ETHANOL EFFECT ON CELL PROLIFERATION

酒精中毒与细胞生长的深刻变化和 扩散。细胞生长受阻的最严重表现是 胎儿酒精综合症，尽管细胞生长改变也可能起到 在贫血、肝硬变和全身疾病的发展过程中起着重要作用 与酒精中毒有关的分解代谢状态。胰岛素的激活- IGF-1受体通过其配体IGF-1和IGF-2发挥作用 在细胞增殖和生存中的关键作用，以及中枢 神经系统发育。已经证明，乙醇在 生理耐受水平，显著降低自磷酸化 通过其配体抑制IGF-1受体，并有效地抑制IGF-1- 介导细胞增殖和保护细胞免于凋亡。现在是时候了 建议研究IGF-1受体和其各自的作用 乙醇抑制细胞增殖中的配体。模型 最初将使用小鼠成纤维细胞系统，因为这些细胞 精致的IGF生长调控，并提供了从基因上 操纵细胞来研究IGF的各种功能成分 信号通路。乙醇对胰岛素样生长因子和胰岛素样生长因子-1的影响 受体mRNA的表达将被研究。乙醇的作用机制 将在纯化的质膜中分析IGF-1受体和 纯化的IGF-1受体制剂。乙醇对人血清白蛋白的影响 IGF-1及其受体阻止细胞凋亡的能力将被研究。 这些研究将扩展到乙醇对IGF-1介导的影响 神经胶质细胞在原代培养中的增殖和存活 已建立的神经胶质瘤细胞系。最后，IGF配体和IGF配体的表达 胎鼠中枢神经系统中的受体 喝醉了乙醇，就会被确定。结果将突出显示 乙醇干扰IGF系统的机制，以及 随之而来的是细胞增殖的中断和可能的CANS的发展， 并可能为更广泛地研究保护措施提供基础。

Alcoholism is associated with profound alterations in cell growth and proliferation. The most serious manifestation of disrupted cell growth is the fetal alcohol syndrome, although altered cell growth may also play a significant role in the development of anemia, cirrhosis, and the general catabolic state associated with alcoholism. The activation of insulin- like growth factor 1 (IGF-1) receptor by its ligands IGF-1 and IGF-2 plays a critical role in cellular proliferation and survival, and central nervous system development. It has been demonstrated that ethanol, at physiologically tolerated levels, markedly reduces the autophosphorylation of the IGF-1 receptor by its ligands, and effectively inhibits IGF-1- mediated cell proliferation and protection from apoptosis. It is now proposed to investigate the respective roles of the IGF-1 receptor and its ligands in the inhibition of cellular proliferation by ethanol. The model system of mouse fibroblasts will be used initially since these cells are exquisitely IGF-growth regulated, and offer the opportunity to genetically manipulate the cells to study the various functional components of the IGF signalling pathway. The in vitro effect of ethanol on IGF and IGF-1 receptor mRNA expression will be studied. The mechanism of ethanol action on the IGF-1 receptor will be analyzed in purified plasma membranes and purified IGF-1 receptor preparations. The effect of ethanol on the ability of IGF-1 and its receptor to prevent apoptosis will be studied. These studies will be extended to the effect of ethanol on IGF-1-mediated proliferation and survival of neuroglial cells in primary cultures and of established glioma cell lines. Lastly, the expression of IGF ligands and receptors in the central nervous system of fetal rats, chronically intoxicated with ethanol, will be determined. The results will highlight the mechanisms by which ethanol interferes with the IGF system, and the consequent disruption of cell proliferation and possibly CANS development, and may provide a basis for more extensive studies of protective measures.