Methamphetamine and HIV-1: NMDAR/D1 mediated neurologic effects

甲基苯丙胺和 HIV-1：NMDAR/D1 介导的神经系统效应

• 批准号: 8227953
• 负责人: Charles F. Mactutus
• 金额: $ 14.5万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8227953
• 关键词: AIDS/HIV problem; Adverse effects; Anti-Retroviral Agents; Apoptotic; Biological Markers; Cell Culture Techniques; Cessation of life; Cocaine; Cognition; Cognitive; Cognitive deficits; Complex; Country; Development; Dopamine D1 Receptor; Dopaminergic Agents; Dose; Enzyme-Linked Immunosorbent Assay; Epidemiologic Studies; European; Genistein; Glutamates; Goals; HIV; HIV Envelope Protein gp120; HIV Infections; HIV Seropositivity; HIV-1; Health; Human; Impaired cognition; Impairment; Individual; Infection; Injury; Kaempferols; Label; Life; Mediating; Medical; Memantine; Memory impairment; Mental Health; Methamphetamine; Methamphetamine dependence; Methods; Midbrain structure; Mitochondria; Modeling; Molecular; N-Methyl-D-Aspartate Receptors; NR1 gene; Nerve Degeneration; Neurocognitive; Neurologic Effect; Neuronal Injury; Neurons; Neuropathogenesis; Neurotoxins; North America; Pathway interactions; Personal Satisfaction; Persons; Prevalence; Process; Proteins; Public Health; Rattus; Recombinants; Recording of previous events; Research; Research Proposals; Risk; Rodent; Role; Signal Transduction; Synapses; System; Testing; Tissues; Toxic effect; Trans-Activators; Variant; Viral Proteins; adverse outcome; base; cognitive function; design; fetal; fighting; improved; in vitro testing; kaempferol; methamphetamine abuse; neuropsychological; neurotoxic; neurotoxicity; outcome forecast; pre-clinical research; protein protein interaction; public health relevance; research study; tat Protein; transmission process

DESCRIPTION (provided by applicant): The additive effects of HIV infection and methamphetamine (METH) abuse on cognitive function represent a serious medical problem. Experimental evidence indicates that neurotoxic viral proteins, particularly HIV-1 Tat and gp120, can cooperate with METH and promote neurodegeneration. However, mechanisms of such cooperation are elusive. Our prior research and preliminary studies indicate that the molecular mechanism of combined METH/Tat and/or METH/gp120 toxicity may involve concurrent adverse effects of these neurotoxins on key components of dopaminergic and glutamatergic transmission systems. This application will test the hypothesis that pathways of direct METH and HIV-1 protein-mediated neurotoxicity congregate to disrupt normal physical interactions between D1 and NMDA receptors. Thus, neurons, which co- express NMDA receptor complexes (NMDAR) and dopamine (DA) D1 receptors may be selectively sensitive to the injury concurrently incited by individually non-toxic doses of METH and HIV-1 proteins. This hypothesis will be tested in vitro using the primary rodent and human neural cell culture models of Tat/gp120/METH neurotoxicity. Faltered functional D1R/NMDAR interactions, which are often referred as "the engine of cognition", may critically influence the development of persistent memory deficits in HIV-positive methamphetamine abusers. The broad goal of our studies is to elucidate the molecular base of additive deleterious cognitive effects of METH and HIV infection. Results of the project will have an impact on the preclinical research of effective protective strategies to improve the health and well-being of METH-dependent individuals living with HIV/AIDS. PUBLIC HEALTH RELEVANCE: The additive effects of HIV infection and methamphetamine (METH) abuse on cognitive function represent a serious medical problem. The present research proposal will investigate the role of D1R/NMDAR interactions in the overlapping pathway of METH/HIV-1 protein neurotoxicity. The broad goal of the research is to elucidate the molecular basis of METH/HIV-induced cognitive deficits.

描述（由申请人提供）：艾滋病毒感染和甲基苯丙胺（甲基苯丙胺）对认知功能的添加作用代表了严重的医学问题。实验证据表明，神经毒性病毒蛋白，尤其是HIV-1 TAT和GP120，可以与METH合作并促进神经退行性。但是，这种合作的机制难以捉摸。我们先前的研究和初步研究表明，联合使用甲基甲基/TAT和/或METH/GP120毒性的分子机制可能涉及这些神经毒素对多巴胺能和谷氨酸疗法透射系统的关键成分的同时不良影响。该应用将检验以下假设：直接甲基和HIV-1蛋白介导的神经毒性的途径聚集在D1和NMDA受体之间破坏正常的物理相互作用。因此，共同表达NMDA受体复合物（NMDAR）和多巴胺（DA）D1受体的神经元可以选择性地敏感，该损伤是由单独的非毒性METH和HIV-1蛋白施加的损伤。该假设将在体外使用TAT/GP120/METH神经毒性的原代啮齿动物和人神经细胞培养模型进行体外检验。经常被称为“认知引擎”的动功能性D1R/NMDAR相互作用可能会严重影响HIV阳性甲基苯丙胺滥用器中持续记忆缺陷的发展。我们研究的广泛目的是阐明甲基甲基和HIV感染的添加性有害认知作用的分子基础。该项目的结果将对有效的保护策略的临床前研究产生影响，以改善与艾滋病毒/艾滋病相关的甲基苯丙胺依赖人的健康和福祉。 公共卫生相关性：艾滋病毒感染和甲基苯丙胺（甲基苯丙胺）对认知功能的添加作用代表了严重的医学问题。本研究建议将研究D1R/NMDAR相互作用在METH/HIV-1蛋白神经毒性重叠途径中的作用。该研究的广泛目标是阐明甲基/HIV诱导的认知缺陷的分子基础。