MECHANISMS OF COCAINE INDUCED EXACCERBATION OF VIRAL MYO

临床证据表明，可卡因滥用者的人体免疫缺陷病毒（艾滋病毒）感染和艾滋病毒相关心肌炎发病率增加。 这些数据表明可卡因的使用和心肌炎病毒的致病性之间的因果关系，我们计划在本提案中进行调查，通过研究一个易于重现的病毒性心肌炎小鼠模型，使用脑心肌炎（EMC）病毒作为HIV的替代品。我们的中心，统一的假设是，可卡因引起的病毒性心肌炎的恶化是一种间接的影响介导的药物诱导的增强心脏中的儿茶酚胺浓度。 当来自体循环和心脏交感神经末梢的局部释放的儿茶酚胺达到毒性浓度时，它们可能损害细胞完整性和特定的细胞和体液防御，使心肌更容易感染。 我们将通过七个具体目标来测试这一假设，这些目标采用了合作研究者实验室目前可用的技术。 I.我们将确定是否慢性可卡因治疗单独可以诱导心肌炎，坏死或细胞凋亡。二.我们将检验这样的假设：接触可卡因可以增强小鼠在接触病毒后对心肌炎的易感性。 三.我们将确定可卡因是否可以增强病毒基因组的持久性。 四.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。 我们将确定可卡因的肾上腺素能或局部麻醉特性是否是增加病毒性心肌炎致病性的原因。 六.我们将测试的假设，即儿茶酚胺介导的刺激肾上腺素能受体的心肌细胞是负责增加病毒心肌病的致病性，通过使用交感神经阻滞剂。 七.我们将证明，可卡因产生的病毒心肌致病性的增强与其他药物，食物和活动，增加儿茶酚胺水平是协同作用的。综上所述，这些结果将提供新的机制信息可卡因滥用者的病毒性心肌炎的病因，应使我们能够确定不同的危险因素，发展心肌炎在一般人群中，并可能提供一个合理的基础上预测谁可能会把自己在使用可卡因，特别是在艾滋病毒暴露的人群中增加额外的风险。

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.