Glial versus Neuronal Caspase-3 in Opioid-HIV gp120 Neurotoxicity

描述（由申请人提供）：艾滋病毒-1是一种全球流行病，主要通过性接触和使用海洛因等注射药物传播。自1990年代中期实施cART（联合积极抗逆转录病毒疗法）以来，感染艾滋病毒-1和艾滋病的人的寿命延长了，这增加了与艾滋病毒-1有关的神经和心理特征。总的来说，这些中枢神经系统缺陷被称为HIV-1相关神经认知障碍（HAND），包括hiv相关痴呆（HAD）和hiv相关脑炎（HIVE）。总的来说，HAND综合征的特征是认知、运动和行为功能障碍；表明基底神经节功能障碍[7,34,42,75]。与患者的高病毒载量相结合，基底神经节内的纹状体区域优先具有高富集的mu-阿片受体（MOR）表达[24]。已知阿片类药物可以调节免疫功能，这种混淆可能会加重HIV-1的发病机制和神经系统并发症[20,44-6,66,74]。HIV-1的病毒外壳糖蛋白gp120是一种已知的神经毒素，是病毒进入和感染所必需的，其细胞外作用对体外和体内的神经元和胶质细胞（小胶质细胞和星形胶质细胞）都是有毒的

DESCRIPTION (provided by applicant): HIV-1 is a global epidemic spread predominantly through sexual contact and through the use of injectable drugs, such as heroin. Since the implementation of cART (Combined Active Antiretroviral Therapy) in the mid 1990's, infected individuals are living longer with HIV-1 and AIDS, which augments the neurological and psychological profiles associated with HIV-1. Collectively, these CNS deficits are known as HIV-1 associated neurocognitive disorders (HAND) and include HIV-associated dementia (HAD) and HIV-associated encephalitis (HIVE). Broadly, HAND syndromes are characterized by cognitive, motor and behavior dysfunctions; indicative of basal ganglia dysfunction [7,34,42,75]. In conjunction with high viral load in patients, the striatal region within the basal ganglia preferentially has a high abundance of mu- opioid receptor (MOR) expression [24]. Opioids are known to modulate immune function and this confound is likely to worsen the pathogenesis and neurological complications of HIV-1 [20,44-6,66,74]. The viral coat glycoprotein of HIV-1, gp120, is an established neurotoxin that is required for viral entry and infection, and its extracellular actions are toxic to neurons and glia (microglia and astrocytes) in vitro and in vivo in both human and rodent models [4,5,9,11,12,15,17,19,35,50,51, 60,61,70]. Our lab and others have demonstrated how opioids potentiate this gp120 induced neurotoxicity [1,28,45]. We have shown that gp120 increases caspase-3 activity and induces apoptosis of striatal neurons. We are interested in better understanding how opioids affect HIV-gp120 induced neurotoxicity within the striatum and specifically want to investigate the role of caspase-3 in both glial and neuronal mediated mechanisms of neurotoxicity. Studies are proposed to determine if glial caspase-3 mediates gp120 neurotoxicity 1 opioids, and to establish whether opioids act via caspase-3 to directly affect neuron injury and/or death in vitro using caspase-3 knockout cells. Finally, we wil employ the use of caspase-3 knockout mice to investigate how genome-wide deletion of the executioner caspase will affect glial and neuronal responses after gp120 1 opioids in vivo. Collectively, the proposed studies will add to the understanding of how caspase-3 plays a role in the interactive co-morbidity of gp120 and opioids in regards to HIV neuropathogenesis. With this information, a better understanding of underlying mechanisms are made possible which lead to new options in therapeutics, which have ramifications for opioid abusers and users infected with HIV-1.