Mechanism of thrombolytic tPA induced intracerebral hemorrhage after stroke

溶栓tPA致脑卒中后脑出血的机制

• 批准号: 8655918
• 负责人: Daniel A Lawrence
• 金额: $ 33.68万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8655918
• 关键词: Alteplase; Blood; Blood - brain barrier anatomy; Blood Vessels; Brain; Brain hemorrhage; Candidate Disease Gene; Cause of Death; Cerebral Edema; Cerebral Ischemia; Cerebral hemisphere hemorrhage; Characteristics; Complex; Development; Diet; Effectiveness; Exclusion Criteria; FDA approved; Fibrinolysis; Fibrinolytic Agents; Functional disorder; Harvest; Hemorrhage; Hyperglycemia; Incidence; Infarction; Intervention; Ischemic Stroke; Location; Mediator of activation protein; Metabolic syndrome; Modeling; Morbidity - disease rate; Mus; Myocardial Infarction; Nature; Neuraxis; Obesity; Outcome; Pathway interactions; Patients; Permeability; Plasminogen; Plasminogen Activator Inhibitor 1; Plasminogen Inactivators; Platelet-Derived Growth Factor; Play; Population Study; Public Health; Regulation; Reperfusion Therapy; Risk; Risk Factors; Role; Safety; Severities; Signal Transduction; Stream; Stroke; Testing; Thrombolytic Therapy; Thrombotic Stroke; Time; United States; Vascular Diseases; Vascular Patency; base; disability; improved; mortality; neuroserpin; neurovascular unit; novel therapeutic intervention; practical application; stroke therapy; thrombolysis

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.

描述（由申请人提供）：中风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。出血性中风的结果通常比缺血性中风更差，并且缺血性中风的出血性转化可显着增加中风的严重程度。使用组织纤溶酶原激活剂（tPA）进行溶栓治疗是唯一被批准的缺血性中风治疗方法，但其使用会增加脑出血（ICH）发生率的显着风险。因此，tPA 仅使有限数量的潜在患者受益。改进和更安全的中风疗法的开发取决于对脑血管系统独特特征的了解，而 tPA 的有限益处部分是由于其在大脑中超出其公认的纤维蛋白溶解作用的意外活动。多项研究表明，脑缺血后，大脑内的 tPA 会增加血脑屏障 (BBB) 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 风险增加表明，tPA 在缺血性中风中的应用面临着独特的挑战。缺血性中风的理想治疗方法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，我们证明大脑内的 tPA 会激活潜在的血小板衍生生长因子 CC (PDGF-CC)，进而增加中风时的 BBB 功能障碍，而阻断该途径可显着减少 BBB 破坏、梗塞面积和溶栓 tPA 引起的脑出血。基于这些观察结果，该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，而在腔外空间，tPA 激活 PDGF-CC，进而促进 BBB 通透性并增加 ICH 的风险。我们将研究 tPA 这种双重作用的机制，并通过专门针对血液或神经血管单元 (NVU) 中的 tPA，并通过检查 NVU 中 PDGF-CC 信号传导调节的下游通路来检验这一假设。