The role of semaphorins in the injured spinal cord

描述（由申请人提供）：第3类信号（Sema3）是神经系统发育过程中涉及轴突引导的排斥信号。它们在成人中枢神经系统（CMS）中的持续表达以及在脊髓损伤（SCI）后病变部位的上调，提出了它们可能导致脊髓损伤后轴突再生失败的可能性。我们将通过使用缺乏SemaS受体复合物信号转导部分的突变小鼠（即丛蛋白A3和A4亚型）来研究这种可能性。本研究的具体目的如下：1)研究破坏3类信号素信号对完全胸椎横断后皮质脊髓、血清素能和上行感觉轴突再生的影响。2)研究破坏3类信号蛋白信号通路对星形胶质细胞-脑膜成纤维细胞边界形成的影响。3)生成条件丛蛋白A4敲除小鼠，分析星形胶质细胞急性缺失丛蛋白A4后其5-HT轴突的再生表型。这项研究将有助于更好地理解化学再生剂如何促进轴突再生失败，以及如何克服这种抑制屏障可能用于治疗脊髓损伤患者。这项研究的结果将增加我们对发育过程中对轴突排斥重要的分子如何对成年哺乳动物中枢神经系统轴突再生产生负面影响的理解。克服这种抑制屏障以增强轴突再生对脊髓损伤患者具有重要的治疗意义。

DESCRIPTION (provided by applicant): Class 3 semaphores (Sema3) are repulsive cues that are involved axon guidance during development of the nervous system. Their continued expression in the adult central nervous system (CMS) as well as their upregulation at the lesion site after spinal cord injury (SCI) raises the possibility that they may contribute to the failure of axonal regeneration after SCI. We will investigate this possibility by using mutant mice that lack the signal transducing moiety of SemaS receptor complex, namely the Plexin A3 and A4 subtypes. The specific aims of this proposal are as follows: 1) Investigate the effect of disrupting class 3 semaphorin signaling on regeneration of the corticospinal, serotonergic, and ascending sensory axons after a complete mid-thoracic transection. 2) Investigate the effect of disrupting class 3 semaphorin signaling on the formation the astrocyte-meningeal fibroblast border. 3) Generate a conditional Plexin A4 knockout mouse and analyze the regenerative phenotype of its 5-HT axons after acute deletion of Plexin A4 in astrocytes. This research will aid in better understanding how chemorepellents can contribute to axon regeneration failure, and how overcoming this inhibitory barrier may be used to treat spinal cord injured patients. The results of this research will increase our understanding of how molecules that are important for repelling axons during development can negatively affect axonal regeneration in the adult mammalian central nervous system. Overcoming this inhibitory barrier to enhance axonal regeneration can have significant therapeutic implications for patients who suffer from spinal cord injury.