芬戈莫德调节免疫功能治疗创伤性脑损伤的机制研究与临床概念验证

脑外伤（TBI）过度炎症反应是继发性脑损伤的重要因素，其所致的神经功能障碍尚缺少有效治疗方法。本单位前期证实脑出血后早期、短时间应用芬戈莫德可显著改善患者神经功能，而应用此药干预TBI小鼠的继发性脑损伤也显示了良好前景，但不同给药时机，不同给药时程对TBI小鼠的作用差异较大，急需对其在TBI中的作用机制进行深入研究。拟通过体外细胞培养和TBI小鼠模型：1）探索芬戈莫德对Treg、NK迁移浸润，小胶质细胞M1和M2亚型转换等功能调控，以及趋化因子表达在此过程中的作用；2）应用流式细胞仪、Cytokine Array等监测局灶脑组织、肺、脾和周围血中免疫细胞和炎性细胞因子变化，探明芬戈莫德对TBI在体免疫调控作用; 3）比较TBI小鼠伤后不同时机、不同疗程给予芬戈莫德干预对神经功能修复的效果；4）按照概念验证研究（POC）规范，开展芬戈莫德治疗TBI的临床验证研究，为开发TBI新疗法奠定基础。

The excessive inflammatory response post traumatic brain injury(TBI) is an important factor of secondary brain injury, and the neurological dysfunction caused by it still lacks effective treatment.The colleagues in our insitute have confirmed that the injured neural function of the cerebral hemorrhage patients is greatly improved by early and short-term application of Fingolimod. Fingolimod also shows good prospects to improve the impaired neural function in the secondary brain injury in TBI mice.However, different timing and different terms of administration of Fingolimod result in significant ouctome in TBI mice. An in-depth study of its active mechanism in TBI is urgent. This study plans to be performed based on the in vitro cell culture system and TBI mice models. 1) Exploration of the modulating ability of Fingolimod on the mobility, invasion and proliferation of Treg and NK cells. The modulation of Fingolimod on the subtypes conversion between M1 and M2 of microglia is also inspected. The role of the chemokine expression in these processes is preliminarily confirmed too; 2) The flow cytometry, cytokine array and other facilities are applied to monitor the function changes of the immunological cells and the released cytokines in the injured brain tissue, lung, spleen and peripheral blood in the TBI mice. The in vivo modulation potential of Fingolimod will then be evaluated. 3 ) The therapeutic effects of the Fingolimod on the impaired neural function of the TBI mice will be compared, which is administrated with different initial time and different administrating term. 4) In accordance with the POC standards, the preliminary clinical validation studies of Fingolimod treatment for TBI patients will be carried out. The POC study will provide the theoretical foundation for developing new therapeutic strategies for TBI.