Cocaine HIV/AIDS, and Antiretrovirals

可卡因 HIV/艾滋病和抗逆转录病毒药物

基本信息

批准号：
8287149
负责人：
WILLIAM LEWIS
金额：
$ 91.78万
依托单位：
EMORY UNIVERSITY
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/8287149
关键词：
AIDS/HIV problem Address American Anti-Retroviral Agents Biochemical Biochemical Genetics Biological Models Cardiac Cardiac Myocytes Cardiomyopathies Cardiotoxicity Cardiovascular system Catecholamines Cessation of life Classification Clinical Cocaine Complex DNA DNA Methylation DNA Microarray Chip Dopamine Echocardiography Electrocardiogram Electron Microscopy Epigenetic Process Event Felis catus Gagging Gene Silencing Genetic HIV HIV Infections HIV-1 Heart Heart failure Hydrogen Peroxide Hypertrophy Immunoprecipitation Infection Knock-out Laboratories Lead Left ventricular structure Light Link Messenger RNA Metabolism Mitochondria Mitochondrial DNA Mixed Function Oxygenases Mus NADPH Oxidase Nuclear Nucleosides Oxidative Stress Pathogenesis Patients Performance Pharmaceutical Preparations Phenotype Physiological Production Proteins Qualifying Reactive Oxygen Species Research Sarcoplasm Site Sudden Death Superoxides Systems Analysis Systems Biology Telemetry Therapeutic Transcript Transgenic Mice Validation antiretroviral therapy biological systems catalase cocaine use human CYBA protein human SOD2 protein in vivo interdisciplinary approach mRNA Expression novel overexpression premature prevent

项目摘要

ABSTRACT Over 34 million Americans have used cocaine and >1.5 million are estimated to use this agent habitually.1 Cocaine causes severe cardiotoxicity and stimulates reactive oxygen species (ROS) production leading to left ventricle hypertrophy and dysfunction.2-4 We showed that cocaine administration to mice transgenic for HIV-1 worsens left ventricle hypertrophy, causes premature death and induces pathological changes that are more severe than those observed in wild-type mice.5 Cocaine use predisposes to human immunodeficiency virus (HIV-1) infection and HIV/AIDS.6, 7 In the developed world, HIV-1 infection is commonly treated with anti-retroviral drugs that have untoward cardiovascular effects, including cardiomyopathy.8-10 Cardiomyopathy in HIV/AIDS patients is prevalent (6%), and has a poor prognosis.11-13 Research from our laboratory and others has shown that gene products of HIV-1 and antiretroviral drugs alter mitochondrial function, stimulate mitochondrial production of ROS, and cause heart failure.14-20 The cardiovascular system is particularly prone to interactions and complications from cocaine and HIV/AIDS, however, mechanisms are poorly understood.2, 9, 10 We propose that the interaction of HIV/AIDS, antiretroviral nucleosides, and cocaine causes alterations in cardiomyocytes through undefined mechanisms that lead to cardiomyopathy and heart failure (Figure 1). The complexity of each scenario requires a systems biology approach to understand their interactions and illuminate therapeutic options. The following aims will be addressed: Aim 1: To define how nDNA genetic and epigenetic events in HIV/AIDS, antiretroviral therapy, and cocaine administration impact cardiomyopathy in vivo. Aim 2: To define genetic and epigenetic events from HIV/AIDS and cocaine that impact mRNA expression and mtDNA abundance in the heart. Aim 3: To prevent cardiomyopathy in HIV/AIDS, cocaine, and antiretrovirals by ameliorating oxidative stress. Our team is uniquely qualified to address the aims. We will employ a multidisciplinary approach to study transcriptional and epigenetic analysis, physiological and biochemical phenotyping and novel mathematical systems analyses to unravel this complex problem.

抽象的超过 3,400 万美国人使用过可卡因，估计超过 150 万美国人习惯性使用这种物质。1 可卡因会导致严重的心脏毒性，并刺激活性氧 (ROS) 的产生，导致左心室收缩。心室肥大和功能障碍。2-4 我们证明，对 HIV-1 转基因小鼠施用可卡因加剧左心室肥大，导致过早死亡并诱发更严重的病理变化比在野生型小鼠中观察到的严重5。使用可卡因容易感染人类免疫缺陷病毒 (HIV-1) 和艾滋病毒/艾滋病。6, 7 在发达国家在世界范围内，HIV-1感染通常用抗逆转录病毒药物治疗，但这些药物会产生不良的心血管影响，包括心肌病。8-10 HIV/AIDS 患者中心肌病很常见 (6%)，并且病情较差预后。11-13 我们实验室和其他实验室的研究表明，HIV-1 和 HIV-1 的基因产物抗逆转录病毒药物改变线粒体功能，刺激线粒体产生 ROS，并导致心脏病失败.14-20 心血管系统特别容易受到可卡因和艾滋病毒/艾滋病的相互作用和并发症，然而，人们对其机制知之甚少。2, 9, 10 我们认为，艾滋病毒/艾滋病、抗逆转录病毒药物之间的相互作用核苷和可卡因通过不确定的机制引起心肌细胞的改变，从而导致心肌病和心力衰竭（图1）。每个场景的复杂性都需要系统生物学方法来了解它们的相互作用并阐明治疗选择。将实现以下目标：目标 1：定义 HIV/AIDS、抗逆转录病毒治疗和治疗中的 nDNA 遗传和表观遗传事件如何可卡因给药对体内心肌病的影响。目标 2：定义影响 mRNA 的 HIV/AIDS 和可卡因的遗传和表观遗传事件心脏中的表达和 mtDNA 丰度。目标 3：通过改善氧化作用来预防艾滋病毒/艾滋病、可卡因和抗逆转录病毒药物引起的心肌病压力。我们的团队具有独特的资质来实现这些目标。我们将采用多学科方法进行研究转录和表观遗传分析、生理生化表型分析以及新颖的数学系统分析来解决这个复杂的问题。