Characterization and cloning of X. tropicalis Craniofacial Mutants

热带 X. 热带菌颅面突变体的表征和克隆

基本信息

批准号：
8300039
负责人：
Mustafa K Khokha
金额：
$ 31.79万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-01 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8300039
关键词：
Affect Biological Models Branchial arch structure Candidate Disease Gene Cell Death Cell division Child Childhood Cloning Congenital Abnormality Data Defect Development Disease Embryo Embryonic Development Endothelin Evolution Exhibits Face Funding Future Genes Genetic Genetic Models Genetic Screening Genomics Glean Goals Grant Head Head and neck structure Health Human Hybrids Infant Infant Mortality Inheritance Patterns Inherited Jaw Lead Learning Messenger RNA Modeling Molecular Morbidity - disease rate Morphogenesis Mus Mutate Mutation Neural Crest Neural Crest Cell Oligonucleotides Pathway interactions Pattern Phenocopy Phenotype Proteins Rana Recombinants Research Personnel Series Severity of illness Signal Transduction Staging Structure System Testing Tissues Transcript Ursidae Family Xenopus Yaws base comparative cost effective craniofacial gene function genetic analysis human disease improved insight knock-down malformation migration mutant novel positional cloning programs research study skeletal

项目摘要

DESCRIPTION (provided by applicant): Craniofacial malformations are among the most common birth defects in children and lead to substantial morbidity and mortality for these infants. Despite the severity of the illness, little is known about the molecular mechanisms that are necessary for correct formation of facial structures. In this proposal, we will investigate craniofacial development in an emerging model system, Xenopus tropicalis. During a recent forward genetic screen, we identified two mutants, jaws and jawbreaker, that exhibit a specific embryonic defect in the development of craniofacial structures. These mutants show a simple Mendelian inheritance pattern suggestive of a single recessive mutant locus. Outside of the craniofacial defect, the remainder of the embryo appears wildtype. It is the goal of this proposal to characterize these two mutants and identify where and when during development craniofacial patterning begins to fail. In a second aim, we will attempt to identify the mutant locus which will greatly improve our understanding of the molecular patterning defect. Because our understanding of craniofacial morphogenesis remains superficial, characterizing these mutants has the potential of substantially improving our understanding of craniofacial development and malformations. In addition, this will represent one of the very first attempts to clone a mutant identified in a forward genetic screen in X. tropicalis. Successful completion of these goals will greatly support future genetic screens in this emerging model system. Birth defects of the head and neck are a common cause of serious illness in infants. Yet, our scientific understanding of how these structures form during embryonic development remains superficial. We propose a series of experiments to analyze two frog mutants that have abnormal jaw structure. A better understanding of these frog mutants can then be used as a model to understand birth defects of the head and neck in humans.

描述（由申请人提供）：颅面畸形是儿童最常见的先天缺陷之一，并导致这些婴儿的大量发病率和死亡率。尽管疾病严重程度，但对于正确形成面部结构所需的分子机制知之甚少。在此提案中，我们将研究新兴模型系统Tropicalis中的颅面发育。在最近的正向遗传筛选中，我们确定了两个突变体，下颌和颌骨断裂器，它们在颅面结构的发展中表现出特定的胚胎缺陷。这些突变体显示出简单的孟德尔遗传模式，暗示了一个隐性突变基因座。在颅面缺陷之外，其余的胚胎出现了野生型。该提案的目的是表征这两个突变体，并确定开发过程中颅面模式的何处和何时开始失败。在第二个目标中，我们将尝试确定突变基因座，这将大大提高我们对分子图案缺陷的理解。因为我们对颅面形态发生的理解仍然是肤浅的，所以这些突变体的表征具有实质上提高我们对颅面发育和畸形的理解的潜力。此外，这将代表在X. tropicalis中的正向遗传筛选中鉴定出的突变体的首次尝试之一。这些目标的成功完成将极大地支持这个新兴模型系统中的未来遗传筛选。头部和颈部的先天缺陷是婴儿严重疾病的常见原因。然而，我们对胚胎发育过程中这些结构如何形成的科学理解仍然是肤浅的。我们提出了一系列实验，以分析两个具有异常下颌结构的青蛙突变体。然后可以更好地理解这些青蛙突变体，以便将人类头部和颈部的先天缺陷作为模型。