Fetal Alcohol Exposure and Neurodevelopment

胎儿酒精暴露与神经发育

• 批准号: 6620919
• 负责人: Rajesh C Miranda
• 金额: $ 25.46万
• 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/6620919
• 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（由申请人提供）：怀孕期间大量饮酒 是颅面和中枢神经系统的主要可预防原因 出生缺陷。这些缺陷包括中面部发育不全， 小头畸形和脑组织质量损失。胎儿酒精暴露量是 特别是与智力低下、注意力不集中的重大风险有关 缺陷、多动症和其他精神健康障碍。酒精会诱发 通过抑制神经发生同时促进神经元发生来减少神经组织 死亡。然而，其根本机制尚不清楚。我们知道 关于酒精针对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之甚少 酒精对大脑的有害作用。因此，我们的中心假设 就是酒精抑制生存和神经发生信号，并且 发育中的大脑皮层中基因表达的相关模式。我们将 在神经发育的大脑皮层模型中检验我们的假设。我们 提出三个具体目标：（＃1）：确定酒精的程度 改变发育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自杀受体和抑制代偿性Akt相关存活 信号。此外，抑制 Fas/Apo-1 可以预防酒精诱发的 细胞凋亡。我们将在胚胎小鼠大脑皮层中测试这些假设 接触酒精的文化。 (#2)：识别神经 p53 相关遗传 受酒精调节的分化模式。 p53是关键 细胞内分化起始因子。基于我们的研究、我们的工作 假设酒精会改变 p53 的激活以防止 皮质中基因表达的分化相关模式。我们将使用 蛋白质免疫印迹分析检查 p53 激活和 cDNA 微阵列 分析以特异性识别受 p53 调控的 p53 相关基因 酒精。 (#3) 鉴定受以下因素调节的神经发生相关基因 酒精在大脑皮层。我们已经鉴定出神经发生相关基因 在胚胎大脑皮层模型中，使用差异杂交 策略。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 以及神经发生相关基因的诱导。会议结束时 拟议的研究，我们希望能够确定一些营养支持 酒精神经毒性的潜在机制。我们还希望能够识别出独特的 受酒精调节的神经发生和分化基因模式 在开发过程中。这些成果将意义重大，因为它们 有望为神经生物学分析提供基础 主要环境致畸剂针对的过程。