NIPBL, Cohesin and Related Structural Birth Defects

描述(由申请人提供)：本计划的长期目标是阐明正常凝集素功能障碍导致多系统发育障碍Cornelia de Lange综合征(CDLS)的方式，并确定在CDLS星座常见的孤立性出生缺陷(如先天性心脏病、腭裂、横隔疝、肢体缺陷)的发病机制中，粘附素功能的下游效应因子是重要的。该项目的PI(Krantz博士)和项目负责人(Lander博士和Dorsett博士)建立了成功的合作，因为PI发现了第一个CDLS基因(NIPBL)，并初步表明粘附素在人类发育障碍中的作用。在该计划开始时，NIPBL和粘附素在哺乳动物发育中的作用在很大程度上是未知的。多塞特博士发现，果蝇中的NIPBL同源基因(NIPB-b)是基因表达的关键调控因子，这一发现引发了最初的假设，即粘附素在基因调控中的非规范作用被破坏是导致CDLS的潜在机制。该计划项目已经并将继续建立在项目负责人可利用的多样化但互补性的优势、经验和资源的基础上。在人类(项目I)、小鼠和斑马鱼(项目II)和果蝇(项目III)中研究这一基因和途径的三管齐下的方法已经导致了关于粘附素及其调节因子如何发挥作用的重大发现，识别了新的CDLS基因，描述了一组统称为“粘附素病”的发育障碍的特征，以及建立了宝贵的资源，包括唯一的Nipb1突变小鼠模型，多个突变果蝇系和世界上最大的粘附素突变人类细胞系和临床信息储存库。在这次更新中，我们的合作团队将继续使用创新的方法来协同表征CDLS中涉及的结构和调节粘附素蛋白的功能、相互作用和作用，以及它们在导致综合症和孤立的人类结构性出生缺陷中的下游靶标。该方案得到一个将为所有三个项目提供燃料的数据和资源共享核心以及一个监督、促进和优化所有项目互动的行政核心的支持。 相关性：CDLS是一种由结构和调节粘附素基因突变引起的多系统发育障碍。最近的发现发现，粘附素作为基因表达的关键调节因子具有非典型性作用，其干扰会导致显著的发育后果。这项计划概述了一项计划，以表征凝集素在基因调控中的功能，识别其效应基因，并评估它们在导致CDL中所见类型的孤立出生缺陷中的作用。

DESCRIPTION (provided by applicant): The long term goal of this Program is to elucidate the manner in which disruption of normal cohesin function results in the multisystem developmental disorder Cornelia de Lange syndrome (CdLS) and to identify downstream effectors of cohesin function that are important in the pathogenesis of more common isolated birth defects of the types (e.g. congenital heart defects, cleft palate, diaphragmatic hernias, limb defects) seen in constellation in CdLS. The PI (Dr. Krantz) and Project Leaders (Dr. Lander and Dr. Dorsett) of this Program established a successful collaboration since the Pi's discovery of the first CdLS gene (NIPBL) and the initial implication of cohesin in human developmental disorders. At the inception of this Program the role of NIPBL and cohesin in mammalian development was largely unknown. Dr. Dorsett's discovery that the NIPBL ortholog in Drosophila (nipped-b) was a key regulator of gene expression, prompted the initial hypothesis that disruption of cohesin's non-canonical role in gene regulation was the underlying mechanism involved in causing CdLS. This Program Project has built, and will continue to build, on the diverse, but complementary, strengths, experience and resources available to the project leaders. A three-pronged approach to studying this gene and pathway in humans (Project I), mouse and zebrafish (Project II) and Drosophila (Project III) has led to significant discoveries into how cohesin and its regulators function, the identification of novel CdLS genes, the characterization of a group of developmental disorders collectively termed "cohesinopathies", as well as the establishment of valuable resources including the only Nipbl mutant mouse model, multiple mutant Drosophila lines and the world's largest repository of cohesin mutant human cell lines and clinical information. In this renewal our collaborative team will use innovative approaches to continue to synergistically characterize the function, interactions and role of the structural and regulatory cohesin proteins involved in CdLS, and their downstream targets, in causing syndromic and isolated human structural birth defects. This Program is supported by a data- and resource-sharing core that will fuel all three Projects and an administrative core to oversee, facilitate and optimize the interactions of all Projects. RELEVANCE: CdLS is a multisystem developmental disorder caused by mutations in structural and regulatory cohesin genes. Recent discoveries have identified a non-canonical role of cohesin as a critical regulator of gene expression, disruption of which results in significant developmental consequences. This Program outlines a plan to characterize cohesin's function in gene regulation, identify its effector genes and evaluate their role in causing isolated birth defects of the types seen in CdLS.