HMGB1促进线粒体DNA损伤修复及保护脓毒症心肌线粒体功能的研究

The Mitochondrial dysfunction is one of the important areas in sepsis, but the research of mtDNA damage repair is less in septic mechanisms. High mobility group protein B1 (HMGB1) which is a kind of late inflammatory mediators involved in the pathogenesis of sepsis with organ dysfunction. But as a nuclear non-histone DNA binding protein , the roles of HMGB1 in maintaining nuclear homeostasis and repair of DNA damage remains unclear in mechanisms of septic orgen damage. The dynamic change of mitochondrial HMBG1, mtDNA damage and ATM protein kinase dependent signal transduction pathways mediating repair mechanisms will are observed in the septic myocardial damage model, the rat septic model and the patients of severe sepsis with organ dysfunction in children in this project, and the effects on mtDNA damage repair and mitochondrial function and the protective effect of sepsis on myocardial injury will be examined by taking HMGB1 and PARP-1 as target.The main purpose of this project is to explore the HMGB1 may improve mitochondrial function, protect myocardial injury in sepsis by regulateing the ATM protein kinase dependent signaling pathway, and facilitating the repair of damaged mtDNA. The targeted intervention for HMGB1 is expected to have a breakthrough in clinical treatment of sepsis.

线粒体功能障碍是脓毒症研究的重要领域, mtDNA损伤的修复机制在脓毒症领域研究较少。高迁移率族蛋白B1（HMGB1）作为一种晚期炎症介质，参与脓毒症器官功能损伤的发病过程，但HMGB1作为细胞核内的非组DNA结合蛋白，参与染色质核的稳定、DNA修复等机制在脓毒症器官功能障碍发病机制中的作用仍不清楚。本项目以脓毒症心肌细胞模型、动物模型及儿童严重脓毒症器官功能障碍为研究对象，观察线粒体HMBG1、mtDNA损伤及修复机制——ATM蛋白激酶依赖性信号转导通路在脓毒症病理过程的动态变化，并针对关键靶点HMGB1及PARP-1进行靶向干预，观察对mtDNA损伤修复与线粒体功能的作用及脓毒症心肌损伤的保护作用，探索HMGB1可能通过影响ATM蛋白激酶依赖性信号转导通路机制，促进mtDNA损伤的修复作用，从而改善线粒体功能，保护脓毒症心肌损伤。其靶向干预有望在脓毒症临床治疗中取得新突破。

高迁移率族蛋白B1（HMGB1）作为一种晚期炎症介质，参与脓毒症器官功能损伤的 发病过程，但HMGB1作为细胞核内的非组DNA结合蛋白，参与染色质核的稳定、DNA修复等 机制在脓毒症器官功能障碍发病机制中的作用仍不清楚。本项目以脓毒症心肌细胞模型、 动物模型为研究对象，探究CircTLK1通过靶向调控miR-17-5p的表达增强PARP1/HMGB1轴介导的线粒体DNA氧化损伤，从而调节脓毒症诱导的心肌细胞凋亡，验证miR-125b通过靶向STAT3/HMGB1轴增强自噬通量以改善脓毒症诱导的心肌病。同时研究HMGB1促进免疫细胞聚集的机制及靶向干预研究，发现HMGB1诱导CD4+ T 细胞整合素α4β1和α4β7表达明显上调，促进CD4+ T细胞自我聚集，触发IL22-STAT3通路激活并引发促炎症因子主动性释放，进一步促进CD4+ T细胞自我聚集，发现T细胞聚集，可能是脓毒症早期免疫异常、导致器官损伤的重要机制。针对CD4+ T 细胞整合素α4β1和α4β7受体分子结构，筛选和修饰的环状 小分子肽，发现环状小分子肽显著抑制HMGB1诱导的CD4+T细胞聚集, 抑制下游IL22-STAT3通路激活及促炎症因子主动性释放，对CD4+T细胞发挥特异性靶向调节作用。研究结果揭示HMGB1在脓毒症心肌病重要的发病机制及靶向干预有望在脓毒症临床治疗中取得新突破。