Vascular repair extends therapeutic window for ischemic stroke

血管修复延长了缺血性中风的治疗窗口

• 批准号: 8801075
• 负责人: CESARIO V BORLONGAN
• 金额: $ 22.43万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-30 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8801075
• 关键词: Acute; Adverse effects; Alteplase; American; Animal Model; Area; Attenuated; Behavioral; Binding; Biological Preservation; Blood - brain barrier anatomy; Blood Vessels; Bone Marrow; Bone Marrow Cells; Bone Marrow Stem Cell; CD34 gene; CSF3 gene; Cell Maturation; Cerebrum; Clinical; Clinical Medicine; Clinical Trials; Coagulation Process; Commit; Data; Endothelial Cells; FDA approved; Fibroblasts; Foundations; Future; Goals; Granulocyte Colony-Stimulating Factor; Hand; Human; Impairment; Injury; Ischemia; Ischemic Stroke; Light; Measures; Mediating; Medical; Methods; Modeling; Motor; Neurologic; Patients; Pharmaceutical Preparations; Plasminogen; Process; Property; Rattus; Recruitment Activity; Reperfusion Therapy; Reporting; Risk; Site; Stem cells; Stroke; Stromal Cells; Testing; Therapeutic; Thrombolytic Therapy; Time; Tissues; Transplantation; Traumatic Brain Injury; Treatment Efficacy; Work; acute stroke; angiogenesis; base; cell injury; clinical application; design; gray matter; improved; innovation; mortality; neurogenesis; neuroinflammation; neuroprotection; neurotoxicity; neurovascular unit; neutrophil; peripheral blood; prevent; public health relevance; reconstitution; repaired; research clinical testing; risk benefit ratio; standard of care; thrombolysis; vasculogenesis; white matter

 DESCRIPTION (provided by applicant): On average, one American has stroke every 40 seconds, and one dies every 4 minutes. Of the different types of stroke, acute ischemic stroke is the most common, and successful treatment of this medical condition remains very challenging. The "clot busting" drug tissue plasminogen activator (tPA) is the only drug approved for clinical use for acute ischemic stroke. However the drug must be initiated within 4.5 h of stroke onset or risk detrimental side effects including intracerebral hemorrhagic transformation (HT). Therefore, an important clinical problem is to develop methods that will extend the limited therapeutic time window of tPA or reduce complications associated with delayed treatment of tPA. The granulocyte-colony stimulating factor (G-CSF) has been shown to exert neuroprotective effects in animal models of ischemia. It is not yet known if the drug could attenuate detrimental side effects of delayed tPA treatment in ischemic stroke. Furthermore, we have shown in a rat model of traumatic brain injury (TBI) that G-CSF monotherapy reduced neuroinflammation in the gray and white matter areas and also ameliorated TBI-induced impairment in endogenous neurogenesis. These findings taken together with reported neuroprotective effects of G-CSF in animal models of ischemia led us to hypothesize that the treatment of G-CSF will also reduce HT associated with delayed treatment of tPA (Aim 1). Treatment with G-CSF mobilizes cells from the bone marrow to the peripheral blood including CD34+ bone marrow stem cells which contain endothelial progenitor cells (EPCs). Several studies suggested that beneficial effects of G-CSF in stroke (e.g. angiogenesis, vasculogenesis, etc.) are mediated by EPCs. Moreover, in a previous study, we have also shown that transplantation of human cerebral endothelial cells attenuated stroke-induced motor and neurological deficits in rats via enhancement of vasculogenesis. In light of these findings, we hypothesized that G-CSF mobilizes EPCs in the setting of tPA-induced HT in stroke, and EPCs attenuate HT via enhancement of vasculogenesis or angiogenesis, processes that preserve the cerebrovasculature (Aim 2). Delayed tPA-induced HT has been attributed to effects of tPA on the neurovascular unit and also via disruption of the blood brain barrier (BBB). We hypothesized that another mechanism underlying neuroprotective effects of G-CSF is via preservation of the integrity of the BBB through vasculogenic and angiogenic effects of recruited EPCs. The long-term goal of this study is to demonstrate that G-CSF in tandem with tPA will reduce delayed tPA-associated complications and also extend the thrombolytic efficacy of tPA. The overall impact is that at the completion of this study, the findings from this work will lay the foundation for the clinical evaluation of G-CSF in attenuating HT associated with delayed treatment of tPA.

 描述（由适用提供）：平均而言，一个美国人每40秒中风一次，一个人每4分钟死亡。在不同类型的中风中，急性缺血性中风是最常见的，对这种疾病的成功治疗仍然非常挑战。 “凝块破坏”的药物组织纤溶酶原激活剂（TPA）是唯一批准用于急性缺血性中风的临床用途的药物。但是，必须在中风发作的4.5小时内启动该药物，或者必须在包括脑内出血转化（HT）（HT）（HT）的风险探测器副作用。因此，一个重要的临床问题是开发将扩展TPA治疗时间窗口有限或减少与TPA延迟治疗有关的并发症的方法。粒细胞 - 固体刺激因子（G-CSF）已证明在缺血动物模型中发挥神经保护作用。尚不清楚该药物是否会减轻缺血性中风中TPA治疗的有害副作用。此外，我们在大鼠脑损伤（TBI）的大鼠模型中表明，G-CSF单药治疗减少了灰色和白质区域的神经炎症，并改善了TBI诱导的内源性神经发生障碍。这些发现与G-CSF在缺血模型中的神经保护作用结合在一起，导致我们假设G-CSF的治疗也将减少与TPA延迟治疗相关的HT（AIM 1）。用G-CSF处理将细胞从骨髓到外周血，包括CD34+骨髓干细胞，这些干细胞包含内皮祖细胞（EPC）。几项研究表明，G-CSF在中风（例如血管生成，血管生成等）中的有益作用是由EPC介导的。此外，在先前的研究中，我们还表明，人脑内皮细胞的移植通过增强血管发生通过增强大鼠的中风诱导的运动和神经元定义。鉴于这些发现，我们假设G-CSF在中风中TPA诱导的HT的情况下动员了EPC，EPCS通过增强血管生成或血管生成而减弱HT，这可以保留大脑脑瘤系统（AIM 2）。 TPA诱导的HT延迟归因于TPA对神经血管单元的影响，并且还归因于血液脑屏障（BBB）的破坏。我们假设G-CSF的另一种神经保护作用是通过招募EPC的血管生成和血管生成作用来保存BBB的完整性。这项研究的长期目标是证明与TPA串联的G-CSF将减少延迟与TPA相关的并发症，并延长TPA的血栓溶解效率。总体影响是，在这项研究完成时，这项工作的发现将为G-CSF的临床评估奠定基础，从而减弱与TPA延迟治疗相关的HT。