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: 8037202
• 负责人: KAZUE HASHIMOTO-TORII
• 金额: $ 8.97万
• 依托单位: YALE UNIVERSITY
• 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 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8037202
• 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; 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; public health relevance; red fluorescent protein

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.

描述（由申请人提供）：酒精作为标准饮食的一部分，在世界各地历史上被广泛消费，而其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。大脑复杂回路的发展特别容易受到酒精的影响，因此酒精被列为增加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，使胎儿酒精暴露和这些疾病之间的联系，在以后的生活中出现的发病机制还不清楚，主要是因为它是不可能检测到受损的胎儿神经细胞之前的疾病表现。该建议的首要目的是1）阐明皮质畸形中的关键信号通路，其随后导致FASD中的精神功能障碍; 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，我们已经获得了初步的数据，HSF 1途径（应激反应途径）是强烈诱导酒精在人类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，可以检测这一途径的激活，使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。具体而言，在指导阶段，我建议通过生物信息学分析确定母亲酒精摄入量改变的关键基因。在独立期，我将1）使用荧光报告系统观察胎儿酒精暴露下HSF 1被激活的细胞的病理特征，2）研究HSF 1在FASD病理皮质发育中的潜在作用。 公共卫生相关性：尽管FASD是认知障碍最可预防的原因，但据估计其在美国的患病率非常高。这项研究将提高我们早期检测神经元损伤的能力和我们对潜在分子机制的了解。因此，它开辟了在出生后/成人生活后期阶段注定发展为智力迟钝的患者的潜伏期进行干预的可能性。