Protease-Regulated Blood Brain Barrier Permeability

项目总结摘要 组织型纤溶酶原激活物(TPA)是一种高度特异的丝氨酸蛋白酶，存在于血管内和血管内。 空间和中枢神经系统(CNS)。在血管内空间，tPA的主要作用是作为一种溶栓剂 酵素。因此，重组tPA是fda批准的唯一治疗慢性阻塞性肺疾病患者的药物。 急性缺血性中风。相反，缺血性损伤的开始也会导致表达的快速上升 和tPA活性在神经血管单位(NVU)的开口侧与发育相关 脑水肿和出血性转化。低密度脂蛋白受体相关蛋白(LRP)是 低密度脂蛋白受体基因家族的成员，与包括tPA在内的多个配体相互作用。紧随其后的是 血管周围星形胶质细胞LRP表达增加 TPA和LRP在缺血性脑损伤早期的相互作用导致 脑水肿。在这个应用中，我们假设tPA和LRP在血管周围的相互作用 星形胶质细胞是调节NVU屏障功能的关键分子机制。此外，我们 认为药物抑制tPA和LRP之间的相互作用可降低 重组组织型纤溶酶原激活剂治疗相关的水肿和出血并发症 急性缺血性中风。这些临床相关研究应该指出抑制tPA-LRP 血管周围星形胶质细胞的结合是一种成功的旨在阻断有害效应的治疗策略。 在保持其作为溶栓剂的有益作用的同时，在NVU的开通侧 血管内空间。

PROJECT SUMMARY ABSTRACT Tissue-type plasminogen activator (tPA) is a highly specific serine proteinase present in both the intravascular space and the central nervous system (CNS). In the intravascular space tPA's main role is as a thrombolytic enzyme. Accordingly, recombinant tPA is the only FDA-approved medication for the treatment of patients with acute ischemic stroke. In contrast, the onset of the ischemic insult also induces a rapid rise in the expression and activity of tPA in the abluminal side of the neurovascular unit (NVU) associated with the development of cerebral edema and hemorrhagic transformation. The low density lipoprotein receptor-related protein (LRP) is a member of the LDL receptor gene family that interacts with multiple ligands including tPA. Following the onset of the ischemic insult there is an increase in LRP expression in perivascular astrocytes and the interaction between tPA and LRP in the early phases of the ischemic insult results in the development of cerebral edema. In this application we hypothesize that the interaction between tPA and LRP in perivascular astrocytes is a key molecular mechanism that regulates the barrier function of the NVU. Furthermore we propose that pharmacological inhibition of the interaction between tPA and LRP decreases the incidence of edema and hemorrhagic complications associated with the administration of recombinant tPA for the treatment of acute ischemic stroke. These clinically relevant studies should indicate whether inhibition of tPA-LRP binding in perivascular astrocytes is a successful therapeutic strategy aimed at blocking the deleterious effects of tPA in the abluminal side of the NVU while maintaining its beneficial role as a thrombolytic in the intravascular space.