ETHANOL EFFECT ON CELL PROLIFERATION

酒精中毒与细胞生长的深刻改变有关， 增殖 细胞生长中断的最严重表现是 胎儿酒精综合征，虽然改变细胞生长也可能发挥作用， 在贫血、肝硬化和一般疾病的发展中起着重要作用。 与酒精中毒有关的分解代谢状态。 胰岛素的激活- 类生长因子1（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发挥关键作用，并且是核心 神经系统发育 已经证明，乙醇， 生理耐受水平，显著降低自磷酸化 IGF-1受体的配体，并有效地抑制IGF-1- 介导的细胞增殖和保护免于凋亡。 现在 建议研究IGF-1受体及其受体的各自作用。 乙醇抑制细胞增殖的配体。 模型 最初将使用小鼠成纤维细胞系统，因为这些细胞 胰岛素样生长因子的生长受到精细的调控，并提供了机会， 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的体外影响 将研究受体mRNA表达。 乙醇的作用机制 将在纯化的质膜中分析IGF-1受体， 纯化的IGF-1受体制剂。 乙醇对 将研究IGF-1及其受体防止细胞凋亡的能力。 这些研究将扩展到乙醇对IGF-1介导的 原代培养物中神经胶质细胞的增殖和存活， 建立胶质瘤细胞系。 最后，IGF配体的表达和 受体在胎鼠中枢神经系统，慢性 酒精中毒，将被确定。 结果将突出显示 乙醇干扰IGF系统的机制，以及 从而破坏细胞增殖和可能的CANS发展， 并可能为更广泛的保护措施研究提供基础。

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.