CARDIOTOXICITY OF STREPTOCOCCAL PYROGENIC EXOTOXINS

链球菌热原性外毒素的心脏毒性

• 批准号: 2218234
• 负责人: Patrick M Schlievert
• 金额: $ 13.71万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-07-01 至 1997-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2218234
• 关键词: Streptococcus infection; Streptococcus pyogenes; affinity chromatography; cardiotoxin; crystallization; epitope mapping; exotoxins; immunotoxicity; laboratory rabbit; lipopolysaccharides; medical complication; molecular pathology; monoclonal antibody; mutant; nucleic acid sequence; polymerase chain reaction; protein purification; protein structure function; pyrogens; rheumatic fever; site directed mutagenesis; superantigens; synthetic peptide; toxic shock syndrome; vascular endothelium

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.

心肌病和心内膜炎在内的心脏并发症 通常使艾滋病毒感染复杂化，尤其是在 疾病。 感染艾滋病毒的注射吸毒者最多 通常受到影响。 与HIV相关的心脏毒性的病因是 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。 这个受赠人正在研究 链球菌热源肠毒素和葡萄球菌的心脏毒性 内心毒素。 该项目的长期目标是两个 折：1）评估链球菌热源外毒素在 引起急性有毒冲击线疾病和后遗症延迟 作为急性风湿热和血管疾病，2）分析 链球菌热源之间的结构功能关系 肠毒素和葡萄球菌肠毒素。 希望后者 研究最终将阐明该作用的分子机理 毒素。 R01HL42125 该计划的目的是继续并扩大正在进行的研究 关于嘧啶核苷类似物对HIV的机制 例如3'Azido-3'-脱氧胸苷和同类物在骨骼上施加毒性 骨髓和其他细胞。 这些机制的启发可能允许 与调节剂的组合疗法的开发 保护或反向宿主毒性而无需抗HIV 在审查下药物的活性。 该项目有两个主要目标： 1）对生化和分子机制负责的描述 对于AZT及其代谢产物的影响3'-氨基-3'-脱氧胸苷 （AMT）在人骨髓细胞中； 2）详细的表征 与人类肝细胞中AZT的酶促减少到AMT 通过细胞色素p-评估潜在的药物相互作用 450途径。