ld IL-2扩增Treg对急性缺血性脑卒中的保护作用及机制研究

Inflammation cascade dominates the whole cerebral injury process in early acute phase of ischemic stroke. Previous studies showed treg cells protect ischemic brain depending on immune regulation. Treg cells play an immunosuppression role to maintain blood-brain-barrier homeostasis. So expanding treg numbers and enhancing treg function may be therapeutic beneficial. Low-dose interleukin 2 (ld IL-2) administration can improve autoimmune and inflammatory diseases outcome with specific expansion of treg cells. Treg cells play immune suppression role through CD39-CD73- Adenosine pathway. This hypothesis has been elucidated in recent animal experiments and clinical trials. Our project plans to use mice focal ischemia/reperfusion model with ld IL-2 administration to investigate on multiple molecular aspects. The comprehensive investigation strategy involves animal level, tissue level and cell level. Firstly, how do treg cells regulate ld IL-2 induced ischemia cerebral protection? Moreover, in ld IL-2 neuroprotection scenario which immune regulation pathway work? Do treg cells play immunosuppression role in CD39-CD73-Adenosine pathway? Our project plans to figure out the underlying mechanism of treg cells protective role by regulating ld IL-2 against acute cerebral ischemia. Then clarify treg's role in CD39-CD73-Adenosine pathway. Our findings would point out new therapeutic strategy in acute ischemic stroke.

缺血性脑卒中超急性期炎性级联反应加重缺血脑损伤,既往研究证实调节性T细胞（treg）可发挥免疫抑制作用，维护血脑屏障免疫平衡从而改善卒中结局，是潜在的治疗靶点。最新动物实验和临床研究发现，低剂量白介素2（low-dose IL-2,ld IL-2）可特异性增加treg数量增强treg功能，改善自身免疫疾病和炎性疾病结局,因treg介导CD39-CD73-腺苷进行免疫调节。因此,本课题拟采用小鼠局灶性缺血再灌模型进行ld IL-2干预,在动物、组织和细胞层面进行多角度分子生物学研究: 1.探索ld IL-2对急性缺血性脑卒中是否具有神经保护作用 2.研究ld IL-2是否在缺血脑组织中特异性增强treg数量及功能 3.研究treg保护缺血脑组织是否通过CD39-CD73-腺苷发挥作用。本课题将阐明ld IL-2扩增treg对急性缺血脑卒中保护作用及机制，为药物及细胞治疗提供新思路。

缺血性脑卒中急性期炎性级联反应加重缺血脑损伤，既往研究证实调节性T细胞（treg）可发挥免疫调节作用，维护血脑屏障免疫平衡，从而改善卒中结局，是潜在治疗靶点，但体内循环treg细胞较少限制其临床应用。既往研究显示，IL-2/IL-2抗原抗体复合物可特异性扩增treg细胞数量并增强treg细胞功能，在调节炎症反应过程中起重要作用，可以改善卒中结局，但具体分子机制及miRNA介导通路并不清楚。因此，我们提出假说：外源性给予IL-2/IL-2抗原抗体复合物后，miRNA芯片技术筛选IL-2/IL-2mAb复合物对缺血脑卒中动物模型的保护作用相关的miRNAs，进行Candidate miRNAs的生物信息学分析及miRNA-X靶基因的生信预测和实验验证，进而明确通过IL-2/IL-2mAb复合物相关潜在miRNA调控treg，发挥其对急性缺血性脑卒中的神经保护作用。本课题总体研究目标是：明确IL-2/IL-2抗原抗体复合物特异性扩增treg信号通路对急性缺血性脑卒中神经保护作用，并探明其潜在分子机制。本课题有望为急性缺血性脑卒中提供新的治疗靶点和治疗策略。