HIV AND COCAINE INTERACTIONS IN THE DEVELOPING BRAIN

艾滋病毒和可卡因在大脑发育中的相互作用

• 批准号: 2898047
• 负责人: AYALLA BARNEA
• 金额: $ 22.83万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-08-01 至 2001-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2898047
• 关键词: HIV envelope protein gp120; biological signal transduction; brain metabolism; cocaine; developmental neurobiology; embryo /fetus cell /tissue; embryo /fetus toxicology; glia; laboratory rat; neuropathology; neuropeptide Y; neurotoxins; neurotrophic factors

DESCRIPTION: (Applicant's Abstract) The goals of this application are to elucidate the cellular and molecular mechanisms by which the HIV envelope protein gpl20 induces dysfunction of peptidergic neurons in the cocaine abused developing brain, with emphasis on one of the most abundant peptidergic neurons -- the neuropeptide Y (NPY) neuron. NPY has been implicated in a wide range of brain functions including mentation and it has been implicated in neuropathological symptoms expressed by cocaine abusing people. Two working hypotheses will be challenged. One, gpl20 induces defective signal transduction (and eventually neuronal death) in the brain of AIDS patients and this is due, in part, to an effect of gpl20 on the neuron itself and/or other cells the secretory products of which regulate neuronal function. Two, cocaine alters the functional state of multiple cellular systems (neurons and/or astrocytes) in the developing brain such that specific neuronal populations become highly susceptible to the neurotaxic effects of gpl20. Two experimental models, operative in our laboratory, are proposed: an in vitro model - fetal NPY neurons derived from intact rats and an in vivo/in vitro model - fetal neurons derived from cocaine-treated pregnant rats. S.A.1. Characterize the biochemical and molecular parameters of cocaine facilitation of gpl20 suppression of the functional state of the cultured NPY neuron. S.A.2. Investigate the nature of the receptor(s) mediating gpl20-induced neuronal dysfunction. S.A.3. Elucidate the role of glial cells in cocaine/gpl20 action on the NPY neurons. The results generated in these studies will provide insight into the mechanisms underlying gpl20 actions in the cocaine abused developing brain, which will serve as the baseline/guide for the design of therapeutic agents for future clinical management and possibly prevention of abnormalities expressed in the brains of HIV-infected people. An important and most timely outcome of this study will be the availability of an in vitro reliable model system to test the efficacy of newly designed therapeutic agents.

描述：(申请人摘要) 这项应用的目标是阐明细胞和分子 HIV包膜蛋白gpl20诱导细胞功能障碍的机制 可卡因滥用发育中的大脑中的肽能神经元，重点是 最丰富的肽能神经元之一--神经肽Y(NPY) 神经元。神经肽Y与广泛的大脑功能有关 包括精神错乱，它与神经病理症状有关 表现为吸食可卡因的人。两个可行的假设是 挑战。其一，gpl20导致信号转导有缺陷(和 最终在艾滋病患者的大脑中)，这是由于 部分，由于gpl20对神经元本身和/或其他细胞的影响 调节神经功能的分泌产物。第二，可卡因改变了 多个细胞系统(神经元和/或 星形胶质细胞)在发育中的大脑中，这样特定的神经元群体 对gp20的神经趋化作用高度敏感。二 提出了在本实验室操作的实验模型：体外实验模型 正常大鼠胎脑NPY神经元模型及体内/体外实验 模型-来自可卡因处理的孕鼠的胚胎神经元。S.A.1。 可卡因的生化和分子参数表征 促进gp20抑制培养的细胞功能状态 NPY神经元。S.A.2。关于受体(S)中介性质的探讨 Gpl20诱导的神经元功能障碍。S.A.3.阐明神经胶质细胞的作用 可卡因/gpl20组细胞对NPY神经元的作用。中生成的结果 这些研究将提供对gpl20背后的机制的洞察。 可卡因的行为会滥用发育中的大脑，这将成为 未来临床治疗药物设计的基准/指南 对大脑表达异常的管理和可能的预防 感染艾滋病毒的人。这项研究的一个重要和最及时的结果 将会有一个体外可靠的模型系统来测试 新设计的治疗剂的疗效。