Proteases in Spinal Cord Plasticity & Regeneration

描述（由申请人提供）： 研究将集中在细胞外蛋白酶，即纤溶酶原激活剂/纤溶酶原（PA/pign）系统在啮齿动物脊髓损伤的突触重塑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基因在周围神经损伤后被诱导，并且是及时PNS再生所需的。研究将致力于评估这些PA/plgn基因在背根神经节感觉轴突再生其脊髓背柱中的CNS侧支的能力中的作用。最重要的是，将进行研究以评估有趣的横膈神经反应（脊髓损伤后突触重塑的一个例子）是否需要诱导PA/pign系统来促进这些突触变化，从而恢复肺功能。将比较各种PA/plgn基因缺陷的小鼠的可塑性和再生能力，以证明对这些蛋白酶活性的任何需求。此外，PA/pign系统[组织型纤溶酶原激活物（tPA）、尿激酶型纤溶酶原激活物（uPA）、纤溶酶原、纤溶酶原激活物-i（PAI 1）和蛋白酶连接蛋白（PN）]在损伤或受损脊髓中的表达将通过用35 S-CRNA探针和这些PA系统蛋白的抗体进行原位杂交来研究，以确定该基因系统是否也在CNS中被诱导，以及它是否在轴突再生和突触可塑性中起作用。对受损脊髓中的这种蛋白酶系统的理解可能使我们能够通过向损伤部位提供PA/plgn或其抑制剂来有效地增强轴突再生。类似地，PA/pign表达对于脊髓损伤下方部位的突触重塑可能是重要的，使得PA/pign基因的诱导可能导致功能的部分恢复。

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.