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（申请人摘要中的逐字记录）所提议的研究将 重点是进一步阐明 CD14 影响的机制 炎症反应。具体目标 1：定义 CD14：LPS在细菌病原体休克反应中的相互作用 各种毒力因素。我们之前已经证明 CD14 缺陷小鼠 对 LPS 和大肠杆菌 0111 的致命作用具有高度抵抗力。 假设一些革兰氏阴性细菌主要会引起休克 通过 CD14:LPS 途径，而其他细菌具有不同的毒力 因素会通过 CD14 独立机制诱发休克。为了测试这个 假设，我们首先研究CD14缺陷和正常人的休克反应 小鼠与表达确定毒力的一组经过充分表征的大肠杆菌 决定因素。接下来，我们将测试 CD14:LPS 相互作用在 盲肠结扎穿刺休克腹膜炎模型。最后，我们 将使用休克的口腔模型来检查 CD14 在响应中的作用 使用独特机制逃避宿主免疫的细胞内生物 防御。这些研究将扩大我们对相对作用的理解 CD14：LPS在细菌引起的休克中的相互作用将开始阐明 CD14:LPS介导的休克与CD14非依赖性休克的作用机制 震惊。具体目标 2：确定 CD14:LPS 相互作用的相对作用 在局部感染的情况下。我们相信系统模型的运行机制 也将在地方层面运作。也就是说，那些引起 CD!14缺陷小鼠的炎症会引起局部炎症反应 在CD14-/-小鼠中，与正常小鼠相似；那些细菌不 对 CD14 缺陷小鼠造成休克不会造成组织损伤，并且会 很快就清空了。这些实验的结果应该补充那些 冲击模型并加深对机制的理解 调节这些细菌的毒力及其在炎症中的作用。具体的 目标 3：确定可溶性 CD14 (sCD14) 在感染性休克和局部感染中的作用 LPS 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 脂多糖；一种通过膜 CD14 刺激，一种通过另一种膜刺激 途径并需要复杂的表演场地。