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：
8258071
负责人：
WILLIAM LEWIS
金额：
$ 1.78万
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/8258071
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 Functional disorder 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 Wild Type Mouse antiretroviral therapy biological systems catalase cocaine use human CYBA protein human SOD2 protein in vivo interdisciplinary approach mRNA Expression novel outcome forecast overexpression premature prevent public health relevance

项目摘要

DESCRIPTION (provided by applicant): Over 34 million Americans have used cocaine and >1.5 million are estimated to use this agent habitually. Cocaine causes severe cardiotoxicity and stimulates reactive oxygen species (ROS) production leading to left ventricle hypertrophy and dysfunction. 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. Cocaine use predisposes to human immunodeficiency virus (HIV-1) infection and HIV/AIDS. In the developed world, HIV-1 infection is commonly treated with anti-retroviral drugs that have untoward cardiovascular effects, including cardiomyopathy. Cardiomyopathy in HIV/AIDS patients is prevalent (6%), and has a poor prognosis. 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. The cardiovascular system is particularly prone to interactions and complications from cocaine and HIV/AIDS, however, mechanisms are poorly understood. 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 mDNA 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. PUBLIC HEALTH RELEVANCE: Cardiomyopathy is linked to HIV/AIDS and cocaine, but those clinical interactions are complex: The purpose of this application is to use a systems biological analytical approach to dissect complex interactions between pathological, physiological, biochemical and genetic events in HIV/AIDS and cocaine. Ultimately, information obtained may help to formulate testable hypotheses about pathogenesis and treatment of cardiomyopathy in HIV/AIDS and cocaine.

描述（由申请人提供）：超过 3400 万美国人使用过可卡因，估计超过 150 万人习惯性使用这种药物。可卡因会引起严重的心脏毒性，并刺激活性氧（ROS）的产生，导致左心室肥大和功能障碍。我们发现，给 HIV-1 转基因小鼠注射可卡因会加剧左心室肥大，导致过早死亡，并诱发比野生型小鼠更严重的病理变化。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。在发达国家，HIV-1 感染通常采用抗逆转录病毒药物治疗，但这些药物会产生不良心血管影响，包括心肌病。 HIV/AIDS 患者中心肌病很常见（6%），且预后较差。我们实验室和其他实验室的研究表明，HIV-1 的基因产物和抗逆转录病毒药物会改变线粒体功能，刺激线粒体产生 ROS，并导致心力衰竭。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的影响，但人们对其机制知之甚少。我们提出，HIV/AIDS、抗逆转录病毒核苷和可卡因的相互作用通过未明确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理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：确定 HIV/AIDS、抗逆转录病毒治疗和可卡因给药中的 nDNA 遗传和表观遗传事件如何影响体内心肌病。目标 2：定义 HIV/AIDS 和可卡因影响心脏 mRNA 表达和 mDNA 丰度的遗传和表观遗传事件。目标 3：通过改善氧化应激来预防艾滋病毒/艾滋病、可卡因和抗逆转录病毒药物引起的心肌病。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来研究转录和表观遗传分析、生理和生化表型以及新颖的数学系统分析，以解决这个复杂的问题。公共卫生相关性：心肌病与 HIV/艾滋病和可卡因有关，但这些临床相互作用很复杂：本应用的目的是使用系统生物分析方法来剖析 HIV/艾滋病中病理、生理、生化和遗传事件之间复杂的相互作用。艾滋病和可卡因。最终，获得的信息可能有助于制定有关艾滋病毒/艾滋病和可卡因心肌病的发病机制和治疗的可检验假设。