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: 9169258
• 负责人: KAZUE HASHIMOTO-TORII
• 金额: $ 36.85万
• 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/9169258
• 关键词: Actins; 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; Foundations; Gene Expression; Gene Expression Alteration; Genes; Housekeeping Gene; Human; Immunoprecipitation; Length; Link; Messenger RNA; MicroRNAs; Modification; Molecular Chaperones; 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; Staging; System; Testing; Tissues; Up-Regulation; 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.

总结 酒精滥用最具破坏性的后果之一是对胎儿发育的致畸作用， 特别是在大脑的发育及其复杂回路的形成方面。这些永久 由酒精滥用引起的发育缺陷被称为胎儿酒精谱系障碍（FASD）。 最近的研究结果表明，胎儿酒精暴露的结果，广泛和适应性 发育中的大脑皮层内基因表达的改变。这种协调的基因表达变化 主要由高度特异性的转录因子和miRNAs调控。此外，最近关于萌芽的研究 酵母和果蝇已经证明，RNA结合蛋白协同调节转录后水平， 对特定类型的mRNA进行修饰以响应快速的环境变化。这种转录后 特定mRNA和RNA结合蛋白的调节复合物，称为RNA操纵子，被认为 在细胞对环境和疾病的适应中起着重要作用。然而，RNA操纵子的反应 哺乳动物大脑中的酒精暴露的结果仍然未知。 我们最近发现RNA结合蛋白Rbm 39在乙醇的刺激下表达上调， 暴露在人类和小鼠胚胎皮层中。我们的初步数据表明， Rbm 39在胚胎中保护神经前体细胞免于细胞死亡和细胞周期阻滞是必需的 暴露于乙醇的小鼠皮质。然而，Rbm 39表达的改变，无论是由于缺失还是获得， 功能，对正常皮质发育没有明显影响。这些结果表明Rbm 39 在酒精暴露中扮演着特殊的角色。此外，我们还发现Rbm 39调节了 特异性mRNA的转录后修饰是适应性细胞保护所必需的， 乙醇因此，我们假设Rbm 39通过RNA-1协调转录后修饰。 操纵子暴露于乙醇后，提供了一个立即和适应性系统，保护细胞内的细胞， 胚胎皮层我们将通过三个独立的目标来检验这一假设。 目的1：通过敲低Rbm 39在胚胎中的表达，明确Rbm 39在神经保护中的作用 暴露在乙醇中的皮质目的2将确定外源性增加Rbm 39对RNA的活性， 操纵子可以进一步减轻乙醇对脑的损伤。Aim 3将检查Rbm 39是否协调 响应于乙醇暴露的特定基因的即时转录后修饰。