Proteases in Spinal Cord Plasticity & Regeneration

细胞外蛋白酶，即纤溶酶原激活物/纤溶酶原（PA/plgn）系统在啮齿动物损伤脊髓突触重构中的潜在作用将是这些研究的重点。PA/plgn系统被认为在轴突生长和突触可塑性中都起作用。最重要的是，研究将进一步阐明小鼠膈神经交叉现象，这是脊髓损伤后突触重塑的一个例子；损伤沉默的膈运动神经元上的突触接触被激活；从而恢复膈运动神经元的活动，促进膈功能的恢复。我们之前已经证明PA/plgn系统基因的诱导对于小鼠膈交叉现象的产生很重要，我们对PA/plgn基因缺失的野生型和敲除小鼠的研究将探索PA系统的诱导促进突触变化的机制，从而允许肺功能的恢复。对PA启动突触可塑性能力的特定分子信号通路的理解可能会提示通过药理学方法实现相同的效果。这些突触接触的激活可能不是膈运动核所独有的，也可能发生在脊髓内的其他部位，导致其他生理功能的部分恢复。从这个项目中获得的机制知识可能会导致转化研究，作为促进人类脊髓损伤后突触形成、再激活和功能恢复的潜在疗法。

The potential role of extracellular proteases, namely the plasminogen activator/ plasminogen (PA/plgn) system in synaptic remodeling in the injured spinal cord of rodents will be the focus of these studies. The PA/plgn system has been suggested to play a role both in axonal outgrowth and synaptic plasticity. Most importantly studies will be performed to further clarify in mice the interesting crossed phrenic nerve phenomenon, an example of synaptic remodeling following spinal cord injury; whereby synaptic contacts on injury-silenced phrenic motor neurons are activated; thereby, restoring phrenic motor neuron activity and promoting recovery of diaphragm function. Having previously shown that induction of PA/plgn system genes is important for generating the crossed phrenic phenomenon in mice, our studies in wildtype and knockout mice deficient in these PA/plgn genes will explore the mechanism(s) by which the induction of the PA system acts to promote the synaptic changes that permit a restoration of lung function. An understanding of specific molecular pathway signaling involved in the ability of PA to initiate this synaptic plasticity may indicate pharmacological approaches to accomplish the same effect. Activation of these synaptic contacts is probably not unique to the phrenic motor nucleus and may occur at additional sites within the spinal cord leading to partial restoration of other physiological functions. The mechanistic knowledge gained from this project may lead to translational studies as a potential therapy to promote synaptic formation, re-activation and recovery of function following human spinal cord injury. 2R01 NS044129-06A2 Seeds, Nicholas