脓毒症是是临床上常见的急重症疾病，死亡率高达40%。虽然目前已明确多脏器衰竭和免疫抑制是导致脓毒症患者死亡的关键因素，但具体分子机制仍不甚清楚。蛋白激酶R (PKR)具有重要的免疫调节功能，是脓毒症中导致免疫抑制乃至死亡的重要分子。在研究PKR的作用机制的过程中我们发现：PKR通过干扰素途径促进Caspase-11的表达；PKR下游效应分子-高迁移率蛋白-1（HMGB1）能促进Caspase-11的活化。Caspase-11是一种蛋白水解酶，在细菌内毒素引起的免疫反应中起重要作用。结合预实验结果—Caspase-11基因的缺失能显著增强小鼠在脓毒症中的细菌清除能力，我们提出：Caspase-11在脓毒症中很可能是导致免疫抑制乃至死亡的重要分子。围绕该科学假设，我们拟进一步研究Caspase-11在脓毒症中的作用及其机制，并初步评估Caspase-11抑制剂在脓毒症动物模型中的疗效。

Sepsis is a common disease in intensive care units, with the mortality rate over 40%. Although it is now clear that multiple organ dysfunction and immunosuppression are critical for the sepsis-induced death, the underlying molecular mechanisms remain largely unknown. Protein kinase R (PKR), an important regulatory molecule in immune responses, contributes importantly to the immunosuppression and death in sepsis. During the course of studying the function of PKR, we found that PKR not only up-regulates the expression of caspase-11 via the interferon signaling but also promotes the activation of caspase-11 via the high mobility group box 1 protein (HMGB1), a downstream factor of PKR. Caspase-11 is a protease that plays an important role in bacterial endotoxin-induced inflammation and programmed immune cell death. Based on our preliminary data, here we proposed that caspase-11 probably contribute importantly to the immunosuppression and the multiple organ dysfunction in sepsis. Based on this hypothesis, we will investigate the role of caspase-11 in the pathogenesis of sepsis with the following aims: 1) To investigate the effect of the genetic deletion of caspase-11 or pharmacological inhibition of caspase-11 on the mortality rate of sepsis, the programmed immune cell death, and the production of vasoactive lipid mediators. 2) To investigate the role cell-type specific caspase-11 in the pathogenesis of sepsis. 3) To investigate the molecular mechanisms by which HMGB1 promotes caspase-11 expression.