Lipid biosignatures of drug addiction

描述（由申请人提供）：我们假设成瘾性药物改变了大脑和外周组织的细胞脂质途径，这种改变影响了向强迫性药物使用的转变。这种想法的一个推论是，外周脂质改变可能被用作成瘾的生物标志物或生物特征（复合生物标志物）。我们实验的目的是通过对脂质组的无偏见评估，发现可能与大鼠（人类成瘾模型）甲基安非他明自我给药有关的脂质功能异常，并确定可能用于筛选暴露和成瘾易感性的外周生物标志物候选物。为了实现这一目标，我们将从获得甲基苯丙胺自我服用和随后戒断该药物的不同阶段的大鼠身上提取组织样本。然后，我们将使用液相色谱/质谱法对样品进行全脂质体分析。最后，我们将处理所获得的信息，并将其与行为和分子数据相结合，以对新描述的脂质异常的功能意义产生可测试的假设。最初的实验发现，暴露于甲基苯丙胺的大鼠的大脑和肝脏组织中存在多种脂质变化。我们有两个具体目标。目的1：发现自我服用甲基苯丙胺的大鼠大脑中的脂质组学异常。我们将(i)分析在自我服用甲基苯丙胺和随后戒断该药物期间的脑脂质组；（ii）探索脂质组学研究发现的显著脂质改变的潜在机制；（iii）测试这些改变是否与自我给药有关；（iv）检查脂质异常是否可以用来监测成瘾的严重程度，因为甲基苯丙胺的自我使用从随意，控制到易感个体的强制摄入。目的2：发现暴露于甲基苯丙胺的大鼠外周组织的脂质组学异常，并确定甲基苯丙胺暴露的候选生物标志物。我们将扩展Aim 1中进行的脂质组学分析，以包括易于活检和/或与大脑代谢相互作用的外周组织（血液、骨骼肌、皮下脂肪、皮肤）。我们还将确定是否预先存在的外周脂质谱差异可能会使大鼠倾向于发展成强迫性成瘾样行为，从而可能成为甲基苯丙胺成瘾的先行生物标志物。对脂质组进行系统和无偏见的研究，以发现与自我给药有关的异常，目前还没有尝试。拟议的研究解决了这一差距，如果成功，将导致发现新的成瘾生物标志物候选物。这项工作将保留7个现有工作岗位，并创造4个新工作岗位。公共卫生相关性：我们建议对各种大鼠组织中的所有脂质（“脂质组”）进行系统和公正的搜索，以确定与甲基苯丙胺成瘾相关的异常，并发现这种疾病的早期生物标志物。

DESCRIPTION (provided by applicant): We hypothesize that addictive drugs alter cellular lipid pathways in brain and peripheral tissues, and that such alterations influence the transition to compulsive drug use. A corollary of this idea is that peripheral lipid alterations might be used as biomarkers or biosignatures (composite biomarkers) of addiction. The goal of our experiments is to discover, through an unbiased evaluation of the lipidome, abnormalities in lipid function that might be involved in methamphetamine self-administration in rats (a model for human addiction) and identify peripheral biomarker candidates that might be used to screen for exposure and vulnerability to addiction. To achieve this goal, we will take tissue samples from rats at different stages of acquisition of methamphetamine self-administration and subsequent abstinence from the drug. We will then conduct lipidome-wide analyses of the samples using liquid chromatography/mass spectrometry. Finally, we will process the information obtained and integrate it with behavioral and molecular data to generate testable hypotheses on the functional significance of newly described lipid abnormalities. Initial experiments have uncovered multiple lipid alterations in brain and liver tissues from methamphetamine-exposed rats. We have two specific aims. Aim 1: To discover lipidomic abnormalities in the brain of rats that self-administer methamphetamine. We will (i) profile the brain lipidome during the acquisition of methamphetamine self-administration and subsequent abstinence from the drug; (ii) explore the mechanisms underlying significant lipid alterations uncovered by our lipidomic work; (iii) test whether such alterations correlate with drug self- administration; and (iv) examine whether lipid abnormalities might be used to monitor the severity of addiction as methamphetamine self-administration progresses from casual, controlled use to compulsive intake in susceptible individuals. Aim 2: To discover lipidomic abnormalities in peripheral tissues of rats exposed to methamphetamine, and identify candidate biomarkers for methamphetamine exposure. We will extend the lipidomic analyses conducted in Aim 1 to include peripheral tissues that are readily accessible to biopsy and/or interact metabolically with the brain (blood, skeletal muscle, subcutaneous fat, skin). We will also determine whether pre-existing differences in peripheral lipid profiles may predispose rats toward developing compulsive addiction-like behavior, and thus be potentially useful as antecedent biomarkers for methamphetamine addiction. A systematic and unbiased search of the lipidome to discover abnormalities associated with drug self- administration has yet to be attempted. The proposed studies address this gap and will result, if successful, in the discovery of novel biomarker candidates for addiction. This work will result in the retention of 7 existing jobs and the creation of 4 new jobs. PUBLIC HEALTH RELEVANCE: We propose to conduct a systematic and unbiased search of all lipids (the 'lipidome') in various rat tissues to identify abnormalities associated with methamphetamine addiction and discover early biomarkers for this disease.