NIPBL, Cohesin and Related Structural Birth Defects

描述（由申请人提供）：本项目的长期目标是阐明正常粘接蛋白功能的破坏导致多系统发育障碍科尼利亚·德·兰格综合征（CdLS）的方式，并确定粘接蛋白功能的下游效应物，这些效应物在CdLS中出现的更常见的孤立出生缺陷类型（如先天性心脏缺陷、腭裂、膈疝、肢体缺陷）的发病机制中起重要作用。自PI发现首个CdLS基因（NIPBL）和粘连蛋白在人类发育障碍中的初步意义以来，该项目的PI （Krantz博士）和项目负责人（Lander博士和Dorsett博士）建立了成功的合作关系。在本计划开始时，NIPBL和粘接蛋白在哺乳动物发育中的作用在很大程度上是未知的。Dorsett博士发现，果蝇的NIPBL同源基因（nipned -b）是基因表达的关键调节因子，这促使了最初的假设，即黏结蛋白在基因调节中的非规范作用的破坏是导致CdLS的潜在机制。本项目已经建立并将继续建立在项目领导者可用的多种但互补的优势、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）中研究该基因和途径的三管齐下的方法已经导致了对粘接蛋白及其调节因子如何起作用的重大发现，鉴定了新的CdLS基因，描述了一组统称为“粘接病”的发育障碍，以及建立了宝贵的资源，包括唯一的Nipbl突变小鼠模型，多突变果蝇系和世界上最大的内聚蛋白突变人类细胞系和临床信息库。在这次更新中，我们的合作团队将使用创新的方法继续协同表征CdLS及其下游靶标中涉及的结构和调节内聚蛋白的功能，相互作用和作用，导致综合征和孤立的人类结构性出生缺陷。该计划由一个数据和资源共享核心和一个管理核心提供支持，前者将为所有三个项目提供动力，后者将监督、促进和优化所有项目的相互作用。

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.