MECHANISMS INVOLVED IN THE SEPTIC SHOCK SYNDROME

感染性休克综合征的机制

• 批准号: 6179743
• 负责人: Nilofer Qureshi
• 金额: $ 21.64万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-05-15 至 2002-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6179743
• 关键词: Escherichia coli; Rhodospirillales; binding proteins; biological signal transduction; blood toxicology; cGMP dependent protein kinase; cell free system; crosslink; disease /disorder model; drug design /synthesis /production; endotoxins; enzyme activity; enzyme inhibitors; high performance liquid chromatography; intermolecular interaction; lipopolysaccharides; macrophage; membrane proteins; mitogen activated protein kinase; scanning electron microscopy; septic shock; swine; thyroxine; tissue /cell culture; transmission electron microscopy

DESCRIPTION: (Adapted from the applicant's abstract) The investigators have analyzed the interactions of LPS with cells of the inflammatory process that can result in mortality in Gram-negative sepsis. A nontoxic lipid A derived from Rhodobacter sphaeroides (RsDPLA) that serves as a LPS antagonist in both in vivo and in vivo experimental conditions was developed. RsDPLA has the potential to be a key therapeutic adjunct to antagonize the initiating stimulus in Gram-negative sepsis, and is also a tool to study LPS-induced signal transduction. The investigators propose to: a) develop a novel, purified, and well characterized LPS crosslinking agent that will allow us to evaluate the interaction of LPS with macrophage membrane protein(s) other than CD14; b) test the hypothesis that RsDPLA blocks the interaction of LPS with a membrane-associated protein that is distinct from CD14; c) show that the cyclic guanosine monophosphate (cGMP)-dependent protein kinases and mitogen-activated protein kinases (MAPK) are involved in the LPS-induced activation of Spl using RsDPLA and several pharmacologic inhibitors; and d) develop an effective therapeutic regimen in the pig septic shock model by using a combination of RsDPLA and other drugs.

描述：（根据申请人的摘要进行了改编）调查人员有 分析了LP与炎症过程细胞的相互作用 可能导致革兰氏阴性败血症的死亡率。 无毒脂质A得出 来自Rhodobacter sphaeroides（RSDPLA），它是LPS拮抗剂 开发了体内和体内实验条件。 RSDPLA具有 成为对抗启动的关键治疗辅助的潜力 革兰氏阴性败血症的刺激，也是研究LPS诱导的工具 信号转导。 调查人员建议：a）开发小说， 纯化且表征良好的LP交联剂，将允许我们 评估LPS与巨噬细胞蛋白的相互作用 比CD14; b）测试RSDPLA阻断LPS相互作用的假设 与CD14不同的膜相关蛋白； c）显示 环状鸟苷单磷酸（CGMP）依赖性蛋白激酶和 有丝分裂原激活的蛋白激酶（MAPK）参与LPS诱导的 使用RSDPLA和几种药理抑制剂激活SPL；和D） 通过 结合RSDPLA和其他药物。