POSTTRAUMATIC SEPSIS--REGULATION OF LPS BINDING PROTEIN

描述：(改编自申请人的摘要)尽管取得了重大进展 护理因意外或重大事故而遭受创伤的外科病人 手术后脓毒症仍然是发病率和死亡率的主要原因 死亡率。解决这个问题的一种方法是通过更好的 了解宿主利用的微生物识别系统。 这些系统允许宿主有效地清除微生物通过 炎症介质的启动级联反应。许多调查人员都有 假设炎症的过度或持续激活 信号/中介通路参与脓毒症的终末器官损伤。这个 研究人员指出，他们发现肝细胞(HC) 表达高水平的内毒素识别分子CD14。 此外，HC CD14的表达显著上调。 内毒素血症或损伤。尽管白细胞被认为是 CD14的主要来源，研究人员假设HC代表一种 局部和系统性CD14的重要来源和以前未被怀疑的来源。 作为一种急性阶段的反应物，他们假设 HC释放的可溶性CD14足以介导内毒素与 外周CD14阴性细胞。可溶性CD14主要集中在 肝脏应调节内毒素与肝脏非实质组织的相互作用 细胞。最后，它们提供了证据，证明HC可以通过改变 基因表达到与生理相关的内毒素水平，他们建议 表面表达的CD14介导了这一反应。 调查人员将在两个目标下研究这些假说：目标I： 确定CD14是如何在肝细胞中调节和处理的。他们会 确定CD14如何在转录和转录水平上受到调控 转录后水平，他们认为这将导致更好的 了解如何以及何时增加HC CD14的表达。他们也 试图确定CD14在HC中是如何差异处理的，以产生两者 膜和可溶性形式的研究将定量CD14是多少 从肝脏中释放出来。目的二：确定的功能 肝细胞来源的CD14。在AIM II下，调查人员计划利用 新试剂(重组大鼠CD14、CD14中和抗体和CD14 基因敲除小鼠)以确定HC来源的CD14的功能作用。他们 我认为，他们的结果应该能为以下公司利用的战略提供关键见解 宿主对微生物入侵的响应及其机制 炎症介质的过度激活会导致级联反应。

DESCRIPTION: (Adapted from the applicant's abstract) Despite major advances in the care of surgical patients suffering trauma from accidents or major surgery, postoperative sepsis remains a major cause of morbidity and mortality. One approach to address this problem is through a better understanding of the microbial recognition systems utilized by the host. These systems permit the host to efficiently clear microbes through the initiation of inflammatory mediator cascades. Many investigators have hypothesized that excessive or persistent activation of inflammatory signaling/mediator pathways contributes to end organ damage in sepsis. The investigators indicate that they have discovered that hepatocytes (HC) express high levels of the endotoxin (LPS) recognition molecule CD14. Furthermore, HC CD14 expression is markedly upregulated following endotoxemia or injury. Although leukocytes have been proposed as the primary source of CD14, the investigators posit that HC represent an important and previously unsuspected source of local and systemic CD14. Acting as an acute phase reactant, they hypothesize that the quantities of soluble CD14 released by HC are sufficient to mediate LPS interaction with CD14-negative cells in the periphery. Soluble CD14 concentrated in the liver should modulate the interaction of LPS with hepatic nonparenchymal cells. Finally, they provide evidence that HC can respond with changes in gene expression to physiologically relevant levels of LPS, and they propose that surface-expressed CD14 mediates this response. The investigators will pursue these hypotheses under two aims: AIM I: To determine how CD14 is regulated and processed in hepatocytes. They will determine how CD14 is regulated at the transcriptional and posttranscriptional levels, which they believe will lead to a better understanding of how and when HC CD14 expression is increased. They also seek to establish how CD14 is differentially processed in HC to produce both membrane and soluble forms in studies which will quantitate how much CD14 is released from the liver. AIM II: To determine the functions of hepatocyte-derived CD14. Under Aim II, the investigators plan to utilize novel reagents (recombinant rat CD14, CD14-neutralizing antibodies, and CD14 knockout mice) to establish the functional roles of HC-derived CD14. They believe their results should yield key insights into strategies utilized by the host to respond to microbial invasion and the mechanisms leading to excessive activation of inflammatory mediator cascades.