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

基本信息

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
项目类别：
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

项目摘要

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）：HIV 感染和甲基苯丙胺 (METH) 滥用对认知功能的叠加影响是一个严重的医学问题。实验证据表明，神经毒性病毒蛋白，特别是 HIV-1 Tat 和 gp120，可以与冰毒协同作用，促进神经退行性变。然而，这种合作的机制却难以捉摸。我们之前的研究和初步研究表明，METH/Tat 和/或 METH/gp120 联合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能传输系统的关键组成部分同时产生的不利影响。该应用将测试以下假设：直接 METH 和 HIV-1 蛋白介导的神经毒性途径聚集在一起，会破坏 D1 和 NMDA 受体之间的正常物理相互作用。因此，共表达 NMDA 受体复合物 (NMDAR) 和多巴胺 (DA) D1 受体的神经元可能对单独无毒剂量的 METH 和 HIV-1 蛋白同时引起的损伤选择性敏感。该假设将使用 Tat/gp120/METH 神经毒性的主要啮齿动物和人类神经细胞培养模型进行体外测试。功能失调的 D1R/NMDAR 相互作用通常被称为“认知引擎”，可能会严重影响 HIV 阳性甲基苯丙胺滥用者持续性记忆缺陷的发展。我们研究的总体目标是阐明甲基苯丙胺和艾滋病毒感染所造成的附加有害认知效应的分子基础。该项目的结果将对有效保护策略的临床前研究产生影响，以改善依赖冰毒的艾滋病毒/艾滋病患者的健康和福祉。公共卫生相关性：HIV 感染和甲基苯丙胺 (METH) 滥用对认知功能的叠加影响是一个严重的医学问题。本研究计划将研究 D1R/NMDAR 相互作用在 METH/HIV-1 蛋白神经毒性重叠途径中的作用。该研究的总体目标是阐明冰毒/艾滋病毒引起的认知缺陷的分子基础。