腭裂新模型的遗传特征

• 批准号: 7739362
• 负责人: Stephen A Murray
• 金额: $ 13.05万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7739362
• 关键词: Affect; Apoptosis; Candidate Disease Gene; Cell physiology; Chromosome Mapping; Chromosomes, Human, Pair 10; Cleaved cell; Cleft Lip; Cleft Palate; Congenital Abnormality; Congenital omphalocele; Data; Defect; Development; Diagnosis; Disease; Distal; Embryo; Etiology; Failure; Foundations; Frequencies; Future; Gene Expression; Gene Expression Regulation; Genes; Genetic; Goals; Health Care Costs; Human; Individual; Lesion; Link; Live Birth; Maps; Methods; Modeling; Molecular; Morphogenesis; Movement; Mus; Mutation; Operative Surgical Procedures; Organ Culture Techniques; Palate; Penetrance; Phenotype; Postoperative Period; Prevention; Public Health; Reporting; Research Proposals; Resolution; Secondary Palate; Staging; Syndrome; Time; Work; base; craniofacial; design; exome; improved; insight; malformation; mouse model; mutant; novel; orofacial; palatogenesis; psychologic; public health relevance; repaired; research study; skeletal; social; stem

DESCRIPTION (provided by applicant): Orofacial clefting is one of the most common birth defects in humans, affecting approximately 1 in 700 live births. This frequency likely stems from the complexity of craniofacial morphogenesis, which requires precise regulation of gene expression changes, alterations in cell physiology and morphogenic movements. Although an increasing number of genes have been linked to cleft lip and cleft palate, the mechanisms governing orofacial malformations remain unclear. The overall objective of this project is to expand our understanding of the genetic basis of orofacial clefting through the use of a novel mouse model of cleft palate. The ENU-induced clfp4 mouse harbors a recessive mutation causing cleft secondary palate, omphalocele and skeletal malformations with high penetrance. While simultaneous presentation of orofacial clefting and body wall defects is observed in human syndromes, there are few mouse models that recapitulate these phenotypes. Preliminary mapping data places the mutation at the distal end of Chromosome 10, a region where this combination of phenotypes has not been reported. Thus, clfp4 likely represents a new model of craniofacial/body wall birth defects. Although preliminary phenotypic analysis has revealed that cleft palate in this mutant results from a failure of palate shelf elevation, efficient design and interpretation of more detailed experiments, such as marker analysis, would be greatly facilitated by identification of the clfp4 causative gene. To develop this unique model of cleft palate and to elucidate the mechanism underlying the phenotype, we propose to identify the gene that underlies the cflp4 mutation through high-resolution genetic mapping and targeted re-sequencing, and perform basic phenotypic analysis to begin to understand the mechanistic basis of the defect. This work will improve our understanding of the molecular networks that regulate palatogenesis, providing a foundation for the development of new methods for the diagnosis, prevention and treatment of cleft palate and other craniofacial disorders. PUBLIC HEALTH RELEVANCE: Orofacial clefting is one of the most common birth defects in humans, affecting 1 in 700 live births. The total health care costs for surgical repair and post-operative therapies is staggering, and the disfigurement of such disorders often have devastating social and psychological consequences for the affected individual. This proposal will expand our understanding of the etiology of orofacial clefting using a novel mouse model of cleft palate and craniofacial malformations, providing a foundation for the development of new methods for the diagnosis, prevention and treatment of cleft palate and other craniofacial disorders.

描述（由申请人提供）：口面裂是人类最常见的出生缺陷之一，影响大约1/700的活产婴儿。这种频率可能源于颅面形态发生的复杂性，这需要精确调节基因表达变化、细胞生理学改变和形态发生运动。虽然越来越多的基因与唇裂和腭裂有关，但控制口面畸形的机制仍不清楚。本项目的总体目标是通过使用一种新的腭裂小鼠模型来扩大我们对口面裂遗传基础的理解。ENU诱导的clfp 4小鼠携带隐性突变，导致继发性腭裂、脐膨出和骨骼畸形，具有高突变率。虽然在人类综合征中观察到口面裂和体壁缺陷的同时呈现，但很少有小鼠模型重现这些表型。初步定位数据将突变定位在染色体10的远端，该区域的表型组合尚未报道。因此，clfp 4可能代表一种新的颅面/体壁出生缺陷模型。虽然初步的表型分析表明，腭裂在这个突变体的结果从失败的腭架海拔，有效的设计和更详细的实验，如标记分析的解释，将大大促进clfp 4致病基因的鉴定。为了开发这种独特的腭裂模型并阐明表型的机制，我们建议通过高分辨率遗传图谱和靶向重测序来识别cflp 4突变的基因，并进行基本的表型分析，以开始了解缺陷的机制基础。这项工作将提高我们对调节腭裂发生的分子网络的理解，为开发诊断，预防和治疗腭裂和其他颅面疾病的新方法提供基础。 公共卫生相关性：口面裂是人类最常见的出生缺陷之一，每700个活产婴儿中就有1个受到影响。手术修复和术后治疗的总保健费用是惊人的，这种疾病的毁容往往对受影响的个人产生毁灭性的社会和心理后果。该建议将扩大我们的口面裂的病因学的理解，使用一种新的腭裂和颅面畸形的小鼠模型，提供了一个基础，为腭裂和其他颅面疾病的诊断，预防和治疗的新方法的发展。