Mechanism of HIV-1 Tat Potentiation of Methamphetamine Neurotoxicity

HIV-1 Tat 增强甲基苯丙胺神经毒性的机制

• 批准号: 8762412
• 负责人: William F Maragos
• 金额: --
• 依托单位: VA VETERANS ADMINISTRATION HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-10-01 至 2016-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8762412
• 关键词: Affect; Basal Ganglia; Behavioral; Brain; Brain Injuries; Caring; Cell Death; Ceramides; Chemosensitization; Cognition; Corpus striatum structure; Cytoplasm; Data; Dementia; Development; Dopamine; Exposure to; Functional disorder; Funding; Genetic; Goals; Grant; HIV-1; Health; Illicit Drugs; Impaired cognition; Individual; Infection; Laboratories; Lead; Mediating; Methamphetamine; Nervous System Trauma; Neuraxis; Neurodegenerative Disorders; Neuronal Injury; Neurons; Neurotransmitters; Parkinson Disease; Pathogenesis; Pathology; Patients; Pharmaceutical Preparations; Play; Population; Presynaptic Terminals; Production; Property; Reactive Oxygen Species; Research; Rest; Risk; Role; Second Messenger Systems; Sex Behavior; Signal Transduction; Smooth Muscle; Structure; Symptoms; System; TNF gene; Therapeutic; Therapeutic Intervention; Tissues; Toxic effect; Tumor Necrosis Factor-alpha; Veterans; Viral; base; behavior measurement; cytokine; drug of abuse; innovation; insight; methamphetamine abuse; motor disorder; neurotoxicity; novel; putamen; research study; second messenger; synergism; tat Protein; vesicular monoamine transporter; vesicular release

DESCRIPTION (provided by applicant): In the central nervous system, basal ganglia structures are highly susceptible to infection with the human immunodeficiency virus-1 (HIV). The HIV-1 protein, Tat, which is involved in viral replication, also plays an important role in the neuronal injury and recapitulates much the pathology seen in HIV-1 infection of the brain. Patients with HIV-1 infection often abuse drugs such as methamphetamine, a drug that is well known to also cause long-term structural and functional changes of the basal ganglia. Previous studies from our laboratory have demonstrated that Tat protein and methamphetamine interacted synergistically to cause profound damage to the basal ganglia dopaminergic neurotransmitter system. Although our earlier studies implicated reactive oxygen species and the cytokine TNF-1, our preliminary data strongly suggest that ceramide-induced alterations of the vesicular monoamine transporter may play a prominent role in the enhanced toxicity of MA seen after exposure to Tat. In this proposal, we will in Specific Aim 1, determine whether HIV-1 Tat alters the compartmentalization of DA in the synaptic terminal. In Specific Aim 2, we will investigate whether the production of the second messenger ceramide is involved in Tat-induced changes in dopamine compartmentalization. Lastly, in Specific Aim 3, we will determine whether ceramide mediates the synergism between Tat and methamphetamine. Both pharmacological and genetic inhibition of ceramide synthesis will be pursued. In studying these interactions, we will examine 1) vesicular mononamine transporter function, 2) dopamine release (vesicular and tissue) 3) dopamine terminal integrity and 4) behavioral measures. The results of these experiments will elucidate a novel role for ceramide signaling in dopaminergic dysfunction, not only in HIV-1, but also in the neuronal injury associated with Parkinson's disease.

描述（由申请人提供）： 在中枢神经系统中，基底神经节结构非常容易感染人类免疫缺陷病毒-1（HIV）。与病毒复制有关的HIV-1蛋白TAT在神经元损伤中也起着重要作用，并概括了大脑HIV-1感染中所见的许多病理。 HIV-1感染的患者经常滥用甲基苯丙胺等药物，甲基苯丙胺众所周知，该药物也会引起基底神经节的长期结构和功能变化。我们实验室的先前研究表明，TAT蛋白和甲基苯丙胺相互作用是协同相互作用的，从而对基底神经节神经蛋白能神经递质系统造成了深远的损害。尽管我们较早的研究涉及活性氧和细胞因子TNF-1，但我们的初步数据强烈表明，神经酰胺诱导的囊泡单胺转运蛋白的变化可能在暴露于TAT后看到的MA的增强毒性中起着重要作用。在此提案中，我们将在特定的目标1中确定HIV-1 TAT是否改变了突触终端中DA的分区化。在特定的目标2中，我们将研究第二信使神经酰胺的产生是否参与了TAT诱导的多巴胺分区化变化。最后，在特定的目标3中，我们将确定神经酰胺是否介导TAT和甲基苯丙胺之间的协同作用。将追求药理学和遗传抑制神经酰胺合成。在研究这些相互作用时，我们将检查1）囊泡单胺转运蛋白功能，2）多巴胺释放（囊泡和组织）3）多巴胺末端完整性和4）行为措施。这些实验的结果将阐明神经酰胺信号在多巴胺能功能障碍中的新作用，不仅在HIV-1中，而且在与帕金森氏病有关的神经元损伤中。