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: 7085994
• 负责人: IAN D. KRANTZ
• 金额: $ 97.32万
• 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 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7085994
• 关键词: birth; clinical research; genes; human; role

DESCRIPTION (provided by applicant): Positional cloning of rare multisystem genetic disorders that follow Mendelian inheritance patterns allows for the identification of genes and molecular pathways that play critical roles in human development. While the impact of disease gene identification on families affected by rare human disorders is tremendous, the true strength of these discoveries comes more from the insight they provide into the pathogenesis of more common and often isolated human structural developmental defects, the genes for which are much more difficult to map. Our recent discovery that mutations in NIPBL cause Cornelia de Lange syndrome (CdLS), a dominantly inherited genetic developmental disorder, provides a starting point to identify downstream genetic targets that are involved in the multiple structural and developmental defects that accompany this diagnosis (craniofacial, limb, gastrointestinal, cardiac, genitourinary and others). The function of NIPBL in mammals is largely unknown, however work in Drosophila has shown that its homolog Nipped B regulates the cohesin complex, and through this function controls long range enhancer-promoter interactions. This program project builds on the strengths, experience and resources available to the project leaders, all of whom have been actively involved in a fruitful collaboration since the identification of NIPBL as the CdLS disease gene. The PI and project leaders will work together to sytematically study NIPBL, its interacting proteins and downstream target genes and to characterize the effects this gene and pathway has on human structural birth defects. A three-pronged approach to studying this gene and pathway in humans (Project I), mouse and zebrafish (Project II) and Drosophila (Project III) will synergistically characterize the function, interactions and role of NIPBL and its downstream targets in causing syndromic and isolated human structural birth defects. This project will be supported by a data- and resource-sharing core that will fuel all three projects and an adminsitrative core to oversee and facilitate and optimize the interactions of all projects. Lay Language: Cornelia de Lange Syndrome (CdLS) is a multisystem developmental disorder caused by mutations in NIPBL, a novel gene involved in regulating downstream genes through long-range enhancerpromoter interactions. This proposal outlines a plan to characterize NIPBL's function, identify its target genes and evaluate their role in causing isolated structural birth defects of the types seen in CdLS.

描述(由申请人提供)：遵循孟德尔遗传模式的罕见多系统遗传疾病的位置克隆允许识别在人类发育中发挥关键作用的基因和分子途径。虽然疾病基因识别对受罕见人类疾病影响的家庭的影响是巨大的，但这些发现的真正力量更多地来自于它们对更常见、往往是孤立的人类结构性发育缺陷的发病机制的洞察，这些缺陷的基因更难绘制。我们最近发现NIPBL突变导致Cornelia de Lange综合征(CDLS)，这是一种主要遗传的遗传发育障碍，为确定下游基因靶点提供了一个起点，这些基因靶点参与了伴随这种诊断而来的多种结构和发育缺陷(头面部、四肢、胃肠道、心脏、生殖泌尿系统等)。NIPBL在哺乳动物中的功能在很大程度上是未知的，然而在果蝇中的研究表明，它的同源基因夹断B调节粘附素复合体，并通过这一功能控制长距离增强子-启动子的相互作用。该方案项目建立在项目负责人可利用的力量、经验和资源的基础上，自确定NIPBL为CDLS疾病基因以来，所有项目负责人都积极参与了富有成效的合作。PI和项目负责人将共同努力，系统地研究NIPBL及其相互作用的蛋白质和下游目标基因，并表征该基因和途径对人类结构性出生缺陷的影响。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将协同地表征NIPBL及其下游靶标在导致综合症和孤立的人类结构性出生缺陷中的功能、相互作用和作用。该项目将由一个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、便利和优化所有项目互动的行政核心提供支助。外行语言：Cornelia de Lange综合征(CDLS)是一种由NIPBL突变引起的多系统发育障碍，NIPBL是一种新基因，参与通过远程增强子和启动子相互作用来调节下游基因。这项建议概述了一项计划，以表征NIPBL的功能，确定其目标基因，并评估它们在导致CDL中所见类型的孤立结构性出生缺陷中的作用。