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

我们先前已经证明，在家族史阳性的酒精中毒患者中，血细胞中的cAMP信号发生了变化：1型腺酰环化酶(AC1)、ACVIII和G&lt；Sα&gt；mR-NA的数量减少。鉴于慢性饮酒引起的细胞内Ca~(2+)-gt；信号的改变以及cAMP信号的变化，我们利用死后人脑和培养的细胞，研究了酒精对细胞内Ca~(2+)&gt；信号的影响。酒精组A549细胞内钙离子结合蛋白AnnexinIV水平升高，A549细胞内AnnexinIV水平升高。细胞下游信号分子cAMP，cAMP反应元件结合蛋白(CREB)有助于调节长时程增强和突触可塑性，EtoH可能影响CREB诱导的基因转录，从而影响神经的分化和发育。我们重点研究了乙醇引起细胞损伤的机制，并研究了神经营养因子…的作用乙醇对神经肉瘤细胞(SH-SY5Y)作用的HIC因子增多。乙醇诱导的细胞损伤呈剂量依赖性。在乙醇处理的SH-SY5Y细胞中，CREB活性和受CREB调控的脑源性神经营养因子(BDNF)的分泌均降低。另一方面，乙醇可激活核转录因子κB的转录活性。提示CREB-BDNF通路损伤和NE-κB激活参与了乙醇损伤和神经元可塑性改变的机制。接下来，我们研究了乙醇对神经干细胞(NSCs)分化的影响。乙醇(20~100 mM)可抑制神经元分化，但不影响存活率。加入IGF-1或BDNF均可减弱乙醇对神经干细胞分化的抑制作用。因此，神经营养因子不仅在分化过程中起重要作用，而且在防御乙醇诱导的细胞损伤中发挥重要作用。较少

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