Cocaine HIV/AIDS, and Antiretrovirals

描述（由申请人提供）：超过3400万美国人使用可卡因，估计有150万人习惯性使用这种药物。可卡因引起严重的心脏毒性，刺激活性氧（ROS）的产生，导致左心室肥厚和功能障碍。我们发现，与野生型小鼠相比，可卡因给药使转基因HIV-1小鼠左心室肥厚恶化，导致过早死亡，并引起更严重的病理改变。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。在发达国家，HIV-1感染通常用抗逆转录病毒药物治疗，这些药物对心血管有不良影响，包括心肌病。心肌病在HIV/AIDS患者中很普遍（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改变线粒体功能，刺激线粒体产生活性氧，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，然而，其机制尚不清楚。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导致心肌细胞的改变，从而导致心肌病和心力衰竭（图1）。每种情况的复杂性需要系统生物学方法来理解它们的相互作用并阐明治疗选择。目标1：定义艾滋病毒/艾滋病、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。目的2：定义影响心脏mRNA表达和dna丰度的HIV/AIDS和可卡因的遗传和表观遗传事件。目的3：通过改善氧化应激来预防HIV/AIDS、可卡因和抗逆转录病毒药物引起的心肌病。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来研究转录和表观遗传分析，生理和生化表型以及新的数学系统分析来解开这个复杂的问题。

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.