The Elucidation of the Neuroprotective Effects of Triazoles Against HIV

三唑类药物对 HIV 的神经保护作用的阐明

基本信息

批准号：
7929330
负责人：
Valerie Toodle
金额：
$ 3.4万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-03-15 至 2012-03-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7929330
关键词：
AIDS Dementia Complex Acids Antifungal Agents Astrocytes Blood - brain barrier anatomy Brain Cell Death Cell membrane Cells Cessation of life Cyclic AMP Diagnosis Disease Drug effect disorder Environment FDA approved Fluconazole Functional disorder Grant HIV HIV Envelope Protein gp120 HIV Infections HIV tat Protein Healthcare Impaired cognition Individual Infection Inflammatory Injury Laboratories Lead Mediating Microglia Mitochondria Necrosis Neurocognitive Neuronal Injury Neurons Neuroprotective Agents Neurotoxins Nitrous Oxide Patients Pharmaceutical Preparations Population Production Proteins Public Health Reactive Oxygen Species Research Toxin Transgenic Mice Triazoles Tumor Necrosis Factor-alpha Viral Proteins antiretroviral therapy burden of illness cell type chemokine drug structure fight against functional group human TNF protein in vivo macrophage monocyte mouse model oxidative damage public health relevance tumor

项目摘要

DESCRIPTION (provided by applicant): HIV-associated dementia (HIVAD) is a challenging illness in healthcare field today. This disease occurs as a result of HIV-infected monocytes and macrophages crossing into the brain via the blood-brain barrier. These infected cells then release various neurotoxins including tumor necrosis alpha (TNF-alpha), nitrous oxide, and chemokines which creates an inflammatory environment in the brain. Additionally, HIV infection typically spreads to microglia while astrocytes become latently infected. The infection of these two cell types can lead to the release of the HIV proteins Tat and gp120 in addition to the neurotoxins previously mentioned. The release of the viral proteins and neurotoxins leads to significant injury and death in neurons, which are not directly infected by the HIV. Neuronal injury and cell death are directly related to the cognitive dysfunctions observed in patients diagnosed with HIVAD; therefore, a neuroprotective agent would be a powerful aid in the fight against this illness. Preliminary studies in our laboratory have identified the FDA-approved antifungal agent fluconazole as a neuroprotective agent against HIV Tat protein and 3-nitroproprionic acid, a toxin used to mimic the oxidative damage, reactive oxygen species production, and ensuing neurodegenration resulting form HIV infection in the brain. The applicant will characterize the neuroprotective effects observed with the drug fluconazole by determining the activity of the drug against HIV gp120, its effect on neuroprogenitor cells, and whether some actions of the drug are mediated by a direct effect on the mitochondria or the cell membrane. Additionally, this grant proposes to investigate the in vivo effects of fluconazole on HIV protein transgenic mouse models. Finally, this grant proposes to investigate the mechanism by which fluconazole is responsible for its neuroprotective effects. Our preliminary studies show that the presence of fluconazole leads to decreased intracellular levels of cyclic adenosine monophosphate (cAMP), an important secondary messenger. We plan to investigate if this inhibition of intracellular cAMP is responsible for fluconazole's neuroprotective effects, and if these effects are mediated by the triazole functional groups present in the drug's structure. PUBLIC HEALTH RELEVANCE: The research is important to public health since HIV-associated neurocognitive disorder (HAND) is becoming more and more prevalent in HIV-infected populations. Additionally, although the use of antiretroviral therapy is now becoming more accessible worldwide, antiretroviral therapy is unable to halt the progression of neurocognitive dysfunction observed in individuals with HAND. Therefore, the identification of fluconazole as a potent neuroprotective agent would greatly reduce the disease burden of HAND.

描述（由申请人提供）：与HIV相关的痴呆（HIVAD）是当今医疗保健领域中充满挑战的疾病。这种疾病是由于艾滋病毒感染的单核细胞和巨噬细胞通过血脑屏障穿越大脑的结果。然后，这些感染的细胞释放了各种神经毒素，包括肿瘤坏死α（TNF-Alpha），一氧化二氮和趋化因子，它们在大脑中产生炎症环境。此外，HIV感染通常会传播到小胶质细胞，而星形胶质细胞则受到潜在感染。除了前面提到的神经毒素外，这两种细胞类型的感染还可能导致HIV蛋白TAT和GP120的释放。病毒蛋白和神经毒素的释放会导致神经元的重大损伤和死亡，而神经元未直接感染HIV。神经元损伤和细胞死亡与诊断为HIVAD的患者观察到的认知功能障碍直接相关。因此，神经保护剂将是对抗这种疾病的有力帮助。我们实验室的初步研究已经确定了FDA批准的抗真菌剂氟康唑是针对HIV TAT蛋白和3-硝基孕妇的神经保护剂，这是一种用于模仿氧化性损伤的毒素，并导致神经脱发的形式的HIV造成神经脱发的形式感染。大脑。申请人将通过确定药物对HIV GP120的活性，对神经元素细胞的作用以及该药物的某些作用是否是通过对线粒体或细胞膜的直接作用介导的，以表征对药物氟康唑观察到的神经保护作用。此外，该赠款建议研究氟康唑对HIV蛋白质转基因小鼠模型的体内影响。最后，该赠款建议研究氟康唑对其神经保护作用负责的机制。我们的初步研究表明，氟康唑的存在导致细胞内循环腺苷单磷酸（CAMP）的降低，这是一个重要的次要信使。我们计划调查这种细胞内cAMP的抑制是否负责氟康唑的神经保护作用，以及这些作用是否是由药物结构中存在的三唑官能团介导的。公共卫生相关性：这项研究对公共卫生很重要，因为与艾滋病毒相关的神经认知障碍（HARD）在感染HIV的人群中变得越来越普遍。此外，尽管现在在全球范围内使用抗逆转录病毒疗法，但抗逆转录病毒疗法无法阻止在有手人中观察到的神经认知功能障碍的进展。因此，将氟康唑鉴定为有效的神经保护剂将大大减轻疾病的负担。