Proteomic Biosignatures of Chronic Drug Exposure

慢性药物暴露的蛋白质组生物特征

• 批准号: 7772366
• 负责人: Howard Schulman
• 金额: $ 0.06万
• 依托单位: PPD DEVELOPMENT LP
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7772366
• 关键词: Animal Model; Antibodies; Arts; Behavioral; Binding Proteins; Biological Assay; Biological Markers; Brain-Derived Neurotrophic Factor; Caring; Chronic; Cocaine; Coupled; Data; Dose; Drug Addiction; Drug Exposure; Drug usage; Early treatment; Feasibility Studies; Goals; Liquid Chromatography; Mass Spectrum Analysis; Measures; Medical; Methylphenidate; Molecular; Monitor; Morphine; Opiates; Patients; Pharmaceutical Preparations; Plasma; Plasma Proteins; Property; Protein Binding; Proteins; Proteome; Proteomics; Rattus; Reproducibility; Research; Saline; Sampling; Schedule; Substance Use Disorder; Testing; Time; Treatment Protocols; Validation; addiction; base; biosignature; candidate marker; candidate validation; cocaine exposure; data mining; dopamine transporter; dysphoria; effective therapy; human subject; inhibitor/antagonist; multiple reaction monitoring; neuroadaptation; neurochemistry; public health relevance; response

DESCRIPTION (provided by applicant): A biosignature based on long-term plasma protein changes specifically associated with chronic drug exposure can be used to identify patients predisposed to repeated drug use and thereby facilitate early intervention. We will test the feasibility of finding such a signature using chronic exposure of rats to addictive drugs and differential proteomic expression. Rats will receive treatment with cocaine or a non-addictive dopamine transporter inhibitor, or morphine, or saline according to a 14 day escalating dose schedule (chronic exposure) and plasma collected up to 75 days following last drug treatment. Proteomic analysis will involve stepwise depletion of abundant plasma proteins followed by liquid chromatography coupled online with mass spectrometry to analyze both the depleted proteome consisting of very low abundance proteins and the bound proteins of intermediate abundance. Proteins whose altered expression is maintained for several weeks, e.g. 30 days, and eventually return to baseline would be candidate biomarkers that could be used to detect recent exposure at a time when the addictive drug can no longer be readily measured. Top candidate will be validated by multiple reaction monitoring in a quantitative multiplexed assay that does not require antibodies to the proteins. Proteomic changes will be examined for temporal correlation with behavioral and neurochemical sequelae of chronic drug treatment that will be measured in parallel. Statistical analysis and data mining will be used to identify a biosignature with the desired properties. A successful feasibility study would stimulate and inform similar studies on human subject samples. PUBLIC HEALTH RELEVANCE: There is an unmet need for analytical biomarkers, a biosignature, of chronic drug exposure that would help to identify patients predisposed to repeated drug. An effective test could become part of routine medical care that would identify patients in need of treatment for substance use disorders and mitigate the personal and societal burdens of drug addiction.

描述（由申请人提供）：基于与长期药物暴露特别相关的长期血浆蛋白变化的生物印记可用于识别易于重复药物使用的患者，从而促进早期干预。我们将通过大鼠长期接触成瘾药物和差异蛋白质组表达来测试寻找这种特征的可行性。大鼠将根据 14 天递增剂量计划（长期暴露）接受可卡因、非成瘾性多巴胺转运蛋白抑制剂、吗啡或盐水治疗，并在最后一次药物治疗后 75 天内收集血浆。蛋白质组分析将涉及逐步去除丰富的血浆蛋白，然后采用液相色谱法与质谱联用，以分析由极低丰度蛋白质组成的耗尽蛋白质组和中等丰度的结合蛋白质。表达改变可维持数周的蛋白质，例如30 天并最终恢复到基线将成为候选生物标志物，可用于在无法再轻易测量成瘾药物时检测最近的暴露情况。最佳候选者将通过定量多重检测中的多重反应监测进行验证，不需要蛋白质抗体。将检查蛋白质组变化与并行测量的慢性药物治疗的行为和神经化学后遗症的时间相关性。统计分析和数据挖掘将用于识别具有所需特性的生物特征。成功的可行性研究将刺激并为针对人类受试者样本的类似研究提供信息。 公共卫生相关性：对慢性药物暴露的分析生物标志物（一种生物特征）的需求尚未得到满足，这将有助于识别易于重复用药的患者。有效的测试可以成为常规医疗护理的一部分，从而识别需要治疗药物滥用障碍的患者，并减轻毒瘾造成的个人和社会负担。