Alcohol Abuse and HIV-1: Mechanisms of Combined CNS Injury and Interventions

酒精滥用和 HIV-1：中枢神经系统联合损伤的机制和干预措施

基本信息

批准号：
8283461
负责人：
James Haorah
金额：
$ 6.97万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-30 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8283461
关键词：
Acetaldehyde Address Affect Alcohol abuse Alcohol consumption Alcohol dependence Alcohol withdrawal syndrome Alcoholism Alcohols American Amino Acid Transporter Animal Feed Animal Model Animals Antioxidants Antiviral Agents Applications Grants Arachidonic Acids Astrocytes Biological Blood - brain barrier anatomy Brain Brain Injuries Cells Central Nervous System Infections Cessation of life Chronic Clinical Research Cognitive deficits Collaborations Cytochrome P-450 CYP2E1 Cytochromes Cytokine Activation Data Dementia Dependence Down-Regulation Encephalitis Endothelium Ethanol Ethanol Metabolism Evaluation Excitatory Amino Acids Exposure to Free Radicals Functional disorder Future Generations Genetic Transcription Glutamate Transporter Glutamates HIV Envelope Protein gp120 HIV-1 Health Human ITPR1 gene Image Immune Immune response Immune system Immunosuppression Impaired cognition Impairment In Vitro Individual Infection Inflammation Inflammation Mediators Inflammatory Injury Interstitial Collagenase Intervention Investigation Lead Levocarnitine Acetyl Link Magnetic Resonance Spectroscopy Maps Matrix Metalloproteinases Measures Mediating Mediator of activation protein Metabolism Metalloproteases Microglia Modeling Molecular Mononuclear Mus NADP NOD/SCID mouse Nerve Degeneration Neuraxis Neuroglia Neuronal Injury Neurons Nitric Oxide Non obese Organ Outcome Oxidative Stress Oxidative Stress Induction Pathway interactions Peripheral Blood Lymphocyte Permeability Pharmaceutical Preparations Phenotype Phospholipase A2 Phospholipase C Phosphorylation Production Prostaglandins Protein Tyrosine Kinase Proteins Radiology Specialty Reaction Reactive Oxygen Species Regulation Research Role Signal Pathway Signal Transduction Specimen Stimulus System TLR4 gene Testing Therapeutic Tight Junctions Time Toll-like receptors Toxic effect United States Viremia Western Blotting Withdrawal Symptom Work Xanthine Oxidase alcohol craving alcohol exposure astrogliosis base brain cell brain tissue central nervous system injury chemokine cytokine diabetic excitotoxicity extracellular feeding human NOS2A protein immunocytochemistry in vivo inhibitor/antagonist insight macrophage methylxanthine migration monocyte nerve injury neuroimaging neuroinflammation neuropathology neurotoxic neurotoxicity novel oxidative damage prevent problem drinker propentofylline protective effect protein expression public health relevance response rho GTP-Binding Proteins src-Family Kinases therapeutic target toll-like receptor 4 uptake white matter

项目摘要

DESCRIPTION (provided by applicant): Alcohol is the most commonly used and abused drug in the United States. Deleterious alcohol-related health effects, attributed to internal organ toxicity, include irreversible brain tissue injury. Brain tissue of chronic alcoholics features neurodegeneration paralleling neuro-cognitive deficits. The causes of HIV-1-associated neurotoxicity, clinically manifesting as HIV-1 associated dementia (HAD), include excitotoxic effects of glutamate, secretory products of chronically activated glial cells, and oxidative stress, similar culprits to ones mediating alcohol-induced neuronal injury. Alcohol abuse and HIV-1 infection of central nervous system (CNS) could result in combined toxic effects leading to neuronal demise and cognitive dysfunction. The current grant application is focused on putative mechanisms of enhanced neurotoxicity in the setting of alcohol abuse and HIV-1 CNS infection. Specifically, we will study unique aspects of astrocyte dysfunction caused by HIV-1 CNS infection and alcohol abuse. We hypothesize that astrocyte dysfunction caused by alcohol metabolites and oxidative stress results in (1) increased glutamate levels via down regulation of excitatory amino acid transporter (EAAT-2, the primary astrocyte glutamate scavenger) causing neuronal injury; (2) production of pro-inflammatory factors (via activation of Src kinases and phospholipase A2); and (3) enhanced activity of metalloproteases (MMPs) resulting in loss of blood brain barrier (BBB) integrity. We mechanistically address the role of oxidative stress in astrocytes leading to production of pro-inflammatory molecules and impairment of glutamate uptake by astrocytes. Using a combination of in vitro systems, an HIVE animal model chronically exposed to alcohol, and in vivo magnetic resonance spectroscopy, we will investigate the astrocyte dysfunction as a focal point of combined effects of HIV-1 and alcohol abuse in the CNS. We will address the following questions: (1) What are the underlying mechanisms causing astrocyte pro-inflammatory phenotype in the setting of alcohol abuse and HIV-1 CNS infection that cause activation of MMPs and BBB dysfunction? (Aim 1); (2) What is the role/contribution of enhanced production of reactive oxygen species, Rho GTPases, and NF-?B signaling in diminished expression and function of EAAT-2 in astrocytes? (Aim 2); (3) How effective are the therapeutics that target oxidative stress and EAAT-2 dysregulation in ameliorating neurotoxicity and BBB impairment in an animal model for HIV-1 encephalitis and alcohol abuse? (Aim 3). Antioxidants and specific signaling inhibitors will be utilized to delineate pathways involved in these effects. We believe that the proposed works are highly significant as they will uncover novel mechanisms involved in the combined effects of HIV-1 and alcohol abuse in the CNS and propose therapeutic approaches based on these investigations. Public Health Relevance: Alcohol is abused by millions of Americans has long lasting toxic effects on the central nervous system. Clinical studies indicated that alcohol dependence has an additive effect on cognitive deficits associated with HIV-1 infection. Current proposal aims to understand mechanisms of combined effects of HIV-1 and alcohol abuse in the brain and to propose neuroprotective therapies.

