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

艾滋病和药物滥用的蛋白质组策略 - HIV 和冰毒 CNS 协同作用

基本信息

批准号：
7858217
负责人：
HOWARD S FOX
金额：
$ 94.55万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-30 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7858217
关键词：
Proteomic Strategies AIDS Drug Abuse

项目摘要

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.

描述(申请人提供)：艾滋病毒感染和滥用药物都是世界性的健康问题，对改进疾病诊断和治疗构成重大障碍。我们假设，实现这些目标的一种方法是通过蛋白质组学。在这方面，我们将利用与神经退行性变，特别是神经艾滋病相关的蛋白质组学研究的良好记录，并将其应用于一项有用的生物标记物发现战略，这些生物标记物可以反映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，重点是甲基苯丙胺(METH)与艾滋病毒结合，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州大学医学中心(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来调查药物滥用(重点是冰毒和艾滋病毒感染)之间的相互关系。在项目1，H.Gendelman，我们将使用经过良好验证的体外系统来进行机制研究，重点是冰毒在胶质细胞串扰过程中对HIV诱导的蛋白质组变化的影响以及由此产生的神经元功能。这些结果将直接提供给H·S·福克斯项目2中的灵长类研究，该项目使用艾滋病和药物滥用的非人类灵长类动物模型，调查受影响脑组织中蛋白质组和上游基因表达的变化，以发现生物标志物和疾病发病机制。这些研究将直接导致对项目3中提出的临床标本的评估，P.Ciborowski。在这个项目中，生物标记物的发现将从特征良好的HIV感染者的临床样本中进行，从他们使用或不使用冰毒的时间点开始。来自项目2的数据，研究了中枢神经系统和等离子体，将被证明是选择候选人的关键。此外，这些研究中的候选蛋白质，以及项目1和2中发现的其他蛋白质，将在人体血浆和脑脊液分析研究中交叉验证。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益处来改善护理。感染艾滋病毒的人和滥用冰毒的人的人口高度重叠。在美国，冰毒的使用正在增加。该项目的相关性在于，它将导致发现艾滋病毒和冰毒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。