ALCOHOL AND CELL ADHESION

乙醇抑制神经细胞和成纤维细胞中L1细胞粘附分子介导的细胞粘附 用人类L1基因转染。因为L1基因突变儿童的大脑与 谈到酒精综合征，L1介导细胞粘附的抑制可能有助于 ETOH的致角质作用。一系列直链和支链醇的结构活性分析 显示出对酒精抑制细胞-细胞粘附的显著结构特异性。而且我们 鉴定了一系列化合物，其拮抗乙醇对L1介导的细胞-细胞粘附的作用， BMP在培养的神经细胞中的形态发生，以及对小鼠全胚胎培养物的发育。的 这一建议的基本假设是，拮抗乙醇抑制L1介导的 细胞-细胞粘附也将防止乙醇致畸作用。本研究有三个具体目标：1。 确定抑制代谢所需的醇类和相关化合物的结构决定因素， 表达L1的细胞中的细胞-细胞粘附以及这种抑制的拮抗作用; 2.确定 乙醇抑制L1粘附并诱导神经元中凋亡性细胞死亡的机制; 3.到 表征L1中对酒精抑制和对酒精抑制的拮抗作用所必需的区域; 4.评价选择的乙醇拮抗剂预防乙醇致畸作用的能力， 小鼠全胚胎培养和在C57 BI/J6小鼠的早期胚胎发生期间。采用的技术 这些研究将包括哺乳动物细胞转染、细胞聚集测定、L1的诱变 分子，小鼠全胚胎培养，以及暴露于 子宫内的乙醇这些实验可能有助于更好地理解乙醇如何与神经细胞相互作用。 并可能揭示乙醇导致出生缺陷的机制。拟议的一个主要目标是 研究的目的是确定减少乙醇致畸作用的化合物。

Ethanol inhibits cell adhesion mediated by the L1 cell adhesion molecule in neural cells and in fibroblasts ransfected with human L1. Because the brains of children with L1 mutations resemble those of children with tal alcohol syndrome, it is possible that inhibition of L1-mediated cell adhesion contributes to the eratogenic 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 dentified 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 prevent 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 determine the mechanism(s) by which ethanol inhibits L1 adhesion and induces apoptotic cell death in neurons; 3. To characterize regions of L1 that are necessary for alcohol inhibition and for antagonism of ethanol inhibition; 4. To evaluate selected ethanol antagonists for their ability to prevent the teratogenic effects of ethanol in mouse whole embryo culture and during early embryogenesis in C57BI/J6 mice. Techniques employed in these studies will include mammalian cell transfection, cell-aggregation assays, mutagenesis of the L1 molecule, mousewhole 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 neura 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.