脓毒症的本质是机体过度释放炎症介质引起的炎性反应失控，阐明调控脓毒症炎症反应的分子机制具有重要意义。我们的前期研究发现长链非编码RNA GAS5（lncRNA GAS5）参与了脓毒症炎症反应的调节，lncRNA GAS5可抑制脓毒症的关键炎症介质HMGB1的胞外释放，而释放至胞外的HMGB1又可下调GAS5，基于对二者交互抑制的创新发现我们提出如下假设：GAS5可能通过吸附并抑制miR-155而上调SIRT1，从而抑制HMGB1的乙酰化，减少HMGB1的胞外释放，发挥抗炎效应；而释放至胞外的HMGB1可能通过活化NF-κB而上调UPF1，进而促进GAS5降解，降低GAS5水平，发挥促炎作用。本项目将通过系列实验深入解析GAS5与HMGB1交互抑制的分子机制，并阐明其在调节脓毒症炎症反应中的重要作用，为探索以GAS5和HMGB1交互抑制环路为靶标的抗脓毒症新策略提供科学依据。

Sepsis is characterized by uncontrolled inflammatory response resulting from excessive release of inflammatory mediators, it is of great significance to elucidate the molecular mechanisms regarding inflammatory response regulation of sepsis.Our preliminary data for the first time showed that lncRNA GAS5 dramatically suppressed the extracellular release of HMGB1, which is the key inflammatory mediator of sepsis. Meanwhile, we found that the extracellular HMGB1 could markedly downregulate GAS5. Furthermore, we did the primary exploration for the molecular mechanism on the reciprocal inhibition between GAS5 and HMGB1, and got several innovative findings. Based on our preliminary discoveries together with previous reports, we hypothesize that GAS5 may repress the extracellular release of HMGB1 by adsorbing and downregulating miR-155, leading to the elevation of SIRT1 and the decrease of HMGB1 acetylation. While extracellular HMGB1 may upregulate UPF1 by activating NF-κB, leading to the accelerated degradation of GAS5, which decreases the level of GAS5. In the present project, we will further illustrate the molecular mechanism regarding the reciprocal inhibition between GAS5 and HMGB1, and clarify its important role in regulating the inflammatory response of sepsis. The expected results of this project may provide scientific evidences for exploring novel anti-sepsis strategies by targeting the reciprocal inhibition loop between GAS5 and HMGB1.