Transcriptome-guided diagnosis and therapy for alcohol use disorder

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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.