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（由申请人提供）：平均每 40 秒就有 1 名美国人中风，每 4 分钟就有 1 名美国人死亡。在不同类型的中风中，急性缺血性中风是最常见的，成功治疗这种疾病仍然非常具有挑战性。 “血栓溶解”药物组织纤溶酶原激活剂 (tPA) 是唯一被批准用于临床治疗急性缺血性中风的药物，但该药物必须在中风发作后 4.5 小时内开始使用，否则可能会产生不健康的副作用。因此，一个重要的临床问题是开发延长 tPA 治疗有限时间窗或减少与粒细胞集落刺激因子 (G-CSF) 延迟治疗相关的并发症的方法。已被证明在缺血性动物模型中发挥神经保护作用，目前尚不清楚该药物是否可以减轻延迟 tPA 治疗对缺血性中风的痛苦副作用。外伤性脑损伤 (TBI) 中，G-CSF 单一疗法可减少灰质和白质区域的神经炎症，并改善 TBI 引起的内源性神经发生损伤。这些发现与报道的 G-CSF 在缺血动物模型中的神经保护作用相结合，引导我们进行研究。培养 G-CSF 治疗也将减少与延迟 tPA 治疗相关的 HT（目标 1）。G-CSF 治疗将细胞从骨髓动员到外周血，包括 CD34+。含有内皮祖细胞 (EPC) 的骨髓干细胞此外，在之前的一项研究中，我们还证明了 G-CSF 对中风的有益作用（例如血管生成、血管生成等）。人脑内皮细胞移植通过增强血管生成减轻了大鼠中风引起的运动和神经缺陷。根据这些发现，我们研究了 G-CSF 的动员。 EPCs 在中风中 tPA 诱导的 HT 中，EPCs 通过增强血管生成或血管生成来减弱 HT，这是保护脑血管系统的过程（目标 2）。我们还发现，G-CSF 的神经保护作用的另一个机制是通过保护血脑屏障的完整性。通过募集的 EPC 的血管生成和血管生成作用实现 BBB 本研究的长期目标是证明 G-CSF 与 tPA 联合使用将减少迟发性 tPA 相关并发症，并延长 tPA 的溶栓疗效。这项研究完成后，这项工作的结果将为 G-CSF 减轻与 tPA 延迟治疗相关的 HT 的临床评估奠定基础。