LAG3调控T细胞糖代谢在脓毒症中的作用与机制研究

项目名称： LAG3调控T细胞糖代谢在脓毒症中的作用与机制研究

项目编号： No.81471845

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 邓小明

作者单位： 中国人民解放军第二军医大学

项目金额： 72万元

中文摘要： 脓毒症是临床棘手难题，免疫抑制是患者死亡重要原因，T细胞功能受抑在其中发挥重要作用。已知，能量代谢是调控细胞功能的基础环节，糖代谢途径是维持T细胞功能的重要能量代谢方式。我们的预实验发现，脓毒症患者免疫细胞出现糖代谢水平异常，其调控方式及病生机制值得深入研究。我们前期研究表明，阻断淋巴细胞活化基因3（LAG3）可改善脓毒症小鼠T细胞功能，并可部分恢复其糖代谢水平。我们提出本项目科学假说：LAG-3通过调节细胞糖代谢途径，影响脓毒症时T细胞功能。本项目将从临床患者、离体细胞及转基因动物，探索下述科学问题：脓毒症时T细胞功能与糖代谢水平异常的关系；LAG3在调控脓毒症时T细胞糖代谢异常中的作用；基于多种激酶通路、转录因子探索LAG3调控T细胞糖代谢异常的具体机制。本研究从能量代谢这一新角度着眼，有助加深对脓毒症病理生理机制的认识，为通过LAG3分子治疗脓毒症提供实验依据。

中文关键词： 脓毒症；多器官功能障碍综合征；能量代谢；T细胞；淋巴细胞活化基因3

英文摘要： Sepsis causes millions of deaths globally each year. Dysfunction of T lymphocytes is the major cause of immunosuppression during sepsis.It is known that metabolism fundamentally underpins T cell function. Glucose metabolism is critical to the activation and differentitaion of T cell into its functioning status.Interestingly, our previous study found that glucose metabolism changed in T cells during sepsis. However, mechanisms that link glucose metabolism to T cell function are poorly understood. Our later research indicated that lymphocyte-activation gene 3 (LAG3) blockade could improve T cell function and restore its glucose metabolism partly. We then propose that LAG3 might be a critical molecure involved in T cell glucose metabolism during sepsis. Our current program was designed to illuminate the role of LAG3 in T cell glucose metabolism regulation from bench to beside, including septic patients,in vitro T cell study, and LAG3 gene knockout mice. The following scientific questions raised need to be resolved. First, the role of glucose metabolism abnormality in T cell dysfunction during sepsis will be illustrated. Second, the role of LAG3 in T cell glucose metabolism regulation in sepsis will be explored. Third, the potential pathways involved in LAG3 mediated T cell glucose metabolism in sepsis will be investigated. Collectively, through the research into the glucose metabolism of T cells during sepsis, our program will provide valuable insights into the mechanisms of sepsis and might raise a new potential therapeutic area in future.

英文关键词： sepsis;MODS;metabolism;T lymphocytes;LAG3