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着蛋白功能的破坏导致多系统发育障碍cornelia de lange综合征（CDLS）以及识别粘着蛋白功能的下游效应子，这些伴有类型的更常见的孤立的生育缺陷（例如，concym concnects concrats concrath fecem concrath fecem neffts feffects concrath fecmectress，肢体缺陷）在CDL中的星座中看到。自PI发现第一个CDLS基因（NIPBL）以来，PI（Krantz博士）和该计划的项目负责人（Lander博士和Dorsett博士）建立了成功的合作，以及粘蛋白在人类发育障碍中的最初含义。在该计划开始时，NIPBL和粘蛋白在哺乳动物发育中的作用在很大程度上是未知的。 Dorsett博士的发现，果蝇（Nipped-B）中的NIPBL直系同源物是基因表达的关键调节剂，这促使最初的假设是，粘附素在基因调控中的非统计性作用的破坏是导致CDLS的基本机制。该计划项目已建立，并将继续建立在项目负责人可用的各种，互补的，优势，经验和资源的基础上。 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模型，多个突变果蝇系和世界上最大的粘蛋白突变体人细胞系和临床信息的存储库。在这种续签中，我们的协作团队将使用创新的方法继续协同表征与CDL相关的结构和调节性粘着蛋白蛋白的功能，相互作用和作用，并在引起综合症和孤立的人类结构出生缺陷方面的下游靶标。该计划得到了数据和资源共享核心的支持，该核心将为所有三个项目和管理核心提供助长，以促进，促进和优化所有项目的交互。 相关性：CDL是由结构和调节性粘着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蛋白是基因表达的关键调节剂的非规范作用，这会导致重大的发育后果。该程序概述了一个计划表征粘蛋白在基因调节中的功能，确定其效应基因的功能，并评估其在引起CDL中所见类型的孤立先天缺陷中的作用。