ROLE OF CD14 AND OTHER LPS RECEPTORS IN ENDOTOXIC SHOCK

描述（来自申请人摘要的逐字逐句） 重点是进一步阐明CD 14影响细胞增殖的机制。 炎症反应。具体目标1：确定联合国的相对作用 CD 14：LPS在细菌性病原体休克反应中的相互作用 各种毒力因子。我们之前已经证明，CD 14缺陷小鼠 对LPS和E.大肠杆菌0111。我们 假设是某些革兰氏阴性菌将主要诱导休克 通过CD 14：LPS途径，而其他细菌具有不同的耐受性， 这些因素将通过CD 14非依赖性机制诱导休克。为了验证这一 假设，我们将首先研究CD 14缺陷和正常的休克反应 小鼠与一组特征良好的E.表达确定毒力的大肠杆菌 决定因素接下来，我们将测试CD 14：LPS相互作用在一个细胞中的作用。 盲肠结扎穿孔致休克腹膜炎模型。最后我们 将使用口服休克模型来检查CD 14在对 利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 CD 14：LPS在细菌诱导休克中的相互作用将开始阐明 CD 14的作用机制：LPS介导的休克与CD 14非依赖性 冲击.具体目标2：确定CD 14：LPS相互作用的相对作用 局部感染。我们认为，运作系统模型的机制 will also也operate操作on the local本地level水平.也就是说，这些细菌 CD炎症！14-缺陷小鼠会引起局部炎症反应 在CD 14-/-小鼠中，与正常小鼠相似;那些不 在CD 14缺陷小鼠中引起休克不会引起组织损伤， 迅速清除。这些实验的结果应能补充 冲击模型，并导致对机制的进一步理解 调节这些细菌的毒力及其在炎症中的作用。具体 目的3：探讨可溶性CD 14（sCD 14）在感染性休克和局部缺血中的作用。 由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， LPS;一种通过膜CD 14刺激，一种通过另一种刺激 途径，需要一个复杂的性能网站。

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.