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Mechanisms and Interventions for Methamphetamine and HIV-1 Induced CNS Injury

甲基苯丙胺和 HIV-1 引起的中枢神经系统损伤的机制和干预措施

基本信息

批准号：
8448346
负责人：
Anuja Ghorpade
金额：
$ 37.54万
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：
2009
资助国家：
美国
起止时间：
2009-04-01 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8448346
关键词：
3-nitrotyrosine Address Adhesions Agonist American Amino Acid Transporter Animal Model Animals Anti-Inflammatory Agents Anti-inflammatory Antioxidants Area Astrocytes Behavior Biological Biological Assay Blood - brain barrier anatomy Brain CCR5 gene CXCR4 gene Cell Adhesion Molecules Cell Survival Cell physiology Cells Central Nervous System Infections Cessation of life Chronic Clinical Research Cocaine Cognitive deficits Consultations Cytoskeleton Data Dementia Detection Down-Regulation Drug usage Electrical Resistance Encephalitis Endothelial Cells Endothelium Excitatory Amino Acid Transporter 2 Functional disorder Future Generations Genetic Transcription Glutamate Transporter Glutamates Guanosine Triphosphate Phosphohydrolases HIV HIV-1 Health Human Immune Immune response Impaired cognition Impairment In Vitro Individual Infection Inflammation Mediators Injury Intervention Investigation Label Lead Leukocytes Levocarnitine Acetyl Link Magnetic Resonance Imaging Measures Mediating Methamphetamine Methamphetamine dependence Modeling Molecular Weight Monomeric GTP-Binding Proteins Mononuclear Mus Myosin Light Chain Kinase NF-kappa B NOD/SCID mouse Nerve Nerve Degeneration Neuraxis Neuroglia Neuronal Injury Neurons Non obese Outcome Oxidative Stress PPAR gamma Pathogenesis Pathway interactions Peripheral Blood Lymphocyte Permeability Pharmaceutical Preparations Phosphorylation Play Production Property Proteins Reactive Oxygen Species Reader Reading Regulation Rewards Risk Role Scheme Secondary to Signal Transduction Specimen Spinal Ganglia Stimulus Surveys Testing Therapeutic Therapeutic Intervention Tight Junctions Time Toxic effect Tracer Transcriptional Activation Trolox Tyrosine 3-Monooxygenase Viral Vitamin E Water Western Blotting Work adipocyte differentiation analog astrogliosis base brain tissue central nervous system injury chemokine cognitive function diabetic excitotoxicity extracellular functional disability immunocytochemistry in vitro Assay in vivo inhibitor/antagonist insight insulin sensitivity mRNA Expression macrophage methamphetamine abuse methamphetamine exposure methylxanthine migration monocyte monolayer nerve injury neuroinflammation neuropsychological neurotoxic neurotoxicity novel prevent propentofylline protective effect protein expression reconstitution research study response stimulant abuse therapeutic target transcription factor uptake

项目摘要

ABSTRACT: Methamphetamine (METH), an addictive stimulant has long lasting toxic effects on the central nervous system (CNS). Clinical studies indicated that METH dependence has an additive effect on neuropsychological deficits associated with HIV-1 infection. Oxidative stress, excitotoxicity, BBB impairment and glial cell activation, all have been independently implicated in the mechanisms of METH- and HIV-1-associated neurotoxicity. This proposal will investigate specific mechanisms operative in HIV-1 CNS infection and METH abuse that lead to an overall increase in oxidative stress and NF-kB signaling resulting in impairment of astrocytes and endothelial cell function. We propose that METH-mediated oxidative stress in astrocytes leads to a down regulation exitotoxic amino acid transporter (EAAT) -2, the primary astrocyte glutamate scavenger, while in endothelial cells, such an increase in oxidative stress results in loss of BBB integrity. Indeed, our preliminary data suggest that METH exposure caused ROS generation in astrocytes and human primary BMVEC, diminished EAAT-2 expression, in astrocytes, decreased BBB integrity in vitro that was restored by antioxidant treatment, caused decreased expression/re-distribution of tight junction proteins, enhanced adhesion and migration of monocytes across endothelial monolayers and activated small GTPases in BMVEC that were previously implicated in the BBB injury during HIV-1 encephalitis (HIVE). New preliminary data demonstrated increased permeability of BBB in vivo in animals exposed to METH that was prevented by antioxidant treatment. This proposal will investigate a novel concept of mechanistic commonality, i.e. METH-mediated oxidative stress exerts its cell-specific effects in astrocytes and endothelial cells aggravating injury caused by HIV-1 CNS infection and delineate therapeutic options for these targets using in vivo studies. Using a combination of in vitro assays and METH/HIVE animal model, we will address the following questions: What is the role(s) of enhanced reactive oxygen species, ROS production and NF-kB signaling in diminished expression/function of EAAT-2 in astrocytes? (Aim 1) What are underlying mechanisms of BBB dysfunction and enhanced monocyte adhesion/migration across brain endothelium (via oxidative stress, interference with NF-kB and GTPase signaling)? (Aim 2); and Can therapeutics decreasing oxidative stress and normalizing EAAT-2 function ameliorate BBB dysfunction and neurotoxicity in an animal model for HIVE and METH abuse? (Aim 3) We will address these questions utilizing primary human astrocytes and brain microvascular cells, in vitro BBB models and evaluate combined effects of METH and HIV-1 relevant stimuli on EAAT-2 and BBB function. Antioxidants and specific signaling inhibitors will be utilized to delineate pathways involved in these effects. Our HIVE animal model will be employed to investigate the biological outcomes of these cell-specific mechanisms in cognitive function, BBB damage and neurotoxicity. We believe that the proposed works are highly significant, as they will uncover novel mechanisms involved in the combined effects of HIV-1 and METH in the CNS and propose therapeutic approaches based on these investigations.

