Neuromolecular consequences of adolescent binge drinking

美国疾病控制与预防中心表示，“酗酒是最常见、最昂贵、最致命的饮酒方式”。这个 青春期是以神经元结构和功能的形成性变化为标志的；因此，酗酒 在这段脆弱的时间内，会导致永久性的神经损伤和成人行为缺陷。 我们的研究和过去十年的其他研究描述了许多持久的和跨代的 青少年酗酒可能导致的神经生物学后果。然而，分子 乙醇如何对细胞微环境产生直接影响以使这些长期持续的微环境永久化的机制 期限效应尚未完全确定。乙醇可以轻易地进入细胞并立即激活细胞 应激反应，这会影响转录和翻译过程以及翻译后 对现有蛋白质的修饰。我们预测乙醇对细胞的这些直接影响 环境使细胞启动，以驱动我们和其他人观察到的长期变化。这项建议是一项 竞争性更新和该项目的下一阶段将机械地定义Etoh如何导致 糖皮质激素受体(GR)的修饰，从而影响GR的长期功能。GRS坐在一个 引导细胞转录组和蛋白质组发生长期变化的关键界面，因为它们是核心 系统和细胞应激反应的分子介体。我们公布的和初步的数据表明 这些细胞内稳态的关键调节因子很容易受到乙醇的干扰，特别是在 青春期。目标1将以绝对定量的方式确定在 利用我们的青少年反复暴饮性酒精暴露与GR机械联系的体内模型的脑 磷酸化与长期的HPA轴功能障碍。此外，我们还将研究小说的后翻译 由青少年暴饮暴食乙醇引起的GR修饰。目标2将确定 在特定的靶基因上与PGR相互作用的蛋白质，并确定乙醇如何破坏这些GR蛋白 协会。目标3将研究乙醇如何诱导选择性GR mRNA剪接及其机制 规范剪接。了解这些基本的分子变化可能会发现新的治疗方法 可以防止细胞信号失控导致晚年行为异常的靶点。

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.