RNA biomarkers for alcohol use disorder

下一代测序和其他组学技术已经刺激了精密技术的发展 医学，但这一领域仍处于酒精使用障碍(AUD)的初级阶段。转录学研究已经 证实饮酒会导致大脑基因表达的广泛变化。脑基因表达 配置文件可以识别酒精依赖的受试者和小鼠，并可用于重新定位 减少啮齿动物过度饮酒的药物。然而，不可能获得 活体病人的大脑样本，这限制了这种方法的翻译潜力。常规血液 长期以来，检测一直是医疗保健的一部分。血液基因组图谱可能被用于非侵入性 确定患者是否有AUD的风险，提供AUD的数据驱动诊断，分层 用于临床试验的不同的AUD患者群体，选择最佳治疗方法，并监测治疗 反应和疾病进展。作为迈向这些目标的第一步，弗格森博士分析了基因表达 慢性间歇性乙醇(CIE)暴露小鼠的血液和脑样本配对模式， 酒精依赖的小鼠模型。CIE的血液基因表达特征预测一种药物 这减少了小鼠的饮酒量，根据血液特征建立的预测模型区分了 CIE和暴露在空气中的小鼠具有很高的准确性。这些结果导致了一种假设，即血液可以作为 脑组织在基于分子的诊断或治疗工具和先进的个性化医学中的替代品 澳元的方法。然而，目前尚不清楚AUD的血液中是否存在AUD的生物学特征 人类人口。此外，需要生物标志物来预测和监测治疗成功和它 目前尚不清楚血液基因表达谱在这方面是否有用。CIE的血液签名 在之前的研究中使用的只在单个时间点检测转录组。因此，动态或 重要基因调控功能的持续转变并未被研究。这些知识上的差距将 在建议的目标中，通过分析酒精过程中多个时间点的血液特征(1)来解决 在人类中戒断(目标1)，(2)通过CIE诱导的酒精发展而跨越多个时间点 小鼠的依赖性(目标2)，以及(3)人类和小鼠的治疗前后(目标3)。最重要的是 假设血液中的基因组图谱将改善AUD的临床治疗，包括 诊断、预后和预测治疗反应。这些目标和相应的培训计划 旨在以弗格森博士以前的研究经验为基础，促进新的科学培训 临床酒精研究和纵向数据、事件发生时间结果数据的生物统计分析 治疗效果评价。拟议的独立之路奖将产生新的知识 关于酒精研究中一个相对未被研究的领域，并使弗格森博士能够建立一个坚实的框架 作为酒精领域的学术翻译神经学家，建立了一个成功的研究项目。

Next generation sequencing and other -omics technologies have spurred the development of precision medicine, but this field is still in its infancy for alcohol use disorder (AUD). Transcriptomic studies have established that alcohol use causes widespread changes in brain gene expression. Brain gene expression profiles can identify alcohol-dependent human subjects and mice and can be used to repurpose pharmaceuticals that reduce excessive alcohol consumption in rodents. However, it is not possible to obtain brain samples from living patients, which limits the translational potential of this approach. Routine blood testing has long been a part of medical care. Blood genomic profiles could potentially be used to non-invasively determine whether a patient is at risk for AUD, provide data-driven diagnosis of AUD, stratify the heterogeneous AUD patient population for clinical trials, select optimal therapy, and monitor treatment response and disease progression. As a first step toward these goals, Dr. Ferguson analyzed gene expression patterns in paired blood and brain samples from mice subjected to chronic intermittent ethanol (CIE) exposure, a mouse model of alcohol dependence. Blood gene expression signatures of CIE predicted a pharmaceutical that reduced alcohol drinking in mice, and predictive models built from blood profiles distinguished between CIE and air-exposed mice with high accuracy. These results lead to the hypothesis that blood can serve as a proxy for brain tissue in molecular-based diagnostic or therapeutic tools and advance personalized medicine approaches for AUD. However, it is not known whether there is a biological signature of AUD in blood from a human population. Furthermore, there is a need for biomarkers to predict and monitor treatment success and it is unknown whether blood gene expression profiles might be useful in this regard. The CIE blood signature used in the previous study assayed the transcriptome only at a single time point. Therefore, the dynamics or ongoing transition of important gene regulatory functions were not investigated. These gaps in knowledge will be addressed in proposed Aims by analyzing blood profiles (1) across multiple time points throughout alcohol withdrawal in humans (Aim 1), (2) across multiple time points through the development of CIE-induced alcohol dependence in mice (Aim 2), and (3) before and after treatment in humans and mice (Aim 3). The overarching hypothesis is that genomic profiles from blood will improve the clinical management of AUD including diagnosis, prognosis, and predicting treatment response. These Aims and the accompanying training plan were designed to build on Dr. Ferguson’s previous research experiences and facilitate new scientific training in clinical alcohol research and biostatistical analyses of longitudinal data, time-to-event outcome data, and treatment effect estimation. The proposed Pathway to Independence Award will generate new knowledge about a relatively unstudied area in alcohol research and enable Dr. Ferguson to establish a solid framework for building a successful research program as an academic translational neuroscientist in the alcohol field.