组织纤溶酶原激活物(tPA)用于脑梗死溶栓治疗，但严格的时间窗及出血副作用限制其广泛使用。tPA在剪切纤溶酶原的同时，酶切并激活血小板源性生长因子(PDGF)-CC从而加剧血脑屏障(BBB)渗漏，引起出血转化。与活化纤溶酶原不同，酶切PDGF-CC依赖tPA-Mac1-LRP1三聚体，且载脂蛋白E模拟短肽COG1410可能干扰该三聚体组装，因此我们提出假说：COG1410通过干扰tPA-Mac1-LRP1三聚体特异性抑制PDGF-CC前体的酶切与活化，减轻BBB破坏，达到防治脑出血并延长溶栓时间窗的目的。本项目将利用线栓和栓塞两种中风模型研究COG1410减轻溶栓时的BBB破坏和脑出血，探索延长溶栓的时间窗，并综合体内和体外方法研究模拟肽对三聚体的干扰及内源性与外源性tPA酶切活性的调节。本项目的策略将在不影响tPA溶栓效果前提下限制其副作用，为拓展tPA的安全和广泛应用做好前期铺垫。

Tissue plasminogen activator (tPA) is used for thrombolytic therapy of cerebral infarction, but it is restricted by strict time window and hemorrhage transformation. In addition to plasminogen, tPA also cleaves and activates plateletate-derived growth factor (PDGF)CC, thus aggravating blood brain barrier (BBB) leakage and causing hemorrhage transformation. Unlike plasminogen, enzymatic digestion of PDGF-CC depends on a TPA-Mac1-LRP1 trimer, and ApoE mimic peptide COG1410 can interfere with the assembly of the trimer. Therefore, we hypothesized that COG1410 could prevent cerebral hemorrhage and prolong the thrombolytic time window by interfering with the tPA-Mac1-LRP1 trimer to specifically inhibit the cleavage and activation of PDGF-CC. In this project, two rat models of stroke (suture and embolic) with tPA thrombolysis were used to investigate whether COG1410 can reduce BBB damage and brain hemorrhage, and whether they can extend the time window of thrombolysis. In addition, the interference of mimic peptide on trimer and the regulation of endogenous and exogenous tPA enzymatic activity were explored by in vivo and in vitro methods. The strategy of this project will restrict the side effects without affecting the tPA thrombolysis efficiency, thus laying a good foundation for expanding the safety and extensive use of tPA.