Transcriptome-guided diagnosis and therapy for alcohol use disorder

1项目概要/摘要 酒精使用障碍（AUD）是一种慢性复发性疾病，也是一个主要的公共卫生问题， 提供3种药物治疗。整合大脑基因的基于系统的计算策略 具有药物基因表达特征的AUD风险啮齿动物模型的4个表达特征显示 5承诺确定减少啮齿动物过量饮酒的化合物。然而，这种方法 6的临床潜力有限，因为不可能从患者身上获得脑标本。识别 7临床上可接近的组织将有助于应用先进的计算方法来识别 8种更好的AUD治疗方法和个性化AUD治疗。为此，拟议的研究旨在 9通过使用受试者内设计来确定血液是否可以用作脑的替代组织， 图10比较了小鼠在长期戒断期间两种组织中的转录水平，这是复发的敏感时间， 11过度饮酒这项研究还将确定全血转录组谱是否可以被 12用于根据酒精依赖状态对受试者进行分类，并通过计算预测化合物 13，减少酒精消费和焦虑和抑郁样行为。临床和机制 从拟议的研究中产生的14个见解应该独立考虑。第一种可能导致 15有效的诊断工具或候选治疗，而第二个将提供洞察力， 16. AUD的病理生理学。这可能是血液转录组至少部分反映了变化的情况 17在大脑中，针对这些变化是治疗性的。也可能是针对血液 18转录组是治疗性的，不管大脑的变化。这项研究将提供重要的新 19关于成瘾研究的一个相对较新和未探索的领域的知识，可以推动基于分子的 20种诊断或治疗工具和个性化医疗方法，用于AUD或其他大脑受损的疾病 第21章受影响的组织

1 Project Summary/Abstract 2 Alcohol Use Disorder (AUD) is a chronic, relapsing condition and a major public health problem with few 3 pharmaceutical treatments available. Systems-based computational strategies that integrate brain gene 4 expression signatures of rodent models of AUD risk with gene expression signatures of pharmaceuticals show 5 promise for identifying compounds that decrease excessive drinking in rodents. However, this methodology 6 has limited clinical potential because it is not possible to obtain brain specimens from patients. Identifying a 7 clinically accessible tissue would facilitate the application of advanced computational approaches to identify 8 better therapeutics for AUD and personalize AUD treatment. To this end, the proposed research aims to 9 determine whether blood can be used as a surrogate tissue for brain by using a within-subjects design to 10 compare transcript levels in both tissues in mice during protracted withdrawal, a sensitive time for relapse to 11 excessive alcohol drinking. The research will also determine whether whole blood transcriptome profiles can be 12 used to classify subjects according to alcohol dependence status and to computationally predict compounds 13 that reduce alcohol consumption and anxiety- and depression-like behavior. The clinical and mechanistic 14 insights that will emerge from the proposed research should be considered independently. The first could lead 15 to effective diagnostic tools or candidate treatments, whereas the second will provide insight into the 16 pathophysiology of AUD. It might be the case that the blood transcriptome at least partially reflects the changes 17 in brain, and that targeting these changes is therapeutic. Or it might be the case that targeting the blood 18 transcriptome is therapeutic, irrespective of brain changes. The proposed study will provide crucial new 19 knowledge about a relatively new and unexplored area of addiction research that could drive molecular-based 20 diagnostic or therapeutic tools and personalized medicine approaches for AUD or other diseases where brain is 21 the primary affected tissue.