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.

项目摘要/摘要 HIV-1感染患者的临床管理中的一个重大问题是缺乏血液生物标志物监测中央物质功能对免疫功能和HIV发病机理的影响神经系统。尽管HIV-1相关痴呆的发病率随着有效的冒险而下降联合抗逆转录病毒疗法，现在已经出现了认知和运动问题的较高患病率。神经认知障碍与面对终身疾病的受感染青少年特别相关。影响艾滋病毒感染的青少年的神经认知功能，尤其是大麻的药物使用是未知。大麻素»9-四氢大麻酚[TCH]，大麻的主要精神活性成分，靶标由脑和中枢神经系统细胞表达的内源性大麻素受体[CB1]，AS 以及免疫细胞[CB2]。 HIV-1感染和大麻使用对免疫的多效后果失调和中枢神经系统和周围免疫中的炎症反应系统，站在HIV-1发病机理和药物滥用之间的界面。系统组合生物学和人类外围血的研究为发展全球概况提供了前所未有的机会由先入为主的范例公正并定义人类的多个参数的复杂系统健康与疾病。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，并涉及系统生物学方法研究人员的纪律团队至：1。定义TCH对转录组和蛋白质组的全球影响在存在或不存在HIV-1感染的情况下，原代人巨噬细胞在体内。巨噬细胞 Vivo为表达CD4的巨噬细胞靶标提供了HIV-1感染的模型，以及的关键调节剂炎症，先天和适应性免疫。这种方法是理解界面的基础 HIV-1感染与人类的物质使用以及与HIV-1感染的体内研究之间的联系人类在目标2。2中提出外周血单核细胞中的全球免疫特征有或没有神经认知障碍的青少年。青少年参加青少年试验网络在一项为期三年的抗逆转录病毒疗法对神经认知功能的影响的研究中将根据自我报告和血液毒理学评估用于药物使用的情况。一项系统生物学研究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结合随着时间的推移。总体目的是使用系统生物学发现与大麻使用相关的新型生物胶片对HIV-1感染青少年的神经认知障碍的免疫学。