Proteases in Spinal Cord Plasticity & Regeneration

描述(申请人提供)：研究将集中于细胞外蛋白水解酶，即纤溶酶原激活物/纤溶酶原(PA/PIGN)系统在啮齿动物受损脊髓突触重建和轴突再生中的潜在作用。PA/PLGN系统被认为在轴突生长和突触可塑性中发挥作用。PA基因是在周围神经损伤后诱导的，是PNS及时再生所必需的。研究将旨在评估这些PA/PLGN基因在背根节感觉神经轴突在脊髓背柱再生CNS侧枝的能力中所起的作用。最重要的是，将进行研究，以评估脊髓损伤后有趣的交叉膈神经反应是否需要PA/PIGN系统的诱导来促进这些突触变化，从而恢复肺功能。缺乏各种PA/plgn基因的小鼠将被比较它们的可塑性和再生能力，以证明这些酶活性是否需要。此外，用35S-CRNA探针和针对PA系统蛋白的抗体进行原位杂交，研究PA/PIGN系统[组织纤溶酶原激活物(TPA)、尿激酶型纤溶酶原激活物(UPA)、纤溶酶原、纤溶酶原激活剂抑制物(PAIL)和蛋白酶连接素(PN)]在损伤或损伤脊髓中的表达，以确定该基因系统是否在中枢神经系统也被诱导，以及它是否在轴突再生和突触可塑性中发挥作用。了解损伤脊髓中的这一酶系统可能使我们能够通过向损伤部位提供PA/PLGN或它们的抑制剂来有效地促进轴突再生。类似地，PA/pign的表达可能对脊髓损伤下方部位的突触重塑很重要，因此PA/pign基因的诱导可能导致部分功能的恢复。

DESCRIPTION (provided by applicant): Studies will focus on the potential role of extracellular proteases, namely the plasminogen activator/plasminogen (PA/pign) system in synaptic remodeling and axonal regeneration in the injured spinal cord of rodents. The PA/plgn system has been suggested to play a role both in axonal outgrowth and synaptic plasticity. The PA genes are induced following peripheral nerve injury and are required for timely PNS regeneration. Studies will be directed at assessing the role of these PA/plgn genes in the ability of dorsal root ganglia sensory axons to regenerate their CNS collaterals in the dorsal column of the spinal cord. Most importantly studies will be performed to assess whether the interesting crossed phrenic nerve response, an example of synaptic remodeling following spinal cord injury, requires the induction of the PA/pign system to promote these synaptic changes that permit a restoration of lung function. Mice deficient in various PA/plgn genes will be compared for their plasticity and regenerative abilities to demonstrate any requirement for these protease activities. Furthermore, expression of the PA/pign system [tissue plasminogen activator (tPA), urokinase plasminogen activator(uPA), plasminogen, plasminogen activator inhibitor-i (PAIl), and protease nexin(PN)] in the lesioned or injured spinal cord will be studied by in situ hybridization with 35S-CRNA probes and antibodies to these PA system proteins, to determine whether this gene system is also induced in the CNS and whether it plays a role in axonal regeneration and synaptic plasticity. An understanding of this protease system in the injured spinal cord may allow us to effectively enhance axonal regeneration by supplying either PA/plgn or their inhibitors to the site of injury. Similarly, PA/pign expression may be important for synaptic remodeling at sites below a spinal cord lesion, such that induction of the PA/pign genes may lead to partial restoration of function.