Blood and Brain Gene Profiling in Stimulant Self-Administration

描述（由申请人提供）：对中枢神经兴奋剂的依赖，包括非法（如可卡因、甲基苯丙胺）和合法（苯丙胺类药物，如阿得拉(c)）精神兴奋剂，在美国构成严重的健康问题。不仅非法兴奋剂的滥用在过去几年中以惊人的速度增加，处方兴奋剂的使用和转移也在增加。然而，在一般人群中，没有生物标志物或生物标志物组可用于辅助诊断兴奋剂滥用和依赖的阶段或进展。使用啮齿动物自我给药模型，我们提出实验来验证血液中特定基因表达特征可以作为区分对照与药物治疗动物的诊断性生物标志物的假设。Illumina微阵列将用于获得自我给药和药物初始大鼠的几个阶段的血液样本的表达谱。发现具有敏感性、特异性和预测能力的生物标志物将是一个巨大的诊断进步，这种诊断工具的发展将受益于大规模分析，以确定疾病特异性的分子标记，从而提供疾病的指纹。提出了两个具体目标：1)在大鼠全血样本中确定一组候选生物标志物（基因），以预测可卡因自我给药的早期和晚期以及强迫戒断可卡因的早期和晚期；2)验证候选生物标志物，并与大鼠兴奋剂自我给药以及强迫戒断（戒断）的早期和晚期的大脑基因表达相关。我们将测试基于表达的标记可以准确区分可卡因自我服用和强迫戒断的阶段和甲基苯丙胺自我服用后的相同阶段的假设。

DESCRIPTION (provided by applicant): Dependence upon central nervous stimulants, including both illicit (e.g., cocaine, methamphetamine) and licit (amphetamine-based medications, e.g., Adderall(c)) psychostimulants, constitutes a serious health problem in the U.S. Not only has abuse of illicit stimulants increased at an alarming rate in the past few years, the use and diversion of prescription stimulants is also on the rise. However, no biomarker or panel of biomarkers is available to assist in diagnosis of stages or progression of stimulant abuse and dependence in the general population. Using a rodent self-administration model, we propose experiments to test the hypothesis that a specific gene expression signature in blood can serve as a diagnostic biomarker that distinguishes control from drug treated animals. Illumina bead microarrays will be used to obtain expression profiles from blood samples at several stages of self-administration of stimulants and drug-naive rats. The discovery of biomarkers with sensitivity, specificity, and predictive power would be a great diagnostic advance and the development of such diagnostic tools would benefit from large-scale analyses to identify disease-specific molecular markers that provide a fingerprint of the condition. Two Specific Aims are proposed: 1) identify a panel of candidate biomarkers (genes) in rat whole blood samples that predicts early and late phases of cocaine self- administration as well as early and late stages of forced abstinence from cocaine, 2) validate candidate biomarkers and correlate with brain gene expression in rat stimulant self-administration as well as early and late stages of forced abstinence (withdrawal). We will test the hypothesis that expression based markers can accurately distinguish between stages of cocaine self-administration and forced abstinence and the same stages following methamphetamine self-administration. PUBLIC HEALTH RELEVANCE: This application will use gene expression profiling in whole blood to identify candidate biomarkers indicative of psychomotor stimulant abuse (cocaine and methamphetamine). Discovery of reliable biomarkers could lead to new drug treatments; and, a molecular screening test for abuse holds promise for treatment and intervention of the disease.