Substance Use and Immunity in HIV+ Adolescents by Systems Biology

系统生物学研究艾滋病毒青少年的物质使用和免疫力

• 批准号: 8287150
• 负责人: Maureen M Goodenow
• 金额: $ 88.76万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-17 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8287150
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Address; Adolescent; Adolescent Medicine Trials Network; Alcohol or Other Drugs use; Animal Model; Anti-Inflammatory Agents; Anti-Retroviral Agents; Anti-inflammatory; Antigen-Presenting Cells; Attenuated; Biological Markers; Blood; Blood - brain barrier anatomy; Blood Cells; Blood specimen; CD4 Positive T Lymphocytes; Cannabinoids; Cannabis; Cell surface; Cells; Chronic; Clinical; Clinical Management; Clinical Trials; Cognitive; Complex; DA10; Data Set; Dementia; Diagnosis; Disease; Disease Progression; Drug usage; Endocannabinoids; Enrollment; Face; Flow Cytometry; Gene Expression Profile; Goals; HIV; HIV-1; Health; Human; Immune; Immune System Diseases; Immune system; Immunity; Immunosuppressive Agents; Impairment; Incidence; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Interdisciplinary Study; Intervention; Lead; Life; Link; Macrophage Activation; Marijuana; Marijuana Smoking; Modeling; Monitor; Motor; Natural Immunity; Neuraxis; Neurocognitive; Outcome; Pathogenesis; Pathway interactions; Patient Self-Report; Patients; Peripheral; Peripheral Blood Mononuclear Cell; Plasma Cells; Plasma Proteins; Population; Prevalence; Proteome; Proteomics; Research Design; Research Personnel; Signal Pathway; Signal Transduction; Substance abuse problem; System; Systems Biology; Tetrahydrocannabinol; Time; Translating; Viral; Virus; abstracting; adaptive immunity; antiretroviral therapy; base; blood toxicology; brain cell; cannabinoid receptor; chemokine; cohort; cytokine; experience; genome-wide; immune activation; immune function; immunoregulation; improved; in vivo; insight; macrophage; monocyte; novel; novel therapeutic intervention; outcome forecast; peripheral blood; protein profiling; response; transcription factor

Project Summary/Abstract A significant problem in the clinical management of HIV-1 infected patients is a lack of blood based biomarkers to monitor the effects of substance use on immune function and HIV pathogenesis in the central nervous system. Although incidence of HIV-1 associated dementia has declined with the advent of effective combination antiretroviral therapies, a greater prevalence of cognitive and motor problems now develop. Neurocognitive impairment is particularly relevant to infected adolescents, who face life-long disease. Impact of substance use, in particular marijuana, on neurocognitive functioning among HIV-infected adolescents is unknown. The cannabinoid ¿9-tetrahydrocannabinol [TCH], the main psychoactive component in marijuana, targets endogenous cannabinoid receptors expressed by cells of brain and central nervous system [CB1], as well as by immune cells [CB2]. Pleiotropic consequences of HIV-1 infection and marijuana use on immune dysregulation, and the inflammatory response in the central nervous system and in the peripheral immune system, stand at the interface between HIV-1 pathogenesis and substance abuse. Combination of systems biology and studies of human peripheral blood provide an unprecedented opportunity to develop global profiles of complex systems that are unbiased by preconceived paradigms and define multiple parameters of human health and disease. Proposed studies are designed to address the four key points of RFA-10-014 Systems Biology, HIV/AIDS, and Substance Abuse and involve systems biology approaches by an interactive multi- disciplinary team of investigators to: 1. Define the global effects of TCH on transcriptome and proteome of primary human macrophages ex vivo in the presence or absence of HIV-1 infection. Macrophages ex vivo provide models for CD4-expressing macrophage targets for HIV-1 infection, as well as key regulators of inflammation, innate and adaptive immunity. The approach is fundamental to understanding the interface between HIV-1 infection and substance use in humans and links with in vivo studies of HIV-1 infection in humans proposed in Objective 2. 2. Define the relationship between marijuana use and modulation of global immune profiles in peripheral blood mononuclear cells within a cohort of HIV-infected adolescents with or without neurocognitive impairment. Adolescents enrolled through the Adolescent Trials Network in a three-year ongoing study of the effects of antiretroviral therapy on neurocognitive function will be assessed for substance use, based on self-reporting and blood toxicology. A systems biology study of peripheral blood cell transcriptome at end of study will be combined with plasma and cell-surface proteomics over time. The overall goal is to use systems biology to discover novel bioprofiles that relate use of marijuana and immunity to neurocognitive impairment in HIV-1 infected adolescents.

项目概要/摘要 HIV-1感染患者临床管理中的一个重要问题是缺乏血液 生物标志物监测物质使用对中枢免疫功能和艾滋病毒发病机制的影响 神经系统。尽管随着有效治疗方法的出现，HIV-1相关痴呆症的发病率有所下降 联合抗逆转录病毒疗法导致认知和运动问题更加普遍。 神经认知障碍与受感染的青少年尤其相关，他们面临终生疾病。的影响 物质使用，特别是大麻，对艾滋病毒感染青少年神经认知功能的影响 未知。大麻素 ¿9-四氢大麻酚 [TCH]，大麻中的主要精神活性成分， 靶向脑和中枢神经系统细胞表达的内源性大麻素受体 [CB1]，如 以及免疫细胞[CB2]。 HIV-1 感染和大麻使用对免疫的多效性影响 失调以及中枢神经系统和周围免疫系统的炎症反应 系统，处于 HIV-1 发病机制和药物滥用之间的界面。系统组合 人类外周血的生物学和研究为发展全球概况提供了前所未有的机会 不受先入为主的范式影响并定义人类的多个参数的复杂系统 健康和疾病。拟议的研究旨在解决 RFA-10-014 系统的四个关键点 生物学、艾滋病毒/艾滋病和药物滥用，并通过交互式多学科涉及系统生物学方法 学科研究小组： 1. 定义 TCH 对转录组和蛋白质组的整体影响 在存在或不存在 HIV-1 感染的情况下，原代人类巨噬细胞离体。巨噬细胞前 vivo 提供了 HIV-1 感染的 CD4 表达巨噬细胞靶标模型，以及关键调节因子 炎症、先天性和适应性免疫。该方法是理解界面的基础 HIV-1 感染与人类物质使用之间的关系以及与 HIV-1 感染体内研究的联系 目标 2 中提出的人类。 2. 定义大麻使用和调节之间的关系 HIV感染者外周血单核细胞的整体免疫特征 有或没有神经认知障碍的青少年。通过青少年计划入学的青少年 试验网络正在进行一项为期三年的抗逆转录病毒治疗对神经认知功能影响的研究 将根据自我报告和血液毒理学评估物质使用情况。系统生物学研究 研究结束时的外周血细胞转录组将与血浆和细胞表面蛋白质组学相结合 随着时间的推移。总体目标是利用系统生物学发现与大麻使用相关的新生物特征 HIV-1 感染青少年对神经认知障碍的免疫力。