Cocaine HIV/AIDS, and Antiretrovirals

摘要 超过3400万美国人使用可卡因，估计有150万人习惯性地使用这种毒剂。 可卡因会造成严重的心脏毒性，并刺激活性氧(ROS)的产生，从而导致左 心脏肥大和功能障碍2-4我们发现对HIV-1转基因小鼠注射可卡因 加重左心室肥厚，导致过早死亡，并诱发更多的病理变化 比在野生型小鼠中观察到的更严重 在发达国家使用可卡因易感染人类免疫缺陷病毒(HIV-1)和艾滋病毒/艾滋病 在世界范围内，HIV-1感染通常用对心血管有不良影响的抗逆转录病毒药物治疗， 包括心肌病。8-10心肌病在HIV/AIDS患者中很常见(6%)，并有较差的 11-13我们实验室和其他机构的研究表明，HIV-1和 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 Failure.14-20 心血管系统特别容易发生可卡因和艾滋病毒/艾滋病的相互作用和并发症， 2、9、10我们认为艾滋病毒/艾滋病、抗逆转录病毒的相互作用 核苷，可卡因通过未明确的机制引起心肌细胞的改变，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 了解它们的相互作用并阐明治疗选择的方法。 将实现以下目标： 目的1：明确nDNA在HIV/AIDS、抗逆转录病毒治疗和 可卡因给药对体内心肌病的影响。 目的2：确定艾滋病毒/艾滋病和可卡因对mRNA产生影响的遗传和表观遗传事件 心脏中线粒体DNA的表达和丰度。 目的3：通过改善氧化作用预防艾滋病毒/艾滋病、可卡因和抗逆转录病毒药物引起的心肌病 压力。 我们的团队是唯一有资格实现这些目标的团队。我们将采用多学科的方法进行研究 转录和表观遗传分析、生理生化表型和新数学 系统分析来解开这个复杂的问题。

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.