Mechanisms leading to cortical dysplasia in Fetal Alcohol Spectrum Disorders

描述（由申请人提供）：作为标准饮食的组成部分，酒在世界各地历史上被广泛消费，而它的滥用无疑会导致对人类生命的严重侵犯。酒精滥用最具破坏性的影响是对胎儿发育的致畸作用，这会导致被称为胎儿酒精谱系障碍（FASD）的永久性出生缺陷。大脑复杂回路的发育特别容易受到酒精的影响，因此酒精被列为增加患自闭症和精神分裂症等精神疾病易感性的主要产前风险因素之一。然而，胎儿酒精暴露与晚年出现的这些疾病之间联系的发病机制尚不清楚，主要是因为在疾病表现之前不可能检测到受损的胎儿神经细胞。本研究的主要目的是：1)阐明导致FASD患者精神功能障碍的皮质畸形的关键信号通路；2)提供一种早期检测酒精应激细胞的潜在方法。通过我们的微阵列分析，我们获得了初步的数据，即HSF1通路（应激反应通路）在人和小鼠胎儿皮质发育中都受到酒精的强烈诱导。我们已经产生了新的小鼠体内报告系统，可以检测这一途径的激活，因此我们可以观察体内酒精应激细胞的行为。为了探讨HSF1在FASD皮层畸形中的潜在作用，我们将采用小鼠体内模型进行研究。具体来说，在指导阶段，我建议通过生物信息学分析来确定母亲饮酒改变的关键基因。在独立阶段，我将1)利用荧光报告系统观察胎儿酒精暴露下HSF1激活细胞的病理特征，2)研究HSF1在FASD病理性皮质发育中的潜在作用。

DESCRIPTION (provided by applicant): 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 teratogenic 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. PUBLIC HEALTH RELEVANCE: Although FASD is the most preventable cause of cognitive disability, its prevalence is estimated to be very high in US. The proposed study will advance our ability for early detection of neuronal damage and our knowledge of underlying molecular mechanisms. Thus it opens the possibility of intervention in the latent period of the patients who are destined to develop mental retardation at later stages in postnatal/adult life.