Novel Pathways of HAARTmediated Neuronal Toxicity in the Central Nervous System

HAART介导中枢神经系统神经元毒性的新途径

基本信息

批准号：
7492484
负责人：
Kelly L Jordan-Sciutto
金额：
$ 52.61万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-05-05 至 2011-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7492484
关键词：
AIDS Dementia Complex Address Adverse effects Affect Anti-Retroviral Agents Autophagocytosis Cells Cessation of life Cognition Disorders Cognitive Dependence Diagnosis Disease Dose Endoplasmic Reticulum Environment Frequencies Functional disorder Future Generations Goals HIV HIV Infections HIV Seropositivity Highly Active Antiretroviral Therapy Human Impaired cognition Incidence Individual Investigation Lead Life Mediating Microglia Minor Mitochondria Modeling Nerve Degeneration Neuraxis Neurocognitive Neurologic Neuronal Dysfunction Neurons Pathway interactions Patients Peripheral Peripheral Nervous System Pharmaceutical Preparations Plasma Prevalence Reactive Oxygen Species Relative (related person)Reporting Signal Pathway Source Stress Testing Therapeutic Toxic effect Viral base biological adaptation to stress design endoplasmic reticulum stress macrophage member mitochondrial dysfunction monocyte neuronal survival neurotoxic neurotoxicity novel protein metabolism

项目摘要

Despite a reduction in the incidence of HIV-associated dementia (HAD) in the era of Highly Active Anti-Retroviral Therapy (HAART), the prevalence of HAD is increasing, as is the frequency of minor cognitive diagnoses in HIV-positive patients. Although HAART is neurotoxic in both the peripheral nervous system and cultured neurons, the contribution of HAART to HIV-associated neurocognitive disorders is unknown. The toxicity of HAART compounds is due to distinct antiretroviral class-dependent mechanisms, such as alteration of protein metabolism and mitochondrial damage-induced generation of ROS (ROS), both of which have been implicated in other neurodegenerative conditions. These mechanisms, as well as HAART drugs themselves, can initiate the endoplasmic reticulum (ER) stress response, a multi-pronged pro-survival signaling pathway that may become deleterious if chronically activated, and autophagy, which has been implicated in neurodegeneration. An understanding of the cellular mechanisms triggered by the different classes of HAART drugs, in both neurons and macrophages, is crucial for guiding the design of new drugs and the assembly of combinational anti-retroviral therapies that minimize neurological impact. We hypothesize that HAART compounds induce neuronal toxicity both directly and indirectly (e.g. alteration of macrophage function), and that these mechanisms are mediated by cell-specific activation of stress responses that differ among classes of HAART compounds. Supporting this hypothesis, we have observed that individual antiretroviral drugs are neurotoxic in CNS cultures and that nontoxic drugs, when applied in recommended HAART combinations, become neurotoxic. We have also demonstrated an increase of downstream indicators of ER stress response activation in neurons and microglia/macrophages of patients with HIV-associated neurocognitive disorders, and in cultures of neurons and monocyte derived macrophages (MDM) following treatment with HAART compounds. Based on these findings, we propose to: 1) Determine the mechanisms of direct neuronal toxicity of HAART drug classes alone and in recommended, therapeutic combinations; 2) Determine the mechanisms of direct toxicity of HAART drug classes (alone and in combination) in monocyte derived macrophages, 3) Determine the contributions of HAART-exposed MDM to neurotoxicity. By investigating the cell-specific mechanisms of HAART toxicity in the central nervous system we will uncover an unexplored source for cognitive impairment in HIV-positive patients, identify targets to mitigate side-effects of HAART compounds that effectively control viral replilcation, and create a model to detect neurotoxicity of current and future HAART compounds alone and in combination.

尽管在高度活跃的抗逆转录病毒疗法（HAART）时代，与HIV相关痴呆（HART）的发生率降低了，但HAT的患病率也在增加，HIV阳性患者的较小认知诊断的频率也在增加。尽管HAART在周围神经系统和培养的神经元中都是神经毒性的，但HAART对HIV相关的神经认知疾病的贡献尚不清楚。 HAART化合物的毒性是由于独特的抗逆转录病毒类依赖性机制引起的，例如蛋白质代谢的改变和线粒体损伤引起的ROS（ROS）的产生（ROS），两者都与其他神经退行性条件有关。这些机制以及HAART药物本身都可以启动内质网应力反应，这是一种多支管的促阳性信号传导途径，如果长期激活，并且自噬可能会变得有害，并且与神经变性相关。对不同类别的HAART触发的细胞机制的理解在神经元和巨噬细胞中，药物对于指导新药的设计以及组合抗逆转录病毒疗法的组装至关重要，以最大程度地减少神经系统影响。我们假设HAART化合物直接和间接诱导神经元毒性（例如，巨噬细胞功能的改变），并且这些机制是通过细胞特异性激活HAART化合物之间不同的应激反应的激活来介导的。在支持这一假设的情况下，我们观察到，单个抗逆转录病毒药物在中枢神经系统培养物中是神经毒性的，并且在推荐的HAART组合中应用无毒药物会成为神经毒性。我们还证明了与HARART化合物治疗后，与HIV相关的神经认知疾病以及神经元和单核细胞衍生巨噬细胞（MDM）的神经元和单核细胞衍生型巨噬细胞（MDM）培养的神经元和巨噬细胞中ER应力反应激活的指标增加了。基于这些发现，我们提出：1）单独和建议的治疗组合，确定HAART药物类别直接神经元毒性的机制； 2）确定单核细胞衍生的巨噬细胞中HAART药物类别直接毒性的机制，3）确定暴露于HAART的MDM对神经毒性的贡献。通过研究中枢神经系统中HAART毒性的细胞特异性机制，我们将发现一个未探索的HIV阳性患者认知障碍来源，确定靶标，以减轻HAART化合物的副作用，从而有效地控制病毒复制，并创建一个模型的单独和未来的HAART HAART组合和组合和组合。