Mechanism of thrombolytic tPA induced intracerebral hemorrhage after stroke

描述（由申请人提供）：卒中是美国发病的主要原因，也是死亡的第三大原因。大多数中风是缺血性的，其中大多数是血栓性的。出血性卒中的结局通常比缺血性卒中更差，缺血性卒中的出血性转化可显著增加卒中的严重程度。组织型纤溶酶原激活剂（tPA）溶栓治疗是唯一获批的缺血性卒中治疗方法，但其使用具有增加脑出血（ICH）发生率的显著风险。因此，tPA仅使有限数量的潜在患者受益。开发更好、更安全的卒中治疗方法取决于对脑血管系统独特特征的理解，tPA获益有限的部分原因是其在脑中的非预期活性超出了其公认的溶瘤作用。几项研究表明，脑内的tPA增加了脑缺血后血脑屏障（BBB）的通透性，虽然对一些接受早期溶栓治疗的患者有明显的益处，但与tPA相关的ICH风险增加证明了其在缺血性卒中中的独特挑战。理想的缺血性卒中治疗应同时促进血管通畅的重建，抑制脑水肿的发展，并减少出血性转化的发生率。在最近的研究中，我们证明了脑内的tPA激活潜伏的血小板衍生生长因子CC（PDGF-CC），这反过来增加了中风中的BBB功能障碍，并且阻断该途径显著减少了BBB破坏、梗死面积和溶栓tPA诱导的ICH。基于这些观察结果，本提案将检验以下假设：在脑缺血期间，tPA发挥双重作用，在血液中，tPA促进血栓溶解并改善再灌注，而在近腔空间中，tPA激活PDGF-CC，这反过来促进BBB渗透性并增加ICH的风险。我们将研究tPA这种双重作用的机制，并通过特异性靶向血液或神经血管单位（NVU）中的tPA，以及通过检查NVU中PDGF-CC信号转导调节的下游通路来验证这一假设。

DESCRIPTION (provided by applicant): Stroke is the leading cause of morbidity and the third leading cause of mortality in the United States. Most strokes are ischemic and the majority of these are thrombotic in origin. Hemorrhagic strokes generally have worse outcomes than for ischemic strokes and hemorrhagic conversion of an ischemic stroke can markedly increase stroke severity. Thrombolytic therapy with tissue plasminogen activator (tPA) is the only approved treatment for ischemic stroke, but its use carries a significant risk for increased incidence of intracerebral hemorrhage (ICH). Thus, tPA only benefits a limited number of potential patients. The development of improved and safer therapies for stroke depends upon understanding the unique characteristics of the cerebrovasculature, and the limited benefit of tPA is due in part to its unanticipated activities in the brain beyond its well established fibrinoytic role. Several studies have demonstrated that tPA within the brain increases blood-brain-barrier (BBB) permeability after cerebral ischemia, and while there are clear benefits to some patients who receive early thrombolytic treatment, the increased risk of ICH associated with tPA demonstrate the unique challenges for its use in ischemic stroke. Ideal treatment for ischemic stroke would simultaneously promote the reestablishment of vascular patency, inhibit the development of cerebral edema, and reduce the incidence of hemorrhagic transformation. In recent studies we demonstrated that tPA within the brain activates latent platelet derived growth factor CC (PDGF- CC), which in turn increases BBB dysfunction in stroke, and that blocking this pathway significantly reduces BBB disruption, infarct size, and thrombolytic tPA induced ICH. Based on these observations, this proposal will test the hypothesis that during cerebral ischemia tPA plays a duel role, in the blood tPA promotes thrombolysis and improves reperfusion, whereas in the abluminal space tPA activates PDGF-CC which in turn promotes BBB permeability and increases the risk of ICH. We will investigate the mechanisms of this duel role of tPA, and test this hypothesis by specifically targeting tPA in blood or in the neurovascular uni (NVU), and by examining down-stream pathways regulated by PDGF-CC signaling in the NVU.