脓毒症是多器官功能衰竭最主要的原因，发病率及死亡率极高，目前缺乏有效的诊断和治疗措施。FAM19A4是本课题组成员首次发现的新细胞因子，目前尚未有在脓毒症中的报道。前期研究发现：FAM19A4在正常组织低表达，在脂多糖刺激的单核巨噬细胞中表达上调；FAM19A4对巨噬细胞具有趋化作用，能促进其吞噬及活性氧自由基的产生；在脓毒症患者及脓毒症模型小鼠血清中，FAM19A4的表达水平明显升高，而在类风湿关节炎等慢性炎症和心外手术患者中表达水平不高； FAM19A4重组蛋白能加速脓毒症小鼠的死亡。我们推测FAM19A4可能参与脓毒症的发生发展。本研究中我们将在脓毒症患者中，研究FAM19A4作为脓毒症的标志物与病情变化及预后的关系；在小鼠脓毒症中，从整体-细胞-分子三个层次，通过FAM19A4的过表达、抗体抑制等方法阐明FAM19A4的表达、功能和作用机制，为脓毒症的治疗提供新的靶点。

Sepsis is the leading cause of multiple organ dysfunction syndrome. The morbidity and mortality of sepsis is very high, but now we lack of effective diagnostic and therapeutic management. FAM19A4 was a new cytokine identified by our research group first time, which didn’t have any report in sepsis until now. It was confirmed in our preliminary work that the expression of FAM19A4 was low in normal tissue, but increased in lipopolysaccharide-stimulated macrophages; FAM19A4 was chemotactic, and could promote the phagocytosis of macrophages and the production of reactive oxygen species. The expression of FAM19A4 increased significantly in serum of sepsis patients or sepsis mice model,but it’s expression is not high in cardiac surgery and chronic inflammation(such as, rheumatoid arthritis) patients; the pre-experiment suggest that the recombinant protein of FAM19A4 can accelerate the death of sepsis model mice. So we speculate that FAM19A4 is involved in the development of sepsis. In this research, we will study the relationship between FAM19A4 and condition changes and prognosis in sepsis patients when FAM19A4 as a marker of sepsis; Meanwhile, we will study the expression, function and the mechanism of FAM19A4 in sepsis mice model in levels of entirety, cell and molecule, through out the over expression and antibody inhibition of FAM19A4, it will provide a new target for the treatment of sepsis.

脓毒症发病率及死亡率极高，目前缺乏有效的治疗措施。FAM19A4是本课题组成员首次发现的新细胞因子，前期工作发现，FAM19A4在脂多糖刺激的单核巨噬细胞中表达上调，FAM19A4具有趋化作用，能促进巨噬细胞的吞噬以及活性氧自由基的产生。据此，本研究在脓毒症患者中检测FAM19A4的表达情况，观察FAM19A4与目前临床应用炎症标志物（CRP、PCT、IL-6）及预后的关系；同时应用盲肠结扎穿孔法（cecal ligation and puncture, CLP）制备小鼠脓毒症模型，通过FAM19A4的过表达、抗体抑制等方法，阐明FAM19A4表达变化对巨噬细胞功能的影响。结果发现，FAM19A4在脓毒症患者中表达较正常对照组和非感染性炎症反应组明显升高，且血清表达水平随患者病情进展逐渐升高，变化趋势与IL-6相关。FAM19A4在脓毒症小鼠中表达明显升高，6小时开始升高，24小时达峰，48小时降至基线水平。FAM19A4能加重炎症反应、加重感染程度、加重器官损伤、增加死亡率，促进巨噬细胞的趋化、吞噬和ROS产生。所以，FAM19A4在脓毒症中有功能的表达，其作用和巨噬细胞有关，从而为脓毒症的治疗提供新靶点，将为脓毒症从基础到临床的研究打开一条新的道路。项目资助待发表SCI论文1篇。培养硕士生1名。项目投入经费10万元，支出9.9477万元，各项支出基本与预算相符。