Neuromolecular consequences of adolescent binge drinking

青少年酗酒的神经分子后果

• 批准号: 10706623
• 负责人: Toni R. Pak
• 金额: $ 37.55万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10706623
• 关键词: Abstinence; Adolescence; Adolescent; Adult; Alcohol abuse; Alcohol consumption; Alcohols; Alternative Splicing; Amino Acid Receptors; Amino Acids; Animal Model; Animals; Anxiety; Behavior; Behavioral; Binding; Brain; Cell physiology; Cells; Cellular Stress; Corticosterone; Data; Disease; EMSA; Environment; Ethanol; Exposure to; Functional disorder; Funding; Genes; Genomics; Glucocorticoid Receptor; Glucocorticoids; Goals; Homeostasis; Immunoprecipitation; Inflammatory; Knowledge; Label; Life; Ligands; Link; Long-Term Effects; Major Depressive Disorder; Mass Spectrum Analysis; Measures; Mediating; Mediator; Mental disorders; Messenger RNA; Modeling; Modification; Molecular; Nervous System Trauma; Neurobiology; Neurons; Pattern; Phase; Phosphorylation; Physiological; Pituitary-Adrenal System; Post-Translational Protein Processing; Process; Proteins; Proteome; Proteomics; Publishing; RIPK1 gene; RNA; RNA Splicing; Receptor Signaling; Reporting; Research; Resistance; Signal Transduction; Stress; Structure; Testing; Time; Transcription Process; Transcription Repressor; Translation Process; United States Substance Abuse and Mental Health Services Administration; Variant; Youth; addiction; adolescent alcohol abuse; adolescent binge drinking; binge drinking; chromatin immunoprecipitation; cost; depressive symptoms; experimental study; glucocorticoid-induced orphan receptor; in vivo Model; inhibitor; new therapeutic target; novel; offspring; prevent; promoter; protein protein interaction; receptor; receptor function; transcription factor; transcriptome; university student

According to the CDC, “binge drinking is the most common, costly and deadliest pattern of alcohol use”. The adolescent period is marked by formative changes in neuronal structure and function; therefore, alcohol abuse during this vulnerable time period can result in permanent neurological damage and adult behavioral deficits. Our research and others from the past decade have described numerous long-lasting and transgenerational neurobiological consequences that can result from adolescent binge drinking. However, the molecular mechanism of how EtOH exerts immediate effects on the cellular microenvironment to perpetuate these long- term effects have not been fully ascertained. EtOH can readily enter cells and immediately activate the cellular stress response, which can then impact transcriptional and translational processes as well as post-translational modifications of existing proteins. We predict these immediate EtOH-induced effects on the cellular environment prime the cell to drive the long-term changes we and others have observed. This proposal is a competitive renewal and this next phase of the project will mechanistically define how EtOH induced modifications to the glucocorticoid receptor (GR), which then impacts long-term GR function. GRs sit at a pivotal interface to direct long-lasting changes in the cellular transcriptome and proteome, as they are the core molecular mediators of the systemic and cellular stress response. Our published and preliminary data suggest that these key mediators of cellular homeostasis are vulnerable to perturbations by EtOH, especially during adolescence. Aim 1 will determine by absolute quantification the amount of phosphorylated GR (pGR) in the brain using our in vivo model of adolescent repeated binge EtOH exposure and mechanistically link GR phosphorylation with long-term HPA axis dysfunction. In addition, we will investigate novel post-translational modifications to GR that are induced by adolescent binge EtOH exposure. Aim 2 will determine the suite of proteins interacting with pGR at specific target genes and identify how EtOH disrupts these GR-protein association. Aim 3 will investigate how EtOH induces alternative GR mRNA splicing and the mechanisms regulating splicing. Understanding these fundamental molecular changes could uncover novel therapeutic targets that may prevent dysregulated cellular signaling leading to behavioral abnormalities later in life.

根据CDC的说法，“酗酒是最常见，最昂贵和最致命的酒精使用模式”。的 青少年时期的特点是神经元结构和功能的形成性变化;因此，酒精滥用 在这个脆弱的时期，可能会导致永久性的神经损伤和成年人的行为缺陷。 我们的研究和过去十年的其他研究已经描述了许多长期和跨代的 青少年酗酒可能导致的神经生物学后果。然而，分子 EtOH如何对细胞微环境产生直接影响以使这些长期存在的机制， 长期影响尚未完全确定。乙醇可以很容易地进入细胞，并立即激活细胞内的 应激反应，然后可以影响转录和翻译过程以及翻译后 对现有蛋白质的改造。我们预测这些直接EtOH诱导的细胞效应， 环境使细胞准备好驱动我们和其他人观察到的长期变化。这项建议是一项 竞争性更新，该项目的下一阶段将机械地定义EtOH如何诱导 糖皮质激素受体（GR）的修饰，然后影响长期GR功能。GRs坐在 关键接口，以指导细胞转录组和蛋白质组的持久变化，因为它们是核心 系统和细胞应激反应的分子介质。我们公布的和初步的数据表明 这些细胞内稳态的关键介质容易受到EtOH的干扰，特别是在 青春期目的1将通过绝对定量来确定细胞中磷酸化GR（pGR）的量。 大脑使用我们的体内模型的青少年反复狂欢乙醇暴露和机械联系GR 磷酸化与长期HPA轴功能障碍。此外，我们将研究新的翻译后 对GR的改变是由青少年过量接触EtOH引起的。目标2将决定 在特定靶基因处与pGR相互作用的蛋白质，并鉴定EtOH如何破坏这些GR蛋白质 协会目的3探讨乙醇诱导GR mRNA选择性剪接的机制 调节剪接。了解这些基本的分子变化可以发现新的治疗方法 这些靶点可以防止细胞信号失调，导致以后生活中的行为异常。