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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

基本信息

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
项目类别：
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

项目摘要

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