Dopamine system as reporter of HIV status and inflammation in Meth abusers

多巴胺系统作为冰毒滥用者艾滋病毒状况和炎症的报告者

• 批准号: 10343776
• 负责人: Maria Cecilia Garibaldi Marcondes
• 金额: $ 43.2万
• 依托单位: SAN DIEGO BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10343776
• 关键词: Affect; Age; Alleles; Anti-Retroviral Agents; Basic Science; Biological Markers; Blood; Brain; CCR5 gene; Cells; Central Nervous System Diseases; Characteristics; Clinical; Cognitive; Cognitive deficits; Data; Development; Dopamine; Dopamine Receptor; Encephalitis; Environment; Equilibrium; Exposure to; Gene Frequency; Genetic; Genetic Polymorphism; Genetic Transcription; Genomics; Genotype; Goals; HIV; HIV Infections; Human; IL6 gene; Immune; Immunologic Markers; Individual; Individual Differences; Inflammation; Inflammatory; Knowledge; Life Expectancy; METH abuser; Methamphetamine; Monitor; Neuraxis; Neuroimmune; Neurologic; Neurologic Deficit; Neurological outcome; Neuropsychology; Neurotransmitters; Nucleotides; Organ; Outcome; Pathogenesis; Performance; Peripheral; Pharmaceutical Preparations; Phenotype; Plasma; Predisposition; Process; Receptor Gene; Reporter; Rewards; Risk; Risk Factors; Role; Sampling; Severities; Signal Transduction; Single Nucleotide Polymorphism; Statistical Models; Syndrome; Testing; Therapeutic; Time; Treatment Efficacy; Viral; Virus; Virus Receptors; Virus Replication; biomarker signature; cognitive development; cognitive function; cognitive performance; comorbidity; design; dopamine system; drug abuser; experience; experimental study; individual variation; inflammatory marker; mathematical model; methamphetamine abuse; methamphetamine user; models and simulation; molecular subtypes; neuroAIDS; neuropathology; peripheral blood; programmed cell death protein 1; psychologic; screening; sex; substance use; tool; translational applications; translational impact

Dopamine system as reporter of HIV status and inflammation in Meth abusers HIV life-expectancy has increased with anti-retrovirals, but the consequences of the virus in end-organs such as the Central Nervous System (CNS) have not been mitigated. Moreover, co-morbidities such as substance use can aggravate CNS disorders in HIV infection, impacting viral replication and inflammation. Methamphetamine (Meth) is a popular addictive drug associated with risk of HIV infection, and a powerful inducer of dopamine (DA), a neurotransmitter that regulates reward circuits in the brain. Inflammatory biomarkers such as plasma CD163 and IL6 levels correlate with HIV-induced cognitive deficits, including in Meth abusers. They indicate that an inflammatory process is taking place in the brain, but may not be able to predict risk of development of CNS inflammation in Meth abusers, or monitor improvements in cognitive performance in the context of HIV. Innate immune cells are the main HIV target cells in the CNS. Importantly, these cells express DA receptors (DRDs), and therefore are responsive to the hyperdopaminergic environment generated by Meth abuse. We hypothesize that the expression of molecules of the DA system, as well as inflammatory markers resulting from DA signaling, are sensitive biomarkers that may be incorporated into a panel of tools with the capacity to predict susceptibility and to assess therapeutic efficacy in the blood of HIV+ subjects that are Meth-abusers. We also hypothesize that the individual genetic background can bias the balance between D1-like and D2-like DRD subtypes, and their resulting inflammatory signatures affecting HIV latency or replication phenotypes. We propose studies in human peripheral cells that bridge basic science findings with translational applications of high impact, for screening DRD subtypes expression levels and sequence, as well as inflammatory signatures associated with these subtypes as predictors of risk to the development of cognitive deficits in Meth abusers, in the context of HIV. Our integrated approach is targeted to predict and monitor neuro-immune-viral disruptions, and generate tools to become incorporated in clinical therapeutic decisions. It will provide invaluable data to fill the existing gap in the knowledge and in the needs of markers with real-time clinical value, with the potential for critically monitoring the efficacy of therapy in the CNS, or for predicting susceptibility to disabling neurological syndromes in HIV+ individuals that are drug abusers.

多巴胺系统作为甲基苯丙胺滥用者HIV状态和炎症的报告者 抗逆转录病毒药物增加了艾滋病毒的预期寿命，但病毒在终末器官中的后果， 因为中枢神经系统（CNS）未得到缓解。此外，合并症，如物质 使用可加重HIV感染时的中枢神经系统疾病，影响病毒复制和炎症。 甲基苯丙胺（Methamphetamine）是一种流行的成瘾性药物，与艾滋病毒感染的风险有关， 多巴胺（DA）的诱导剂，多巴胺是一种调节大脑中奖励回路的神经递质。炎性 诸如血浆CD 163和IL 6水平的生物标志物与HIV诱导的认知缺陷相关，包括 吸毒者。它们表明大脑中正在发生炎症过程，但可能无法 预测甲基苯丙胺滥用者中枢神经系统炎症发生的风险，或监测认知功能的改善 在艾滋病毒方面的表现。先天性免疫细胞是CNS中主要的HIV靶细胞。重要的是， 这些细胞表达DA受体（DRD），因此对高多巴胺能环境有反应 是由滥用冰毒引起的我们假设DA系统分子的表达，以及 由DA信号传导产生的炎性标志物是敏感的生物标志物，其可以掺入到炎症反应中。 一组能够预测易感性和评估HIV+血液治疗效果的工具 这些人都是滥用冰毒的人。我们还假设，个人的遗传背景可以偏见， D1样和D2样DRD亚型之间的平衡，以及它们产生的影响HIV的炎症特征 潜伏或复制表型。我们建议在人类外周细胞中进行研究， 具有高影响力的转化应用的科学发现，用于筛查DRD亚型 表达水平和序列，以及与这些亚型相关的炎症特征， 在HIV背景下，甲基苯丙胺滥用者认知缺陷发展风险的预测因素。我们 综合方法的目标是预测和监测神经免疫病毒破坏，并产生工具， 纳入临床治疗决策。它将提供宝贵的数据，以填补现有的差距， 知识和具有实时临床价值的标记物的需求，具有关键监测的潜力 CNS治疗的疗效，或预测HIV+患者对致残性神经系统综合征的易感性 吸毒的人。