CIRP通过调控巨噬细胞极化参与急性肝衰竭发生的作用及机制研究

巨噬细胞极化失衡是急性肝衰竭（ALF）细胞因子风暴形成的核心机制。冷休克蛋白CIRP是一种新的炎症因子，但其与巨噬细胞极化的关系尚不清楚。我们的预实验发现ALF患者血清CIRP显著增高；CIRP敲除鼠诱发ALF后细胞因子风暴减轻；CIRP刺激巨噬细胞后M1型细胞比例增高，M2型降低。我们应用SELEX技术筛选出一组能特异性结合CIRP并抑制其与受体结合的CIRP核酸适配体。因此我们假设：CIRP以自分泌的方式诱导巨噬细胞向M1型极化，促进ALF发生；CIRP核酸适配体能特异性抑制CIRP活性，缓解其致病效应。我们拟通过临床分析和体内外实验明确CIRP在ALF中的表达；利用CIRP基因敲除小鼠和重组蛋白揭示CIRP在ALF巨噬细胞极化中的作用及分子机制；同时筛选CIRP核酸适配体，验证其对CIRP的抑制作用和ALF的治疗效果。本项目将揭示ALF发生的新机制，为CIRP的靶向治疗提供新方法。

Imbalance of macrophage polarization plays a pivotal role in cytokine storm formation during acute liver failure (ALF). Cold-inducible RNA-binding protein (CIRP) is a newly identified inflammatory factor; however, it remains unknown whether CIRP regulates macrophage polarization. Our preliminary study showed that the level of serum CIRP was significantly increased in ALF patients, and the cytokine storm was alleviated after ALF model in CIRP knockout mice. Meanwhile, we found that the proportion of M1 type macrophages were increased and M2-type macrophages were decreased after CIRP stimulation. Moreover, we have screened a group of CIRP aptamers by using SELEX that can specifically bind to CIRP and inhibit its binding to the receptor. Therefore, we hypothesized that CIRP induces the M1-type polarization of macrophages in an autocrine way to promote the occurrence of ALF. CIRP aptamer may specifically inhibit the activity of CIRP and alleviate its pathogenic effect. We intend to identify the expression of CIRP in ALF through clinical analysis and basic study. Meanwhile, CIRP knockout mice and CIRP recombinant protein will be used to explore the role and mechanism of CIRP in macrophages polarization in ALF. Additionally, the effect of CIRP aptamer on CIRP activity and ALF will be verified. This project will propose a new theory of ALF occurrence and provide a new method for CIRP targeted therapy.