ROLE OF OPIATES IN ALCOHOL INDUCED NEUROTOXICITY

阿片类药物在酒精引起的神经毒性中的作用

• 批准号: 6044907
• 负责人: DIPAK KUMAR SARKAR
• 金额: $ 23.08万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-08-01 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6044907
• 关键词: adenylate cyclase; alcoholism /alcohol abuse; apoptosis; calcium channel; cyclic AMP; embryo /fetus tissue /cell culture; embryo /fetus toxicology; endorphins; ethanol; fetal alcohol syndrome; genetic transcription; hypothalamus; laboratory rat; messenger RNA; neurotoxicology; protein kinase C; transforming growth factors; western blottings

DESCRIPTION: (Adapted from the Investigator's Abstract) Exposure of a fetus to ethanol can lead to development of fetal alcohol syndrome, which is characterized by various morphological and behavioral deficits in fetal alcohol-exposed offspring. These offspring often show abnormalities in stress responses. Recent studies have revealed a possibility that the stress response anomalies seen in the FAE offspring are related to the functional abnormalities of hypothalamic beta-endorphin- (b-EP) producing neurons. However, there is not sufficient information available on the effect of ethanol on b-endorphin neuronal growth and differentiation. The present proposal will address this issue by studying the in vivo and in vitro effects of ethanol on beta-endorphin neuron growth and differentiation using rat as an animal model. The proposed research will test the hypotheses that ethanol exposure during the developmental period induces programmed cell death in b-EP neurons and that cAMP and transforming growth factor-beta1 (TGF-beta1) may be involved in controlling the ethanol-induced neurotoxicity. Specific objectives of this proposal are to: 1) determine the action of ethanol on b-EP neuronal growth and differentiation and the consequence on the development of the functional b-EP neurons, 2) identify the role of the cAMP system in ethanol neurotoxic action on b-EP neurons, 3) evaluate the role of TGF-beta in ethanol neurotoxic action on b-EP neurons, 4) study the signaling mechanisms of the ethanol neurotoxic action on b-EP neurons. Ethanol's action on programmed cell death in the b-EP neurons will be studied both in vivo and in vitro using biochemical and immunocytochemical techniques. The mechanism of ethanol's neurotoxic action on b-EP neurons will be determined using a rat fetal hypothalamic neuronal cell culture system. Two-pronged approaches will be applied to study the mechanisms of the ethanol neurotoxic action; one to pharmacologically manipulate the signal transduction systems, another to measure the intracellular level of these signal transducers by histological, biochemical and molecular techniques.

描述：（改编自研究者摘要）胎儿暴露于 酒精会导致胎儿酒精综合征的发展， 以胎儿的各种形态和行为缺陷为特征 酒精暴露的后代这些后代在压力下经常表现出异常 应答最近的研究表明压力反应 在FAE后代中看到的异常与功能异常有关 下丘脑β-内啡肽（b-EP）产生神经元。然而， 关于乙醇对b-内啡肽影响的现有充分资料 神经元的生长和分化。 本提案将通过研究体内和体内的 乙醇对β-内啡肽神经元生长和分化的影响 以大鼠为动物模型。拟议中的研究将检验这些假设 在发育期间暴露于乙醇会诱导程序化细胞 b-EP神经元死亡，cAMP和转化生长因子β 1 （TGF-β 1）可能参与控制乙醇诱导的神经毒性。 本提案的具体目标是：1）确定乙醇的作用 对b-EP神经元生长和分化的影响以及对 功能性b-EP神经元的发育，2）确定cAMP的作用 系统在乙醇对b-EP神经元的神经毒性作用中的作用，3）评估 TGF-β参与乙醇对b-EP神经元的神经毒性作用; 4）研究TGF-β对b-EP神经元的信号转导 乙醇对b-EP神经元的神经毒性作用机制。乙醇作用 对b-EP神经元中程序性细胞死亡的影响将在体内和 在体外使用生物化学和免疫细胞化学技术。的机理 乙醇对b-EP神经元的神经毒性作用将使用大鼠 胎儿下丘脑神经元细胞培养系统。双管齐下的方法将是 应用于研究乙醇神经毒性作用的机制;一个， 操纵信号转导系统，另一个是 通过组织学测量这些信号转导子的细胞内水平， 生物化学和分子技术。