The post-genomic research for the pathophysiology and treatment of alcohol and drug addictions.

我们以前的研究表明，家族史阳性的酒精中毒患者血细胞中cAMP信号发生了改变：1型腺苷酸环化酶（AC 1）、ACVIII和G_s α mRNA的定量减少。由于长期饮酒引起的细胞内Ca^<2+>信号的改变与cAMP信号一样受到关注，我们使用死后人脑和培养细胞研究了酒精对Ca^<2+>信号的影响。酒精中毒患者的Ca^2+结合蛋白膜联蛋白IV水平升高，酒精处理的A549细胞膜联蛋白IV水平升高。cAMP的下游信号分子cAMP反应元件结合蛋白（CREB）参与长时程增强和突触可塑性的调节，乙醇可能通过影响CREB诱导的基因转录，从而影响神经细胞的分化和发育。我们着重探讨了乙醇诱导细胞损伤的机制，并研究了神经营养素在其中的作用。 ...更多信息 hic因子对EtOH与神经母细胞瘤细胞（SH-SY 5 Y）作用的影响。乙醇对细胞的损伤呈剂量依赖性。乙醇处理后SH-SY 5 Y细胞CREB活性降低，受CREB调控的脑源性神经营养因子（BDNF）分泌减少。另一方面，NF-κB的转录活性被乙醇激活。提示CREB-BDNF通路受损和NE-κB活化减少参与了乙醇引起的神经元损伤和可塑性改变的机制。我们接下来研究了EtOH对神经干细胞（NSC）中神经元分化的影响。EtOH（20 - 100 mM）抑制神经元分化，而不影响存活率。IGF-1或BDNF的加入减弱了EtOH对NSC分化的抑制作用。因此，这表明，神经营养因子发挥重要作用，不仅在分化，而且还防御EtOH诱导的细胞损伤。少

We have previously demonstrated that the cellular cAMP-signaling is changed in blood cells in family-history positive alcoholic patients : quantitative reduction of type 1 adenylyl cyclase(AC1), ACVIII and G_<sα> mRNA. Since the cellular Ca^<2+> signaling alternation by the chronic alcohol consumption has been attended as well as cAMP signaling, we investigated the effect of alcohol on the Ca^<2+> signaling, using postmortem human brains and cultured cells. The Ca^<2+>-binding protein, annexinIV was increased in the alcoholic patients, and the level of annexinIV was increased in alcohol-treated A549 cells. The cellular downstream signaling molecule of cAMP,cAMP responsive element binding protein(CREB) helps to regulate long-term potentiation and synaptic plasticity, it is plausible that EtOH affects the CREB-induced gene transcriptions, which may affect neural differentiation/development. We focused on the mechanism of the EtOH induced cell damage and examined the role of the neurotrop … More hic factor on the effect of EtOH with neurobalstoma cells(SH-SY5Y). The cellular damage was induced by Ethanol treatment in dose-dependently. The CREB activity and the secretion of brain-derived neurotrophic factor(BDNF) which expression is regulated by CREB were both diminished in the ethanol treated SH-SY5Y cells. On the other hand, the transcriptional activity of NF-κB was activated by Ethanol. These are demonstrated that the decrased CREB-BDNF pathway impairment and NE-κB activation are involved in the mechanisms of Ethanol induced damage and neuronalplasticity change. We next investigated the effects of EtOH on neuronal differentiation in neural stem cells(NSCs). EtOH(20 to 100mM) inhibited neuronal differentiation, without affecting survival rate. The addition, of either IGF-1 or BDNF diminished inhibitory effect of EtOH on NSC differentiation. Thus, it is suggested that neurotrophic factors play important roles not only in differentiation but also defense from EtOH-induced cellular damage. Less