RNA biomarkers for alcohol use disorder

下一代测序和其他组学技术促进了精确测序的发展。 医学，但这一领域仍处于起步阶段的酒精使用障碍（AUD）。转录组学研究 酒精使用导致大脑基因表达的广泛变化。脑基因表达 可以识别酒精依赖的人类受试者和小鼠， 减少啮齿动物过量饮酒的药物。但是，无法获得 这限制了这种方法的转化潜力。常规血液 长期以来，测试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地 确定患者是否存在AUD风险，提供AUD的数据驱动诊断， 用于临床试验的异质性AUD患者人群，选择最佳治疗并监测治疗 反应和疾病进展。作为实现这些目标的第一步，弗格森博士分析了基因表达， 来自经受慢性间歇性乙醇（CIE）暴露的小鼠的成对血液和脑样品中的模式， 酒精依赖的小鼠模型。CIE的血液基因表达特征预测药物 减少了小鼠的饮酒量，并根据血液特征建立了预测模型， CIE和空气暴露小鼠的准确性很高。这些结果导致了这样的假设，即血液可以作为 脑组织在分子诊断或治疗工具中的替代物以及先进的个性化医疗 接近AUD。然而，目前尚不清楚是否有一个生物签名的AUD血液从一个 人口。此外，还需要生物标志物来预测和监测治疗成功， 目前尚不清楚血液基因表达谱在这方面是否有用。CIE的血液特征 在先前的研究中使用的方法仅在单个时间点测定转录组。因此，动力学或 没有研究重要基因调节功能的持续转变。这些知识差距将 通过分析整个酒精过程中多个时间点的血液特征（1），在拟定的目标中得到解决 人类戒断（目标1），（2）通过CIE诱导的酒精发展在多个时间点 在小鼠中的依赖性（目的2），和（3）在人类和小鼠中的治疗之前和之后（目的3）。总体 假设来自血液的基因组谱将改善AUD的临床管理，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 旨在建立在弗格森博士以前的研究经验，并促进新的科学培训， 临床酒精研究和纵向数据的生物统计学分析，事件发生时间结局数据，以及 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研究的领域，并使弗格森博士建立了一个坚实的框架， 作为酒精领域的学术翻译神经科学家，他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.