Tissue Plasminogen Activator and Neuronal Degeneration

性状（由申请方提供）：蛋白酶组织纤溶酶原激活剂 (tPA)与中枢神经系统的神经元死亡有关 （CNS）。我们现在已经发现，tPA也会影响受损后的神经元， 外周神经系统（PNS）。在小鼠坐骨神经中，tPA是 在挤压损伤后被雪旺细胞上调，表明在 保护组织或造成损伤。调查这一 我们检查了缺乏tPA或纤溶酶原的小鼠。两种基因型 在挤压后加重了损伤，表明tPA/纤溶酶原系统 是组织对损伤的有益反应我们还发现 纤维蛋白广泛地沉积在损伤的神经中。去除纤维蛋白 从老鼠身上遗传或克隆的， 在不存在tPA或纤溶酶原的情况下观察到的损伤增加。这些 结果表明，tPA纤溶酶原系统的作用是清除纤维蛋白 从受伤的神经。我们还发现，纤维蛋白沉积抑制了 损伤后的再生阶段。本申请建议扩展这项工作 通过：1）确定纤维蛋白沉积抑制坐骨神经痛的机制， 2）分析tPA/纤溶酶原系统在神经再生中的作用; 小鼠和大鼠CNS变性模型的详细信息;和3）评估新的 作为减少神经损伤的治疗策略的纤维蛋白去除方法 促进再生。

DESCRIPTION (provided by applicant): The protease tissue plasminogen activator (tPA) has been implicated in neuronal death in the central nervous system (CNS). We have now found that tPA also affects neurons after damage in the peripheral nervous system (PNS). In the mouse sciatic nerve, tPA is up-regulated by Schwann cells after crush injury, suggesting a role in either protecting the tissue or contributing to the damage. To investigate this question, we examined mice that lack either tPA or plasminogen. Both genotypes have exacerbated damage after crush, indicating that the tPA/plasminogen system is a beneficial response of the tissue to injury. We have also found that fibrin is extensively deposited in the injured nerve. Removal of fibrin genetically or pharmacologically from mice protects their sciatic nerve from the increased injury observed in the absence of tPA or plasminogen. These results indicate that the role of the tPAlplasminogen system is to clear fibrin from the injured nerve. We have also found that fibrin deposition inhibits the regenerative phase after injury. This application proposes to extend this work by: 1), determining themechanism by which fibrin deposition inhibits sciatic nerve regeneration; 2) analyzing the role of the tPA/plasminogen system in mouse and rat models of CNS degeneration in great detail; and 3) evaluating new methods for fibrin removal as therapeutic strategies to reduce nerve damage and promote regeneration.