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3400万美国人使用了可卡因，估计有150万种习惯使用该代理。可卡因会引起严重的心脏毒性，并刺激导致左心室肥大和功能障碍的活性氧（ROS）产生。我们表明，对HIV-1的小鼠可卡因给药会使左心室肥大恶化，导致过早死亡，并诱导比野生型小鼠观察到的更严重的病理变化。可卡因对人免疫缺陷病毒（HIV-1）感染和艾滋病毒/艾滋病的使用易感性。在发达国家，HIV-1感染通常被抗逆转录病毒药物治疗，这些药物具有不良心血管效应，包括心肌病。艾滋病毒/艾滋病患者的心肌病很普遍（6％），预后较差。我们实验室和其他实验室的研究表明，HIV-1和抗逆转录病毒药物的基因产物会改变线粒体功能，刺激ROS的线粒体产生，并引起心力衰竭。心血管系统特别容易出现可卡因和艾滋病毒/艾滋病的相互作用和并发症，但是，机制知之甚少。我们提出，艾滋病毒/艾滋病，抗逆转录病毒核苷和可卡因的相互作用通过导致心肌病和心力衰竭的不确定机制引起心肌细胞的改变（图1）。每种情况的复杂性需要一种系统生物学方法来了解其相互作用并阐明治疗选择。将解决以下目的：目标1：定义NDNA遗传和表观遗传事件如何在艾滋病毒/艾滋病，抗逆转录病毒疗法和可卡因给药中如何影响心肌病。目的2：从HIV/AIDS和可卡因定义遗传和表观遗传事件，影响心脏中的mRNA表达和MDNA丰度。目标3：通过改善氧化应激，以防止艾滋病毒/艾滋病，可卡因和抗逆转录病毒中的心肌病。我们的团队具有独特的资格来解决目标。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型数学系统分析以揭示这个复杂的问题。公共卫生相关性：心肌病与HIV/AIDS和可卡因有关，但是这些临床相互作用很复杂：本应用的目的是使用系统的生物学分析方法来解剖HIV/AIDS和Cocaine中的病理，生理，生物化学和遗传事件之间的病理，生理，生化和遗传事件。最终，获得的信息可能有助于提出有关HIV/AIDS和可卡因的心肌病的发病机理和治疗的可检验的假设。