PROJECT II: Vertebrate Animal Models of Cornelia de Lange Syndrome

项目二：Cornelia de Lange 综合征的脊椎动物模型

• 批准号: 8378230
• 负责人: Arthur D Lander
• 金额: $ 50.67万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8378230
• 关键词: Address; Alleles; Animal Model; Animals; Atrial Heart Septal Defects; Back; Behavioral; Binding; Body Size; Bone Growth; Bruck-de Lange syndrome; Cardiac; Cell Line; Chromosome Cohesion; Congenital Abnormality; Congenital Heart Defects; Craniofacial Abnormalities; DNA Sequence; Defect; Development; Embryo; Embryonic Development; Endocardium; Endoderm; Etiology; Event; Exhibits; Failure to Thrive; FarGo; Fishes; Frequencies; Functional disorder; Gene Expression; Gene Expression Profiling; Gene Expression Regulation; Gene Targeting; General Population; Genes; Genetic; Goals; Health; Heart; Heart Septal Defects; Human; In Situ; Individual; Instruction; Introns; Left; Link; Mediating; Mesoderm; Modeling; Molecular; Morphogenesis; Mouse Strains; Mus; Mutant Strains Mice; Mutation; Myocardium; Nature; Neural Crest; Obesity; Pathway interactions; Pattern; Phenocopy; Phenotype; Principal Investigator; Probability; Proteins; Research; Role; Secondary to; Seizures; Syndrome; System; Testing; Time; Tissues; Transgenic Mice; Ursidae Family; Ventricular septum; Vertebrates; Work; Zebrafish; body system; cardiogenesis; cell type; cohesin; combinatorial; functional restoration; gastrulation; gene function; human disease; insight; migration; mutant; novel; prevent; progenitor; protein complex; recombinase; research study

Cornelia de Lange Syndrome (CdLS) is a multi-organ system constellation of birth defects caused by dysfunction of cohesin, a protein complex required for chromosome cohesion, and recently implicated in the regulation of gene expression. This work will continue the development and analysis of two animal models of A//pib/-deficiency, the most common genetic cause of CdLS. The Nipbl+I- mouse replicates many features of CdLS including a high frequency of cardiac septal abnormalities. The A//pW-morphant zebrafish also displays cardiac defects, as well as gut defects that are typical of CdLS. In both systems, Nipbl deficiency appears to cause hundreds of relatively small, often tissue-specific, changes in gene expression, just as has been seen in cell lines from individuals with CdLS. The goal of the proposed work is to exploit the mouse and fish models to (1) understand the origins of heart defects in CdLS, and (2) determine the extent to which major structural defects in CdLS have a combinatorial etiology-i.e. arise as the result of synergistic interactions among small changes in the expression of multiple genes. The first aim will be accomplished using newly-developed transgenic mouse lines that harbor conditional/invertible (FLEx) alleles of Nipbl, which may be successively toggled from functionally-mutant to wildtype, and back again to mutant. Using these mouse lines, the timing and cell type(s) of origin of cardiac septal defects will be pinpointed, and potentially causal changes in gene expression identified. The second aim will be accomplished using a zebrafish model of CdLS. Experiments in this aim will focus on the identification of new potential Nipbl "target" genes, and the quantitative manipulation of their expression during early embryogenesis. Accomplishing these aims should not only aid in understanding, treating and/or preventing birth defects in CdLS; it is also likely to provide novel insights into the origins of non-syndromic birth defects, which are much more common, but may also frequently result from combinatorial interactions among small-effect alleles in the general population. RELEVANCE (See instructions): The impact of structural birth defects on human health is enormous. Animal models of Cornelia de Lange Syndrome (CdLS) will be exploited to generate new insights into the origins of birth defects, especially those of the heart and gut. Because of the way the gene defect underlying this syndrome works, there is a good probability that the results obtained will be directly relevant to common causes of birth defects in the general population.

Cornelia de Lange 综合征 (CdLS) 是一种由以下原因引起的多器官系统出生缺陷： 粘连蛋白（一种染色体粘连所需的蛋白质复合物）功能障碍，最近与 基因表达的调控。这项工作将继续开发和分析两种动物 A//pib/-缺陷模型，这是 CdLS 最常见的遗传原因。 Nipbl+I- 小鼠复制 CdLS 的许多特征包括心房间隔异常的高频率。 A//pW-变形体 斑马鱼还表现出心脏缺陷以及 CdLS 典型的肠道缺陷。在两个系统中， Nipbl 缺陷似乎会导致数百个相对较小的、通常是组织特异性的基因变化 表达，正如在 CdLS 患者的细胞系中所看到的那样。拟议工作的目标 是利用小鼠和鱼模型来 (1) 了解 CdLS 心脏缺陷的起源，以及 (2) 确定 CdLS 中主要结构缺陷具有组合病因的程度，即出现 作为多个基因表达的微小变化之间协同相互作用的结果。这 第一个目标将使用新开发的转基因小鼠品系来实现 Nipbl 的条件/可逆 (FLEx) 等位基因，可以从功能突变中连续切换 到野生型，然后再回到突变型。使用这些小鼠系，起源的时间和细胞类型 将查明心脏间隔缺陷，并确定基因表达的潜在因果变化。 第二个目标将使用 CdLS 的斑马鱼模型来实现。为此目的进行的实验将集中于 关于新的潜在 Nipbl“目标”基因的鉴定及其定量操作 早期胚胎发生过程中的表达。 实现这些目标不仅有助于了解、治疗和/或预防出生缺陷 镉LS；它还可能为非综合征性出生缺陷的起源提供新的见解，这些缺陷是 更常见，但也可能经常是由小效应之间的组合相互作用造成的 一般人群中的等位基因。 相关性（参见说明）： 结构性出生缺陷对人类健康的影响是巨大的。科妮莉亚·德·朗格的动物模型 综合症（CdLS）将被用来对出生缺陷的起源产生新的见解，特别是 那些内心和肠道的。由于这种综合征背后的基因缺陷的作用方式， 所获得的结果很可能与出生缺陷的常见原因直接相关 普通民众。