描述（由申请人提供）：酒精是美国最常用和滥用的药物。与酒精相关的有害健康影响（归因于内脏器官毒性）包括不可逆的脑组织损伤。慢性酗酒者的脑组织具有与神经认知缺陷并行的神经变性。 HIV-1 相关神经毒性的原因，临床上表现为 HIV-1 相关痴呆 (HAD)，包括谷氨酸的兴奋毒性作用、长期激活的神经胶质细胞的分泌产物和氧化应激，与介导酒精引起的神经元损伤的罪魁祸首类似。。酗酒和中枢神经系统 (CNS) HIV-1 感染可能会产生综合毒性作用，导致神经元死亡和认知功能障碍。目前的拨款申请主要集中在酗酒和 HIV-1 中枢神经系统感染情况下增强神经毒性的假定机制。具体来说，我们将研究 HIV-1 CNS 感染和酗酒引起的星形胶质细胞功能障碍的独特方面。我们假设由酒精代谢物和氧化应激引起的星形胶质细胞功能障碍导致（1）通过下调兴奋性氨基酸转运蛋白（EAAT-2，主要的星形胶质细胞谷氨酸清除剂）增加谷氨酸水平，从而导致神经元损伤； (2) 产生促炎因子（通过激活 Src 激酶和磷脂酶 A2）； (3) 金属蛋白酶 (MMP) 活性增强，导致血脑屏障 (BBB) 完整性丧失。我们从机制上解决了星形胶质细胞中氧化应激的作用，导致星形胶质细胞产生促炎分子并损害星形胶质细胞的谷氨酸摄取。结合使用体外系统、长期暴露于酒精的 HIVE 动物模型和体内磁共振波谱，我们将研究星形胶质细胞功能障碍作为 HIV-1 和酒精滥用对 CNS 的综合影响的焦点。我们将解决以下问题：（1）在酗酒和 HIV-1 CNS 感染的情况下，导致星形胶质细胞促炎表型的潜在机制是什么？导致 MMP 激活和 BBB 功能障碍？（目标 1）； (2) 星形胶质细胞中活性氧、Rho GTPases 和 NF-κB 信号传导的增强在 EAAT-2 表达和功能减弱中起什么作用/贡献？（目标 2）； (3) 在 HIV-1 脑炎和酒精滥用动物模型中，针对氧化应激和 EAAT-2 失调的治疗方法在改善神经毒性和 BBB 损伤方面的效果如何？（目标 3）。抗氧化剂和特定信号抑制剂将用于描绘这些效应所涉及的途径。我们相信，拟议的工作非常重要，因为它们将揭示 HIV-1 和酒精滥用在中枢神经系统中联合作用的新机制，并根据这些研究提出治疗方法。公共卫生相关性：数百万美国人滥用酒精，对中枢神经系统产生长期持久的毒性作用。临床研究表明，酒精依赖对 HIV-1 感染相关的认知缺陷具有累加效应。目前的提案旨在了解 HIV-1 和酒精滥用对大脑的联合影响机制，并提出神经保护疗法。