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， 在护理因事故或重大事故而遭受创伤的外科病人时， 手术后脓毒症仍然是发病的主要原因， mortality. 解决这个问题的一个方法是通过一个更好的 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， 炎症介质级联的启动。 许多研究者 假设过度或持续的炎症激活 信号传导/介体途径有助于脓毒症中的终末器官损伤。 的 研究人员指出，他们发现肝细胞（HC） 表达高水平的内毒素（LPS）识别分子CD 14。 此外，HC CD 14表达在以下情况下显著上调： 内毒素血症或损伤。 尽管白细胞被认为是 作为CD 14的主要来源，研究人员认为HC代表了一种 重要的和以前未被怀疑的局部和系统性CD 14来源。 作为急性期反应物，他们假设， HC释放可溶性CD 14足以介导LPS与 CD 14阴性细胞在外周。 可溶性CD 14集中在 肝脏应调节LPS与肝非实质细胞的相互作用 细胞 最后，他们提供的证据表明，HC可以响应的变化， 基因表达的生理相关水平的LPS，他们提出， 表面表达的CD 14介导了这种反应。 研究人员将根据两个目标来研究这些假设：目标一：为了 确定CD 14是如何在肝细胞中调节和加工的。 他们将 确定CD 14如何在转录水平上调节， 转录后水平，他们认为这将导致更好的 了解HC CD 14表达如何以及何时增加。 他们还 试图确定CD 14是如何在HC中差异化加工以产生 膜和可溶性形式的研究，这将定量多少CD 14是 从肝脏中释放出来。 目的二：确定的功能 肝细胞来源的CD 14。 根据目标二，调查人员计划利用 新型试剂（重组大鼠CD 14、CD 14中和抗体和CD 14 敲除小鼠）以确定HC衍生的CD 14的功能作用。 他们 我相信他们的研究结果应该能为我们提供关键的见解， 宿主对微生物入侵的反应以及导致 炎症介质级联的过度激活。

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.