DEVELOPMENT AND GENETICS OF NEURAL TUBE DEFECTS

这项研究的长期目标是理解常态 神经形成的过程，这导致形成闭合的神经 管，整个中枢神经系统的前身，并 了解中断这一关键过程的机制 神经管缺陷(NTDS)的起源。神经管疾病，如脊柱裂， 是人类最常见、最严重的先天畸形。 小鼠的神经形成在所有实际目的上都与在 人类。此外，一些基因突变的小鼠也可以作为 人类疾病的动物模型，这些模型提供了独特的 优势是它们提供了连续和可重现的来源 实验材料。对这些动物模型的透彻理解 可能最终导致人类NTDS的预防或治疗。 这项研究的首要目标之一是定义细胞的模式 正常神经形成过程中细胞形状的移动和变化 在哺乳动物身上。此外，外胚层中正常细胞的命运和谱系 而中胚层将被确定。在描述了这些过程之后 在正常小鼠中，它们将在卷尾突变小鼠中进行检测 确定是否有与神经管有关的中断和因果关系 叛逃。这些事件将在整个胚胎培养中使用一种 各种酶、荧光和逆转录病毒标记物 细胞的运动。 很明显，如果你预防神经管缺陷，你就会 预防由此导致的神经损伤。然而，与之相反， 全面预防该缺陷，具有极其重要的临床意义 减少神经缺陷。卷尾突变体提供了一种 研究NTDS对神经元的影响的独特机会 区分以确定是否存在关键时期 开放的神经管对神经系统的损害最大。这将是 用几种单抗检查以监测神经元 卷尾小鼠的分化及其与正常结果的比较 一窝产仔。 最后，将进行各种遗传研究，以确定 卷尾基因的染色体定位和紧密鉴定 连锁遗传标记。此外，还将尝试寻找一种 遗传背景将提高基因的外显性和表现力 并确定其他改变表达的遗传基因座 这种疾病的危害。这些其他基因可以提供重要的线索 NTDS的原因和可能的预防手段。

The long-term objectives of this research are to understand the normal process of neurulation, which results in the formation of a closed neural tube, the precursor of the entire central nervous system, and to understand the mechanisms by which this critical process is disrupted in the genesis of neural tube defects (NTDs). NTDs, such as spina bifida, are among the most common and most severe human congenital malformations. Neurulation in mice is for all practical purposes identical to that in humans. In addition, a number of genetically mutant mice are available as animal models of the human disease, and these offer the distinct advantage that they provide a continuous and reproducible source of experimental material. A thorough understanding of such animal models could eventually lead to the prevention or treatment of human NTDs. One of the first aims of this research is to define the patterns of cell movements and changes in cell shapes that occur during normal neurulation in mammals. In addition, normal cell fates and lineages in the epiblast and mesoblast will be determined. Having characterized these processes in normal mice, they will be examined in the curly tail mutant mouse to determine if any are disrupted and causally related to the neural tube defect. These events will be studied in whole embryo cultures using a variety of enzyme, fluorescent, and retroviral markers to follow the movements of cells. It is obvious that if you prevent the neural tube defect, you will prevent the resulting neurological impairments. However, in lieu of total prevention of the defect, it is of extreme clinical importance to reduce the neurological deficits. The curly tail mutant provides a unique opportunity to examine the effects of NTDs on neuronal differentiation to determine if there are critical periods during which the open neural tube is most damaging to the nervous system. This will be examined using several monoclonal antibodies to monitor neuronal differentiation in curly tail mice and to compare the results to normal littermates. Finally, a variety of genetic studies will be conducted to determine the chromosomal location of the curly tail gene and to identify closely linked genetic markers. In addition, attempts will be made to find a genetic background that will improve the penetrance and expressivity of this mutant and to identify other genetic loci that modify the expression of the disease. These other genes could offer important clues to the causes of NTDs and possible means of prevention.