Transcriptome-guided diagnosis and therapy for alcohol use disorder

转录组指导的酒精使用障碍诊断和治疗

基本信息

批准号：
10092805
负责人：
Laura Brockway Ferguson
金额：
$ 1.96万
依托单位：
UNIVERSITY OF TEXAS AT AUSTIN
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-01 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10092805
关键词：
Acids Affect Air Alcohol consumption Alcohol dependence Alcohol withdrawal syndrome Alcoholism Alcohols Amygdaloid structure Animals Anxiety Area Behavior Biological Bipolar Disorder Blood Brain Brain Diseases Chronic Clinic Clinical Clinical Trials Code Complex Computer Analysis Data Databases Dependence Diagnosis Diagnostic Discriminant Analysis Disease Ethanol Female Functional disorder Gene Expression Gene Expression Profile Genes Healthcare Heavy Drinking Human Knowledge Lead Least-Squares Analysis Libraries Logistic Regressions Marble Measures Mental Depression Mental disorders Methodology Molecular Mus Network-based Neurodegenerative Disorders Nucleus Accumbens Pathway Analysis Pathway interactions Patients Pattern Performance Pergolide Pharmaceutical Preparations Pharmacologic Substance Pharmacotherapy Population Prefrontal Cortex Proteins Public Health Relapse Research Rodent Rodent Model Schizophrenia Specimen Structure of terminal stria nuclei of preoptic region System Tail Suspension Testing Therapeutic Time Tissues Transcript Translating Ventral Tegmental Area Whole Blood Withdrawal addiction alcohol abuse therapy alcohol availability alcohol use disorder artificial neural network base binge drinking brain tissue clinical development design differential expression disorder risk drug candidate forced swim test genome-wide analysis improved in vivo insight machine learning algorithm male negative affect novel marker personalized medicine problem drinker random forest success tool transcriptome transcriptome sequencing vapor

项目摘要

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.

1 项目概要/摘要 2 酒精使用障碍 (AUD) 是一种慢性、复发性疾病，也是一个重大公共卫生问题，很少有人关注可用 3 种药物治疗。基于系统的整合大脑基因的计算策略 4个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 有望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取脑标本。识别一个 7 临床可访问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 疗法和个性化 AUD 治疗。为此，拟议的研究旨在 9 通过使用受试者内部设计来确定血液是否可以用作大脑的替代组织 10 比较了长期戒断期间小鼠两种组织中的转录水平，这是复发的敏感时间 11.过量饮酒。该研究还将确定全血转录组谱是否可以 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 减少饮酒以及类似焦虑和抑郁的行为。临床和机制应独立考虑拟议研究中产生的 14 条见解。第一个可能会导致 15 有效的诊断工具或候选治疗方法，而第二个将提供对 16 AUD 的病理生理学。血液转录组可能至少部分反映了这些变化 17 在大脑中，针对这些变化具有治疗作用。或者可能是针对血液的情况 18 转录组具有治疗作用，与大脑的变化无关。拟议的研究将提供重要的新 19 关于成瘾研究相对较新且未经探索的领域的知识，该领域可能会推动基于分子的研究针对 AUD 或其他脑部疾病的 20 种诊断或治疗工具以及个性化医疗方法 21 主要受影响的组织。