循环组蛋白作为新的DAMP在ACLF发展中的作用及机制研究

系统性炎症是慢加急性肝衰竭（ACLF）发生发展中的核心环节，但其关键的调控分子及具体信号转导机制尚未明确。作为一种新的损伤相关分子模式（DAMP），循环组蛋白在维持炎症中发挥重要作用，但其在ACLF中的病理作用尚无人研究。申请者前期工作发现：循环组蛋白水平与ACLF患者体内炎症水平、疾病严重程度及预后密切相关，同时体外实验证实细胞外组蛋白可以促进caspase11激活从而诱导细胞焦亡发生。因此，申请者提出“循环组蛋白作为新的DAMP是调控ACLF进展的关键蛋白”的科学假说，拟采用多种细胞系及基因敲除小鼠，建立多个动物模型，收集大量临床标本及资料，试图从分子、细胞、动物及临床水平揭示循环组蛋白调控焦死亡及系统性炎症从而促进ACLF发生进展的作用新机制及核心信号通路。开展本项目研究，可望阐明循环组蛋白在ACLF发生发展中的作用及具体分子机制，为ACLF的早期诊断及治疗提供新的思路及靶点。

It is of great importance to explore the mechanisms and effective therapeutic targets of acute-on-chronic liver failure (ACLF). Systemic inflammation is critical for the initiation and progression of ACLF, but the identifiable mediator and signal transduction pathway remain exclusive. Circulating histone is a novel inflammation-related damage-associated molecular pattern (DAMP) however its role in ACLF still remains largely unknown. Our previous work demonstrated that the level of circulating histone is significantly elevated in ACLF patients and correlates with disease severity as well as prognosis. In vivo experiments demonstrate that DAMPs are responsible for programmed cell death. Based on these findings, we hypothesize that circulating histone is an important regulator in the pathology of ACLF. In this study, we will focus on the molecular mechanisms and signaling pathways of circulating histones mediated systemic inflammation and cell death in the pathogenesis of ACLF. We will use several cell lines，primary cells and gene modified mice to identify the core mechanism involving in circulating histone-modulated ACLF progression. We hope to clarify the novel role of circulating histone in modulating pyroptosis and systemic inflammation to promote ACLF progression, and provide evidence for therapeutic intervention targeted histone in the diagnosis and therapy of ACLF.