Mechanisms leading to cortical dysplasia in Fetal Alcohol Spectrum Disorders

导致胎儿酒精谱系障碍皮质发育不良的机制

• 批准号: 8481897
• 负责人: KAZUE HASHIMOTO-TORII
• 金额: $ 22.83万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8481897
• 关键词: Achievement; Adult; Alcohol consumption; Alcoholic Intoxication; Alcohols; Autistic Disorder; Bioinformatics; Brain; Brain Injuries; Candidate Disease Gene; Cells; Cellular Stress; Cerebral cortex; Characteristics; Cognitive; Complex; Congenital Abnormality; Cortical Dysplasia; Cortical Malformation; Data; Defect; Development; Diet; Disease; Early Diagnosis; Electroporation; Embryonic Development; Experimental Designs; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; Fetal Development; Fluorescence; Functional disorder; Gene Expression; Genes; Goals; HSF1; Human; In Situ Hybridization; In Vitro; Intervention; Knockout Mice; Knowledge; Life; Link; Mental Retardation; Mental disorders; Mentors; Methods; Microarray Analysis; Molecular; Mus; Neurons; Pathway interactions; Patients; Phase; Phenotype; Predisposition; Pregnancy; Prevalence; Process; Psyche structure; RNA Interference; Reporter; Research; Role; Schizophrenia; Screening procedure; Series; Signal Pathway; Staging; System; Therapeutic; Transgenic Organisms; abstracting; alcohol behavior; alcohol exposure; alcohol misuse; assault; base; biological adaptation to stress; disability; fetal; in utero; in vivo; in vivo Model; migration; novel; postnatal; prenatal risk factor; red fluorescent protein

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.

6.项目总结/摘要 作为标准饮食的一部分，酒精在历史上在世界各地被广泛消费， 滥用无疑会严重危害人的生命。酒精滥用最具破坏性的影响是 对胎儿发育的致畸作用，导致称为胎儿酒精谱的永久性出生缺陷 疾病（FASD）。大脑复杂回路的发育特别容易受到酒精的影响，因此， 酒精被列为产前主要风险因素之一，增加了对自闭症等精神疾病的易感性 和精神分裂症然而，使胎儿酒精暴露与胎儿酒精暴露之间联系的发病机制， 这些在生命后期出现的疾病尚不清楚，主要是因为不可能检测出受损的胎儿。 在疾病出现之前，神经细胞。本提案的首要目标是：1）阐明关键信号 皮质畸形中的通路，其随后导致FASD中的精神功能障碍，以及2）提供 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 初步数据表明，HSF 1途径（一种应激反应途径）在两种人类中均被酒精强烈诱导。 和小鼠胎儿皮质发育。我们已经产生了新的小鼠体内报告系统，可以检测 激活这一通路，以便我们可以观察体内酒精应激细胞的行为。为了研究 HSF 1在FASD皮质畸形中的潜在作用，我们将使用小鼠体内模型进行研究。 具体来说，在指导阶段，我建议确定母亲饮酒改变的关键基因 通过生物信息学分析。在独立阶段，我将1）观察 使用荧光报告系统，其中HSF 1在胎儿酒精暴露下被激活的细胞，和2） 研究HSF 1在FASD病理性皮质发育中的潜在作用。