Restoration of Recurrent-Laryngeal-Nerve Function after Injury in a Rat Model

描述（由申请人提供）：单侧声带麻痹是甲状腺手术的主要并发症，通常由喉返神经（RLN）损伤引起。RLN损伤导致喉部固有肌肉失去张力，可使声音消失，产生呼吸困难，并显著增加误吸的风险。对于RLN挤压损伤，唯一的治疗方法是“观察等待”轴突的自发再生和喉肌的再神经支配。对于横断的RLNs，首选的治疗方法是手术吻合神经段，然后同样希望自发再生和神经再生。两种治疗方法都能恢复肌肉张力，但神经再生效率低，需要数月时间。即使如此，由于异常的再神经支配导致的联动性，声带仍不能恢复有目的的运动和声门完全关闭，但只要有再神经支配，通过手术操作喉部肌肉，喉部功能就可以进一步改善。在这个项目中，我们将开发制造可控损伤的工具，并测试一种简单、安全的药物治疗的功效，以显著加速神经再生。在目标1中，我们将开发定量可重复的RLN挤压损伤和定量技术，以研究导致的声带麻痹和功能性神经再生。在Aim 2中，我们将检验连续给锂加速RLN挤压损伤后神经再生的假设。锂调节神经营养因子通路中的糖原合成酶激酶3，促进生长锥活性和神经突延伸。为了这两个目的，功能结果将通过发声分析、体积脉搏图、定量视频喉镜检查和喉肌电图定期监测。医生和基础科学家之间多学科合作的结果将对临床产生直接的实际影响

DESCRIPTION (provided by applicant): Unilateral vocal-fold paralysis is a major complication from thyroid surgery and commonly results from trauma to the recurrent laryngeal nerve (RLN). The loss of tone in the intrinsic muscles of the larynx due to RLN injury can eliminate voice, produce breathing difficulties, and significantly increase risk for aspiration. For crush injuries o the RLN, the only treatment is "watchful waiting" for spontaneous regeneration of axons and reinnervation of laryngeal muscles. For transected RLNs, the preferred treatment is surgical anastomosis of nerve segments followed by the same hopes for spontaneous regeneration and reinnervation. Both treatments can restore muscle tone, but reinnervation is inefficient and takes many months. Even then, purposeful movement of the vocal folds and complete glottic closure are not restored because of synkinesis from aberrant reinnervation, but, as long as there is reinnervation, laryngeal function can be further improved with surgical manipulation of laryngeal muscles. In this project, we will develop tools for producing controlled injury and test the efficacy of a simple, safe pharmacological treatment to significantly accelerate reinnervation. In Aim 1, we will develop quantitatively reproducible RLN crush injuries and quantitative techniques for the study of resulting vocal fold paralysis and functional reinnervation. In Aim 2, we will test the hypothesis that continuous lithium administration accelerates reinnervation after RLN crush injury. Lithium modulates glycogen synthase kinase 3 in the neurotrophin pathway and promotes growth-cone activity and neurite extension. For both aims, functional outcomes will be monitored at regular intervals by vocalization analysis, plethysmography, quantitative video laryngoscopy, and larynx electromyography. The results of this multidisciplinary collaboration between physicians and basic scientists will have direct practical clinical impact on the treatment of patients with unilateral vocal-fold paralysis. The quantitative tools for nerve injury and functional assessment, and the pharmacological treatment to accelerate axonal sprouting and reinnervation will have significant impact on all types of peripheral nerve injury.