GENETIC BASIS OF CLEFT LIP AND PALATE

唇腭裂的遗传基础

基本信息

批准号：
7904362
负责人：
RULANG JIANG
金额：
$ 20.53万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7904362
关键词：
Adolescence Affect Animal Model Biochemical Genetics Biological Models Candidate Disease Gene Chromosome Mapping Chromosomes Cleaved cell Cleft Lip Cleft Palate Cleft lip with or without cleft palate Complex Congenital Abnormality Dancer mutation Data Defect Dental Development Diagnosis Ectopic Expression Embryo Environmental Risk Factor Etiology Exons Face Gene Expression Gene Mutation Genes Genetic Goals Heterozygote Homologous Gene Homozygote Human Individual Labyrinth Lead Lesion Live Birth Medical Mesenchyme Messenger RNA Modeling Molecular Molecular Genetics Molecular Profiling Mus Mutant Strains Mice Mutation Names Operative Surgical Procedures Organ Pathogenesis Pathway interactions Phenotype Prevention Process Protein Isoforms Proteins Race Research Sequence Analysis Signal Pathway Signal Transduction Signaling Pathway Gene Speech Tissues Transgenic Mice Zinc Fingers base cleft lip and palate craniofacial gene cloning gene function homeodomain infancy insight method development mutant mutant mouse model orofacial positional cloning promoter psychologic transcription factor

项目摘要

DESCRIPTION (provided by applicant): The long-term goal of this proposed research is to understand the molecular genetic mechanisms of craniofacial development and of orofacial cleft pathogenesis. Orofacial clefts, including cleft lip and cleft palate, are common birth defects that affect approximately 1 in 700 live births worldwide. Individuals with facial clefts undergo extensive surgical, dental, speech and psychological therapies that usually last for many years from infancy through the teenage years. Despite the frequent occurrence and extensive costly medical treatments associated with such birth defects, the causes and the pathogenic processes that lead to cleft lip and/or cleft palate are not well understood. Recent studies in animal model systems showed that development of the face, like development of other organs, are largely controlled by genetic factors. Indeed, there is accumulating evidence that specific gene mutations are associated with orofacial clefting. We have recently found that a spontaneous mutation, named Twirler, that causes cleft lip with cleft palate in homozygous mutant mice, is associated with alteration of the Zfhx1a gene. Interestingly, the Zfhx1a gene function is required for normal craniofacial development because a targeted disruption in this gene caused craniofacial defects including cleft palate in mice. The Zfhx1a gene is evolutionarily conserved and mutations in the human homolog causes multiple developmental defects. Moreover, the Zfhx1a gene product has been shown to interact with and regulate Bmp and Tgf-beta signaling, major molecular pathways regulating normal craniofacial development and involved in cleft lip/palate pathogenesis in mice and humans. Thus, we propose to determine the exact genetic lesion and the developmental mechanisms underlying facial cleft formation in the Twirler mutant mice. We will also determine the genetic interactions of Twirler/Zfhx1a with the Bmp/Tgf- beta signaling pathways during craniofacial development. These studies will greatly increase our understanding of the pathogenic mechanisms underlying orofacial cleft formation and will lead to development of methods for better diagnosis, treatment and/or prevention of orofacial clefting.

描述（由申请人提供）：这项拟议的研究的长期目标是了解颅面发育的分子遗传机制和口面裂口发病机理。包括唇裂和口感在内的口腔裂缝是常见的先天缺陷，影响了全世界700个活产中大约100名。具有面部裂缝的人会接受广泛的外科手术，牙科，言语和心理疗法，通常从婴儿期到十几岁。尽管经常发生和与此类出生缺陷有关的广泛昂贵的医疗治疗，但导致唇裂和/或left裂的原因和致病过程尚不清楚。动物模型系统的最新研究表明，面部的发展，例如其他器官的发展，在很大程度上受到遗传因素的控制。确实，有积累的证据表明特定基因突变与口面裂相关。我们最近发现，一个名为wwirler的自发突变与纯合突变小鼠中的left裂唇裂，与ZFHX1A基因的改变有关。有趣的是，正常颅面发育需要ZFHX1A基因功能，因为该基因的靶向破坏会导致小鼠颅面缺陷，包括小鼠的裂口。 ZFHX1A基因在进化上是保守的，人类同源物中的突变会导致多种发育缺陷。此外，ZFHX1A基因产物已显示出与BMP和TGF-β信号的相互作用，这是调节正常颅面发育的主要分子途径，并参与小鼠和人类的唇lip/paine发病机理。因此，我们建议确定旋转器突变小鼠面部裂口形成的确切遗传病变和发育机制。我们还将在颅面发育过程中确定旋转器/ZFHX1A与BMP/TGF-β信号通路的遗传相互作用。这些研究将大大提高我们对形成裂口基础的致病机制的理解，并将导致开发更好的诊断，治疗和/或预防口面裂裂的方法。