ROLE OF CD14 AND OTHER LPS RECEPTORS IN ENDOTOXIC SHOCK

CD14 和其他 LPS 受体在内毒素休克中的作用

• 批准号: 7315275
• 负责人: Sanna M Goyert
• 金额: $ 39.4万
• 依托单位: CITY COLLEGE OF NEW YORK
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-01-01 至 2007-12-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7315275
• 关键词: CD14 molecule; Escherichia coli; Staphylococcus aureus; antigen receptors; bacteria infection mechanism; bacterial antigens; bacterial genetics; bacterial proteins; disease /disorder model; endotoxins; gene expression; gene targeting; gram negative bacteria; gram positive bacteria; host organism interaction; inflammation; laboratory mouse; lipopolysaccharides; microorganism immunology; molecular pathology; protein structure; receptor expression; septic shock; tissue /cell culture; virulence

DESCRIPTION (Verbatim from the applicant's abstract) The studies proposed will focus on further elucidating mechanisms through which CD14 influences the inflammatory response. Specific Aim 1: To define the relative role of the CD14:LPS interaction in the shock response to bacterial pathogens posessing various virulence fqactors. We have previously shown that CD14-deficient mice are highly resistant to the lethal effects of LPS and E. Coli 0111. Our hypothesis is that some Gram-negative bacteria will induce shock predominently via the CD14:LPS pathway while other bacteria having different virulance factors will induce shock via CD14 independent mechanisms. To test this hypothesis, we will first study the shock response of CD14-deficient and normal mice to a well characterized panel of E. coli expressing defined virulence determinants. Next, we will test the role of the CD14:LPS interaction in a peritonitis model of shock induced by cecal ligation and puncture. Finally, we will use an oral model of shock to examine the role of CD14 in the response to intracellular organisms that use unique mechanisms to evade the host immune defense. These studies will expand our understanding of the relative roleof the CD14:LPS interaction in shock induced by bacteria and will begin to elucidate the mechanisms operating in CD14:LPS mediated shock versus CD14-independent shock. Specific Aim 2: To define the relative role of the CD14:LPS interaction in local infection. We believe that the mechanisms operating systemic models will also operateon the local level. That is, those bacteria which cause inflammation in CD!14-deficient mice will cause a local inflammatory response in CD14-/- mice, similar to that of normal mice; those bacteria which do not cause shock in CD14-deficient mice will not cause tissue damage and will be quickly cleared. The results from these experiments should complement those in the shock model and lead to an enhanced understandingf of the mechanisms regulating virulence of these bacteria and their role im imflammation. Specific Aim 3: To determine the role of soluble CD14 (sCD14) in septic shock and local inflammation induced by LPS and various bacteria (Gram-negative, Gram-positive). Studies suggest that there are two pathways for activation with LPS; One that stimulates via membrane CD14 and one that stimulates via another pathway and requires a complex of performance sites.

描述(从申请人的摘要中逐字摘录)建议的研究将 重点是进一步阐明CD14影响血管生成的机制。 炎症反应。具体目标1：确定 CD14：细菌致病菌休克反应中的内毒素相互作用 各种毒力因子。我们之前已经证明了CD14缺陷小鼠 对内毒素和E.Coli 0111的致死作用具有高度抵抗力。我们的 假说是一些革兰氏阴性菌会引起休克 通过CD14：LPs途径，而其他细菌具有不同的毒力 这些因素将通过CD14独立机制诱发休克。为了测试这一点 假设，我们将首先研究CD14缺陷和正常的休克反应 小鼠对一组具有良好特性的表达明确毒力的大肠杆菌 决定因素。接下来，我们将测试CD14：LP交互作用在 盲肠结扎穿孔致休克腹膜炎模型的建立。最后，我们 将使用口服休克模型来研究CD14在应对 使用独特机制逃避宿主免疫的细胞内有机体 防守。这些研究将扩大我们对 CD14：细菌休克中的内毒素相互作用并将开始阐明 CD14的作用机制：内毒素介导的休克与CD14非依赖性 令人震惊。具体目标2：确定CD14：LPs相互作用的相对作用 在局部感染中。我们认为，运行系统模型的机制 也将在地方一级运作。也就是说，那些能引起 CD！14缺陷小鼠的炎症将引起局部炎症反应 在CD14-/-小鼠中，与正常小鼠相似；那些不 引起CD14缺陷小鼠休克不会造成组织损伤 很快就清场了。这些实验的结果应该是对 激波模型，并导致对机理的进一步理解 调节这些细菌的毒力及其在感染中的作用。特定的 目的3：探讨可溶性CD14(SCD14)在感染性休克和局部出血中的作用。 脂多糖和各种细菌(革兰氏阴性， 革兰氏阳性)。研究表明，有两种激活途径 一种是通过膜CD14刺激，另一种是通过另一种刺激 这是一条途径，需要复杂的表演场地。