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感染患者的临床管理中的一个重大问题是缺乏基于血液的生物标志物来监测中枢神经系统中药物使用对免疫功能和HIV发病机理的影响。尽管随着有效组合抗逆转录病毒疗法的出现，HIV-1相关痴呆的发生率却有所下降，但现在认知和运动问题的患病率更高。神经认知障碍与面对终身疾病的受感染青少年特别相关。物质使用的影响，尤其是大麻对HIV感染的青少年神经认知功能的影响尚不清楚。大麻的主要精神活性成分大麻醇[TCH]靶向由脑和中枢神经系统细胞表达的内源性大麻素受体[CB1]以及免疫细胞[CB2]。 HIV-1感染和大麻使用对免疫失调的多效后果，中枢神经系统和周围免疫系统中的炎症反应，位于HIV-1发病机理和药物滥用之间的界面。系统生物学和人类外周血研究的结合提供了一个前所未有的机会，可以开发出由先入为主的范式毫无偏见的复杂系统的全球概况，并定义了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，艾滋病毒/艾滋病和药物滥用的四个关键点，并涉及一个互动的研究人员的互动型多学科团队的系统生物学方法。巨噬细胞在体内为表达CD4的巨噬细胞靶标提供了HIV-1感染的模型，以及炎症，先天和适应性免疫的关键调节剂。该方法是理解人类中HIV-1感染与物质使用之间的界面以及与目标2。2。2中的人类中HIV-1感染的体内研究之间的界面。定义大麻使用和对周围血液单核细胞中全球免疫特征的调节之间的关系，或者是Neuurcement或Neurective neurent of Neurent contive neurenctive contive of Neurenctive contivation或ne Neurcotive in neurective contivation neurenclear compant的界面。基于自我报告和血液毒理学，将评估通过青少年试验网络入学的青少年在进行了为期三年的抗逆转录病毒治疗对神经认知功能的影响的三年研究。研究结束时周围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合并。总体目标是使用系统生物学来发现新型的生物植物，将大麻和免疫力与HIV-1感染青少年中的神经认知障碍联系起来。 公共卫生相关性：拟议的研究使用系统生物学策略来开发新型的生物膜，这些生物植物将大麻用于免疫功能障碍的人体巨噬细胞的免疫功能障碍，并在体内全身体内与HIV-1感染青少年中的神经认知障碍。系统生物学和人类外周血研究的结合提供了一个前所未有的机会，可以发现由先入为主的范式公正的复杂系统的全球概况。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。