TISSUE PLASMINOGEN ACTIVATOR AND NEURONAL DEGENERATION

描述(研究人员摘要)：胞外蛋白酶已被 与哺乳动物中枢神经系统的各种功能有关 (CNS)。然而，很难分析这些可能的功能 在活体内。用一种实验模型诱导小鼠神经元损伤 海马区，我们已经证明了缺乏丝氨酸蛋白酶tPA的小鼠 (TPA-/-)对神经元变性具有显著的抵抗力。缺水小鼠 对于纤溶酶原，经典的tPA底物，表现出同样的抗性 表型为tPA-/-小鼠。TPA和纤溶酶原都是在 在海马体中，蛋白分解活性的表达似乎是 受内源性抑制物调节。最后，输注tPA/纤溶酶 进入野生型小鼠海马区的抑制剂也可以产生抵抗力 导致神经元死亡。一个中心假说从这些结果和从 在其他实验室工作： TPA和纤溶酶的胞外蛋白水解级联反应介导神经元 哺乳动物中枢神经系统的细胞死亡。 在这一应用中，我们建议研究通过 TPA/纤溶酶在中枢神经系统中的作用 纤溶酶原激活剂和纤溶酶的结构和催化特性是什么 对退化来说很关键？能鉴定出蛋白酶抑制剂吗？ 参与调节神经元死亡，并具有治疗作用 有可能延缓退变吗？2)有内源性蛋白酶吗？ 有助于调节tPA和纤溶酶活性的抑制物？3)什么是 由神经元和小胶质细胞产生的tPA各自的作用？4)什么是 其被tPA和/或纤溶酶切割的特定底物介导神经元 退化？回答这些问题将有助于通过以下方式定义机制 其中tPA和纤溶酶原在海马体中起作用，并可能 对许多神经退行性疾病的治疗具有重要意义。

DESCRIPTION (Investigator's Abstract): Extracellular proteases have been implicated in various functions in the mammalian central nervous system (CNS). However, it has been difficult to analyze these possible functions in vivo. Using an experimental model to induce neuronal damage in the mouse hippocampus, we have shown that mice deficient for the serine protease tPA (tPA-/-) are strikingly resistant to neuronal degeneration. Mice deficient for plasminogen, the classical tPA substrate, exhibit the same resistant phenotype as the tPA-/- mice. Both tPA and plasminogen are synthesized in the hippocampus, and the expression of proteolytic activity appears to be modulated by endogenous inhibitors. Finally, infusion of tPA/plasmin inhibitors into the hippocampus of wild-type mice can also confer resistance to neuronal death. A central hypothesis emerges from these results and from work in other laboratories: An extracellular proteolytic cascade of tPA and plasmin mediates neuronal cell death in the mammalian CNS. In this application, we propose to investigate the mechanism by which tPA/plasmin function in the CNS by addressing the following questions: 1) What structural and catalytic characteristics of tPA and plasmin are critical for degeneration? Can protease inhibitors be identified that participate in regulating neuronal death, and that have therapeutic potential in retarding degeneration? 2) Are there endogenous protease inhibitors that help regulate tPA and plasmin activity? 3) What are the respective roles of tPA produced by neurons and microglia? 4) What are the specific substrates whose cleavage by tPA and/or plasmin mediates neuronal degeneration? Answering these questions will help define the mechanism by which tPA and plasminogen function in the hippocampus, and could have implications for the treatment of many neurodegenerative disorders.