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

基本信息

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
项目类别：
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

项目摘要

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.

多巴胺系统是毒药滥用者的艾滋病毒状况和炎症的记者抗逆转录病毒病毒的艾滋病毒预期增加，但是这种病毒的后果在这种情况下的后果由于中枢神经系统（CNS）尚未缓解。此外，诸如物质之类的合并症使用会加剧艾滋病毒感染中的中枢神经系统疾病，从而影响病毒复制和炎症。甲基苯丙胺（甲基苯丙胺）是一种流行的成瘾药物，与艾滋病毒感染的风险相关，有力多巴胺（DA）的诱导剂，一种神经递质，可调节大脑中的奖励电路。炎症等离子体CD163和IL6水平等生物标志物与HIV诱导的认知缺陷相关，包括滥用冰毒。他们表明在大脑中正在发生炎症过程，但可能无法预测甲基甲基苯丙胺炎症的发育风险，或监测认知的改善在艾滋病毒背景下的表现。先天免疫细胞是中枢神经系统中的主要艾滋病毒靶细胞。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产生。我们假设DA系统分子的表达以及由DA信号引起的炎症标记物是敏感的生物标志物，可以掺入具有预测易感性并评估HIV+血液治疗功效的工具小组被捕集者的受试者。我们还假设单个遗传背景会偏向 D1状和D2状的DRD亚型之间的平衡及其产生的炎症性特征影响HIV 潜伏期或复制表型。我们建议在人类外围细胞中进行研究，以桥接基本具有高影响力的转化应用的科学发现，用于筛选DRD子类型表达水平和顺序以及与这些亚型相关的炎症特征在艾滋病毒的背景下，毒药中认知缺陷发展的风险预测因素。我们的综合方法旨在预测和监视神经免疫 - 病毒破坏，并生成工具纳入临床治疗决策中。它将提供宝贵的数据，以填补现有的空白知识和有实时临床价值的标记的需求，并有可能进行严格监测治疗在中枢神经系统中的功效，或预测在HIV+中禁用神经系统综合征的敏感性是滥用者的人。