ROLE OF OPIATES IN ALCOHOL-INDUCED NEUROTOXICITY

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。

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.