Proteomic Biosignatures of Chronic Drug Exposure

慢性药物暴露的蛋白质组生物特征

• 批准号: 8008725
• 负责人: Howard Schulman
• 金额: $ 44.52万
• 依托单位: CAPRION PROTEOMICS USA, LLC
• 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 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8008725
• 关键词: Chronic; Drug Exposure; Proteomics; biosignature

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）：基于长期血浆蛋白变化的生物签名与慢性药物暴露有关的长期变化可用于识别易于重复使用药物使用的患者，从而促进早期干预。我们将测试使用大鼠慢性暴露于成瘾性药物和差异蛋白质组学表达的可行性。根据可卡因或非添加性多巴胺转运蛋白抑制剂或吗啡或盐水的治疗，根据14天的剂量时间表（慢性暴露），并在上次药物治疗后收集了长达75天的血浆。蛋白质组学分析将涉及丰富的血浆蛋白的逐步消耗，然后是液相色谱与质谱耦合的液相色谱法，以分析由非常低的丰度蛋白和中等含量的结合蛋白组成的耗尽蛋白质组。蛋白质的表达改变了几周，例如30天，最终返回基线将是候选生物标志物，可用于在无法再测量的上瘾药物的时候检测最近的暴露。在不需要蛋白质抗体的定量多路复用测定中，将通过多个反应监测来验证顶级候选者。将检查蛋白质组学的变化与将平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签名。一项成功的可行性研究将刺激并为人类受试者样本提供类似的研究。 公共卫生相关性：对慢性药物暴露的分析生物标志物（一种生物签名）的需求未满足，这将有助于鉴定出患有重复药物的患者。有效的测试可能成为常规医疗服务的一部分，该医疗服务将确定需要治疗的患者使用药物使用障碍，并减轻药物成瘾的个人和社会负担。