CARDIOTOXICITY OF STREPTOCOCCAL PYROGENIC EXOTOXINS

心脏并发症，包括心肌病和心内膜炎 艾滋病病毒感染经常并发症，特别是在病程后期， 这种疾病 注射吸毒者感染艾滋病毒的人数最多 普遍受到影响。 HIV相关心脏毒性的病因是 尚不清楚，尽管有些人认为这与并发感染有关， 其他细菌和病毒病原体。 该受赠方正在研究 链球菌致热原肠毒素和葡萄球菌肠毒素的心脏毒性 内毒素对心脏的影响 该项目的长期目标有两个 倍数：1）评价链球菌致热性外毒素在 引起急性中毒性休克和延迟后遗症， 急性风湿热和血管疾病; 2）分析 致热原链球菌结构与功能关系的研究 肠毒素和葡萄球菌肠毒素。 希望后者 研究将最终澄清的分子机制的行动， 毒素 R01HL42125 该计划的目标是继续和扩大正在进行的研究 嘧啶核苷类似物抗HIV活性的机制 例如3 ′叠氮基-3 ′-脱氧胸苷和对骨产生毒性同类物 骨髓和其他细胞。 这些机制的激发可能允许 与调节剂的联合治疗的开发， 保护或逆转宿主毒性而不损害抗HIV 药物的活性受到审查。 该项目有两个主要目标： 1)生物化学和分子机制的描述 AZT及其代谢物3'-氨基-3'-脱氧胸苷的作用 (AMT)在人骨髓细胞中;和2） 人肝细胞中AZT酶促还原为AMT 评价通过细胞色素P- 450路。

Cardiac complications including cardiomyopathy and endocarditis frequently complicate HIV infections particularly late in the course of the disease. Injection drug users infected with HIV are the most commonly affected. The etiology of HIV-related cardiotoxicity is unclear, although some believe it is related to concurrent infection with other bacterial and viral pathogens. This grantee is studying the cardiotoxicity of streptococcal pyrogenic enterotoxins and staphylococcal endotoxins on the heart. The long term goals of this project are two fold: 1) to evaluate the role of streptococcal pyrogenic exotoxins in causing both acute toxic shock line illnesses and delayed sequelae such as acute rheumatic fever and vascular diseases and 2) to analyze the structure function relationships among the streptococcal pyrogenic enterotoxins and staphylococcal enterotoxin. It is hoped that the latter studies will ultimately clarify the molecular mechanism of action of the toxins. R01HL42125 The objective of this program is to continue and expand ongoing studies on the mechanism by which pyrimidine nucleoside analog active against HIV such as 3'azido-3'-deoxythymidine and congeners exert toxicity on bone marrow and other cells. The elicitation of these mechanisms may permit the development of a combination therapy with modulating agents that protect or reverse host toxicity without impairment of the anti-HIV activity of the drug under scrutiny. This project has two major aims: 1) the description of the biochemical and molecular mechanism responsible for the effects of AZT and its metabolite, 3'-amino-3'-deoxythymidine (AMT) in human marrow cells; and 2) the detailed characterization of the enzymatic reduction of AZT to AMT in human hepatocytes with the evaluation of potential drug-drug interactions through the cytochrome P- 450 pathway.