Mechanisms of axon guidance in laryngeal reinnervation following injury of the recurrent laryngeal nerve

喉返神经损伤后喉部神经支配的轴突引导机制

• 批准号: 10200760
• 负责人: Michael Pitman
• 金额: $ 60.32万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10200760
• 关键词: Adult; Axon; Businesses; Chronic Disease; Chronic Obstructive Airway Disease; Chronology; Congestive Heart Failure; Controlled Environment; Cues; Data; Development; Disease; Dysphonia; Embryology; Exhibits; Fright; Frustration; Functional disorder; Future; Goals; Growth Cones; Impairment; In Vitro; Injury; Knowledge; Laboratories; Laryngeal Injury; Laryngeal muscle structure; Larynx; Lead; Mental Depression; Modeling; Modification; Molecular; Morbidity - disease rate; Motion; Motor Neurons; Muscle; NTN1 gene; Nerve Regeneration; Operative Surgical Procedures; Paralysed; Pathway interactions; Patients; Pattern; Persons; Play; Process; Productivity; Quality of life; Rattus; Receptor Signaling; Recurrent Laryngeal Nerve; Research; Role; Signal Transduction; Synkinesis; System; Testing; United States; Up-Regulation; Voice; Work; axon growth; axon guidance; axonal pathfinding; disability payment; experimental study; glial cell-line derived neurotrophic factor; in vivo Model; loved ones; muscle reinnervation; nerve injury; nerve supply; neuronal survival; nucleus ambiguus; optimal treatments; receptor; receptor expression; regenerative growth; reinnervation; restoration; virtual; vocal cord

PROJECT SUMMARY: Recurrent laryngeal nerve (RLN) injury occurs in tens of thousands of patients per year in the United States. It results in synkinetic reinnervation inducing vocal fold paralysis and severe dysphonia. This produces significant patient morbidity as the voice is a unique and integral part of each person's identity, impacting virtually every aspect of our daily lives, from speaking to loved ones, to engaging in business or simply completing daily tasks. Voice dysfunction leads to fear and isolation, as well as impaired quality of life, disability claims and lost worker productivity similar to severe chronic diseases, resulting in a significant societal burden. Current therapies are suboptimal and there are no treatments that can restore vocal fold motion and normal voice. There are critical gaps in our knowledge about the molecular mechanisms underlying axonal guidance during nerve regeneration. Our long-term goals are to identify the expression and actions of guidance cues and to manipulate them to guide selective, non-synkinetic reinnervation of the laryngeal muscles after RLN injury, with restoration of normal vocal fold function and normal voice. Our previous work has revealed that in both embryologic development and post-RLN injury, laryngeal muscles are innervated in similar sequences. Yet, post-RLN injury reinnervation is disordered, resulting in synkinesis with vocal fold dysfunction. Our laboratory has identified Netrin-1 and GDNF as the factors most likely to play a central role in axon guidance during RLN regeneration. We have shown that their expression in laryngeal muscles and the expression of their receptors in the nucleus ambiguus (NA) are chronologically coordinated with axonal reinnervation. We have demonstrated that manipulation of these guidance cues can alter the pattern of reinnervation. These findings suggest a controlled but dysfunctional expression of guidance cues resulting in synkinetic reinnervation and vocal fold paralysis after RLN injury. In comparison, developmental innervation, which is also tightly controlled chronologically, results in normal vocal fold function. Our central hypothesis is that Netrin-1 and GDNF are critical guidance cues in laryngeal reinnervation. Further, manipulation of their pathways post-RLN injury to mimic those seen during normal development will in result in selective, non- synkinetic reinnervation with restoration of normal vocal fold function. Guided by strong preliminary data, we seek to pursue the following three Specific Aims: 1) to describe the patterns of expression of GDNF, Netrin-1, and their receptors during innervation of the larynx in development 2) to describe the pathways that modulate the function of GDNF, Netrin-1 and their receptors during innervation in development and during reinnervation post-RLN injury and 3) to evaluate in vitro the effects of modulating pathways in the NA and muscle. This research will broadly impact the field of nerve regeneration, advancing our knowledge of the mechanisms of axonal pathfinding with the potential to transform the treatment of vocal fold paralysis.

项目总结：喉返神经（RLN）损伤发生在成千上万的患者， 年在美国。它导致联合运动神经再支配诱发声带麻痹和严重的 发音困难这产生了显着的病人发病率的声音是一个独特的和不可分割的一部分，每一个 一个人的身份，几乎影响到我们日常生活的方方面面，从与亲人交谈，到参与 工作，或者只是完成日常任务。声音功能障碍导致恐惧和孤立，以及受损 生活质量、残疾索赔和工人生产力损失类似于严重的慢性病， 沉重的社会负担。目前的治疗是次优的，没有治疗可以恢复声乐 褶皱运动和正常的声音。在我们的知识中， 神经再生过程中的轴突引导。我们的长期目标是识别表达， 引导线索的行动，并操纵它们来引导选择性的，非联动的神经支配。 喉返神经损伤后的喉肌，恢复正常的声带功能和正常的声音。 我们以前的工作表明，在胚胎发育和喉返神经损伤后， 都有类似的神经支配然而，喉返神经损伤后神经再支配紊乱，导致联带运动 声带功能障碍我们的实验室已经确定Netrin-1和GDNF是最有可能发挥作用的因素。 在喉返神经再生过程中轴突引导的中心作用。我们已经证明，它们在喉中的表达 肌肉及其受体在疑核（NA）中的表达是时间协调的 轴突神经再生我们已经证明，操纵这些指导线索可以改变 神经再支配模式 这些发现表明，一个控制，但功能失调的表达的指导线索，导致联动 喉返神经损伤后的神经再支配和声带麻痹。相比之下，发育神经支配， 也严格控制时序，导致正常的声带功能。我们的核心假设是， Netrin-1和GDNF是喉神经再支配的重要指导因子。此外，操纵他们的 RLN损伤后模仿正常发育过程中所见的通路将导致选择性的，非 联合运动神经再支配，恢复正常声带功能。根据初步数据，我们 寻求追求以下三个具体目标：1）描述GDNF、Netrin-1的表达模式， 和它们的受体在喉的神经支配过程中的发展2）描述的途径，调节 GDNF、Netrin-1及其受体在发育期神经支配和神经再支配中的作用 RLN损伤后，以及3）在体外评估NA和肌肉中调节途径的作用。这 研究将广泛影响神经再生领域，推进我们对神经再生机制的认识。 轴索寻路有可能改变声带麻痹的治疗。