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

基本信息

批准号：
10663855
负责人：
Michael Pitman
金额：
$ 62.78万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10663855
关键词：
Adult Axon Businesses Chronic Disease Chronic Obstructive Pulmonary Disease Chronology Communication 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 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

项目摘要

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.

项目摘要：喉神经（RLN）损伤发生在数以万计的患者中在美国。它导致融合的连接诱导声带瘫痪和严重烦躁不安。这会产生严重的患者发病率，因为声音是每个人的独特而组成的一部分人的身份，几乎影响我们日常生活的各个方面，从与亲人说话到参与业务或简单地完成日常任务。声音功能障碍会导致恐惧和孤立以及受损生活质量，残疾主张和工人失去的生产力类似于严重的慢性疾病，导致重大社会负担。当前的疗法是次优的，没有可以恢复人声的治疗方法折叠运动和正常的声音。我们关于分子机制的知识存在关键的差距神经再生过程中的轴突引导。我们的长期目标是确定表达和指导提示的行动并操纵它们以指导选择性的非合成性增强 RLN损伤后的喉肌，并恢复正常的人声折叠功能和正常语音。我们以前的工作表明，在胚胎发育和RLN损伤中，喉肌肉以相似的序列支配。然而，RLN后损伤加剧是无序的，导致了同步性具有声带功能障碍。我们的实验室已经确定Netrin-1和GDNF是最有可能发挥的因素 RLN再生过程中的轴突指导中的中心作用。我们已经证明了它们在喉中的表达肌肉及其受体在歧义核（NA）中的表达是按时间顺序协调的与轴突增强。我们已经证明，操纵这些指导提示可以改变重新支配模式。这些发现表明指导提示的受控但功能失调，导致Syninetic RLN损伤后的重新支配和声带瘫痪。相比之下，发展神经同样按时间顺序进行严格控制，从而导致正常的人声折叠功能。我们的中心假设是 NETRIN-1和GDNF是喉部加剧的关键指导线索。此外，操纵他们的 RLN后对模仿正常发育过程中看到的途径损伤将导致选择性，非 - 通过恢复正常的人声折叠功能来恢复同步。在强大的初步数据的指导下，我们寻求追求以下三个具体目标：1）描述GDNF，Netrin-1的表达方式及其受体在发育中喉的神经支配期间2）描述调节的途径 GDNF，Netrin-1及其受体的功能在发育神经支配期间和加剧期间的功能 RLN损伤和3）在体外评估NA和肌肉中调节途径的影响。这研究将广泛影响神经再生领域，促进我们对机制的了解轴突途径，具有转化声带瘫痪处理的潜力。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Expression of Glial Cell-Derived Neurotrophic Factor Receptors Within Nucleus Ambiguus During Rat Development.

DOI：
10.1002/lary.30440
发表时间：
2023-09
期刊：
LARYNGOSCOPE
影响因子：
2.6
作者：
Blount, Quinton;Hernandez-Morato, Ignacio;Moayedi, Yalda;Pitman, Michael J.
通讯作者：
Pitman, Michael J.

A review of the peripheral proprioceptive apparatus in the larynx.

DOI：
10.3389/fnana.2023.1114817
发表时间：
2023
期刊：
Frontiers in neuroanatomy
影响因子：
2.9
作者：
通讯作者：

An optimized method for high-quality RNA extraction from distinctive intrinsic laryngeal muscles in the rat model.

DOI：
10.1038/s41598-022-25643-y
发表时间：
2022-12-15
期刊：
SCIENTIFIC REPORTS
影响因子：
4.6
作者：
Kemfack, Angela M.;Hernandez-Morato, Ignacio;Moayedi, Yalda;Pitman, Michael J.
通讯作者：
Pitman, Michael J.

Temporal expression of Laminin-111 in the developing rat larynx.