PROJECT II: Vertebrate Animal Models of Cornelia de Lange Syndrome

Cornelia de Lange综合征(CDLS)是一种多器官系统的出生缺陷星座，由 粘附素功能障碍，一种染色体凝聚所需的蛋白质复合体，最近被认为与 基因表达的调节。这项工作将继续开发和分析两种动物 A//PIB/-缺乏症的模型，这是CDLS最常见的遗传原因。Nipbl i-鼠标可以复制 CDLS的许多特征包括高频率的心脏间隔异常。A//PW变形剂 斑马鱼也会表现出心脏缺陷和肠道缺陷，这是CDLS的典型特征。在这两个系统中， Nipb1缺乏似乎会导致数百个相对较小的、通常是组织特有的基因变化。 表达，就像已经在CDL患者的细胞系中看到的那样。拟议工作的目标是 是利用小鼠和鱼类模型来(1)了解CDL心脏缺陷的起源，以及(2) 确定CDL中主要结构缺陷具有组合病因学的程度--即浮起 由于多个基因表达的微小变化之间的协同作用。这个 第一个目标将使用新开发的转基因小鼠品系来实现 Nipb1的条件/可逆(Flex)等位基因，可能从功能突变中连续切换 到野生型，再回到变种人。使用这些小鼠系，时间和细胞类型(S)的起源 心脏间隔缺陷将被精确定位，并确定基因表达的潜在原因变化。 第二个目标将使用CDLS的斑马鱼模型来实现。以此为目标的实验将集中于 新的潜在Nipb1“靶”基因的鉴定及其定量调控 在早期胚胎发育过程中的表达。 实现这些目标不仅应该有助于了解、治疗和/或预防出生缺陷 CDLS；它还可能为非综合征出生缺陷的起源提供新的见解，这些出生缺陷是 更常见，但也可能经常是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(请参阅说明)： 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 心灵和胆量的。由于这种综合症背后的基因缺陷的工作方式，有 所获得的结果很有可能与导致出生缺陷的常见原因直接相关。 普通民众。

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.