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: 10542737
• 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 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10542737
• 关键词: Affect; Age; Alleles; Anti-Retroviral Agents; Basic Science; Biological Markers; Blood; Brain; CCR5 gene; Cells; Central Nervous System; 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; 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; Risk Marker; 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 function; cognitive performance; comorbidity; design; dopamine system; drug abuser; experience; experimental study; improved; individual variation; inflammatory marker; mathematical model; methamphetamine abuse; methamphetamine user; models and simulation; molecular subtypes; neuroAIDS; neuropathology; peripheral blood; programmed cell death protein 1; risk prediction; 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.

多巴胺系统是吸毒者HIV状态和炎症反应的报告 艾滋病毒的预期寿命随着抗逆转录病毒药物的使用而增加，但病毒在终末器官如 因为中枢神经系统(CNS)并未得到缓解。此外，物质等共病 使用可加重艾滋病毒感染中的中枢神经系统紊乱，影响病毒复制和炎症。 甲基苯丙胺(Meth)是一种流行的成瘾药物，与艾滋病毒感染的风险有关，而且是一种强大的 多巴胺(DA)的诱导剂，一种调节大脑奖赏回路的神经递质。炎症性 血浆CD163和IL6水平等生物标记物与艾滋病毒诱导的认知障碍相关，包括在 冰毒滥用者。它们表明大脑中正在发生炎症过程，但可能无法做到 预测吸毒者发生中枢神经系统炎症的风险，或监测认知能力的改善 在艾滋病毒方面的表现。先天免疫细胞是中枢神经系统中HIV的主要靶细胞。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 由滥用甲基苯丙胺所产生。我们假设DA系统分子的表达，以及 由DA信号转导产生的炎症标志物是敏感的生物标志物，可能被整合到 能够预测HIV+血液中的易感性和评估治疗效果的工具小组 吸食冰毒的受试者。我们还假设，个体遗传背景可能会使 D1样和D2样DRD亚型之间的平衡及其导致的影响HIV的炎症信号 潜伏期或复制表型。我们建议在人类外周细胞中进行研究，以连接基本的 具有高影响力的翻译应用的科学发现，用于筛选DRD亚型 表达水平和序列，以及与这些亚型相关的炎症信号，如 艾滋病毒背景下Meth滥用者发展认知缺陷风险的预测因素。我们的 综合方法的目标是预测和监控神经免疫病毒破坏，并生成工具来 纳入临床治疗决策。它将提供宝贵的数据来填补现有的空白 了解和满足具有实时临床价值、有可能进行危重监测的标记物的需求 中枢神经系统治疗的疗效，或预测HIV+患者出现致残神经综合征的易感性 吸毒者的个人。

项目成果

Methamphetamine signals transcription of IL1β and TNFα in a reactive oxygen species-dependent manner and interacts with HIV-1 Tat to decrease antioxidant defense mechanisms.

• DOI: 10.3389/fncel.2022.911060
• 发表时间: 2022
• 期刊: FRONTIERS IN CELLULAR NEUROSCIENCE
• 影响因子: 5.3
• 作者: Basova, Liana V. V.;Vien, Whitney;Bortell, Nikki;Najera, Julia A. A.;Marcondes, Maria Cecilia Garibaldi
• 通讯作者: Marcondes, Maria Cecilia Garibaldi

Macrophages and brown adipocytes cross-communicate to modulate a thermogenic program following methamphetamine exposure.

• DOI: 10.1080/02656736.2020.1849822
• 发表时间: 2020
• 期刊: International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group