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: 8264763
• 负责人: ANNE LEIGHTON CALOF
• 金额: $ 116.82万
• 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/8264763
• 关键词: Bruck-de Lange syndrome; Cleft Palate; Clinical; Collaborations; Congenital Abnormality; Congenital Heart Defects; Data; Defect; Development; Diaphragmatic Hernia; Drosophila genus; Gene Expression; Gene Expression Regulation; Genes; Goals; Human; Human Cell Line; Limb structure; Mus; Mutation; Orthologous Gene; Pathogenesis; Pathway interactions; Proteins; Regulator Genes; Resource Sharing; Resources; Role; Zebrafish; cohesin; developmental disease; experience; innovation; mutant; mutant mouse model; novel; programs; repository

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（由申请人提供）：该计划的长期目标是阐明正常粘连蛋白功能破坏导致多系统发育障碍 Cornelia de Lange 综合征 (CdLS) 的方式，并确定粘连蛋白功能的下游效应器，这些效应器在更常见的孤立出生缺陷类型（例如先天性心脏缺陷、腭裂、膈疝、 肢体缺陷）在 CdLS 的星座中看到。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) 以及粘连蛋白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 和粘连蛋白在哺乳动物发育中的作用很大程度上是未知的。 Dorsett 博士发现果蝇中的 NIPBL 直向同源物 (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：粘连蛋白在基因调节中的非典型作用的破坏是导致 CdLS 的潜在机制。该计划项目已经并将继续建立在项目领导者可用的多样化但互补的优势、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）中研究该基因和通路的三管齐下的方法已经在粘连蛋白及其调节因子的功能、新的 CdLS 基因的鉴定、统称为“粘连蛋白病”的一组发育障碍的表征以及包括唯一的 Nipbl 突变小鼠在内的宝贵资源的建立方面取得了重大发现。 模型、多个突变果蝇系以及世界上最大的粘连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方法，继续协同表征 CdLS 中涉及的结构和调节粘连蛋白及其下游靶标在导致综合征和孤立的人类结构出生缺陷中的功能、相互作用和作用。该计划得到数据和资源共享核心的支持，该核心将为所有三个项目提供动力，并由管理核心来监督、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粘连蛋白基因突变引起的多系统发育障碍。最近的发现已经确定了粘连蛋白作为基因表达的关键调节因子的非典型作用，其破坏会导致显着的发育后果。该计划概述了一项计划，旨在描述粘连蛋白在基因调控中的功能，识别其效应基因并评估它们在导致 CdLS 中所见类型的孤立出生缺陷中的作用。