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: 8145254
• 负责人: Maureen M Goodenow
• 金额: $ 91.01万
• 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/8145254
• 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; 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; public health relevance; response; transcription factor

DESCRIPTION (provided by applicant): 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 delta-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. PUBLIC HEALTH RELEVANCE: The proposed studies use systems biology strategy to develop novel bioprofiles that relate marijuana use to immune dysfunction in primary human macrophages ex vivo and systemically in vivo with neurocognitive impairment in HIV-1 infected adolescents. Combination of systems biology and studies of human peripheral blood provide an unprecedented opportunity to discover global profiles of complex systems that are unbiased by preconceived paradigms. Outcomes will translate to improved diagnosis, prognosis and treatment of HIV-1 associated neurocognitive impairment in adolescents.

描述（由申请人提供）：HIV-1感染患者临床管理中的一个重要问题是缺乏基于血液的生物标志物来监测物质使用对中枢神经系统免疫功能和HIV发病机制的影响。尽管随着有效的联合抗逆转录病毒疗法的出现，HIV-1相关痴呆的发病率有所下降，但认知和运动问题的患病率却越来越高。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。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尚不清楚。大麻素 delta-9-四氢大麻酚 [TCH] 是大麻中的主要精神活性成分，其目标是脑和中枢神经系统细胞 [CB1] 以及免疫细胞 [CB2] 表达的内源性大麻素受体。 HIV-1 感染和吸食大麻对免疫失调以及中枢神经系统和外周免疫系统炎症反应的多效性影响是 HIV-1 发病机制和药物滥用之间的交叉点。系统生物学和人类外周血研究的结合提供了前所未有的机会来开发复杂系统的全球概况，这些系统不受先入为主的范式的影响，并定义人类健康和疾病的多个参数。拟议的研究旨在解决 RFA-10-014 系统生物学、HIV/AIDS 和药物滥用的四个关键点，并涉及由交互式多学科研究小组采用的系统生物学方法： 1. 确定 TCH 对存在或不存在 HIV-1 感染的情况下体外原代人类巨噬细胞转录组和蛋白质组的整体影响。离体巨噬细胞为 HIV-1 感染的表达 CD4 的巨噬细胞靶标以及炎症、先天性和适应性免疫的关键调节因子提供了模型。该方法对于理解人类 HIV-1 感染和物质使用之间的关系以及与目标 2 中提出的人类 HIV-1 感染体内研究的联系至关重要。 2. 确定一组患有或不患有神经认知障碍的 HIV 感染青少年中大麻使用与外周血单核细胞整体免疫特征调节之间的关系。通过青少年试验网络参加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青少年的物质使用情况。随着时间的推移，研究结束时的外周血细胞转录组的系统生物学研究将与血浆和细胞表面蛋白质组学相结合。总体目标是利用系统生物学来发现新的生物特征，将大麻的使用和免疫与 HIV-1 感染青少年的神经认知障碍联系起来。 公共健康相关性：拟议的研究利用系统生物学策略来开发新的生物特征，将大麻的使用与原代人类巨噬细胞离体和体内系统性免疫功能障碍与 HIV-1 感染青少年的神经认知障碍联系起来。系统生物学和人类外周血研究的结合提供了前所未有的机会来发现不受先入为主的范式影响的复杂系统的整体概况。结果将转化为改善青少年 HIV-1 相关神经认知障碍的诊断、预后和治疗。