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

描述(申请人提供)：HIV-1是一种全球流行病，主要通过性接触和使用注射毒品，如海洛因传播。自20世纪90年代中期实施CART(联合积极抗逆转录病毒治疗)以来，感染者感染艾滋病毒-1和艾滋病的时间更长，这增加了与艾滋病毒-1相关的神经和心理特征。总而言之，这些中枢神经系统缺陷被称为艾滋病毒-1相关性神经认知障碍(HAND)，包括艾滋病毒相关性痴呆(HAD)和艾滋病毒相关性脑炎(HIVE)。广泛地说，手部综合征的特征是认知、运动和行为功能障碍；预示着基底节功能障碍[7，34，42，75]。伴随着患者的高病毒载量，基底节内的纹状体区域优先有高丰度的mU-阿片受体(MOR)表达[24]。阿片类药物已知可以调节免疫功能，这种混淆可能会恶化HIV-1的发病机制和神经系统并发症[20，44-6，66，74]。HIV-1的病毒衣壳糖蛋白gp120是一种公认的神经毒素，是病毒进入和感染所必需的，其细胞外作用在体外和体内对神经元和神经胶质细胞(小胶质细胞和星形胶质细胞)具有毒性。 在人类和啮齿动物模型中[4，5，9，11，12，15，17，19，35，50，51，60，61，70]。我们的实验室和其他人已经证明了阿片类药物如何增强gp120诱导的神经毒性[1，28，45]。我们发现gp120可以增强caspase-3的活性并诱导纹状体神经元的凋亡。我们有兴趣更好地了解阿片类药物如何影响HIV-gp120在纹状体内诱导的神经毒性，特别是想要研究caspase-3在神经胶质和神经元介导的神经毒性机制中的作用。有人建议进行研究，以确定胶质细胞caspase-3是否介导gp120神经毒性1阿片类药物，并利用caspase-3基因敲除细胞在体外确定阿片类药物是否通过caspase-3直接影响神经元损伤和/或死亡。最后，我们将使用caspase-3基因敲除的小鼠来研究在活体内gp120 1阿片类药物后，全基因组范围内的执行者caspase的缺失如何影响神经胶质和神经元的反应。总而言之，拟议的研究将增加对caspase-3如何在gp120和阿片类药物在艾滋病毒神经发病中交互作用的共同发病中的作用的理解。有了这些信息，就有可能更好地了解潜在的机制，从而在治疗方面产生新的选择，这对阿片类药物滥用者和感染艾滋病毒-1的使用者有影响。 公共卫生相关性：艾滋病毒阳性的阿片类药物滥用者表现出加速发展为艾滋病的趋势，由于目前的抗逆转录病毒疗法使感染者的寿命更长，因此艾滋病毒相关的神经认知障碍，包括痴呆症的发病率增加。我们的研究将有助于确定潜在的治疗药物，用于预防和治疗使用和/或滥用阿片类药物的HIV阳性患者的神经认知功能障碍。

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. PUBLIC HEALTH RELEVANCE: HIV-positive opioid drug abusers show an expedited progression to AIDS and since infected individuals are living longer with current antiretroviral therapy there is an increasing rate of HIV-associated neurocognitive disorders including dementia. Our research will help identify potential therapeutic agents for the prevention and treatment of neurocognitive dysfunction in HIV-positive individuals using and/or abusing opioids.