RNA biomarkers for alcohol use disorder

酒精使用障碍的 RNA 生物标志物

• 批准号: 10808532
• 负责人: Laura Brockway Ferguson
• 金额: $ 13.55万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-20 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10808532
• 关键词: Address; Aftercare; Air; Alcohol consumption; Alcohol dependence; Alcohol withdrawal syndrome; Alcohols; Area; Award; Behavior assessment; Biological; Biological Assay; Biological Markers; Biometry; Blood; Blood Tests; Blood specimen; Brain; Caring; Chronic; Classification; Clinical; Clinical Management; Clinical Trials; Clinical assessments; Data; Development; Diagnosis; Diagnostic; Digoxin; Disease Management; Disease Progression; Drug Prescriptions; Escalator; Ethanol; Ethics; Event; Experimental Designs; Exposure to; Foundations; Future; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Genes; Genetic Transcription; Goals; Health Personnel; Heavy Drinking; Heterogeneity; Human; Individual; Institutional Review Boards; Joints; Knowledge; Medical; Messenger RNA; Methods; Modeling; Molecular; Monitor; Mus; Naltrexone; Observational Study; Outcome; Pathway interactions; Patient Monitoring; Patients; Pharmacologic Substance; Pharmacotherapy; Physicians; Population; Prediction of Response to Therapy; Process; Prognosis; Proxy; Publishing; RNA; Regulator Genes; Research; Risk; Rodent; Sampling; Screening procedure; Selection for Treatments; Solid; Specimen; Techniques; Technology; Testing; Therapeutic; Time; Training; Withdrawal; Work; alcohol availability; alcohol exposure; alcohol research; alcohol risk; alcohol seeking behavior; alcohol use disorder; brain tissue; design; differential expression; drinking; experience; experimental analysis; experimental study; forest; genomic profiles; human subject; improved; infancy; insight; longitudinal analysis; minimally invasive; model building; molecular marker; mouse model; next generation sequencing; optimal treatments; patient population; patient stratification; personalized medicine; potential biomarker; precision medicine; predicting response; predictive marker; predictive modeling; programs; prospective; protocol development; recruit; responders and non-responders; response; risk prediction; statistics; success; tool; transcriptome; transcriptome sequencing; transcriptomics; translational potential; treatment effect; treatment response; vapor

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.

下一代测序和其他 - 组技术已经刺激了精度的发展 药物，但该领域仍处于酒精使用障碍（AUD）的起步阶段。转录组研究已有 确定饮酒会导致脑基因表达的宽度变化。脑基因表达 概况可以识别依赖酒精的人类受试者和小鼠，可用于改革 减少啮齿动物过量饮酒的药物。但是，不可能获得 来自活着患者的大脑样本限制了这种方法的翻译潜力。常规的血液 长期以来，测试一直是医疗服务的一部分。血液基因组谱可能可用于非侵入性 确定患者是否有AUD风险，提供数据驱动的AUD诊断，对 异构AUD患者人群进行临床试验，选择最佳治疗和监测治疗 反应和疾病进展。作为朝着这些目标的第一步，弗格森博士分析了基因表达 受到慢性间歇性乙醇（CIE）暴露的小鼠的配对血液和脑样本的模式， 酒精依赖的小鼠模型。 CIE的血液基因表达信号预测了药物 减少了小鼠的饮酒，以及从分化的血液谱建立的预测模型 CIE和空气暴露的小鼠精确。这些结果导致了一个假设，即血液可以用作 基于分子的诊断或治疗工具中脑组织的代理，并推进个性化医学 AUD的方法。但是，尚不清楚是否有来自AUD的生物学签名 人口。此外，生物标志物需要预测和监测治疗成功，它 尚不清楚血液基因表达谱在这方面可能有用。 CIE血液签名 在先前的研究中使用仅在一个时间点断言转录组。因此，动态或 未研究重要基因调节功能的持续过渡。这些知识中的差距将 在拟议的目标中可以通过分析的血液谱（1）在整个酒精中多个时间点解决 通过开发CIE引起的专辑，在人类中撤出（AIM 1），（2）在多个时间点上 在人类和小鼠治疗前后，小鼠的依赖性（AIM 2）和（3）（AIM 3）。总体 假设是，血液中的基因组特征将改善AUD的临床管理 诊断，预后和预测治疗反应。这些目标和参与培训计划 旨在基于弗格森博士以前的研究经验，并促进了新的科学培训 纵向数据，事件时间结果数据和临床酒精研究和生物统计分析 治疗效应估计。拟议的独立奖项将产生新知识 关于酒精研究中相对未研究的领域，并使弗格森博士能够建立一个可靠的框架 作为在酒精领域的学术翻译神经科学家建立成功的研究计划。