AMPK-ACC通路调控脂质过氧化介导的CD4+T细胞焦亡改善脓毒症免疫抑制的机制研究

目前脓毒症的死亡率仍居高不下，但死亡高峰正由过度炎症反应期后移到免疫抑制期，T细胞大量程序性死亡是后者的重要成因。焦亡是一种新的细胞程序性死亡方式，我们曾率先报道了脓毒症时CD4+T细胞会发生焦亡，但其调控机制尚不明确。我们的后续研究发现脂质过氧化反应介导了CD4+T细胞焦亡。据此，本项目提出假设: 脂质代谢的关键调控通路AMPK-ACC能通过减轻脂质过氧化反应来抑制CD4+T细胞焦亡，最终改善脓毒症免疫抑制状态。为验证该设想，本项目拟:1、观察AMPK-ACC通路活化、脂质过氧化和焦亡在脓毒症后CD4+T细胞中的发生规律; 2、探究CD4+T细胞AMPK-ACC通路对脓毒症免疫抑制的调控作用及机制; 3、评价创伤脓毒症患者外周血CD4+T细胞AMPK-ACC通路活化的临床检测意义。本项目将丰富对脓毒症后免疫代谢变化和免疫抑制形成机制的认识，并为脓毒症的预测和治疗提供新的靶点。

Mortality of sepsis is still in high level but the peak of death has changed from early hyper-inflammatory phase to late immune-suppressive phase. Excessive programmed cell death (PCD) of T cells is considered the main reason for immune-paralysis. Our previous work found that CD4+T cell pyroptosis, a new manner of PCD, participated in the formation of sepsis immunosuppression, which was mediated by the increased lipid peroxidation. It is hypothesized in this study that AMPK-ACC, a key signal pathway in lipid metabolism, may suppress CD4+T cell pyroptosis though regulating lipid peroxidation, and eventually ameliorates the immune-suppression after sepsis. Therefore, in present proposal, we will conduct the following studies: 1. To observe the development of AMPK-ACC pathway activation, lipid peroxidation and pyroptosis in CD4+T cell after sepsis. 2. To explore the role and mechanism of AMPK-ACC pathway in modulating immune-paralysis after sepsis. 3. To evaluate the clinical significance of AMPK-ACC pathway stimulation of CD4+T cell in peripheral blood of traumatic sepsis patients. The fulfillment of this proposal will enrich our knowledge in immune-metabolism characteristic and immunosuppression after sepsis, which may provide a new target in prediction and therapy for sepsis.