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。辅酶A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可导致左心室肥大，导致过早死亡，并诱导比野生型小鼠更严重的病理变化。使用可卡因易感染人体免疫缺陷病毒（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%），预后很差。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改变了线粒体功能，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，但对机制知之甚少。我们认为，HIV/AIDS、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方案。 目的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。 目的2：确定影响心脏mRNA表达和mDNA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，生理和生化表型和新的数学系统分析，以解开这个复杂的问题。 公共卫生相关性：心肌病与艾滋病毒/艾滋病和可卡因有关，但这些临床相互作用是复杂的：本申请的目的是使用系统生物学分析方法来剖析艾滋病毒/艾滋病和可卡因中病理，生理，生化和遗传事件之间的复杂相互作用。最终，获得的信息可能有助于制定可验证的假设的发病机制和治疗心肌病的艾滋病毒/艾滋病和可卡因。

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.