“PPARγ-RNF146-WNT”通路调节单核细胞代谢重编程在PICS中的作用机制研究

单核细胞代谢重编程参与脓毒症持续性炎症-免疫抑制-分解代谢综合征（PICS）的致病机制，脓毒症中未受刺激骨髓单核细胞（NBMM）通过代谢重编程诱导训练免疫，环指蛋白146（RNF146）在其中显著上调。RNF146是E3泛素连接酶，介导AXIN1泛素化，激活WNT通路，WNT与PPARγ相拮抗，二者平衡调节代谢重编程。预实验提示：PICS小鼠存在训练免疫特点；RNF146沉默下调NBMM糖酵解和炎症因子水平，RNF146激活依赖PPARγ通路下游蛋白。据此提出假设：PPARγ与WNT通路通过RNF146介导的AXIN1泛素化平衡，是影响NBMM代谢重编程的核心机制，参与PICS训练免疫诱导。本课题将在临床、动物及细胞实验水平上，研究“PPARγ-RNF146-WNT/β-catenin”调节NBMM代谢重编程功能，阐明该信号通路在PICS中的作用机制，为临床开发针对性治疗方案提供理论基础。

Metabolic reprogramming of monocytes is involved in the pathogenesis of persistent inflammation-immunosuppressive-catabolic syndrome (PICS) in sepsis. Naïve bone marrow monocytes (NBMM) in sepsis can induce "trained immunity" by metabolic reprogramming. Ring finger protein 146 (RNF146) is significantly upregulated in sepsis induced NBMM metabolic reprogramming. RNF146 is a ubiquitin ligase which can mediate ubiquitination and degradation of AXIN1 protein and activate the WNT signaling pathway. While PPARγ and WNT signaling pathways have antagonistic effects. The balance between the two regulates metabolic reprogramming. The preliminary experiment of this project indicated that "trained immunity" could be found in PICS mice. The knock-down of RNF146 reduced the glycolysis and inflammatory factor levels in NBMM. The activation of RNF146 depended on the downstream protein activation in PPARγ pathway. Based on this, we propose a hypothesis: "PPARγ and WNT signaling pathways balance via RNF146 regulated ubiquitination of AXIN1 is the core mechanism affecting metabolic reprogramming of NBMM cells and plays a critical role in the induction of trained immunity in PICS." This study will explore the function of “PPARγ-RNF146-WNT/β-catenin” pathway in regulating metabolic reprogramming of NBMM cells at the level of clinical samples, animal models, and cellular experiments. The clarification of this mechanism and its function in PICS pathogenesis will provide theoretical basis for clinical development of targeted treatments.