Plasminogen activator promotes recovery following spinal cord injury.
Plasminogen activator promotes recovery following spinal cord injury.
复制标题
DOI：
10.1007/s10571-011-9701-6
复制
发表时间：
2011-08
影响因子：
4
通讯作者：
Minor K
中科院分区：
文献类型：
--
作者：
Seeds N;Mikesell S;Vest R;Bugge T;Schaller K;Minor K
纤溶酶原激活剂在与交叉膈现象（CPP）相关的突触可塑性和脊髓损伤后呼吸功能的恢复中发挥重要作用。使用纤溶酶原激活剂/纤溶酶系统中缺乏各种基因的基因敲除小鼠的遗传方法表明，在 C2 半切后的第一个小时内需要诱导尿激酶纤溶酶原激活剂 (uPA)，以获得 CPP 反应。 uPA 敲除小鼠没有表现出 CPP 反应特有的膈运动神经元突触的结构重塑。如图所示，uPA 通过与其受体 uPAR 结合而不是作为蛋白酶以细胞信号传导方式发挥作用，因为 uPAR 敲除小鼠或具有无法与 uPAR 结合的修饰 uPA 的敲入小鼠都无法生成 CPP 并恢复呼吸功能。与 uPA 敲除小鼠相比，C57Bl/6 小鼠 C2 半切后膈运动核中诱导的 mRNA 的微阵列数据和实时 PCR 分析表明，下游潜在的细胞信号级联可能涉及 β-整合素和 Src 以及其他途径。这些 uPA 介导的信号通路的鉴定可能提供在药理学上上调颈脊髓损伤后膈运动神经元活动恢复所需的突触可塑性的机会。
Plasminogen activators play an important role in synaptic plasticity associated with the crossed phrenic phenomenon (CPP) and recovery of respiratory function after spinal cord injury. A genetic approach using knockout mice lacking various genes in the plasminogen activator/plasmin system has shown that induction of urokinase plasminogen activator (uPA) is required during the first hour after a C2-hemisection for the acquisition of the CPP response. The uPA knockout mice do not show the structural remodeling of phrenic motor neuron synapses characteristic of the CPP response. As shown here uPA acts in a cell signaling manner via binding to its receptor uPAR rather than as a protease, since uPAR knockout mice or knock-in mice possessing a modified uPA that is unable to bind to uPAR both fail to generate a CPP and recover respiratory function. Microarray data and real-time PCR analysis of mRNAs induced in the phrenic motor nucleus after C2-hemisection in C57Bl/6 mice as compared to uPA knockout mice indicate a potential cell signaling cascade downstream possibly involving β-integrin and Src, and other pathways. Identification of these uPA-mediated signaling pathways may provide the opportunity to pharmacologically upregulate the synaptic plasticity necessary for recovery of phrenic motoneuron activity following cervical spinal cord injury.