The role of semaphorins in the injured spinal cord

描述（由申请人提供）：3类信号量（Sema 3）是在神经系统发育期间涉及轴突引导的排斥性线索。它们在成人中枢神经系统（CMS）中的持续表达以及它们在脊髓损伤（SCI）后病变部位的上调增加了它们可能导致SCI后轴突再生失败的可能性。我们将通过使用缺乏SemaS受体复合物的信号转导部分（即丛状蛋白A3和A4亚型）的突变小鼠来研究这种可能性。本提案的具体目的如下：1）研究在完全胸中部横断后，干扰3类脑信号蛋白信号传导对皮质脊髓、肾上腺素能和上行感觉轴突再生的影响。2)研究干扰3类脑信号蛋白信号对星形胶质细胞-脑膜成纤维细胞边界形成的影响。3)产生条件性丛蛋白A4敲除小鼠并分析星形胶质细胞中丛蛋白A4急性缺失后其5-HT轴突的再生表型。这项研究将有助于更好地了解化学排斥剂如何导致轴突再生失败，以及如何克服这种抑制性屏障来治疗脊髓损伤患者。这项研究的结果将增加我们对发育过程中排斥轴突的重要分子如何对成年哺乳动物中枢神经系统的轴突再生产生负面影响的理解。克服这种抑制性屏障以增强轴突再生可以对患有脊髓损伤的患者具有显著的治疗意义。

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.