内毒素结合蛋白通过抑制STAT3线粒体转位改善脓毒症代谢紊乱的机制及靶向干预研究

炎症反应失调和细胞代谢功能絮乱是脓毒症高死亡率的重要因素。LPS结合蛋白（LBP）结合LPS，调控炎症反应。临床研究指出，LBP基因突变与代谢紊乱的发生有关，目前机制不清。本组前期研究发现LBP敲除: （1）显著降低脓毒症大鼠炎症反应；（2） 显著增加脓毒症大鼠晚期死亡率；（3）显著促进STAT3 丝氨酸727位磷酸化，导致STAT3线粒体转位及线粒体损伤。我们提出科学假说：LBP抑制STAT3磷酸化和线粒体转位，保护细胞代谢功能。本项目拟：在细胞水平探索LBP介导线粒体损伤的分子机制；在动物水平观察LBP敲除联合靶向干预STAT3线粒体转位改善脓毒症治疗效果；在临床水平观察LBP单核苷酸多态性与STAT3信号通路相关代谢功能改变及脓毒症预后相关性，为临床脓毒症治疗提供新思路。

In the development of sepsis ,the pro-inflammatory response was associated with metabolism dysfunction, and caused multi-organ failure. The inflammatory response in sepsis was induced by increased serum LPS levels. LBP can binding with LPS, and modulate the severity of inflammatory response. In our previous study, we found that the LBP knockout in rat promoted STAT3 S727 phosphorylation, and increase the translocation of STAT3 to mitochondria, which in turn, increase the production of ROS, and caused mitochondria injury. It is reported that the activation of mTOR activated STAT3 S727 phosphorylation. We hypothesize that LBP inhibited STAT3 S727 phosphorylation, as well as the translocation of STAT3 to mitochondria, to promotes the function of metabolism. This project is designed to explore the modulation of LBP on metabolism function, by using a LBP knockout and conditional knock-in mouse model in vitro and in vivo. Moreover, the association of LBP-SNPs with the severity of inflammatory response, metabolism function and the outcome of the septic patients will be observed. If our hypothesis holds, we can contribute to an better understanding of the pathomechanism of sepsis, and to achieve a more effective therapeutic strategy by LBP inhibition combine with targeting the STAT3 mitochondria translocation.