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: 2713145
• 负责人: AYALLA BARNEA
• 金额: $ 22.17万
• 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 2000-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2713145
• 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） 本申请的目的是阐明细胞和分子的 HIV包膜蛋白gp 120诱导免疫功能障碍的机制 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） neuron. 神经肽Y与脑的多种功能有关 包括精神状态，它与神经病理学症状有关， 可卡因滥用者的表现。 两个工作假设将是 质疑 第一，gp 120诱导有缺陷的信号转导（和 最终神经元死亡），这是由于， 部分地，由于gp 120对神经元本身和/或其它细胞的作用， 其分泌产物调节神经元功能。 第二，可卡因 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，使得特定的神经元群体 变得对GP 120的神经毒性作用高度敏感。 两 实验模型，在我们的实验室操作，提出：在体外 模型-来自完整大鼠的胎儿NPY神经元和体内/体外 模型-来自可卡因处理的妊娠大鼠的胎儿神经元。 S.A.1. 确定可卡因的生化和分子参数 促进gp 120抑制培养的细胞的功能状态 NPY神经元 S.A.2. 研究受体介导的性质 GP 120诱导的神经元功能障碍。 S.A.3. 阐明胶质细胞的作用 cocaine/gp 120对NPY神经元的作用。 中生成的结果 这些研究将提供对gp 120潜在机制的深入了解 可卡因滥用的大脑发育中的行为，这将作为 未来临床治疗药物设计的基线/指南 管理并可能预防大脑中表达的异常 艾滋病毒感染者的数量。 这项研究的一个重要和最及时的成果是 将是体外可靠模型系统的可用性，以测试 新设计的治疗剂的功效。