MECHANISMS OF COCAINE INDUCED EXACCERBATION OF VIRAL MYO

临床证据表明，可卡因滥用者人类免疫缺陷病毒(HIV)感染和HIV相关性心肌炎的发病率增加。这些数据表明了可卡因使用和心肌炎病毒致病性之间的因果关系，我们计划在这项建议中通过研究一种使用脑心肌炎(EMC)病毒作为HIV替代品的易重复性的病毒性心肌炎小鼠模型来研究这一点。我们的中心，统一的假设是可卡因诱导的病毒性心肌炎的恶化是由药物诱导的心脏中儿茶酚胺浓度增加所介导的间接效应。当来自体循环的儿茶酚胺和心脏交感神经末梢的局部释放达到有毒浓度时，它们可能会损害细胞完整性和特定的细胞和体液身体防御，使心肌更容易受到感染。我们将通过七个具体的目标来检验这一假设，这些目标采用了目前合作研究人员实验室中可用的技术。我们将确定单用慢性可卡因治疗是否会导致心肌炎、坏死或细胞凋亡。我们将检验这样的假设，即暴露于可卡因可以提高小鼠在暴露于病毒后对心肌炎的易感性。我们将确定可卡因是否可以增强病毒基因组的持久性。我们将通过测量T细胞功能和IgM水平来确定可卡因是否会损害针对病毒感染的特定身体防御能力。我们将确定可卡因的肾上腺素或局部麻醉特性是否导致病毒性心肌炎致病性增加。我们将验证儿茶酚胺介导的对心肌细胞上肾上腺素能受体的刺激是通过使用交感神经降解剂增加病毒性心肌炎致病性的假设。我们将证明可卡因增强病毒性心肌炎的致病性与其他药物、食物和增加儿茶酚胺水平的活动是协同作用的。综上所述，这些结果将为可卡因滥用者病毒性心肌炎的病因提供新的机制信息，使我们能够识别在普通人群中发生心肌炎的不同危险因素，并可能为预测谁可能因使用可卡因而增加额外风险提供合理的基础，特别是在接触艾滋病毒的人群中。

Clinical evidence suggests that cocaine abusers have an increased incidence of Human Immunodeficiency Virus (HIV) infection and HIV-related myocarditis. These data indicate a causal relationship between cocaine use and myocarditic viral pathogenicity, which we plan to investigate in this proposal by studying a readily reproducible murine model of viral myocarditis using Encephalomyocarditis (EMC) Virus as a surrogate for HIV. Our central, unifying hypothesis is that cocaine-induced exacerbation of viral myocarditis is an indirect effect mediated by drug-induced enhancement of catecholamine concentrations in the heart. When catecholamines from the systemic circulation and local release at cardiac sympathetic nerve endings reach toxic concentrations, they may compromise cellular integrity and specific cellular and humoral body defenses, making the myocardium more susceptible to infection. We will test this hypothesis by means of seven specific aims that employ techniques currently available in the laboratories of the collaborating Investigators. I. We will determine whether chronic cocaine treatment alone can induce myocarditis, necrosis or apoptosis. II. We will test the hypothesis that exposure to cocaine can enhance the susceptibility of mice to myocarditis after virus exposure. III. We will determine whether cocaine can enhance persistence of the viral genome. IV. We will determine whether cocaine can impair specific body defenses against viral infection by measuring T cell function and IgM levels. V. We will determine whether the adrenergic or local anesthetic properties of cocaine are responsible for increased viral myocarditic pathogenicity. VI. We will test the hypothesis that catecholamine-mediated stimulation of the adrenergic receptors on myocytes is responsible for increased viral myocarditic pathogenicity by use of sympatholytic agents. VII. We will demonstrate that the enhancement of viral myocarditic pathogenicity produced by cocaine is synergistic with other drugs, foods and activities that increase catecholamine levels. Taken together, these results will provide new mechanistic information about the etiology of viral myocarditis in cocaine abusers, should allow us to identify distinct risk factors for developing myocarditis in the general population, and may provide a rational basis for predicting who may place themselves at increased additional risk by the use of cocaine, particularly among the HIV-exposed population.