The roles of alcohol-inducible RNA-operons in the fetal brain

酒精诱导的 RNA 操纵子在胎儿大脑中的作用

• 批准号: 9753070
• 负责人: KAZUE HASHIMOTO-TORII
• 金额: $ 34.49万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9753070
• 关键词: Adult; Adverse effects; Alcohols; Area; Biological Process; Brain; Brain Injuries; Cell Cycle; Cell Cycle Arrest; Cell Death; Cells; Cerebral cortex; Communities; Complex; Congenital Abnormality; Data; Development; Disease; Drosophila genus; Electroporation; Embryo; Environment; Ethanol; Event; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; Fetal Development; Fetal alcohol effects; Foundations; Gene Expression; Gene Expression Alteration; Genes; Genetic Transcription; Housekeeping Gene; Human; Immunoprecipitation; Length; Link; Messenger RNA; MicroRNAs; Modification; Molecular; Morphogenesis; Mus; Names; Neurons; Operon; Oral Administration; Play; Post-Transcriptional Regulation; RNA; RNA Recognition Motif; RNA Splicing; RNA-Binding Proteins; Regimen; Regulation; Research; Role; Saccharomycetales; Specific qualifier value; System; Teratogenic effects; Testing; Tissues; Up-Regulation; alcohol consequences; alcohol effect; alcohol exposure; alcohol misuse; alcohol research; alcohol response; cell injury; design; environmental change; fetal; gain of function; genome-wide; in utero; in vivo; innovation; knock-down; migration; mutant; nerve stem cell; novel; novel strategies; overexpression; prenatal; prevent; relating to nervous system; response; small hairpin RNA; transcription factor; transcriptome sequencing

Summary One of the most devastating consequences of alcohol misuse is its teratogenic effects on fetal development, particularly in the development of the brain and the formation of its complex circuitry. These permanent developmental deficits caused by alcohol misuse are referred to as Fetal Alcohol Spectrum Disorder (FASD). Recent findings have demonstrated that fetal alcohol exposure results in wide-ranging and adaptive alterations of gene expression within the developing cerebral cortex. Such coordinated gene expression changes are regulated mainly by highly specified transcription factors and miRNAs. In addition, recent studies on budding yeast and fruit fly have demonstrated that RNA binding proteins coordinately regulate the post-transcriptional modification of specific types of mRNAs in response to rapid environmental changes. This post-transcriptional regulatory complex of specific mRNAs and RNA binding proteins, known as RNA-operons, are suggested to have important roles in cellular adaptation to environment and diseases. However, the response of RNA-operons as a result of alcohol exposure within the mammalian brain remains unknown. We have recently found that the RNA binding protein, Rbm39, is upregulated in response to ethanol exposure in both the human and mouse embryonic cortex. Our preliminary data suggests that the upregulation of Rbm39 is required for protecting neural progenitor cells from both cell death and cell cycle arrest in embryonic mouse cortices exposed to ethanol. However, alterations in Rbm39 expression, whether due to loss- or gain-of- function, do not show obvious effects on normal cortical development. These results suggest that the Rbm39 plays specific roles resulting from ethanol exposure. In addition, we have found that the Rbm39 regulates the post-transcriptional modifications of specific mRNAs that are required for adaptive cellular protection from ethanol. Therefore, we hypothesize that the Rbm39 coordinates post-transcriptional modification through RNA- operons after exposure to ethanol, providing an immediate and adaptive system in protecting cells within the embryonic cortex. We will examine this hypothesis through three discrete aims. Aim 1 will define the requirement of Rbm39 for neural protection by knocking down Rbm39 in embryonic cortices exposed to ethanol. Aim 2 will determine whether exogenous increased of Rbm39 activity on RNA- operons can further reduce the brain damages by ethanol. Aim3 will examine whether Rbm39 orchestrates immediate post-transcriptional modification of specific genes in response to ethanol exposure.

概括 滥用酒精的最毁灭性后果之一是其对胎儿发育的致力作用， 特别是在大脑的发展及其复杂电路的形成中。这些永久 滥用酒精引起的发育缺陷称为胎儿酒精谱系障碍（FASD）。 最近的发现表明，胎儿酒精暴露会导致广泛和自适应 在发育中的大脑皮层中基因表达的改变。这种协调的基因表达变化 主要由高度指定的转录因子和miRNA调节。此外，关于萌芽的最新研究 酵母菌和果蝇证明RNA结合蛋白协同调节转录后 修改特定类型的mRNA，以响应快速的环境变化。此后转录 建议特异性mRNA和RNA结合蛋白（称为RNA-Operons）的调节复合物。 在适应环境和疾病的细胞适应中具有重要作用。但是，RNA-Operons的响应 由于哺乳动物大脑内的酒精暴露是未知的。 我们最近发现，RNA结合蛋白RBM39响应于乙醇而被上调 人类和小鼠胚胎皮质的暴露。我们的初步数据表明上调 保护神经祖细胞免受细胞死亡和细胞周期停滞在胚胎中所必需的RBM39是必需的 小鼠皮质暴露于乙醇。但是，无论是由于损失还是获取，RBM39表达的改变 功能，不要对正常皮质发育显示明显的影响。这些结果表明RBM39 扮演乙醇暴露引起的特定角色。此外，我们发现RBM39调节 自适应细胞保护所需的特定mRNA的转录后修饰 乙醇。因此，我们假设RBM39在转录后通过RNA-坐标 暴露于乙醇后的操纵子，为保护细胞的细胞提供了直接和自适应系统 胚胎皮质。我们将通过三个离散目的来检验这一假设。 AIM 1将通过在Embryonic中击倒RBM39来定义RBM39对神经保护的需求 皮质暴露于乙醇。 AIM 2将确定RBM39活性在RNA-的活性中是否增加 操纵子可以进一步减少乙醇的大脑损害。 AIM3将检查RBM39是否编排 响应于乙醇暴露的特定基因的立即转录后修饰。