NEURAL TUBE DEFECTS

描述(申请人提供)：神经管缺陷(NTD)大约发生在 美国的出生率为千分之一。尽管已经从这些事件中学到了很多东西 缺陷，叶酸治疗显著减少了这些缺陷的发生，大大 还有待学习。据估计，可能有50%或更多的人 NTDS有遗传原因，尽管负责的基因通常不是 为人所知。据认为，环境影响对那些 基因缺陷，但在什么水平上还不清楚。该计划项目将 使用几个模型来检查这些问题，目的是提高 关于非专利药物遗传成分的知识。该项目汇集了六个 杜克大学的调查人员将在这方面进行合作 有问题。这六个项目包括： (1)John Klingensmith，他将研究全渗透NTD的基础 骨形态发生蛋白拮抗剂noggin突变小鼠的表型。他会错误地表达 突变的BMP受体通过Cre/lox系统确定BMP信号转导途径 控制背部发育。 (2)将跟踪功能丧失初步研究的埃里克·迈耶斯(Erik Meyers) 表明BMP和成纤维细胞生长因子信号家族之间的平衡是 正常的神经管构图和关闭所需的。CRE/loxP分析将 异位定位表达增强或降低的 这些组件作为功能的测试。 (3)David McClay，他将检查正常情况下的定量粘附性变化 神经管关闭，并将这些数据与纯合子完全有 穿透性NTD和杂合子，无明显异常表型。这个 假设杂合子仍然会有一个可测量的 粘附力不足。 (4)丹·基哈特，他将研究DPP突变体(果蝇中的BMP同源物)，他说 导致背部闭合失败。这个过程有很多细胞 类似于哺乳动物神经管闭合的形态发生特性。 他将在寻找需要其产物的基因的过程中筛选突变基因 对于TGFbeta信号功能，包括形态发生的细胞方面。 (5)埃尔伍德·林尼将使用一种新的启动子捕获逆转录病毒载体，他的 为鉴定和分离神经过程中表达的基因而建的实验室 斑马鱼的管状发育。 (6)Marcy Speer，根据本PO1的其他组成部分，他将检查 导致人类患NTDS的遗传因素，其最终目的是 描述基因之间以及基因与基因之间的相互作用 环境，最终导致预防这些疾病的机制 频繁的出生缺陷。

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.