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

基本信息

批准号：
8489268
负责人：
Maureen M Goodenow
金额：
$ 83.09万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
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/8489268
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

项目摘要

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尽管随着有效性的出现，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的大麻素。 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 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。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，原代人巨噬细胞离体。 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通过青少年项目登记的有或没有神经认知障碍的青少年。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的系统生物学研究来评估物质使用情况。研究结束时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。