NEURAL TUBE DEFECTS

神经管缺陷

• 批准号: 6659820
• 负责人: DAVID MCCLAY
• 金额: $ 103.36万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-01 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6659820
• 关键词: congenital nervous system disorder; developmental neurobiology; disease /disorder model; embryology; gene expression; molecular pathology; neural plate /tube; neurogenesis; neurogenetics; neuroregulation; protein structure function

DESCRIPTION (Provided by applicant): Neural tube defects (NTDs) occur in about 1/1000 births in the United States. Though much has been learned from these defects, and folate treatment has significantly reduced their occurrence, much remains to be learned. It has been estimated that perhaps 50% or more of all NTDs have a genetic cause though the genes responsible generally are not known. There is thought to be an influence of environmental effects on those genetic deficits, but at what level is not known. This program project will use several models to examine these questions with the goal of increasing knowledge of the genetic component of NTDs. The project brings together six investigators at Duke University who will work collaboratively on this problem. The six projects include: (1) John Klingensmith, who will study the basis of fully-penetrant NTD phenotypes in mice mutant for the BMP antagonist noggin. He will misexpress mutant BMP receptors via the Cre/lox system to determine how BMP signaling controls dorsal development. (2) Erik Meyers who will follow preliminary loss of function studies indicating that a balance between the BMP and Fgf signaling families is required for normal neural tube patterning and closure. Cre/loxP analysis will ectopically localize either increased expression or decreased expression of these components as a test of function. (3) David McClay who will examine quantitative adhesion changes during normal neural tube closure and compare those data with homozygotes having a fully penetrant NTD and heterozygotes with no visible abnormal phenotype. The hypothesis is that the heterozygotes will nevertheless have a measurable deficit in adhesion. (4) Dan Kiehart who will study dpp mutants (the BMP homolog in flies) that cause a failure in dorsal closure. This process has many cellular morphogenetic properties that are similar to neural tube closure in mammals. He will screen for mutants in a search for genes whose products are required for TGFbeta signaling function including cellular aspects of morphogenesis. (5) Elwood Linney who will use a new promoter trap retroviral vector that his laboratory constructed to identify and isolate genes expressed during neural tube development in zebrafish. (6) Marcy Speer, who, based on the other components of this PO1, will examine the hereditary factors predisposing humans to NTDs, with the ultimate aim of characterizing interactions between genes and between genes and the environment, eventually leading to mechanisms for the prevention of these frequent birth defects.

描述（申请人提供）：神经管缺陷（NTD）发生在大约 美国的1/1000分。虽然从中学到了很多 缺陷和叶酸治疗显着降低了其发生，很多 还有待学习。据估计，大概有50％或更多 NTD具有遗传原因，尽管负责的基因通常不是 已知。人们认为环境影响对那些 遗传缺陷，但在什么水平上。这个程序项目将 使用多种模型检查这些问题，目的是增加 了解NTD的遗传成分。该项目汇集了六个 杜克大学的调查人员将在此协作 问题。六个项目包括： （1）John Klingensmith，他将研究完全渗透剂NTD的基础 BMP拮抗剂Noggin的小鼠突变体的表型。他将Misexpress 通过CRE/LOX系统突变BMP受体，以确定BMP信号如何 控制背侧发展。 （2）将遵循初步丧失功能研究的埃里克·迈耶斯（Erik Meyers） 表明BMP和FGF信号系列之间的平衡是 正常的神经管模式和闭合所需。 CRE/LOXP分析将 从异位定位表达增加或表达降低 这些组件作为功能测试。 （3）大卫·麦克莱（David McClay）将在正常情况下检查定量粘附变化 神经管闭合并将这些数据与具有完全的纯合子进行比较 渗透性NTD和杂合子，没有明显异常表型。这 假设是杂合子将具有可测量的 粘附不足。 （4）丹·基哈特（Dan Kiehart 导致背闭合失败。这个过程有许多细胞 与哺乳动物中神经管闭合相似的形态发生特性。 他将在搜索需要产品的基因中筛选突变体 用于TGFBETA信号传导功能，包括形态发生的细胞方面。 （5）Elwood Linney将使用新的发起人陷阱逆转录病毒向量 实验室构建旨在识别和隔离神经期间表达的基因 斑马鱼的管发育。 （6）Marcy Speer，基于该PO1的其他组成部分，他将研究 遗传因素使人类诱使NTD，最终目的是 表征基因之间以及基因与基因之间的相互作用 环境，最终导致了预防这些的机制 经常出生缺陷。