NEURAL TUBE DEFECTS IN MICE

小鼠神经管缺陷

• 批准号: 2201379
• 负责人: THOMAS W SADLER
• 金额: $ 21.35万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-05-01 至 1997-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2201379
• 关键词: alcohols; antisense nucleic acid; cell death; central nervous system disorders; cooperative study; developmental neurobiology; electron microscopy; embryo /fetus culture; folate; gene expression; genetically modified animals; histogenesis; in situ hybridization; laboratory mouse; light microscopy; mutant; neural plate /tube; oligonucleotides; receptor; retinoate; retinoid binding proteins; stainings; superoxide dismutase; teratogens; valproate; zinc

The origins of neural tube defects (NTDs) and, indeed, of factors responsible for neurulation itself are poorly understood. One reason for this lack of understanding is the complexity of the process, which involves coordination among multiple cell types and intra- and extracellular events to successfully complete neurulation. Disruption of any of these events can result in an abnormality. one such event is cell death, which occurs normally (physiological) during neurulation and contributes to the process, but which may be increased by teratogens and/or genetic causes and contribute to NTDs. This project will examine the role of cell death in normal and abnormal development using the curly tail (ct) mouse mutant and gene-teratogen interactions as models. Also, potential regulation of cell death by retinoic acid, its receptors and its binding proteins will be investigated. These goals will be accomplished by: 1) determining the patterns of cell death in specific cell populations in ct and control mice and comparing these patterns to those produced by teratogens known to affect specific cell populations, i.e. valproate and alcohol (neuroepithelial and primitive streak cells) and retinoic acid (gut endoderm and primitive streak cells) ; 2) determining the sensitivity of ct embryos to teratogen exposure, i.e. gene teratogen interactions; 3) determining the roles of zinc, folate, and superoxide dismutase as potential factors for preventing or curing NTDs; 4) determining the patterns of expression of retinoic acid receptors and binding proteins (CRBP and CRABP) in the presence and absence of retinoids using in situ hybridization and a transgene with a LacZ reporter; 5) determining the function of the retinoic acid receptors and binding proteins using antisense oligonucleotides and whole embryo culture. Together these studies will provide information on the pathogenesis and mechanisms of NTDs in ct and normal mice and will enhance the understanding of this morphogenetic event. In turn, the results may suggest avenues of prevention for birth defects such as spina bifida.

神经管缺陷（NTD）及其因素的起源 负责神经本身的理解很少。 一个原因 缺乏理解是过程的复杂性， 涉及多种细胞类型的协调以及内部和 细胞外事件成功完成神经。 破坏 这些事件中的任何一个都可能导致异常。一个这样的事件就是单元 死亡，在神经期间正常发生（生理）和 为该过程做出贡献，但可能会因Teratogens而增加 和/或遗传原因并促成NTD。 这个项目将检查 细胞死亡在正常和使用卷曲异常发育中的作用 尾部（CT）小鼠突变体和基因性交相互作用作为模型。 还， 视黄酸，其受体和 将研究其结合蛋白。 这些目标将是 通过：1）确定特定细胞死亡的模式 CT和对照小鼠中的细胞群体，将这些模式与 那些由已知影响特定细胞群体的Teratogen产生的 即丙戊酸和酒精（神经上皮和原始条纹细胞） 和视黄酸（肠内胚层和原始条纹细胞）； 2） 确定CT胚胎对致畸的敏感性，即 基因多病的相互作用； 3）确定锌，叶酸的作用 和超氧化物歧化酶作为预防或固化的潜在因素 NTD; 4）确定视黄酸表达的模式 在存在的情况下，受体和结合蛋白（CRBP和CRABP） 使用原位杂交缺乏类维生素，而与A的转基因 LACZ记者； 5）确定视黄酸受体的功能 使用反义寡核苷酸和整个胚胎结合蛋白质 文化。 这些研究将共同​​提供有关 CT和正常小鼠中NTD的发病机理和机制，将会 增强对这种形态发生事件的理解。 反过来 结果可能表明预防途径（例如脊柱） 叶。