HIV infection and drugs of abuse in neuroglial function

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的风险更高，出现从轻微损害到坦率痴呆(HIV-D)的认知缺陷的风险更高。在HIV-D和药物滥用中，神经元功能障碍是认知障碍的一个关键机制是神经胶质功能障碍。谷氨酸代谢、趋化因子和细胞因子的特异性改变可能与兴奋性毒性和中枢神经系统炎症有关。该项目的总体目标是研究滥用药物(DOA)，如可卡因和海洛因，以及与艾滋病毒-1感染相结合，是否协同影响谷氨酸或选定的趋化因子水平，导致神经元和神经胶质功能障碍。中心假设是DOA与HIV-1感染产物协同作用，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，我们将研究DOA，如可卡因和海洛因以及HIV-1感染对1)谷氨酸摄取和谷氨酸转运体(GT)以及2)参与中枢神经系统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，将研究有和没有药物滥用史的具有神经学特征的HIV-D患者的脑组织，以确定GT和趋化因子的表达情况，以及这些情况与神经胶质反应的相关性。第二，为了进一步评估可卡因和海洛因在HIV感染中的作用，我们将使用一个新的人类器官型脑培养模型。这些培养物将提供操纵条件的能力，评估影响GT和趋化因子的因素，并监测兴奋性毒性。第三，我们将使用猕猴SIV模型的脑组织，这是一个研究得很好的HIV感染动物模型，来评估GT和兴奋毒性的概况，并确定这些因素如何影响神经炎性变化的概况。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造成的伤害机制，并将为设计更有效的治疗方法提供洞察。

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.