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：
8072571
负责人：
Valerie Toodle
金额：
$ 2.12万
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/8072571
关键词：
AIDS Dementia Complex Acids Anti-Retroviral Agents Antifungal Agents Astrocytes Biological Assay Blood - brain barrier anatomy Brain Carbon Cell Death Cell membrane Cells Cerebrospinal Fluid Cessation of life Clinical Trials Cyclic AMP Cytochrome P450 DNA Diagnosis Disease Drug effect disorder Environment Enzymes Ergosterol FDA approved Failure Family Fluconazole Functional disorder Grant HIV HIV Envelope Protein gp120 HIV Infections HIV tat Protein HIV-1 Healthcare Impaired cognition Impairment In Vitro Individual Infection Inflammatory Injury Laboratories Lead Mediating Microglia Mitochondria Mitochondrial Proteins Mycoses Necrosis Nerve Degeneration Neurocognitive Neuronal Injury Neurons Neuropathogenesis Neuroprotective Agents Neurotoxins Nitrogen Nitrous Oxide Patients Penetration Pharmaceutical Preparations Population Production Property Proteins Public Health Reactive Oxygen Species Research Screening procedure Sterol Biosynthesis Pathway Toxin Transgenic Mice Triazoles Tumor Necrosis Factor-alpha Viral Viral Proteins Virus Water antiretroviral therapy burden of illness cell type chemokine drug development drug structure effective therapy fight against functional group fungus human TNF protein in vivo macrophage member monocyte mouse model neuroprotection oxidative damage phosphoric diester hydrolase prevent tumor

项目摘要

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.

与HIV相关的痴呆症（Hivad）在当今医疗保健领域是一种具有挑战性的疾病。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。在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-硝基孕激素酸的神经保护剂，这是一种模仿氧化性损伤，活性氧的产生，并导致神经脱发的毒素。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。