HIV infection and drugs of abuse in neuroglial function

HIV 感染和滥用药物对神经胶质细胞功能的影响

• 批准号: 6931494
• 负责人: CARLOS A PARDO-VILLAMIZAR
• 金额: $ 17.2万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-15 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6931494
• 关键词: AIDS dementia complex; HIV envelope protein gp120; HIV infections; animal tissue; chemoattractants; chemokine; cocaine; comorbidity; drug abuse; gene expression; glia; glutamate transporter; glutamates; heroin; human tissue; inflammation; macrophage; monocyte; neurons; neuropathology; neuropharmacology; neurotoxicology; neurotransmitter metabolism; organ culture

DESCRIPTION (provided by applicant): HIV-1 infection and drug abuse are major public health problems in the United States. Drug users are at higher risk for contracting HIV infection and for developing cognitive deficits ranging from minor impairment to frank dementia (HIV-D). A key mechanism of neuronal dysfunction underlying the cognitive impairment in both HIV-D and drug abuse is neuroglial dysfunction. Specific alterations in glutamate metabolism, chemokines and cytokines may contribute to both excitotoxicity and CNS inflammation. The overall goal of this project is to examine whether drugs of abuse (DOA) such as cocaine and heroin, and in combination with HIV-1 infection, synergistically affect levels of glutamate or selected chemokines, resulting in neuronal and glial dysfunction. The central hypothesis is that DOA act synergistically with the products of HIV-1 infection and influence pathways of excitotoxicity, inflammation and neuroglial responses. To address this hypothesis, we will examine the effects of DOA such cocaine and heroin and HIV-1 infection on 1) glutamate uptake and glutamate transporters (GT) and 2) chemokines involved in CNS inflammation such Macrophage Chemoattractant Protein-1 (MCP-1), Stromal derived factor-1 (SDF-1) and fractalkine. First, brain tissues from neurologically characterized patients with HIV-D with and without a history of drug abuse, will be studied to determine the profile of GT and chemokine expression and how these profiles correlate with neuroglial responses. Second, to further assess the role of cocaine and heroin in association with HIV infection, we will use a novel model of human organotypic brain cultures. These cultures will provide the ability to manipulate conditions, assess factors that affect both GT and chemokines, and monitor excitotoxicity. Third, we will use brain tissues from the macaque SIV model, a well studied animal model of HIV infection, to assess the profile of GT and excitotoxicity and determine how these factors affect the profile of neuroinflammatory changes. The results of these studies will facilitate a better understanding of the mechanisms of injury in HIV infection and drug abuse and will provide insight into the design of more effective therapeutics.

描述（由申请人提供）： HIV-1感染和药物滥用是美国的主要公共卫生问题。吸毒者感染艾滋病毒和出现认知缺陷的风险更高，从轻微损害到明显痴呆（艾滋病毒-D）。神经胶质细胞功能障碍是HIV-D和药物滥用中认知障碍的一个关键机制。谷氨酸代谢、趋化因子和细胞因子的特定改变可能导致兴奋性毒性和CNS炎症。该项目的总体目标是检查滥用药物（DOA），如可卡因和海洛因，并与HIV-1感染相结合，是否协同影响谷氨酸或选定的趋化因子的水平，导致神经元和神经胶质功能障碍。核心假设是DOA与HIV-1感染的产物协同作用，并影响兴奋性毒性、炎症和神经胶质反应的途径。为了解决这一假设，我们将检查DOA（如可卡因和海洛因）和HIV-1感染对1）谷氨酸摄取和谷氨酸转运蛋白（GT）和2）参与CNS炎症的趋化因子（如巨噬细胞趋化蛋白-1（MCP-1）、基质衍生因子-1（SDF-1）和fractalkine）的影响。首先，将研究具有神经学特征的有和没有药物滥用史的HIV-D患者的脑组织，以确定GT和趋化因子表达的概况以及这些概况如何与神经胶质细胞反应相关。其次，为了进一步评估可卡因和海洛因与HIV感染相关的作用，我们将使用一种新的人类器官型脑培养模型。这些培养物将提供操纵条件、评估影响GT和趋化因子的因素以及监测兴奋性毒性的能力。第三，我们将使用来自猕猴SIV模型的脑组织，这是一种研究充分的HIV感染动物模型，以评估GT和兴奋性毒性的概况，并确定这些因素如何影响神经炎症变化的概况。这些研究的结果将有助于更好地了解艾滋病毒感染和药物滥用中的损伤机制，并将为设计更有效的治疗方法提供见解。