Proteomic Strategies for AIDS and Drug Abuse - HIV and METH CNS Synergy

说明（由申请人提供）：艾滋病毒感染和滥用药物都是世界范围的健康问题，对改进疾病诊断和治疗构成重大障碍。我们认为达到这些目标的一种方法是通过蛋白质组学。在这方面，我们将利用与神经变性，特别是神经艾滋病相关的蛋白质组学研究的良好记录，并将其应用于有用的生物标志物发现策略，这些生物标志物反映了细胞对艾滋病毒感染和药物滥用的反应，这些反应可以转化为人类疾病。这一目标推动了三项拟议的研究，这些研究的主题是甲基苯丙胺（冰毒）与艾滋病毒结合会增加神经胶质激活对大脑的破坏性影响，损害神经认知功能。我们将利用内布拉斯加大学医学中心（UNMC）、斯克里普斯研究所（TSRI）和加州大学圣地亚哥分校（UCSD）三个机构的科学和技术专长，调查药物滥用（重点是冰毒和艾滋病毒感染）之间的相互关系。在项目1中，H.E. Gendelman，我们将使用经过验证的体外系统进行机制研究，重点研究甲基安非他明对hiv诱导的胶质串扰期间蛋白质组学变化的影响以及由此产生的神经元功能。这些结果将直接用于项目2中的灵长类动物研究，H. S. Fox，该项目使用艾滋病和药物滥用的非人类灵长类动物模型，研究蛋白质组的变化以及受影响脑组织中的上游基因表达，以发现生物标志物和疾病发病机制。这些研究将直接导致项目3，P. Ciborowski提出的临床标本的评估。在这个项目中，生物标志物的发现将在临床样本中进行，这些样本来自于具有良好特征的个体，HIV感染者，从他们使用或不使用冰毒的时间点。项目2的数据，检查中枢神经系统和血浆，将被证明是选择候选人的必要条件。此外，这些研究中的候选蛋白，以及项目1和项目2中发现的其他蛋白，将在人类血浆和脑脊液分析研究中进行交叉验证。这些综合研究将把细胞生物学、病毒学、免疫学和动物发病机制的结果带到床边，试图通过诊断和临床效益来改善护理。感染艾滋病毒的人群和滥用冰毒的人群有很大的重叠。在美国，使用冰毒的人数正在增加。这个项目的相关性在于，它将导致发现HIV和甲基安非他明相互作用损害大脑的机制，并识别标记疾病过程的蛋白质，并作为治疗干预的目标。

DESCRIPTION (provided by applicant): Both HIV-infection and drugs of abuse are worldwide health problems and pose significant obstacles for improved disease diagnosis and treatment. We posit that one approach to reach these goals is through proteomics. In this regard, we will use a well developed track record in proteomics research relevant to neurodegeneration and specifically neuroAIDS and apply it to a strategy for useful biomarker discovery that reflect cellular responses to HIV infection and drug abuse, which can be translated to human disease. This aim drives three proposed studies focusing on the theme that methamphetamine (METH) combines with HIV to increase the damaging affect of glial activation on the brain, impairing neurocognitive functions. We will utilize the scientific and technical expertise of three institutions at the University of Nebraska Medical Center (UNMC), the Scripps Research Institute (TSRI), and the University of California San Diego (UCSD) to investigate the interrelationships between drug abuse (with a focus on METH and HIV infection. In project 1, H.E. Gendelman, we will use well-validated in vitro systems to perform mechanistic investigations focusing on the influence of METH on HIV-induced proteomic changes during glial crosstalk and resulting neuronal function. These results will feed directly into the primate studies in projects 2, H. S. Fox, which uses the nonhuman primate model of AIDS and drug abuse, investigating changes in the proteome as well as up-stream gene expression in affected brain tissue for both biomarker discovery and disease pathogenesis. These studies will lead directly into evaluation of clinical specimens proposed in project 3, P. Ciborowski. In this project, biomarker discovery will be performed on plasma from clinical samples of well-characterized individuals, HIV infected, from time points when they are using, or not using, METH. Data from Project 2, examining both the CNS and plasma, will prove essential in selecting candidates. Furthermore, such candidates from these studies, as well as other proteins uncovered from Projects 1 and 2, will be cross-validated in studies of human plasma and CSF analysis. These integrated studies will bring results from cell biology, virology, immunology, and animal pathogenesis to the bedside in attempts to improve care through diagnostic and clinical benefits. There is a high overlap in the population of people who are HIV infected and those who abuse METH. METH use is on the increase in the US. The relevance of this project is that it will result in the discovery of the mechanisms that HIV and METH interact to damage the brain, and identify proteins mark disease processes and serve as targets of therapeutic intervention.