基于NAD+/SIRT1通路探讨脓毒症肌病线粒体损伤的发生机制及补充烟酰胺核糖的保护作用

Sepsis myopathy (SIM) is a common complication of severe infections. It would lead to delayed weaning of ventilator, increased mortality rate in early phase, and lead to limb disability and poor prognosis in chronic phase. The pathogenesis of SIM is still not clear, and the effective treatment is lack. Our previous studies demonstrated that mitochondrial injury was involved in the occurrence of SIM, and the mitochondrial showed different forms of injury between acute and chronic SIM phases. Sirtuin 1 (SIRT1) is a key regulator of mitochondria which attracted much attention in recent years. It plays a differentially regulated role in mitochondrial function of acute and chronic disease models, and might be related with the different mitochondrial injury forms in SIM different phases. The expression and activity of SIRT1 are affected by NAD+ levels. Nicotinamide ribose (NR) is a natural NAD+ precursor, and has been suggested its mitochondrial regulatory potential in recent years. Based on our previous studies, by conducting researches involved with cell, animals and clinical patients, we aimed to verify the following hypotheses: 1. SIRT1 and its downstream mitochondrial biogenesis, oxidative stress and inflammatory injury pathways play different regulatory roles in acute and chronic SIM; 2. NR supplementation plays a protective role in the SIM induced skeletal muscle mitochondrial injury through NAD + / SIRT1 pathway, and will further ameliorate symptoms and improve prognosis of SIM in acute and chronic phases. This study will broaden the current understanding of the mechanism of SIM and provide a new treatment candidate and therapeutic target for SIM.

脓毒症肌病（SIM）是重症感染常见并发症，急性期致撤机困难、死亡率增加，慢性期致肢体残障、不良预后增多。其发病机制尚不明确，治疗手段匮乏。前期研究显示线粒体损伤极可能参与SIM发生，且在急、慢性期的损伤形式表现不同。去乙酰化酶1（SIRT1）是近年受到关注的一个关键线粒体调控因子，在急、慢性疾病模型中对线粒体功能发挥差异化调控，这也与SIM急、慢性期线粒体不同损伤形式相呼应。SIRT1表达和活性受NAD+水平影响，烟酰胺核糖（NR）是一种天然NAD+前体，近年研究提示了其线粒体调控潜力。基于此，我们拟在细胞、动物和临床三个维度，验证以下假设：1、SIRT1及下游线粒体生物合成、氧化应激和炎症损伤调控通路在SIM急、慢性期发挥不同调控作用；2、NR通过NAD+/SIRT1途径减轻SIM骨骼肌线粒体损伤，改善疾病急、慢性期症状和预后。本研究将拓宽当前对SIM发生机制的认识、提供新的治疗靶点。

脓毒症肌病（SIM）等器官功能损伤是重症感染的常见并发症，导致患者病死率增加，但发病机制尚不明确，治疗手段匮乏。本项目阐述了NAD+、SIRT1及其下游线粒体代谢调控通路在SIM骨骼肌线粒体损伤中发挥的作用，阐明了补充烟酰胺核糖对SIM骨骼肌线粒体损伤的保护作用及临床益处。研究对代谢调控脓毒症炎症失衡和器官损伤的机制进行了相关探讨，并发现了鲍曼不动杆菌脓毒症若干重要毒力因子识别和干预措施。上述研究成果为脓毒症的治疗提供了新的治疗靶点和干预方向。