Tissue Plasminogen Activator and Neuronal Degeneration

组织纤溶酶原激活剂和神经元变性

• 批准号: 6529205
• 负责人: SIDNEY STRICKLAND
• 金额: $ 41.75万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-06-01 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6529205
• 关键词: extracellular matrix; fibrin; gene targeting; hippocampus; laboratory mouse; laboratory rat; microglia; nerve injury; nervous system regeneration; neural degeneration; neurons; plasminogen activator; protein structure function; sciatic nerve

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.

描述（由申请人提供）：蛋白酶组织纤溶酶原激活剂 (tPA) 与中枢神经系统神经元死亡有关 （中枢神经系统）。我们现在发现 tPA 也会影响神经元受损后的情况 周围神经系统（PNS）。在小鼠坐骨神经中，tPA 挤压损伤后雪旺细胞上调，表明在以下任一过程中都起作用 保护组织或造成损伤。为了调查此事 为了回答这个问题，我们检查了缺乏 tPA 或纤溶酶原的小鼠。两种基因型 挤压后损伤加剧，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 纤维蛋白广泛沉积在受伤的神经中。去除纤维蛋白 来自小鼠的遗传或药理作用可保护其坐骨神经免受 在没有 tPA 或纤溶酶原的情况下观察到的损伤增加。这些 结果表明tPA1纤溶酶原系统的作用是清除纤维蛋白 来自受伤的神经。我们还发现，纤维蛋白沉积会抑制 受伤后的再生阶段。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 神经再生； 2）分析tPA/纤溶酶原系统在 小鼠和大鼠中枢神经系统变性模型的详细信息； 3）评估新的 去除纤维蛋白的方法作为减少神经损伤的治疗策略 促进再生。