ETHANOL AND PHOSPHOINOSITIDES DURING BRAIN DEVELOPMENT

大脑发育过程中的乙醇和磷脂

• 批准号: 2000232
• 负责人: LUCIO G COSTA
• 金额: $ 18.59万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-09-27 至 2000-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2000232
• 关键词: acetylcholine; astrocytes; calcium flux; cell growth regulation; cell proliferation; cellular pathology; developmental genetics; developmental neurobiology; embryo /fetus toxicology; ethanol; fetal alcohol syndrome; gene induction /repression; laboratory rat; micrencephaly; mitogens; mixed tissue /cell culture; muscarinic receptor; neurotoxicology; phosphatidylinositols; phospholipase C; protein kinase C; receptor binding; regulatory gene; tissue /cell culture

DESCRIPTION: The profound and deleterious effects that ethanol exerts on the developing brain are well established, yet the mechanism(s) involved in its neurotoxic effects remain elusive. Receptors for neurotransmitters and growth factors and their cell signaling systems are increasingly recognized as playing relevant roles in various aspects o rain development. In the last few years we have pursued the hypothesis that the metabolism of phosphoinositides coupled to activation of acetylcholine muscarinic receptors may represent a relevant target for the developmental neurotoxicity of ethanol. Our studies have shown that ethanol exerts a dose-, age-, brain region- and neurotransmitter - specific inhibition of this biochemical response, and have demonstrated a strong correlation between disruption of muscarinic receptor - stimulated phosphoinositide metabolism during the brain growth spurt and long-lasting microencephaly. As proliferation of glial cells is a major event occurring during the in growth spurt, and following observations that acetylcholine can act as a mitogen in astrocytes, we have formulated the hypothesis that disruption of acetylcholine - driven glial cell proliferation may play a primary role in the developmental neurotoxicity of ethanol, and may provide a direct causal link between the observe inhibition of phosphoinositide metabolism and the ensuing microencephaly. The focus of the propose -experiments has shifted from investigations of the effects of ethanol in vivo or in vitro in brain slices or mixed cultures, to the study of its interactions with a selected glial cell population (astrocytes) in vitro. We believe that this shirt represents a logical progression toward a more comprehensive understanding of the sequence of event :hat may link our initial observations of the effects of ethanol on phosphoinositide metabolism to the observe neurotoxic endpoints, such as microencephaly. The specific aims of this proposal are: 1. To investigate selected signal transduction pathways involved in the mitogenic effect of acetylcholine in cultured cortical astrocytes. These will include the hydrolysis of phosphoinositides and phosphatidylcholine, mobilization of intracellular calcium, activation of protein kinase C and induction of immediate - early - genes. 2. To investigate the molecular pathways involved in the observed inhibition by ethanol of the mitogenic action of acetylcholine in astrocytes.

描述：乙醇对乙醇的深刻和有害影响 发育中的大脑已经建立了良好，但涉及的机制 它的神经毒性作用仍然难以捉摸。 神经递质的受体和 生长因子及其细胞信号系统越来越多地认识到 作为雨水开发的各个方面中的相关角色。 在 最近几年，我们提出了这样的假设 磷酸肌醇与乙酰胆碱毒蕈碱的激活结合 受体可能代表发育的相关目标 乙醇的神经毒性。 我们的研究表明，乙醇施加 剂量，年龄，大脑区域和神经递质 - 特异性抑制 这种生化反应，并表现出很强的相关性 毒蕈碱受体的破坏 - 刺激的磷酸肌醇 大脑生长过程中的代谢和持久的小脑。 由于神经胶质细胞的增殖是在IN期间发生的主要事件 生长突变，并在观察到乙酰胆碱可以充当 星形胶质细胞中有丝分裂原，我们提出了这样的假设 乙酰胆碱 - 驱动的神经胶质细胞增殖可能在 乙醇的发育神经毒性，可能会提供直接的因果关系 观察到磷酸肌醇代谢的抑制与 随之而来的微脑。 提议的重点发生了变化 从对乙醇在体内或大脑体外的作用的研究 切片或混合培养物，研究其与选定的相互作用 胶质细胞种群（星形胶质细胞）体外。 我们相信这件衬衫 代表了向更全面理解的逻辑发展 事件的顺序：帽子可能会链接我们对 乙醇对观察神经毒性的磷酸肌醇代谢的影响 终点，例如小脑。 该提案的具体目的是： 1。调查涉及的选定信号转导途径 乙酰胆碱在培养的皮质星形胶质细胞中的有丝分裂作用。 这些 将包括磷酸肌醇和磷脂酰胆碱的水解， 动员细胞内钙，蛋白激酶C和 诱导直接 - 早期基因。 2。研究分子 乙醇抑制有丝分裂的抑制作用涉及的途径 乙酰胆碱在星形胶质细胞中的作用。