摘要：甲基苯丙胺（METH）是一种成瘾性兴奋剂，对中枢神经系统具有长期持久的毒性作用（CNS）。临床研究表明，METH依赖对神经心理缺陷具有累加效应与HIV-1感染有关。氧化应激、兴奋性毒性、BBB损伤和胶质细胞活化，所有已经独立地涉及METH-和HIV-1-相关神经毒性的机制。这一项提案将研究HIV-1中枢神经系统感染和甲基苯丙胺滥用的具体机制，氧化应激和NF-kB信号传导的总体增加导致星形胶质细胞受损，内皮细胞功能我们认为，星形胶质细胞中的MET介导的氧化应激导致了星形胶质细胞的凋亡。调节外向毒性氨基酸转运蛋白（EAAT）-2，主要的星形胶质细胞谷氨酸清除剂，而在在内皮细胞中，这种氧化应激的增加导致BBB完整性的丧失。事实上，我们的初步数据表明METH暴露引起星形胶质细胞和人原代BMVEC中ROS的产生，星形胶质细胞中EAAT-2表达的减少，降低了体外BBB的完整性，处理，引起紧密连接蛋白的表达/重新分布减少，粘附增强， BMVEC中单核细胞穿过内皮细胞单层的迁移和活化的小GTP酶，先前在HIV-1脑炎（HIVE）期间涉及BBB损伤。新的初步数据表明，在暴露于METH的动物中，体内血脑屏障通透性增加，抗氧化剂可预防这种情况治疗该提案将研究一种新的机制共性概念，即METH介导的氧化应激在星形胶质细胞和内皮细胞中发挥其细胞特异性作用，加重损伤引起的HIV-1中枢神经系统感染，并描绘这些目标的治疗方案，使用体内问题研究使用体外试验和METH/HIVE动物模型的组合，我们将解决以下问题问题：增强的活性氧、ROS产生和NF-kB信号在 EAAT-2在星形胶质细胞中的表达/功能减弱？(Aim 1）血脑屏障的潜在机制是什么功能障碍和增强的单核细胞粘附/迁移穿过脑内皮（通过氧化应激，干扰NF-kB和GT3信号传导）？(Aim 2）;以及可以降低氧化应激的治疗剂 EAAT-2功能正常化可改善HIVE动物模型中的BBB功能障碍和神经毒性滥用冰毒？(Aim 3）我们将利用原代人类星形胶质细胞和脑来解决这些问题。微血管细胞，体外BBB模型，并评估METH和HIV-1相关刺激对 EAAT-2和BBB功能。抗氧化剂和特定的信号传导抑制剂将被用来描绘途径参与这些影响。我们的HIVE动物模型将用于研究这些细胞特异性机制在认知功能，BBB损伤和神经毒性。我们认为所提出的工作是非常重要的，因为他们将揭示新的机制，涉及的联合效应 HIV-1和METH在中枢神经系统中的作用，并提出基于这些研究的治疗方法。