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）：中风是美国发病率的主要原因，也是美国死亡率的第三个主要原因。大多数中风是缺血性的，其中大多数是血栓形成的。出血性中风通常比缺血性中风更差，缺血性中风的出血转化可以显着增加中风的严重程度。用组织纤溶酶原激活剂（TPA）进行溶栓治疗是唯一批准的缺血性中风治疗方法，但其使用量很大，脑出血（ICH）的发生率增加。因此，TPA仅受益于有限数量的潜在患者。改进和更安全的中风疗法的发展取决于了解大脑的独特特征，而TPA的有限益处部分归因于其在大脑中的意外活动超出其建立良好的纤维纤维角色。几项研究表明，大脑内的TPA增加了脑缺血后的血脑 - 障碍物（BBB）渗透性，尽管对于某些接受早期溶栓治疗的患者有明显的好处，但与TPA相关的ICH风险增加了，与TPA相关的风险增加了其在缺血性streoke中使用的独特挑战。缺血性中风的理想治疗方法同时促进了血管通畅的重建，抑制脑水肿的发展并减少出血转化的发生率。在最近的研究中，我们表明大脑内的TPA激活潜在的血小板衍生的生长因子CC（PDGF-CC），这又会增加中风中的BBB功能障碍，并且阻碍了该途径可显着降低BBB的破坏，梗塞大小和溶栓TPA诱导的ICH。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在血液中发挥了决斗作用，在血液中，TPA促进溶栓并改善再灌注，而在Abluminal Space中，PDGF-CC激活PDGF-CC，这反过来促进了BBB的常规性和增加的风险。我们将研究TPA这种决斗作用的机制，并通过专门针对血液或神经血管UNI（NVU）中的TPA以及检查NVU中PDGF-CC信号调节的下游途径来检验该假设。