Mutagenesis and Murine Embyonic Development

诱变和小鼠胚胎发育

• 批准号: 7863919
• 负责人: DAVID R. BEIER
• 金额: $ 0.88万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2009-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7863919
• 关键词: Affect; Biochemical; Biology; Chromosome Mapping; Cleft Palate; Congenital Abnormality; Defect; Development; Dysostoses; Embryonic Development; Etiology; Exfoliative Dermatitis; Gene Targeting; Genes; Heart Diseases; Human; Induced Mutation; Maps; Modeling; Mus; Mutagenesis; Mutant Strains Mice; Mutate; Mutation; Phenotype; Play; Polycystic Kidney Diseases; Robin bird; Role; Screening procedure; Sensitivity and Specificity; Syndrome; Technology; Work; base; human disease; malformation; mutant; positional cloning

DESCRIPTION (provided by applicant): We have undertaken a project to generate models of human congenital defects by screening ENU-mutagenized mice for recessive mutations affecting late embryonic development. The screen incorporated a genetic mapping component, with an aim to facilitate the positional cloning and functional characterization of the mutant genes. The strategy has worked well, and we have generated many mutant lines with phenotypes similar to human malformation syndromes and birth defects. The spectrum of abnormalities found to date is remarkably varied; for example, we have generated models of spondylocostal dysostosis, Robin sequence, congenital diaphragmatic defect, non-syndromic cleft palate, polycystic kidney disease, epidermal bullosa, non-bullosa congenital icthyosiform erythroderma, and structural heart disease. We have mapped a number of these, and identified the mutated locus in 9 lines. To accomplish this, we have taken advantage of efficent technologies for genetic mapping and positional cloning. The functions for many of the genes we have identified are not well understood, and we have initated a variety of biochemical and developmental studies to explore them. In addition to characterizing the biology of the defects in the mutant mice, we have in several cases established that the genes we identified play a role in the causation of human disease. Thus, all of the premises that were the basis of our original proposal have been experimentally validated. In this continuation proposal we hope to refine the specificity and sensitivity of the screen and optimize several aspects of the analysis, while maintaining the fundamental approach that has thus far proven so productive.

描述（由申请人提供）：我们开展了一个项目，通过筛选 ENU 诱变小鼠的隐性突变来生成人类先天缺陷模型。 胚胎发育晚期。该屏幕包含遗传图谱组件，目的是 促进突变基因的定位克隆和功能表征。该策略效果很好，我们已经产生了许多表型类似于 人类畸形综合症和出生缺陷。迄今为止发现的异常现象多种多样；例如，我们已经生成了脊椎肋骨发育不全、罗宾序列、先天性膈肌缺损、非综合征性腭裂、多囊肾病、表皮大疱、非大疱性先天性鱼鳞病样红皮病和结构性心脏病的模型。我们已经绘制了其中的一些图谱，并确定了 9 行中的突变位点。为了实现这一目标，我们利用了高效的基因作图和定位克隆技术。我们已经鉴定的许多基因的功能尚不清楚，我们已经启动了各种生化和发育研究来探索它们。除了表征突变小鼠缺陷的生物学特征之外，我们还在一些案例中确定了我们确定的基因在人类疾病的病因中发挥着作用。因此，作为我们最初提案基础的所有前提都已经过实验验证。在这个延续提案中，我们希望改进筛选的特异性和敏感性，并优化分析的几个方面，同时保持迄今为止已被证明非常有效的基本方法。