Mechanisms leading to cortical dysplasia in Fetal Alcohol Spectrum Disorders

6.项目摘要/摘要 酒精作为标准饮食的一部分，历史上在世界各地被广泛消费，而它的 滥用无疑会导致对人类生命的严重攻击。酒精滥用最具破坏性的后果是 对胎儿发育的致畸作用，这会导致称为胎儿酒精谱的永久性出生缺陷 精神障碍(FASD)。大脑复杂回路的发展特别容易受到酒精的影响，因此 酒精被列为增加自闭症等精神疾病易感性的主要产前风险因素之一 和精神分裂症。然而，将胎儿酒精暴露与酒精污染联系起来的致病机制 这些在生命后期出现的疾病并不被理解，主要是因为无法检测到受损的胎儿 神经细胞在疾病出现之前就表现出来。这项建议的首要目标是1)阐明关键信号 皮质畸形中的通路(S)，从而导致FASD的精神功能障碍和2)提供一种 酒精应激细胞早期检测的潜在方法。通过我们的基因芯片分析，我们已经获得了 初步数据表明，HSF1途径(一种应激反应途径)在两人中都被酒精强烈诱导 和小鼠胚胎皮质发育。我们已经产生了新的小鼠体内报告系统，可以检测到 激活这一途径，这样我们就可以观察酒精应激细胞在体内的行为。为了调查 HSF1在FASD皮质畸形中的潜在作用，我们将利用小鼠体内模型进行研究。 具体地说，在指导阶段，我建议识别因母亲饮酒而改变的关键基因 通过生物信息学分析。在独立阶段，我将1)观察其病理特点 使用荧光报告系统在胎儿酒精暴露下激活HSF1的细胞，以及2) 探讨HSF1在FASD病理性皮质发育中的作用。

6. Project Summary/Abstract Alcohol has been widely consumed historically around the world, as a component of the standard diet, while its misuse undoubtedly leads to a serious assault on human life. The most devastating effect of alcohol misuse is a teratogenetic action on fetal development, which causes the permanent birth defects called Fetal Alcohol Spectrum Disorder (FASD). The development of complex circuitry of the brain is particularly vulnerable to alcohol, and therefore alcohol is listed as one of major prenatal risk factors that increase susceptibility to mental illnesses, such as autism and schizophrenia. However, the pathogenetic mechanisms that make the link between fetal alcohol exposure and these disorders that appear later in life are not understood, mostly because it is not possible to detect damaged fetal nerve cells prior to the disease manifestation. The overriding aim of this proposal is 1) to elucidate critical signaling pathway(s) in cortical malformation, which subsequently leads to mental dysfunction in FASD and 2) to provide a potential method of early detection of alcohol-stressed cells. Through our microarray analysis, we have obtained preliminary data that the HSF1 pathway (a stress response pathway) is strongly induced by alcohol in both human and mouse fetal cortical development. We have generated novel mouse in vivo reporter systems that can detect activation of this pathway, so that we can observe the behavior of alcohol-stressed cells in vivo. In order to investigate potential roles of HSF1 in cortical malformation in FASD, we will conduct research using mouse in vivo model. Specifically, during in the mentored phase, I propose to identify critical genes altered by maternal alcohol intake through bioinformatics analysis. During the independent phase, I will 1) observe the pathological characteristics of the cells in which HSF1 is activated under fetal alcohol exposure using fluorescence reporter systems, and 2) investigate the potential role of HSF1 in pathological cortical development in FASD.