选择性S1PR1调节增强低剂量阿替普酶溶栓效应的作用及机制

组织型纤溶酶原激活物（tPA）溶栓是缺血性脑卒中再灌注治疗的唯一药物，但受限于狭窄治疗窗和脑出血风险，仅有不到5%的卒中患者最终从中获益。与标准剂量相比，低剂量tPA降低出血风险，但增加残疾率。因此，当前迫切需要新的辅助治疗手段，以增强低剂量tPA溶栓效应但保留其低出血风险的益处。申请人已发表的研究证实，选择性S1PR1调节减少脑微动脉内淋巴细胞数量、血栓体积以及血栓和血管壁间的黏附。因此，申请人推测选择性S1PR1调节可以通过抑制淋巴细胞侵入神经血管单元、下调血管内皮细胞黏附分子表达，从而增强低剂量tPA的溶栓效应。本课题将结合双光子活体成像和小鼠脑皮层微动脉血栓模型，研究选择性S1PR1调节：①对低剂量tPA溶栓效应的实时动态影响；②增强低剂量tPA溶栓效应的细胞及分子机制。本课题的实施将推动S1PR1调节作为低剂量tPA溶栓的辅助治疗，为缺血性脑卒中的免疫干预提供新的策略。

Thrombolysis with tissue-type plasminogen activator (tPA) is the only proved drug for the treatment of ischemic stroke, however, limited by the narrow treatment window and the risk of cerebral hemorrhage, only 3% of stroke patients benefit. Compared with standard doses, low doses of tPA reduced the risk of bleeding but increased disability rates. Adjuvant therapies are urgently needed to enhance the thrombolytic effect of low-dose tPA while retaining its low bleeding risk safety. The applicant has demonstrated that selective S1PR1 modulator can inhibit lymphocyte invasion into vascular nerve units and reduce blood flow loss after intravascular thrombosis through the two-photon in vivo imaging in mice. Therefore, the applicant hypothesizes that selective S1PR1 regulation can enhance the intensity of thrombolysis at low doses of tPA and maintain BBB integrity. This project will combine two-photon in vivo imaging and mouse microthrombosis model to test selective S1PR1 modulation:1) The dynamic effect on the efficacy of low dose tPA thrombolysis; 2) The cellular and molecular mechanisms that enhance the efficacy of low dose tPA thrombolysis. This project will provide a new strategy for the treatment of ischemic stroke by promoting the combination of immune intervention represented by S1PR1 modulator and low dose tPA thrombolysis.