Dynorphin and Glial Cell Immunomodulation

描述(申请人提供)：HIV相关性痴呆(HAD)的神经发病机制涉及病毒蛋白、神经胶质细胞(小胶质细胞和星形胶质细胞)和介体(细胞因子/趋化因子和神经毒素)之间的复杂相互作用。越来越多的流行病学、组织病理学和分子证据表明，阿片类和可卡因等滥用物质促进了这种毁灭性大脑疾病的发展。然而，与阿片类药物相比，kappa-阿片受体(KOR)配体具有神经保护作用，而阿片类药物对Mu-阿片受体具有高亲和力。在这项拨款申请中提出的研究的基本假设是，KOR配体通过抑制小胶质细胞和星形胶质细胞的神经致病机制而对HIV-1相关的脑部疾病产生有益的影响。基于大量文献表明KOR配体阻断对可卡因的反应，本研究项目的第二个假设是可卡因通过增强小胶质细胞和星形胶质细胞的神经致病机制而对HIV-1相关性脑病产生有害影响，KOR配体将阻断可卡因的这些作用。为了验证这些假设，我们设计了几种与HIV-1神经发病机制相关的人类细胞培养模型(和功能分析)：小胶质细胞(HIV-1和神经致病介质的表达)、星形胶质细胞(趋化因子产生和谷氨酸摄取)、混合神经元/神经胶质细胞(凋亡)和神经前体细胞(增殖、分化和迁移)。在计划的实验中，将把选定的KOR配体的效果与可卡因进行比较，并评估KOR配体对可卡因的抑制作用。重点将放在确定KOR配体和可卡因的作用机制以及KOR配体阻断可卡因的神经致病作用的机制上。根据初步研究的结果，拟议的研究将对这些机制产生新的见解，因此，这项研究计划将促进寻找预防和治疗HAD的新干预措施的长期目标。

DESCRIPTION (provided by applicant): The neuropathogenesis of HIV-associated dementia (HAD) involves a complex interaction between viral proteins, glial cells (microglia and astrocytes), and mediators (cytokines/chemokines and neurotoxins). A growing body of epidemiological, histopathological, and molecular evidence indicates that substances of abuse, such as, opiates and cocaine, foster development of this devastating brain disorder. However, in contrast to opiates, which have high affinity for mu-opioid receptors, kappa-opioid receptor (KOR) ligands have been shown to have neuroprotective effects. The primary hypothesis underlying the research proposed in this grant application is that KOR ligands have a beneficial influence on HIV-1-related brain disease due to their inhibitory effects on neuropathogenic mechanisms of microglia and astrocytes. Based upon a substantial literature indicating that KOR ligands block responses to cocaine, a secondary hypothesis of this research project is that cocaine has a deleterious influence on HIV-1-related brain disease due to its potentiating effects on neuropathogenic mechanisms of microglia and astrocytes and that KOR ligands will block these effects of cocaine. To test these hypotheses, experiments have been designed using several human cell culture models (and functional assays) that are relevant to HIV-1 neuropathogenesis: microglial cells (expression of HIV-1 and neuropathogenic mediators), astrocytes (chemokine production and glutamate uptake), mixed neuronal/glial cells (apoptosis) and neural progenitor cells (proliferation, differentiation, and migration). In the experiments planned, the effects of selected KOR ligands, some of which have shown promise for treatment of cocaine addiction, will be compared to cocaine, and the inhibitory effects of KOR ligands on cocaine will be assessed. Major emphasis will be placed on defining the mechanisms underlying the effects of KOR ligands and cocaine and mechanisms whereby KOR ligands block the neuropathogenic effects of cocaine. Based upon the results of preliminary studies, the research proposed will yield new insights into these mechanisms and as a result this research project will foster the long-term goal of discovering new interventions for the prevention and treatment of HAD.