Transcriptome-guided diagnosis and therapy for alcohol use disorder

1项目摘要/摘要 2酒精使用障碍(AUD)是一种慢性、复发性疾病，是一个主要的公共健康问题，很少 提供3种药物治疗。整合大脑基因的基于系统的计算策略 AUD风险啮齿动物模型的表达特征与药物的基因表达特征显示 5承诺识别出减少啮齿动物过度饮酒的化合物。然而，这种方法论 6的临床潜力有限，因为不可能从患者身上获得脑组织标本。确定 临床上可获得的组织将有助于应用先进的计算方法来识别 8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大脑的替代组织 10比较长期戒断期间小鼠两个组织中转录水平的变化，这段时间是复发的敏感期 11过度饮酒。这项研究还将确定全血转录组图谱是否可以 12用于根据酒精依赖状况对受试者进行分类，并通过计算预测化合物 13减少饮酒和焦虑--以及类似抑郁的行为。临床和机械学 14.拟议研究将产生的见解应独立考虑。第一个可能会导致 15个用于有效的诊断工具或候选治疗，而第二个将提供对 16 AUD的病理生理学。可能的情况是，血液转录组至少部分反映了这种变化 17在大脑中，而针对这些变化是有治疗作用的。或者可能是以血液为目标的情况 18转录组具有治疗作用，与大脑变化无关。拟议的研究将提供至关重要的新的 19了解一个相对较新和未被探索的成瘾研究领域，这可能会推动基于分子的 针对AUD或其他脑部疾病的20种诊断或治疗工具和个性化药物方法 21受影响的主要组织。

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.