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）创伤引起。由于喉返神经损伤导致的喉内肌张力丧失可消除声音，产生呼吸困难，并显著增加误吸风险。对于喉返神经挤压伤，唯一的治疗方法是“观察等待”轴突的自发再生和喉肌的神经再支配。对于横断的RLN，首选的治疗方法是神经节段的手术吻合，然后同样希望自发再生和神经再支配。这两种治疗方法都能恢复肌肉张力，但神经移植效率低下，需要数月时间。即使这样，声带的有目的的运动和声门的完全关闭也不能恢复，因为异常神经再支配引起的联带运动，但是，只要有神经再支配，喉功能可以通过喉肌的手术操作进一步改善。 在这个项目中，我们将开发用于产生控制性损伤的工具，并测试一种简单、安全的药物治疗的有效性，以显着加速神经再支配。在目标1中，我们将发展定量可重复的喉返神经挤压损伤和定量技术，用于研究声带麻痹和功能性神经再支配。在目标2中，我们将检验连续锂给药加速喉返神经挤压损伤后神经再支配的假设。锂调节神经营养因子途径中的糖原合成酶激酶3，并促进生长锥活性和神经突延伸。对于这两个目标，将通过发声分析、体积描记术、定量视频喉镜和喉肌电图定期监测功能结局。 医生和基础科学家之间的这种多学科合作的结果将对临床产生直接的实际影响， 单侧声带麻痹患者的治疗。神经损伤和功能评估的定量工具以及加速轴突发芽和神经再支配的药物治疗将对所有类型的周围神经损伤产生重大影响。

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.