Peripheral biomarkers of cocaine dependence and relapse

可卡因依赖和复发的外周生物标志物

• 批准号: 7762581
• 负责人: Jun Qu
• 金额: $ 31.7万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7762581
• 关键词: Acute; Address; Animal Model; Animals; Archives; Behavioral; Bioinformatics; Biological; Biological Markers; Blood; Blood Cells; Blood specimen; Brain region; Characteristics; Chemicals; Chronic; Clinical Research; Cocaine; Cocaine Abuse; Cocaine Dependence; Complex; Dependence; Detection; Diagnosis; Drug Addiction; Drug Controls; Drug Evaluation; Drug Exposure; Drug abuse; Drug usage; Evaluation; Experimental Designs; Family; Follow-Up Studies; Goals; Immunoassay; Investigation; Isotopes; Link; Lipids; Liquid Chromatography; Liquid substance; Mass Spectrum Analysis; Methods; Modeling; Molecular Profiling; Monitor; Morbidity - disease rate; Neuropeptides; Nucleic Acids; Obsessive compulsive behavior; Outcome; Pattern; Peptides; Peripheral; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phenotype; Plasma; Post-Translational Protein Processing; Preparation; Procedures; Process; Protein Analysis; Proteins; Proteome; Proteomics; Rattus; Recording of previous events; Recovery; Relapse; Relative (related person); Reproducibility; Role; Running; Sampling; Schedule; Scourge; Seeds; Self Administration; Series; Signal Transduction; Societies; Source; Stress; Technology; Testing; Time; Tissues; Validation; Withdrawal; addiction; allostasis; base; behavior test; biosignature; cocaine exposure; cocaine use; cost; dependence relapse; design; diagnosis evaluation; drug of abuse; improved; interest; liquid chromatography mass spectrometry; minimally invasive; multiple reaction monitoring; nano; nanoprocess; nanoscale; neuroadaptation; neurochemistry; novel; numb protein; outcome forecast; peripheral blood; programs; protein expression; public health relevance; relating to nervous system; small molecule; stem

DESCRIPTION (provided by applicant): The goal of this application is to identify candidate biomarkers which, in combination, may constitute a lingering biosignature that is informative of cocaine abuse history over a protracted period of time. The neurochemical and behavioral manifestations of chronic cocaine abuse are known to endure for a considerable duration, and given the role of neuropeptides and other secreted proteins in compulsive behaviors, drug abuse, and addiction, we hypothesize that the proteome of biophases that can be obtained, by minimally-invasive means, may contain families of biomarkers that reflect the well-established neurochemical alterations and constitute a peripherally-accessable cocaine abuse biosignature. Our approach is to apply recent inter-related analytical advances in sample processing, nano-scale liquid chromatography (nano-LC), and mass spectrometry (MS) that enhance the suitability of nano-LC/MS approaches for the analysis of highly complex proteomic samples such as tissues or bodily fluids. These advances provide: (i) highly quantitative recovery of tissue or sample proteins, (ii) highly reproducible, selective, and sensitive expression profiling of proteins, (iii) quantification of significantly greater numbers of proteins, and (iv) highly sensitive, multiplexed quantification of specific proteins of interest and (v) their PTM status. In the context of a well-controlled and validated rat model of cocaine abuse and withdrawal, samples will be obtained from naive- and drug-withdrawn animals both before and during a relapse of cocaine administration. Proteomes of select neural centers and blood will be contrasted to assemble lists of abuse-selective biomarker candidates, and their importance will be ranked by the commonality among replicates, the magnitude of change, and bioinformatic criteria relating them plausibly as drug-abuse responsive. In the second phase, the top-prioritized candidates will be confirmed and absolute quantification will be performed; matched plasma samples will be interrogated for these candidate biomarkers to identify promising constituents of a biosignature. Finally, using a rat model of addiction involving self- administration, we will attempt to refine biosignature candidates in terms of use/abuse vs. dependence/addiction, to determinate the exclusivity of these markers for drug addiction. By employing these linked analytical technologies and a well-validated animal model, we aim to investigate, identify, and validate potential biosignatures of cocaine abuse and relapse, based upon differential comparison of proteins in peripheral blood samples, which could aid in diagnosis, evaluation of therapy, and monitoring of recovery. PUBLIC HEALTH RELEVANCE: Chronic use of drugs of abuse represents a scourge to users and society. The ability to obtain information about use patterns beyond the period of time in which drug or metabolites are detectable in blood would have broad applications in diagnosis, estimation of prognosis, personalization of treatment, evaluation of drug effects, and detection of relapse. We propose to combine novel analytical advances in liquid chromatography, mass spectrometry (LC/MS), and sample preparation, along with a series of validated animal models, to interrogate samples that are obtainable by minimally-invasive means, such as blood, to achieve the elusive goal of identifying families of persistent biomarkers, comprising a biosignature, of chronic cocaine abuse and addiction.

描述（由申请人提供）：本申请的目的是确定候选生物标志物，结合使用，该标志物可能构成挥之不去的生物签名，该生物签名在长时间的一段时间内为可卡因滥用历史提供了信息。众所周知，慢性可卡因滥用的神经化学和行为表现会持续相当长的持续时间，并且鉴于神经肽和其他分泌的蛋白质在强迫性行为，药物滥用和成瘾中的作用，我们假设我们假设可以通过最小化的生物群体获得生物群的蛋白质组，可能会构成生物剂，可能会构成亲密的属性，并且可能会构成生物群的范围。构成可卡因滥用生物签名。我们的方法是在样品加工，纳米级液相色谱（纳米-LC）和质谱（MS）中应用最新相关的分析进展，从而增强了纳米-LC/MS方法的适用性，以分析高度复杂的蛋白质组织样品，例如组织或身体流动性。这些进展提供了：（i）组织或样品蛋白的高度定量恢复，（ii）蛋白质的高度可重复，选择性和敏感的表达分析，（iii）量化蛋白质数量明显更大的量化，以及（iv）高度敏感的，高度敏感的，对感兴趣的特定蛋白质和（v）其PTM状态的多重蛋白质定量。在可卡因滥用和戒断的良好控制和验证的大鼠模型的背景下，在可卡因给药的复发之前和期间，将从幼稚和毒品中的动物中获得样品。精选神经中心和血液的蛋白质组织将形成鲜明的对比，以组装滥用选择性生物标志物候选者的清单，其重要性将由复制，变化的幅度和生物信息学标准中的共同点所排名，使它们与药物滥用反应效果有关。在第二阶段，将确认最优先的候选人，并将执行绝对定量。匹配的等离子体样品将询问这些候选生物标志物，以识别有希望的生物签名成分。最后，使用涉及自我管理的大鼠成瘾模型，我们将尝试根据使用/滥用/依赖/成瘾来完善生物签名候选者，以确定这些标志物对吸毒成瘾的排他性。通过采用这些连接的分析技术和验证良好的动物模型，我们旨在根据外周血样本中蛋白质的差异比较可卡因滥用和复发的潜在生物签名，这可以有助于诊断，评估治疗和恢复恢复。 公共卫生相关性：长期使用滥用药物对用户和社会造成了祸害。在血液中可检测到的药物或代谢产物时，获得有关使用模式的信息的能力将在诊断，预后估计，治疗个性化，药物影响评估以及对复发的发现方面具有广泛的应用。我们建议将液相色谱，质谱法（LC/MS）和样品制备以及一系列经过验证的动物模型的新分析进展结合在一起，以询问可以通过最小侵入性手段（例如血液）获得的样品，以实现难以实现的持久生物标志物的难以实现的目标。