ROLE OF OPIATES IN ALCOHOL INDUCED NEUROTOXICITY

描述：(改编自《调查者摘要》)胎儿暴露于 酒精会导致胎儿酒精综合症的发展，这是 以胎儿的各种形态和行为缺陷为特征 暴露在酒精中的后代。这些后代经常在压力下表现出异常 回应。最近的研究表明，压力反应有可能 FAE子代的异常与功能异常有关 下丘脑产生β-内啡肽(b-EP)的神经元。然而，没有 关于乙醇对β-内啡肽影响的充分信息 神经元的生长和分化。 目前的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 发育期酒精暴露可诱导程序化细胞 B-EP神经元死亡与cAMP和转化生长因子-β1 (转化生长因子-β1)可能参与控制乙醇所致的神经毒性。 该提案的具体目标是：1)确定乙醇的作用 B-EP神经元的生长和分化及其对脑损伤的影响 功能性b-EP神经元的发育，2)cAMP的作用 乙醇系统对b-EP神经元的神经毒性作用，3)评估 乙醇中转化生长因子-β对b-EP神经元的神经毒性作用，4)信号转导研究 乙醇对b-EP神经元的神经毒性作用机制。乙醇的作用 关于b-EP神经元的程序性细胞死亡的研究将在体内和 使用生化和免疫细胞化学技术进行体外培养。它的作用机制 乙醇对b-EP神经元的神经毒性作用将通过大鼠 胎儿下丘脑神经细胞培养系统。双管齐下的方法将是 应用于乙醇神经毒性作用机制的研究 从药理上操纵信号转导系统，另一种是 通过组织学方法测量这些信号转导分子的细胞内水平， 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.