Fetal Alcohol Exposure and Neurodevelopment

胎儿酒精暴露与神经发育

• 批准号: 6423577
• 负责人: Rajesh C Miranda
• 金额: $ 25.24万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-03-01 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6423577
• 关键词: CD95 molecule; alcohols; apoptosis; biological signal transduction; cell differentiation; cell migration; cell proliferation; cerebral cortex; developmental neurobiology; embryo /fetus toxicology; gene expression; laboratory mouse; microarray technology; neurogenesis; neurotoxicology; p53 gene /protein; phosphorylation; tissue /cell culture; western blottings

DESCRIPTION (provided by applicant): Heavy alcohol consumption during pregnancy is the leading preventable cause of craniofacial and central nervous system birth defects. These defects include hypodevelopment of the mid-face, microcephaly, and loss of brain tissue mass. Fetal alcohol exposure is especially linked to a significant risk for mental retardation, attention deficits, hyperactivity and other mental health disorders. Alcohol induces a loss of neural tissue by inhibiting neurogenesis while promoting neuronal death. However, the underlying mechanisms are not well understood. We know little about the neurotrophic mechanisms that are targeted by alcohol. We also know little about the gene transcription gestalt that is associated with the deleterious actions of alcohol on the brain. Therefore, our central hypothesis is that is that alcohol suppresses survival and neurogenesis signals, and related patterns of gene expression in the developing cerebral cortex. We will test our hypothesis in cerebral cortical models of neural development. We propose three specific aims: (#1): To identify the extent to which alcohol alters the balance between developmental cell-suicide and survival mechanisms. Our working hypotheses are that alcohol will increase activation of Fas/Apo [apoptosis]-1 suicide receptor and repress compensatory Akt-related survival signals. Furthermore, inhibition of Fas/Apo-1 will prevent alcohol-induced apoptosis. We will test these hypotheses in embryonic mouse cerebral cortical cultures exposed to alcohol. (#2): To identify neural p53-associated genetic differentiation patterns that are regulated by alcohol. p53 is a key intracellular initiator of differentiation. Based on our studies, our working hypothesis is that alcohol alters p53 activation to prevent differentiation-related patterns of gene expression in the cortex. We will use western immunoblot analyses to examine p53 activation, and cDNA microarray analyses to specifically identify p53-associated genes that are regulated by alcohol. (#3) To identify neurogenesis-related genes that are regulated by alcohol in the cerebral cortex. We have identified neurogenesis-related genes in an embryonic cerebral cortical model, using differential hybridization strategies. Based on our data, our working hypothesis is that alcohol will suppress expression of proliferation-associated genes in embryonic cortex. We will use cDNA microarrays to identify relationships between alcohol exposure and induction of genes related to neurogenesis. At the conclusion of the proposed research, we expect to have identified some of the trophic support mechanisms underlying alcohol neurotoxicity. We also expect to identify unique neurogenesis and differentiation gene patterns that are regulated by alcohol during development. These outcomes will be significant because they are expected to provide the foundations for an analysis of neurobiological processes targeted by a leading environmental teratogen.

描述(申请人提供)：怀孕期间大量饮酒 是导致头面部和中枢神经系统疾病的主要可预防原因 先天缺陷。这些缺陷包括面部中部发育不足， 小头畸形和脑组织质量丧失。胎儿酒精暴露是 尤其是与精神发育迟缓的重大风险有关，注意力 缺陷、多动症和其他精神健康障碍。酒精诱导了一种 在促进神经元的同时抑制神经发生而造成神经组织的损失 死亡。然而，潜在的机制还没有被很好地理解。我们知道 对酒精靶向的神经营养机制知之甚少。我们也 对与基因转录格式塔相关的知识知之甚少 酒精对大脑的有害行为。因此，我们的中心假设 那就是酒精抑制了生存和神经发生信号，而且 发育中大脑皮层基因表达的相关模式。我们会 在大脑皮层神经发育模型中测试我们的假设。我们 提出三个具体目标：(#1)确定酒精在多大程度上 改变发育中的细胞自杀和生存机制之间的平衡。 我们的工作假设是酒精会增加Fas/Apo的激活 [细胞凋亡]-1自杀受体与抑制Akt相关的代偿性生存 信号。此外，抑制Fas/Apo-1将阻止酒精诱导 细胞凋亡。我们将在胚胎小鼠大脑皮层测试这些假说。 暴露在酒精中的文化。(#2)：确定神经性P53相关基因 受酒精调控的分化模式。P53是一把钥匙 细胞内分化的起始者。根据我们的研究，我们的工作 假说是酒精改变了P53的激活以防止 皮质中与分化相关的基因表达模式。我们将使用 免疫印迹分析检测P53活性和基因芯片 分析以特定识别P53相关基因，由 酒精。(#3)确定神经发生相关基因受 大脑皮层中的酒精。我们已经确定了与神经发生相关的基因 在胚胎大脑皮层模型中，使用差异杂交 战略。根据我们的数据，我们的工作假设是酒精会 抑制胚胎皮质中增殖相关基因的表达。我们 将使用cDNA微阵列来识别酒精暴露之间的关系 和诱导与神经发生相关的基因。在结束时， 拟议的研究，我们预计已经确定了一些营养支持 酒精神经毒性的潜在机制。我们还希望识别独特的 酒精调控的神经发生和分化基因模式 在开发过程中。这些结果将是重要的，因为它们是 有望为神经生物学的分析提供基础 被一位领先的环境畸形者瞄准的过程。