Cocaine HIV/AIDS, and Antiretrovirals

可卡因 HIV/艾滋病和抗逆转录病毒药物

• 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
• 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

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3400万美国人使用了可卡因，估计有150万的美国人习惯使用该代理。1 可卡因会引起严重的心脏毒性，并刺激导致左的活性氧（ROS）产生 心室肥大和功能障碍。2-4我们表明可卡因对HIV-1的小鼠转基因的给药 恶化左心室肥大，导致过早死亡并诱导病理变化，这更多 比在野生型小鼠中观察到的严重。5 可卡因使用易于人类免疫缺陷病毒（HIV-1）感染和HIV/AID.6，在发达的 世界，HIV-1感染通常用具有不良心血管效应的抗逆转录病毒药物治疗 包括心肌病在内的8-10艾滋病毒/艾滋病患者的心肌病很普遍（6％），较差 预后。11-13我们实验室和其他人的研究表明，HIV-1和HIV-1和 抗逆转录病毒药物改变线粒体功能，刺激ROS的线粒体产生，并引起心脏 失败14-20 心血管系统尤其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。2、9、10我们提出艾滋病毒/艾滋病的相互作用，抗逆转录病毒 核苷和可卡因通过未定义的机制导致心肌细胞的改变 心肌病和心力衰竭（图1）。每种情况的复杂性需要系统生物学 了解他们的相互作用并阐明治疗选择的方法。 以下目标将被解决： 目标1：定义NDNA遗传和表观遗传事件如何在HIV/AIDS，抗逆转录病毒疗法和 可卡因给药在体内影响心肌病。 目的2：从影响mRNA的HIV/AIDS和可卡因定义遗传和表观遗传事件 心脏表达和mtDNA丰度。 目标3：通过改善氧化剂，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 压力。 我们的团队具有独特的资格来解决目标。我们将采用多学科的方法来学习 转录和表观遗传分析，生理和生化表型和新型数学 系统分析以解散这个复杂的问题。