NIPBL, Cohesin and Related Structural Birth Defects

NIPBL、粘连蛋白和相关结构性出生缺陷

• 批准号: 8079355
• 负责人: ANNE LEIGHTON CALOF
• 金额: $ 119.04万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8079355
• 关键词: NIPBL; Cohesin; Related; Structural; Birth

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.

描述（申请人提供）：该项目的长期目标是阐明正常的粘附素功能破坏导致多系统发育障碍科尔内利亚德兰格综合征（CdLS）的方式，并确定粘附素功能的下游效应物，这些下游效应物在以下类型的更常见的孤立出生缺陷的发病机制中是重要的（例如先天性心脏缺陷、腭裂、脑疝、肢体缺陷）。该项目的PI（Krantz博士）和项目负责人（Lander博士和Dorsett博士）自PI发现第一个CdLS基因（NIPBL）和粘附素在人类发育障碍中的初步意义以来，建立了成功的合作。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。Dorsett博士发现果蝇中的NIPBL直系同源物（nipped-b）是基因表达的关键调节因子，这促使人们提出了最初的假设，即粘附素在基因调节中的非经典作用的破坏是导致CdLS的潜在机制。该计划项目已经建立并将继续建立在项目领导人可用的多样化但互补的优势，经验和资源上。研究人类这种基因和途径的三管齐下的方法（项目一）、小鼠和斑马鱼（项目二）和果蝇（项目III）已经导致了关于粘着蛋白及其调节剂如何起作用的重大发现，新CdLS基因的鉴定，统称为“粘着蛋白病”的一组发育障碍的表征，以及建立宝贵的资源，包括唯一的Nipbl突变小鼠模型、多个突变果蝇系和世界上最大的cohesin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中涉及的结构和调节粘附蛋白及其下游靶点在引起综合征和孤立的人类结构性出生缺陷中的功能，相互作用和作用。该计划由一个数据和资源共享核心和一个行政核心提供支持，该核心将为所有三个项目提供动力，该核心将监督、促进和优化所有项目的互动。 相关性：CdLS是一种由结构和调节性粘附素基因突变引起的多系统发育障碍。最近的发现已经确定了一个非典型的作用，凝聚素作为一个关键的基因表达调控，中断的结果在显着的发展后果。该计划概述了一项计划，以表征粘连蛋白在基因调控中的功能，确定其效应基因，并评估其在导致CdLS中所见的孤立出生缺陷类型中的作用。