ALCOHOL AND CELL ADHESION

描述：(改编自《调查者摘要》)乙醇抑制细胞 神经细胞中L1细胞黏附分子介导的黏附 转人L1基因的成纤维细胞。因为L1儿童的大脑 突变类似于患有胎儿酒精综合征的儿童，它是 L1介导的细胞黏附的抑制可能参与了 乙醇的致畸作用。一系列化合物的结构活性分析 直链和支链醇表现出显著的结构 酒精抑制细胞间黏附的特异性。此外，我们有 确定了一系列化合物，这些化合物可以拮抗乙醇对 L1介导的细胞间黏附，对培养神经细胞BMP形态发生的影响 以及对小鼠全胚胎培养的影响。潜在的 这一提议的假设是，拮抗乙醇的化合物 抑制L1介导的细胞间黏附也将拮抗乙醇 畸形症。拟议的研究有三个具体目标：1.确定 所需的醇和相关化合物的结构决定因素 抑制L1表达细胞的细胞间黏附及拮抗作用 这种抑制的特征；2.表征L1的区域，这些区域是 酒精抑制及对乙醇抑制的拮抗作用；3.评价 选择性乙醇拮抗剂预防致畸作用的研究 乙醇对小鼠全胚胎培养及早期胚胎发育的影响 在C57BL/6J小鼠体内。这些研究中使用的技术将包括哺乳动物 细胞转染法，细胞聚集法，L1分子诱变， 小鼠全胚胎培养及小鼠宏观和微观分析 在子宫中暴露在乙醇中。这些实验可能会带来更好的 了解乙醇如何与神经蛋白质相互作用并可能揭示 酒精导致出生缺陷的机制。建议的主要目标是 研究的目的是找出能降低致畸作用的化合物 乙醇。

DESCRIPTION: (Adapted from the Investigator’s Abstract) Ethanol inhibits cell adhesion mediated by the L1 cell adhesion molecule in neural cells and fibroblasts transfected with human L1. Because the brains of children with L1 mutations resemble those of children with fetal alcohol syndrome, it is possible that inhibition of L1-mediated cell adhesion contributes to the teratogenic effects of ETOH. Structure activity analysis of a series of straight and branch-chain alcohols demonstrates remarkable structural specificity for alcohol inhibition of cell-cell adhesion. Moreover, we have identified a series of compounds that antagonize the effects of ethanol on L1-mediated cell-cell adhesion, on BMP morphogenesis in cultured neural cells, and on the development of mouse whole embryo cultures. The underlying hypothesis of this proposal is that compounds that antagonize ethanol inhibition of L1-mediated cell-cell adhesion will also antagonize ethanol teratogenesis. The proposed research has three specific aims: 1. To identify the structural determinants of alcohols and related compounds that are required for inhibition of cell-cell adhesion in L1-expressing cells and for antagonism of this inhibition; 2. To characterize regions of L1 that are necessary for alcohol inhibition and for antagonism of ethanol inhibition; 3. To evaluate selective ethanol antagonists for their ability to prevent the teratogenic effects of ethanol in mouse whole embryo culture and during early embryogenesis in C57BL/6J mice. Techniques employed in these studies will include mammalian cell transfection, cell-aggregation assays, mutagenesis of the L1 molecule, mouse whole embryo culture, and macroscopic and microscopic analysis of mice exposed to ethanol in utero. These experiments may lead to a better understanding of how ethanol interacts with neural proteins and may reveal mechanisms whereby ethanol causes birth defects. A major goal of the proposed research is to identify compounds that reduce the teratogenic effects of ethanol.