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(申请人提供)：在美国，中风是导致发病的首要原因，也是导致死亡的第三大原因。大多数中风是缺血性的，其中大多数是血栓性的。出血性中风的预后通常比缺血性中风更差，而缺血性中风的出血性转化可以显着增加中风的严重性。组织纤溶酶原激活剂(TPA)溶栓治疗是唯一被批准的治疗缺血性中风的方法，但其使用具有增加脑出血(ICH)发生率的显著风险。因此，tPA只对有限数量的潜在患者有利。改善和更安全的中风治疗方法的发展取决于对脑血管系统的独特特征的了解，而tPA的有限益处部分是由于它在大脑中的意外活动超出了其公认的纤溶作用。一些研究表明，脑内的tPA增加了脑缺血后血脑屏障(BBB)的通透性，虽然对一些早期接受溶栓治疗的患者有明显的好处，但与tPA相关的脑出血风险的增加表明，tPA在缺血性中风中的应用面临着独特的挑战。理想的治疗方法是同时促进血管再通畅，抑制脑水肿的发展，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激活了潜在的血小板衍生生长因子CC(PDGF-CC)，进而增加了卒中患者的血脑屏障功能障碍，阻断这一通路显著减少了血脑屏障的破坏、梗死面积和溶栓tPA诱导的脑出血。基于这些观察，这一建议将检验这样的假设：在脑缺血期间，tPA起双重作用，在血液中，tPA促进血栓溶解和改善再灌注，而在腔隙中，tPA激活PDGF-CC，进而促进血脑屏障通透性，增加脑出血的风险。我们将研究tPA的这种双重作用的机制，并通过在血液或神经血管单位(NVU)中特异性地靶向tPA，以及通过检查NVU中受PDGF-CC信号调节的下游通路来检验这一假说。